Objective:To test the hypothesis that there is shared regional or global functional connectivity dysfunction in a large cohort with isolated focal dystonia affecting different body regions compared to control participants. In this case-control study we obtained resting-state MRI scans (3-4 7.3 minute runs) with eyes closed in participants with focal dystonia (cranial [17], cervical [13], laryngeal [18], limb [10]) and age- and sex-matched controls.Methods:Rigorous preprocessing for all analyses was performed to minimize effect of head motion during scan acquisition (dystonia N=58, control N=47 analyzed). We assessed regional functional connectivity by computing a seed-correlation map between putamen, pallidum, and sensorimotor cortex and all brain voxels. We assessed significant group differences on a cluster-wise basis. In a separate analysis, we applied 300 seed regions across the cortex, cerebellum, basal ganglia and thalamus to comprehensively sample the whole brain. We obtained participant whole-brain correlation matrices by computing the correlation between seed average time courses for each seed pair. Weighted object-oriented data analysis assessed group-level whole-brain differences.Results:Participants with focal dystonia had decreased functional connectivity at the regional level, within the striatum and between lateral primary sensorimotor cortex and ventral intraparietal area, whereas whole-brain correlation matrices did not differ between focal dystonia and control groups. Rigorous quality control measures eliminated spurious large-scale functional connectivity differences between groups.Conclusion:Regional functional connectivity differences, not global network level dysfunction, contributes to common pathophysiological mechanisms in isolated focal dystonia. Rigorous quality control eliminated spurious large-scale network differences between focal dystonia and control participants.
Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Ninety percent of patients who present with metastatic and 30% to 40% of patients with nonmetastatic disease experience relapse, creating an urgent need for novel therapeutic strategies. The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are important for mitosis, motility, and cell survival. Upregulation of Met/HGF signaling via receptor overexpression, amplification, or mutation drives the proliferation, invasiveness, and metastasis of a variety of cancer cells, including OS, prompting the development of Met/HGF inhibitors. OS cells depend on Met overexpression because introduction of dominant-negative Met inhibits in vivo tumorigenicity. Despite the importance of Met/HGF signaling in the development and maintenance of OS, the potential efficacy of pharmacologic Met inhibition in OS has been addressed only in in vitro studies. PF-2341066 is an orally bioavailable, selective ATP-competitive Met inhibitor that showed promising results recently in a phase I clinical trial in non-small cell lung cancer (NSCLC) patients. We tested the ability of PF-2341066 to inhibit malignant properties of osteosarcoma cells in vitro and orthotopic xenograft growth in vivo. In vitro, PF-2341066 inhibited osteosarcoma behavior associated with primary tumor growth (eg, proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). In nude mice treated with PF-2341066 via oral gavage, the growth and associated osteolysis and extracortical bone matrix formation of osteosarcoma xenografts were inhibited by PF-2341066. PF-2341066 may represent an effective new systemic therapy for localized and potentially disseminated osteosarcoma. ß
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