An in-depth examination of strength in subjects with self-reported chronic ankle instability and mechanical laxity

Kaminski, ThomasContext: Lateral ankle sprains commonly occur within the athletic population. However, athletes who sustain one ankle sprain have a higher risk of recurrent episodes that frequently lead to chronic ankle instability (CAI). CAI is a multifactorial diagnosis that includes mechanical and functional instability components. Mechanical instability generally includes ligamentous laxity, whereas functional instability includes neuromuscular aspects and strength. However, the impact of laxity and CAI on ankle strength remains un. Objective: To compare ankle strength (PF, DF, INV and EV) measurements in athletes who have mechanical laxity and who present with reported chronic ankle instability after a history of unilateral ankle sprains. Design: Retrospective study. Participants: 165 participants including 97 males and 68 females (height = 178.01cm, weight = 78.7 kg, age = 18.5 years). Interventions: An injury history questionnaire and Cumberland Ankle Instability Tool (CAIT) were administered to determine the number of previous ankle sprains and the presence of self-reported CAI. Laxity of the ankle joint was determined using a portable ankle arthrometer measuring anterior displacement in millimeters and inversion rotation in degrees. Strength was measured using a Kin Com isokinetic dynamometer and peak torque for the four different ankle motions were recorded. Main Outcome Measures: The independent variable was group status as determined by either (1) ankle instability (CAIT scores) and (2) ankle laxity (arthrometry measurement). The dependent variables are peak torque strength measures, concentric (CON) and eccentric (ECC) in two velocities (30°/sec & 120 °/sec), in all ankle motions. Results: 24 subjects (14.54%) had both anterior and INV/EV laxity and 74 of the 165 participants (44.84%) had self-reported CAI in their injured ankle. The laxity group presented with less PF CON strength at 30°/sec (t=-2.567, p=.011) and EV CON strength at 120 °/sec (t=-2.137, p=.034) than those who did not have laxity. A trend toward significance was seen for ECC (t=-1.905, p=.059) and CON PF at 120 °/sec (t=-1.852, p=.066). No significance was found between those with or without CAI and their strength measurements. Conclusion: Plantar flexion and eversion strength was significantly less in those without laxity compared to their contralateral, uninjured ankle, exhibiting a need for specific rehabilitation of the specific muscle groups. Even though no significant differences were found with CAI, significance was found with gender and right versus left ankle, exposing that our understanding of CAI as a diagnosis and its relationship with strength is not fully understood.University of Delaware, Department of Kinesiology and Applied PhysiologyM.S

Ankle strength deficits in a cohort of college athletes with chronic ankle instability

Context: Lateral ankle sprains commonly occur in an athletic population and can lead to chronic ankle instability. Objective: To compare ankle strength measurements in athletes who have mechanical laxity and report functional instability after a history of unilateral ankle sprains. Design: Retrospective cohort. Setting: Athletic Training Research Lab. Participants: A total of 165 National Collegiate Athletic Association Division I athletes, 97 males and 68 females, with history of unilateral ankle sprains participated. Main Outcome Measures: Functional ankle instability was determined by Cumberland Ankle Instability Tool scores and mechanical ankle instability by the participant having both anterior and inversion/eversion laxity. Peak torque strength measures, concentric and eccentric, in 2 velocities were measured. Results: Of the 165 participants, 24 subjects had both anterior and inversion/eversion laxity and 74 self-reported functional ankle instability on their injured ankle. The mechanical ankle instability group presented with significantly lower plantar flexion concentric strength at 30°/s (139.7 [43.7] N·m) (P = .01) and eversion concentric strength at 120°/s (14.8 [5.3] N·m) (P = .03) than the contralateral, uninjured ankle (166.3 [56.8] N·m, 17.4 [6.2] N·m, respectively). Conclusion: College athletes who present with mechanical laxity on a previously injured ankle exhibit plantar flexion and eversion strength deficits between ankles

Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis1

Glioblastomas, like other solid tumors, have extensive areas of hypoxia and necrosis. The importance of hypoxia in driving tumor growth is receiving increased attention. Hypoxia-inducible factor 1 (HIF-1) is one of the master regulators that orchestrate the cellular responses to hypoxia. It is a heterodimeric transcription factor composed of α and β subunits. The α subunit is stable in hypoxic conditions but is rapidly degraded in normoxia. The function of HIF-1 is also modulated by several molecular mechanisms that regulate its synthesis, degradation, and transcriptional activity. Upon stabilization or activation, HIF-1 translocates to the nucleus and induces transcription of its downstream target genes. Most important to gliomagenesis, HIF-1 is a potent activator of angiogenesis and invasion through its upregulation of target genes critical for these functions. Activation of the HIF-1 pathway is a common feature of gliomas and may explain the intense vascular hyperplasia often seen in glioblastoma multiforme. Activation of HIF results in the activation of vascular endothelial growth factors, vascular endothelial growth factor receptors, matrix metalloproteinases, plasminogen activator inhibitor, transforming growth factors α and β, angiopoietin and Tie receptors, endothelin-1, inducible nitric oxide synthase, adrenomedullin, and erythropoietin, which all affect glioma angiogenesis. In conclusion, HIF is a critical regulatory factor in the tumor microenvironment because of its central role in promoting proangiogenic and invasive properties. While HIF activation strongly promotes angiogenesis, the emerging vasculature is often abnormal, leading to a vicious cycle that causes further hypoxia and HIF upregulation

Targeting CD74 in multiple myeloma with the novel, site-specific antibody-drug conjugate STRO-001.

