Background The aim of this study was to determine long-term survival and clinical outcomes of the surface replacement trapeziometacarpal joint prosthesis (SR (TM) TMC) and to evaluate implant... Show moreBackground The aim of this study was to determine long-term survival and clinical outcomes of the surface replacement trapeziometacarpal joint prosthesis (SR (TM) TMC) and to evaluate implant migration using radiostereometric analysis (RSA).MethodsIn this clinical long-term follow-up study outcomes of ten patients who received the SR (TM) TMC joint prosthesis were evaluated using DASH and Nelson scores, Visual Analogue Scale (VAS) of pain, and key pinch strength. RSA-radiographs were obtained direct postoperatively and 6months, 1, 5 and 10years postoperatively and were analyzed using model-based RSA software.ResultsDuring follow-up, two early revisions took place. Mean pre-operative DASH and Nelson scores were 54 (SD 15) and 54 (SD 17), improved significantly after 6months (DASH 25 (SD 20), Nelson 75 (SD 18)) and remained excellent during long-term follow-up in all patients with a stable implant. At final follow-up, clinical scores deteriorated clearly in two patients with a loose implant in situ.ConclusionsLong-term survival of the SR (TM) TMC joint prosthesis is relatively poor. However, clinical outcomes improved significantly in the short-term and remained excellent in the long-term in those patients with a stable implant, but deteriorated clearly in case of loosening. The role of RSA in TMC joint arthroplasty is potentially valuable but needs to be further investigated. Several challenges of RSA in the TMC joint have been addressed by the authors and suggestions to optimize RSA-data are given.Trial registrationThis study was registered in the Netherlands Trial Register (NL7126). Show less
BackgroundFrequent activation of the co-transcriptional factor YAP is observed in a large number of solid tumors. Activated YAP associates with enhancer loci via TEAD4-DNA-binding protein and... Show moreBackgroundFrequent activation of the co-transcriptional factor YAP is observed in a large number of solid tumors. Activated YAP associates with enhancer loci via TEAD4-DNA-binding protein and stimulates cancer aggressiveness. Although thousands of YAP/TEAD4 binding-sites are annotated, their functional importance is unknown. Here, we aim at further identification of enhancer elements that are required for YAP functions.ResultsWe first apply genome-wide ChIP profiling of YAP to systematically identify enhancers that are bound by YAP/TEAD4. Next, we implement a genetic approach to uncover functions of YAP/TEAD4-associated enhancers, demonstrate its robustness, and use it to reveal a network of enhancers required for YAP-mediated proliferation. We focus on Enhancer(TRAM2), as its target gene TRAM2 shows the strongest expression-correlation with YAP activity in nearly all tumor types. Interestingly, TRAM2 phenocopies the YAP-induced cell proliferation, migration, and invasion phenotypes and correlates with poor patient survival. Mechanistically, we identify FSTL-1 as a major direct client of TRAM2 that is involved in these phenotypes. Thus, TRAM2 is a key novel mediator of YAP-induced oncogenic proliferation and cellular invasiveness.ConclusionsYAP is a transcription co-factor that binds to thousands of enhancer loci and stimulates tumor aggressiveness. Using unbiased functional approaches, we dissect YAP enhancer network and characterize TRAM2 as a novel mediator of cellular proliferation, migration, and invasion. Our findings elucidate how YAP induces cancer aggressiveness and may assist diagnosis of cancer metastasis. Show less
