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The prevalence of CD79B and MYD88 mutations in PCNSLs was considerably higher than reported in systemic diffuse large B-cell lymphomas. This observation could reflect the paucity of antigen stimuli from the immune system in the central nervous system (CNS) and the necessity to substitute them by the constitutive activation of CD79B and MYD88 that would initiate the signalling cascades. These hotspot mutations may serve as a genetic hallmark for PCNSL serving as a genetic marker for diagnose and potential targets for molecular therapy.

BackgroundManifestations of reperfusion injury include myocyte death leading to infarction, contractile dysfunction, and vascular injury characterized by the “no-reflow” phenomenon. Mitochondria-produced reactive oxygen species are believed to be centrally involved in each of these aspects of reperfusion injury, although currently no therapies reduce reperfusion injury by targeting mitochondria specifically.Methods and ResultsWe investigated the cardioprotective effects of a mitochondria-targeted peptide, Bendavia (Stealth Peptides), across a spectrum of experimental cardiac ischemia/reperfusion models. Postischemic administration of Bendavia reduced infarct size in an in vivo sheep model by 15% (P=0.02) and in an ex vivo guinea pig model by 38% to 42% (P<0.05). In an in vivo rabbit model, the extent of coronary no-reflow was assessed with Thioflavin S staining and was significantly smaller in the Bendavia group for any given ischemic risk area than in the control group (P=0.0085). Myocardial uptake of Bendavia was ≈25% per minute, and uptake remained consistent throughout reperfusion. Postischemic recovery of cardiac hemodynamics was not influenced by Bendavia in any of the models studied. Isolated myocytes exposed to hypoxia/reoxygenation showed improved survival when treated with Bendavia. This protection appeared to be mediated by lowered reactive oxygen species–mediated cell death during reoxygenation, associated with sustainment of mitochondrial membrane potential in Bendavia-treated myocytes.ConclusionsPostischemic administration of Bendavia protected against reperfusion injury in several distinct models of injury. These data suggest that Bendavia is a mitochondria-targeted therapy that reduces reperfusion injury by maintaining mitochondrial energetics and suppressing cellular reactive oxygen species levels. (J Am Heart Assoc. 2012;1:e001644 doi: 10.1161/JAHA.112.001644.)

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Increased myocardial wall stress after myocardial infarction (MI) initiates the process of adverse left ventricular (LV) remodeling that is manifest as progressive LV dilatation, loss of global contractile function, and symptomatic heart failure, and recent work has shown that reduction in wall stress through injectable bulking agents attenuates these outcomes. In this study, hyaluronic acid (HA) was functionalized to exhibit controlled and tunable mechanics and degradation once crosslinked, in an attempt to assess the temporal dependency of mechanical stabilization in LV remodeling. Specifically, two hydrolytically degrading (low and high HeMA-HA, degrading in ~3 and 10 weeks, respectively) and two stable (low and high MeHA, little mass loss even after 8 weeks) hydrogels with similar initial mechanics (low: ~7 kPa, high: ~35–40 kPa) were evaluated in an ovine model of MI. Generally, the more stable hydrogels maintained myocardial wall thickness in the apical and basilar regions more efficiently (low MeHA: apical: 6.5mm, basilar: 7mm, high MeHA: apical: 7.0mm basilar: 7.2mm) than the hydrolytically degrading hydrogels (low HeMA-HA: apical: 3.5mm, basilar: 6.0mm, high HeMA-HA: apical: 4.1mm, basilar: 6.1mm); however, all hydrogel groups were improved compared to infarct controls (IC) (apical: 2.2mm, basilar: 4.6mm). Histological analysis at 8 weeks demonstrated that although both degradable hydrogels resulted in increased inflammation, all treatments resulted in increased vessel formation compared to IC. Further evaluation revealed that while high HeMA-HA and high MeHA maintained reduced LV volumes at 2 weeks, high MeHA was more effective at 8 weeks, implying that longer wall stabilization is needed for volume maintenance. All hydrogel groups resulted in better cardiac output (CO) values than IC.