ALBERT

Description: Background Aberrations in Capicua (CIC) have recently been implicated as a negative prognostic factor in a multitude of cancer types through the derepression of targets downstream of the mitogen-activated protein kinase (MAPK) signaling cascade, such as oncogenic E26 transformation-specific (ETS) transcription factors. The Ataxin-family protein ATXN1L has previously been reported to interact with CIC in both developmental and disease contexts to facilitate the repression of CIC target genes and promote the post-translational stability of CIC. However, little is known about the mechanisms at the base of ATXN1L-mediated CIC post-translational stability. Results Functional in vitro studies utilizing ATXN1LKO human cell lines revealed that loss of ATXN1L leads to the accumulation of polyubiquitinated CIC protein, promoting its degradation through the proteasome. Although transcriptomic signatures of ATXN1LKO cell lines indicated upregulation of the mitogen-activated protein kinase pathway, ERK activity was found to contribute to CIC function but not stability. Degradation of CIC protein following loss of ATXN1L was instead observed to be mediated by the E3 ubiquitin ligase TRIM25 which was further validated using glioma-derived cell lines and the TCGA breast carcinoma and liver hepatocellular carcinoma cohorts. Conclusions The post-translational regulation of CIC through ATXN1L and TRIM25 independent of ERK activity suggests that the regulation of CIC stability and function is more intricate than previously appreciated and involves several independent pathways. As CIC status has become a prognostic factor in several cancer types, further knowledge into the mechanisms which govern CIC stability and function may prove useful for future therapeutic approaches.

Description: The thickness of the tibial polyethylene (PE) insert is a critical parameter to ensure optimal soft-tissue balancing in the intraoperative decision-making procedure of total knee arthroplasty (TKA). However, there is a paucity of information about the kinetic response to PE insert thickness variations in the tibiofemoral (TF) joint, and subsequently, the secondary effects on the patellofemoral (PF) biomechanics. Therefore, the purpose of this study was to investigate the influence of varying PE insert thickness on the ligament and TF compressive forces, as well as on the PF forces and kinematics, after a cruciate-retaining TKA. A previous patient-specific musculoskeletal model of TKA was adapted to simulate a chair-rising motion in which PE insert thickness was varied with 2 mm increments or decrements compared to the reference case (9 mm), from 5 mm up to 13 mm. Greater PE insert thickness resulted in higher ligament forces and concurrently increased the TF compressive force by 21% (13 mm), but slightly unloaded the PF joint with 7% (13 mm) while shifting the patella distally in the trochlear groove, compared to the reference case. Thinner PE inserts showed an opposite trend. Our findings suggest that the optimal PE insert thickness selection is a trade-off between the kinetic outcomes of the TF and PF joints.