Can Functional Movement Assessment Predict Football Head Impact Biomechanics?

PURPOSE: The purposes of this study was to determine functional movement assessments' ability to predict head impact biomechanics in college football players and to determine whether head impact biomechanics could explain preseason to postseason changes in functional movement performance. METHODS: Participants (N = 44; mass, 109.0 ± 20.8 kg; age, 20.0 ± 1.3 yr) underwent two preseason and postseason functional movement assessment screenings: 1) Fusionetics Movement Efficiency Test and 2) Landing Error Scoring System (LESS). Fusionetics is scored 0 to 100, and participants were categorized into the following movement quality groups as previously published: good (≥75), moderate (50-75), and poor (<50). The LESS is scored 0 to 17, and participants were categorized into the following previously published movement quality groups: good (≤5 errors), moderate (6-7 errors), and poor (>7 errors). The Head Impact Telemetry (HIT) System measured head impact frequency and magnitude (linear acceleration and rotational acceleration). An encoder with six single-axis accelerometers was inserted between the padding of a commercially available Riddell football helmet. We used random intercepts general linear-mixed models to analyze our data. RESULTS: There were no effects of preseason movement assessment group on the two Head Impact Telemetry System impact outcomes: linear acceleration and rotational acceleration. Head impact frequency did not significantly predict preseason to postseason score changes obtained from the Fusionetics (F1,36 = 0.22, P = 0.643, R = 0.006) or the LESS (F1,36 < 0.01, P = 0.988, R < 0.001) assessments. CONCLUSIONS: Previous research has demonstrated an association between concussion and musculoskeletal injury, as well as functional movement assessment performance and musculoskeletal injury. The functional movement assessments chosen may not be sensitive enough to detect neurological and neuromuscular differences within the sample and subtle changes after sustaining head impacts.

Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.

Interactions between kinases and small molecule inhibitors can be activation state dependent. A detailed understanding of inhibitor binding therefore requires characterizing interactions across multiple activation states. We have systematically explored the effects of ABL1 activation loop phosphorylation and PDGFR family autoinhibitory juxtamembrane domain docking on inhibitor binding affinity. For a diverse compound set, the affinity patterns correctly classify inhibitors as having type I or type II binding modes, and we show that juxtamembrane domain docking can have dramatic negative effects on inhibitor affinity. The results have allowed us to associate ligand-induced conformational changes observed in cocrystal structures with specific energetic costs. The approach we describe enables investigation of the complex relationship between kinase activation state and compound binding affinity and should facilitate strategic inhibitor design.

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases.

To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved "gatekeeper" threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib- and BMS-354825-resistant ABL(T315I) kinase. The KIT/FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D/T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitinib- and erlotinib-resistant EGFR(L858R/T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib/erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of next-generation drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy.

A small molecule-kinase interaction map for clinical kinase inhibitors.

Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.

Tumour necrosis factor-alpha gene polymorphisms and Alzheimer's disease.

Recent findings suggest that production of pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), is increased in the brains of people with Alzheimer's disease (AD). We used direct sequencing methods on a section of the enhancer/promoter region and on a smaller fragment located 10.5 kb upstream of the TNF-alpha gene to respectively examine TNF-alpha polymorphisms and TNF-a and -b microsatellite alleles in a cohort of 235 post-mortem confirmed AD and 130 control cases. None of the TNF-alpha point mutations or microsatellite alleles investigated proved to be independent risk factors for AD. However, when -308/A, -238/G and TNF-a2 were examined as a 2-1-2 haplotype, we observed that the absence of that haplotype was significantly associated with AD (P = 0.014, Fisher's exact test) suggesting that the 2-1-2 haplotype may be protective against AD.