ABSTRACT
BACKGROUND: The Buffalo Concussion Treadmill Test (BCTT) is a graded exertion test for assessing exercise tolerance after concussion, but its utility is limited for certain populations. HYPOTHESIS: We developed the Buffalo Concussion Bike Test (BCBT) and tested its comparability with the BCTT. We hypothesize that heart rate (HR) at symptom exacerbation on the BCBT will be equivalent to the BCTT. STUDY DESIGN: Case-control study. LEVEL OF EVIDENCE: Level 3. METHODS: Adolescents with acute concussion (AC) (n = 20; mean age, 15.9 ± 1.1 years; 60% male) presenting to a concussion clinic within 10 days of injury and age- and sex-matched healthy controls (n = 20; mean age, 15.9 ± 1.1 years; 60% male) performed the BCTT at first visit and returned within 3 days to perform the BCBT. Test duration, HR, symptom severity (measured using a visual analog scale), and exertion (measured using the Borg Rating of Perceived Exertion) were collected during each test. RESULTS: Adolescents with AC who were exercise intolerant on the BCTT were also intolerant on the BCBT, with symptom exacerbation occurring at a mean 8.1 ± 2.8 minutes on the BCTT versus 14.6 ± 6.0 minutes on the BCBT (P < 0.01). Two 1-sided t tests showed that the HR at symptom exacerbation in AC patients (137 ± 28 bpm on BCTT vs 135 ± 25 bpm on BCBT; 95% CI, <0.01-0.03) and at voluntary exhaustion for controls (175 ± 13 bpm on BCTT vs 175 ± 13 bpm on BCBT; 95% CI, 0.03-0.03) on each test were statistically equivalent. CONCLUSION: The HR at symptom exacerbation on BCBT is equivalent to the BCTT for the assessment of exercise tolerance after concussion in adolescents. CLINICAL RELEVANCE: The BCBT can be used in patients with limited mobility or for research interventions that require limited participant motion.
Subject(s)
Athletic Injuries/diagnosis , Brain Concussion/diagnosis , Exercise Test/methods , Adolescent , Case-Control Studies , Exercise Tolerance/physiology , Female , Heart Rate/physiology , Humans , MaleABSTRACT
INTRODUCTION: HDAC isoform-specific inhibitors may improve the therapeutic window while limiting toxicities. Developing inhibitors against class I isoforms poses difficulties as they share high homology among their catalytic sites; however, HDAC8 is structurally unique compared to other class I isoforms. HDAC8 inhibitors are novel compounds and have affinity for class I HDAC isoforms demonstrating anti-cancer effects; little is known about their activity in malignant peripheral nerve sheath tumors (MPNST). Recently, we demonstrated anti-MPNST efficacy of HDAC8i in human and murine-derived MPNST pre-clinical models; we now seek to consider the potential therapeutic inhibition of HDAC8 in MPNST. METHODS: Four Human MPNST cell lines, a murine-derived MPNST cell line, and two HDAC8 inhibitors (PCI-34051, PCI-48012; Pharmacyclics, Inc. Sunnyvale, CA) were studied. Proliferation was determined using MTS and clonogenic assays. Effects on cell cycle were determined via PI FACS analysis; effects on apoptosis were determined using Annexin V-PI FACS analysis and cleaved caspase 3 expression. In vivo growth effects of HDAC8i were evaluated using MPNST xenograft models. 2D gel electrophoresis and mass spectrometry were used to identify potential HDAC8 deacetylation substrates. RESULTS: HDAC8i induced cell growth inhibition and marked S-phase cell cycle arrest in human and murine-derived MPNST cells. Relative to control, HDAC8i induced apoptosis in both human and murine-derived MPNST cells. HDAC8i exhibited significant effects on MPNST xenograft growth (p=0.001) and tumor weight (p=0.02). Four potential HDAC8 substrate targets were identified using a proteomic approach: PARK7, HMGB1, PGAM1, PRDX6. CONCLUSIONS: MPNST is an aggressive sarcoma that is notoriously therapy-resistant, hence the urgent need for improved anti-MPNST therapies. HDAC8 inhibition may be useful for MPNST by improving efficacy while limiting toxicities as compared to pan-HDACis.
