Background: The purpose of this study was to evaluate the clinical outcomes and the level of sports activity following arthroscopic microfracture for osteochondral lesions of the tibial plafond. Methods: A retrospective review was conducted for patients who underwent arthroscopic microfracture surgery for osteochondral lesions of the tibial plafond from January 2014 to June 2017. For functional evaluation, the visual analog scale (VAS) pain score, Foot and Ankle Ability Measure (FAAM) score, and Short Form-12 (SF-12) general health questionnaire were used. We also investigated the level of sports activity before and after the surgery. Sixteen patients were included in this study, and the mean follow-up period was 29.8 months. Results: The mean VAS score improved from 8.3 (range, 6-10) preoperatively to 1.8 (range, 0-4) postoperatively. The mean FAAM score was improved from 57.6 (range, 6.0-88.9) for the activities of daily living subscale and 34.5 (range, 3.1-92.6) for the sports subscale to 84.3 (range, 46.4-100.0) and 65.2 (range, 23.3-55.1) for each subscale, respectively, at the final follow-up. There were also improvements in the SF-12 score, from 36.3 (range, 23.3-55.1) preoperatively to 46.0 (range, 18.9-56.6) postoperatively for the SF-12 PCS, and from 41.3 (range, 14.2-65.0) preoperatively to 52.6 (range, 32.8-60.8) postoperatively for the SF-12 MCS. All functional scores showed significant differences clinically and statistically at the final follow-up. The level of sports activity after the surgery was significantly lower than their level before the surgery ( P = .012). Conclusion: Arthroscopic microfracture provided satisfactory clinical outcomes for osteochondral lesions of the tibial plafond. Though all the patients in this study were able to return to sports activity after the surgery, the postoperative level of sports activity was significantly lower than their preoperative level. Level of Evidence: Level IV, retrospective case series.
Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Herein we describe the synthesis and biological activity of an LPC-mimetic electrophilic affinity label that targets the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of quaternary ammonium derivative-containing vinyl sulfone analogs of LPC that function as irreversible inhibitors of ATX and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 – 0.39 μM, consistent with a Ki of 3.50 μM for inhibition of ATX by the C16H33 vinyl sulfone analog CVS-16 (10b). A phenyl vinyl sulfone control compound, PVS-16, lacking the choline-like quaternary ammonium mimicking head group moiety, had little effect on cell viability and did not inhibit ATX. Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo.
The regulator of G protein signaling 10 (RGS10) protein is a GTPase activating protein that accelerates the hydrolysis of GTP and therefore canonically inactivates G proteins, ultimately terminating signaling. Rheb is a small GTPase protein that shuttles between its GDP- and GTP-bound forms to activate mTOR. Since RGS10 suppression augments ovarian cancer cell viability, we sought to elucidate the molecular mechanism. Following RGS10 suppression in serum-free conditions, phosphorylation of mTOR, the eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), p70S6K and S6 Ribosomal Protein appear. Furthermore, suppressing RGS10 increases activated Rheb, suggesting RGS10 antagonizes mTOR signaling via the small G-protein. The effects of RGS10 suppression are enhanced after stimulating cells with the growth factor, lysophosphatidic acid, and reduced with mTOR inhibitors, temsirolimus and INK-128. Suppression of RGS10 leads to an increase in cell proliferation, even in the presence of etoposide. In summary, the RGS10 suppression increases Rheb-GTP and mTOR signaling in ovarian cancer cells. Our results suggest that RGS10 could serve in a novel, and previously unknown, role by accelerating the hydrolysis of GTP from Rheb in ovarian cancer cells.
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