Inhibition of the Janus-associated kinases (JAK) with ruxolitinib (RUX) reduces graft-versus-host disease (GVHD) in preclinical and clinical models. In total 19 allograft recipients with moderate/severe steroid-dependent chronic GVHD received RUX as ≥2nd line salvage. RUX was well tolerated, and led to complete/partial resolution of oral (92/7%), cutaneous (82/0%), hepatic (71/28%), gastro-intestinal (75/17%), musculoskeletal (33/67%), pulmonary (0/80%), scleroderma (0/75%), vaginal (0/75%), and ocular (0/100%) chronic GVHD. Overall 18 achieved partial response and 1 complete response according to NIH Consensus Criteria. Responses occurred early and were sustained which enabled discontinuation (68%) or reduction of steroids to physiologic doses (21%). We conclude that RUX is an effective steroid-sparing agent in chronic GVHD.
Self-injurious behavior (SIB) is a debilitating characteristic that is prevalent across a broad spectrum of neurodevelopmental disorders. In most of these disorders, some individuals exhibit SIB, whereas others do not. However, the neurobiological mechanisms that confer vulnerability are virtually unexplored. We examined innate characteristics that contribute to vulnerability or resistance for SIB in an animal model of the behavioral pathology. Eighteen outbred Long-Evans rats were screened for behavioral responsiveness to the mild stress of a novel environment. The rats were then categorized as high responders (HR; those rats that had the highest locomotor counts) or low responders (LR; those rats that had lower locomotor counts) by median split. All the rats were then given daily injections of the indirect monoamine agonist pemoline (150 mg/kg/day) for 10 days, and self-injury was evaluated. All 9 HR rats and 5 of the 9 LR rats exhibited self-injury. The HR rats spent more time self-injuring, injured more body sites, and caused larger areas of tissue damage than the LR rats did. Furthermore, the behavioral responsiveness to novelty stress was significantly correlated with each of these measures of self-injury. The HR rats did not exhibit substantially enhanced responses on other measures of psychostimulant action (stereotypy, grooming, locomotion, rearing). Accordingly, vulnerability to develop pemoline-induced SIB is positively correlated with, and can be predicted based upon, a behavioral measure of innate stress responsiveness. These findings suggest that characteristics that are common in developmental disorders may help predispose afflicted individuals to self-injure. The findings also extend the variety of behavioral pathologies (e.g. drug addiction) for which the HR/LR model predicts vulnerability.
Skeletal muscle, a highly active tissue, makes up 40% of the total body weight. This tissue relies on mitochondria for ATP production, calcium homeostasis, and programed cell death. Mitochondrial phospholipid composition, namely, cardiolipin (CL), influences the functional efficiency of mitochondrial proteins, specifically cytochrome c. The interaction of CL with cytochrome c in the presence of free radicals induces structural and functional changes promoting peroxidase activity and cytochrome c release, a key event in the initiation of apoptosis. The CL acyl chain degree of saturation has been implicated in the cytochrome c to cytochrome c peroxidase transition in liposomal models. However, mitochondrial membranes are composed of differing CL acyl chain composition. Currently, it is unclear how differing CL acyl chain composition utilizing liposomes will influence the cytochrome c form and function as a peroxidase. Thus, this study examined the role of CL acyl chain saturation within liposomes broadly reflecting the relative CL composition of mitochondrial membranes from healthy and dystrophic mouse muscle on cytochrome c conformation and function. Despite no differences in protein conformation or function between healthy and dystrophic liposomes, cytochrome c's affinity to CL increased with greater unsaturation. These findings suggest that increasing CL acyl chain saturation, as implicated in muscle wasting diseases, may not influence cytochrome c transformation and function as a peroxidase but may alter its interaction with CL, potentially impacting further downstream effects.
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