Age, graft size, and Tegner activity level as predictors of failure in anterior cruciate ligament reconstruction with hamstring autograft.

BACKGROUND: Patient age, Tegner activity level, and graft size could be factors that influence the outcome of anterior cruciate ligament reconstruction (ACLR) with hamstring autografts. HYPOTHESIS: Decreased graft size, higher Tegner activity score, and younger age are associated with an increased failure rate of ACLR, represented by continued knee laxity and revision surgery. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 98 patients who had undergone ACLR with hamstring tendon autografts between 2000 and 2007 were identified from a computerized relational database. Inclusion criteria consisted of a minimum of 2 years of follow-up, all age groups, and all activity levels. Exclusion criteria consisted of treatment with other grafts or previous ligament surgery, previous ACL repairs, bilateral ACL injuries, and associated ligament tears. Failure was defined as a 2+ Lachman result, positive pivot shift, and 5-mm difference or more on KT-1000 arthrometer measurement. RESULTS: Fifteen of the 98 ACLRs (15.3%) were defined as failures. Of the failures, 12 of 48 (25%) occurred in patients aged 25 years and younger, whereas 3 of 50 (6%) occurred in patients older than 25 years. There was a statistically significant association when comparing failure rate and age groups (P = .009); however, a significant association was not found between graft size and failure rate in the entire study population (P = .135) or within the different age groups (age ≤25 years vs. >25 years) based on failure rate (P = .390 and P = .165, respectively). No statistical significance was found when Tegner activity level and failure rate were compared in the overall study population (P = .463) or within age groups (≤25 years, P = .707; >25 years, P = .174). CONCLUSION: In this study population, younger patients (≤25 years) demonstrated a higher failure rate compared with the over-25 age group. A statistically significant difference was not found in terms of graft size and activity level correlating with failure rate in ACL reconstruction with hamstring autograft.

Suppression of epidermal growth factor receptor signaling by protein kinase C-alpha activation requires CD82, caveolin-1, and ganglioside.

Activation of protein kinase C (PKC)-alpha decreases normal and neoplastic cell proliferation by inhibiting epidermal growth factor receptor (EGFR)-related signaling. The molecular interactions upstream to PKC-alpha that influence its suppression of EGFR, however, are poorly understood. We have found that caveolin-1, tetraspanin CD82, and ganglioside GM3 enable the association of EGFR with PKC-alpha, ultimately leading to inhibition of EGFR signaling. GM3- and CD82-induced inhibition of EGFR signaling requires PKC-alpha translocation and serine/threonine phosphorylation, which eventually triggers EGFR Thr654 phosphorylation and receptor internalization. Within this ordered complex of signaling molecules, the ability of CD82 to associate with PKC-alpha requires the presence of caveolin-1, whereas the interaction of caveolin-1 or PKC-alpha with EGFR requires the presence of CD82 and ganglioside GM3. Disruption of the membrane with methyl-beta-cyclodextrin dissociates the EGFR/GM3/caveolin-1/CD82/PKC-alpha complex and prevents the inhibitory effect of PKC-alpha on EGFR phosphorylation, suggesting that caveolin-1, CD82, and ganglioside interact with EGFR and PKC-alpha within intact cholesterol-enriched membrane microdomains. Given the role of these membrane molecules in suppressing EGFR signaling, up-regulation of GM3, caveolin-1, and CD82 function may be an effective adjunctive therapy for treating epithelial cell malignancies.

Ganglioside GM3 promotes carcinoma cell proliferation via urokinase plasminogen activator-induced extracellular signal-regulated kinase-independent p70S6 kinase signaling.

Overexpression of NeuAcalpha2-3Galbeta1-4Glcbeta1-Cer (GM3), a major ganglioside of cutaneous tumor cell membranes, inhibits ligand-dependent and ligand-independent activation of the epidermal growth factor (EGF) receptor in normal and neoplastic epithelial cells. This leads to the suppression of Ras/extracellular signal-regulated kinase (ERK) activation and, in the presence of EGF or fibronectin, inhibits cell proliferation. However, some tumor cells show increased levels of GM3, and vaccines that target GM3 can inhibit the growth of neoplastic cells in vivo, especially melanomas. We report that in the presence of urokinase plasminogen activator (uPA), overexpression of GM3 paradoxically increases the proliferation of carcinoma cells by augmenting ERK-independent p70S6 kinase activation. Functional blockade of uPA receptor (uPAR) or inhibition of p70S6 kinase, but not inhibition of Ras/ERK signaling, suppresses this GM3-induced stimulation of cell proliferation. The ERK-independent activation of p70S6 kinase involves phosphorylation at threonine-389, threonine-421/serine-424, and serine-411 sites with intermediate phosphatidylinositol 3 kinase and protein kinase C-zeta activation. These studies implicate gangliosides as enhancers of uPAR-related signaling and suggest that the response to GM3 depends on the local concentration of uPA. Therapeutic modalities that target or supplement gangliosides may require concomitant treatment that suppresses EGFR or uPAR signaling, respectively, to control neoplastic cell proliferation.