Identification of Genes That Promote or Antagonize Somatic Homolog Pairing Using a High-Throughput FISH–Based Screen

The pairing of homologous chromosomes is a fundamental feature of the meiotic cell. In addition, a number of species exhibit homolog pairing in nonmeiotic, somatic cells as well, with evidence for its impact on both gene regulation and double-strand break (DSB) repair. An extreme example of somatic pairing can be observed in Drosophila melanogaster, where homologous chromosomes remain aligned throughout most of development. However, our understanding of the mechanism of somatic homolog pairing remains unclear, as only a few genes have been implicated in this process. In this study, we introduce a novel high-throughput fluorescent in situ hybridization (FISH) technology that enabled us to conduct a genome-wide RNAi screen for factors involved in the robust somatic pairing observed in Drosophila. We identified both candidate “pairing promoting genes” and candidate “anti-pairing genes,” providing evidence that pairing is a dynamic process that can be both enhanced and antagonized. Many of the genes found to be important for promoting pairing are highly enriched for functions associated with mitotic cell division, suggesting a genetic framework for a long-standing link between chromosome dynamics during mitosis and nuclear organization during interphase. In contrast, several of the candidate anti-pairing genes have known interphase functions associated with S-phase progression, DNA replication, and chromatin compaction, including several components of the condensin II complex. In combination with a variety of secondary assays, these results provide insights into the mechanism and dynamics of somatic pairing

OBSERVE-5: Observational postmarketing safety surveillance registry of etanercept for the treatment of psoriasis final 5-year results

BackgroundOBSERVE-5 was a 5-year Food and Drug Administration–mandated surveillance registry of patients with psoriasis.ObjectiveWe sought to assess long-term etanercept safety and effectiveness.MethodsPatients with moderate to severe psoriasis enrolled; a single baseline dose of etanercept was required. Key outcome measures included serious adverse events, serious infectious events, events of medical interest, psoriasis-affected body surface area, physician global assessment score, and Dermatology Life Quality Index score. Safety outcomes were assessed relative to data from the MarketScan database.ResultsFor 2510 patients, 5-year cumulative incidence was 22.2% (95% confidence interval [CI] 20.3%-24.2%) for serious adverse events; 6.5% (95% CI 5.4%-7.7%) for serious infectious events; 3.2% (95% CI 2.3%-4.1%) for malignancies excluding nonmelanoma skin cancer; 3.6% (95% CI 2.7%-4.5%) for nonmelanoma skin cancer; 2.8% (95% CI 2.0%-3.6%) for coronary artery disease; 0.7% (95% CI 0.3%-1.2%) for psoriasis worsening; 0.2% (95% CI 0.0%-0.4%) for central nervous system demyelinating disorder; 0.1% (95% CI 0.0%-0.3%) for lymphoma and for tuberculosis; and 0.1% (95% CI 0.0%-0.2%) for opportunistic infection and for lupus; 55 fatal events were reported. Rates of malignancies, lymphomas, nonmelanoma skin cancer, and hospitalization-associated infections were not higher than expected relative to administrative claims data. The percentage of patients rated as clear/almost clear was 12% at baseline, which increased to 51% at month 6 and remained relatively stable throughout 5 years.LimitationsNo internal comparator group was included; rare events may not have been detected.ConclusionNo new safety signals were observed with long-term, real-world etanercept use