STRO-001 is a site-specific, predominantly single-species, fully human, aglycosylated anti-CD74 antibody-drug conjugate incorporating a non-cleavable linker-maytansinoid warhead with a drug-antibody ratio of 2 which was produced by a novel cell-free antibody synthesis platform. We examined the potential pharmacodynamics and anti-tumor effects of STRO-001 in multiple myeloma (MM). CD74 expression was assessed in MM cell lines and primary bone marrow (BM) MM biopsies. CD74 mRNA was detectable in CD138+ enriched plasma cells from 100% (892/892) of patients with newly diagnosed MM. Immunohistochemistry confirmed CD74 expression in 35/36 BM biopsies from patients with newly diagnosed and relapsed/refractory MM. Cytotoxicity assays demonstrated nanomolar STRO-001 potency in 4/6 MM cell lines. In ARP-1 and MM.1S tumor-bearing mice, repeat STRO-001 dosing provided significant antitumor activity with eradication of malignant hCD138+ BM plasma cells and prolonged survival. In a luciferase-expressing MM.1S xenograft model, dose-dependent STRO-001 efficacy was confirmed using bioluminescent imaging and BM tumor burden quantification. Consistent with the intended pharmacodynamic effect, STRO-001 induced dose-responsive, reversible B-cell and monocyte depletion in cynomolgus monkeys, up to a maximum tolerated 10 mg/kg, with no evidence of off-target toxicity. Collectively, these data suggest that STRO-001 is a promising therapeutic agent for the treatment of MM

Targeting CD74 in multiple myeloma with the novel, site-specific antibody-drug conjugate STRO-001.

STRO-001 is a site-specific, predominantly single-species, fully human, aglycosylated anti-CD74 antibody-drug conjugate incorporating a non-cleavable linker-maytansinoid warhead with a drug-antibody ratio of 2 which was produced by a novel cell-free antibody synthesis platform. We examined the potential pharmacodynamics and anti-tumor effects of STRO-001 in multiple myeloma (MM). CD74 expression was assessed in MM cell lines and primary bone marrow (BM) MM biopsies. CD74 mRNA was detectable in CD138+ enriched plasma cells from 100% (892/892) of patients with newly diagnosed MM. Immunohistochemistry confirmed CD74 expression in 35/36 BM biopsies from patients with newly diagnosed and relapsed/refractory MM. Cytotoxicity assays demonstrated nanomolar STRO-001 potency in 4/6 MM cell lines. In ARP-1 and MM.1S tumor-bearing mice, repeat STRO-001 dosing provided significant antitumor activity with eradication of malignant hCD138+ BM plasma cells and prolonged survival. In a luciferase-expressing MM.1S xenograft model, dose-dependent STRO-001 efficacy was confirmed using bioluminescent imaging and BM tumor burden quantification. Consistent with the intended pharmacodynamic effect, STRO-001 induced dose-responsive, reversible B-cell and monocyte depletion in cynomolgus monkeys, up to a maximum tolerated 10 mg/kg, with no evidence of off-target toxicity. Collectively, these data suggest that STRO-001 is a promising therapeutic agent for the treatment of MM

Radiographic progression-free survival as a response biomarker in metastatic castration-resistant prostate cancer : COU-AA-302 results

Purpose. Progression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) trials has been inconsistently defined and poorly associated with overall survival (OS). A reproducible quantitative definition of radiographic PFS (rPFS) was tested for association with a coprimary end point of OS in a randomized trial of abiraterone in patients with mCRPC. Patients and Methods. rPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 12 weeks after random assignment, and/or progression in nodes or viscera on cross-sectional imaging, or death. rPFS was assessed by independent review at 15% of deaths and by investigator review at 15% and 40% of deaths. rPFS and OS association was evaluated by Spearman’s correlation. Results. A total of 1,088 patients were randomly assigned to abiraterone plus prednisone or prednisone alone. At first interim analysis, the hazard ratio (HR) by independent review was 0.43 (95% CI, 0.35 to 0.52; P < .001; abiraterone plus prednisone: median rPFS, not estimable; prednisone: median rPFS, 8.3 months). Similar HRs were obtained by investigator review at the first two interim analyses (HR, 0.49; 95% CI, 0.41 to 0.60; P < .001 and HR, 0.53; 95% CI, 0.45 to 0.62; P < .001, respectively), validating the imaging data assay used. Spearman’s correlation coefficient between rPFS and OS was 0.72. Conclusion. rPFS was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials