Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN–DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBNYW/AA. Overexpression of CRBN wild-type protein, but not CRBNYW/AA mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21WAF-1 expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.

Background: A protective effect on injury risk in youth sports through neuromuscular warm-up training routines has consistently been demonstrated. However, there is a paucity of information regarding the quantity and quality of coach-led injury prevention programs and its impact on the physical performance of players.Objective: The aim of this cluster-randomized controlled trial was to assess whether different delivery methods of an injury prevention program (FIFA 11+) to coaches could improve player performance, and to examine the effect of player adherence on performance and injury risk.Method: During the 2011 football season (May-August), coaches of 31 Tier 1-3 level teams were introduced to the 11+ through either an unsupervised website or a coach-focused workshop with and without additional on-field supervisions. Playing exposure, adherence to the 11+, and injuries were recorded for female 13-18-year old players. Performance testing included the Star Excursion Balance Test (SEBT), single-leg balance, triple hop, and jumping-over-a-bar tests.Results: Complete pre-and post-season performance tests were available for 226 players (66.5%).Compared to the unsupervised group, single-leg balance (OR=2.8; 95% CI 1.1-4.6) and the anterior direction of the SEBT improved significantly in the on-field supervised group of players (OR=4.7; 2.2-7.1), while jumping decreased (OR=-5.1;-9.9--0.2). However, significant improvements in 5 out of 6 reach distances in the SEBT were found, favoring players who highly adhered to the 11+. Also, injury risk was lower for those players (IRR=0.28, 95% CI: 0.10-0.79).Conclusion: Different delivery methods of the FIFA 11+ to coaches influenced players´ physical performance minimally. However, high player adherence to the 11+ resulted in significant improvements in functional balance and reduced injury risk.

NCT01860755.

Among 11- to 12-year-old ice hockey players, playing in a league in which body checking is permitted compared with playing in a league in which body checking is not permitted was associated with a 3-fold increased risk of all game-related injuries and the categories of concussion, severe injury, and severe concussion.

SummaryCereblon (CRBN), the molecular target of lenalidomide and pomalidomide, is a substrate receptor of the cullin ring E3 ubiquitin ligase complex, CRL4CRBN. T cell co-stimulation by lenalidomide or pomalidomide is cereblon dependent: however, the CRL4CRBN substrates responsible for T cell co-stimulation have yet to be identified. Here we demonstrate that interaction of the transcription factors Ikaros (IKZF1, encoded by the IKZF1 gene) and Aiolos (IKZF3, encoded by the IKZF3 gene) with CRL4CRBN is induced by lenalidomide or pomalidomide. Each agent promotes Aiolos and Ikaros binding to CRL4CRBN with enhanced ubiquitination leading to cereblon-dependent proteosomal degradation in T lymphocytes. We confirm that Aiolos and Ikaros are transcriptional repressors of interleukin-2 expression. The findings link lenalidomide- or pomalidomide-induced degradation of these transcriptional suppressors to well documented T cell activation. Importantly, Aiolos could serve as a proximal pharmacodynamic marker for lenalidomide and pomalidomide, as healthy human subjects administered lenalidomide demonstrated Aiolos degradation in their peripheral T cells. In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of Ikaros and Aiolos to CRL4CRBN, leading to their ubiquitination, subsequent proteasomal degradation and T cell activation.