Vemurafenib (PLX4032), a selective inhibitor of Braf, has been approved by the US Food and Drug Administration for the treatment of unresectable or metastatic melanoma in patients with Braf(V600E) mutations. Many patients treated with vemurafenib initially display dramatic improvement, with decreases in both risk of death and tumor progression. Acquired resistance, however, rapidly arises in previously sensitive cells. We attempted to overcome this resistance by targeting the signal transducer and activator of transcription 3 (STAT3)-paired box homeotic gene 3 (PAX3)-signaling pathway, which is upregulated, owing to fibroblast growth factor 2 (FGF2) secretion or increased kinase activity, with the Braf(V600E) mutation. We found that activation of Stat3 or overexpression of PAX3 induced resistance to vemurafenib in melanoma cells. In addition, PAX3 or Stat3 silencing inhibited the growth of melanoma cells with acquired resistance to vemurafenib. Furthermore, treatment with the Stat3 inhibitor, WP1066, resulted in growth inhibition in both vemurafenib-sensitive and -resistant melanoma cells. Significantly, vemurafenib stimulation induced FGF2 secretion from keratinocytes and fibroblasts, which might uncover, at least in part, the mechanisms underlying targeting Stat3-PAX3 signaling to overcome the acquired resistance to vemurafenib. Our results suggest that Stat3-targeted therapy is a new therapeutic strategy to overcome the acquired resistance to vemurafenib in the treatment of melanoma.

Current strategies for bone regeneration after traumatic injury often fail to provide adequate healing and integration. Here, we combined the poly (ethylene glycol) diacrylate (PEGDA) hydrogel with allogeneic "carrier" cells transduced with an adenovirus expressing BMP2. The system is unique in that the biomaterial encapsulates the cells, shielding them and thus suppressing destructive inflammatory processes. Using this system, complete healing of a 5 mm-long femur defect in a rat model occurs in under 3 weeks, through secretion of 100-fold lower levels of protein as compared to doses of recombinant BMP2 protein used in studies which lead to healing in 2-3 months. New bone formation was evaluated radiographically, histologically, and biomechanically at 2, 3, 6, 9, and 12 weeks after surgery. Rapid bone formation bridged the defect area and reliably integrated into the adjacent skeletal bone as early as 2 weeks. At 3 weeks, biomechanical analysis showed the new bone to possess 79% of torsional strength of the intact contralateral femur. Histological evaluation showed normal bone healing, with no infiltration of inflammatory cells with the bone being stable approximately 1 year later. We propose that these osteoinductive microspheres offer a more efficacious and safer clinical option over the use of rhBMP2. ß

Purpose of Review Arthroscopic Bankart repair is commonly utilized for shoulder stabilization in patients with anterior shoulder instability with minimum glenoid bone loss. The purpose of this review is to provide the indications, surgical technique, complications, and recent outcomes in arthroscopic Bankart repair for shoulder instability. Recent Findings Improvements in arthroscopic techniques have led to better patient outcomes, as well as an improved understanding of the pathoanatomy of instability. More recent studies have shown that one of the potential failures of primary arthroscopic repair may be due to unaddressed bone loss. This underscores the importance of evaluating glenoid bone loss and proper patient selection for this procedure to ensure successful outcome. Summary When indicated, arthroscopic stabilization is the treatment of choice for many surgeons due to its lower morbidity and low overall complication rate. Future work must focus on longer-term outcomes in patients undergoing arthroscopic Bankart repair, as well as the clinical outcomes of new fixation techniques, augmentation techniques, and the effect of glenoid bone loss in outcome.

» Although anterior cruciate ligament reconstruction (ACL-R) yields generally favorable results, bone tunnel enlargement (BTE) commonly has been reported after ACL-R.» While the exact clinical ramifications of tibial widening on functional outcomes are variable, it is thought that widening may potentially play a role in late failure following ACL-R.» The prevalence of tunnel enlargement is related particularly to hamstring autografts, with some authors reporting rates ranging from 25% to 100% in femoral tunnels and 29% to 100% in tibial tunnels after ACL-R.» BTE is difficult to manage, particularly in the setting of revision ACL-R. The mechanisms underlying BTE after ACL-R are associated with a complex interplay between biological and mechanical factors.