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Background-Platelet-rich thrombi are resistant to lysis by tissue plasminogen activator (tPA). Plasminogen activator inhibitor-1 (PAI-1), a rapid inhibitor of tPA, may contribute to arterial thrombolysis resistance. However, few data are available regarding the effect of PAI-1 on arterial thrombolysis in animals. We used a murine carotid injury model to test the hypothesis that PAI-1 inhibits thrombolysis mediated by pharmacological concentrations of tPA. Methods and Results-Platelet-rich thrombi were induced in wild-type mice (PAI-1 ϩ/ϩ; nϭ11) and PAI-1-deficient mice (PAI-1 Ϫ/Ϫ; nϭ11) with ferric chloride. Baseline carotid blood flows and mean occlusion times did not differ between PAI-1 ϩ/ϩ and PAI-1 Ϫ/Ϫ mice. Clot lysis was induced by infusion of heparin (200 U/kg bolus, 70 U ⅐ kg Ϫ1 ⅐ h Ϫ1 drip), human plasminogen (50 mg/kg), and tPA at 20 (nϭ10) or 100 (nϭ12) g ⅐ kg Ϫ1 ⅐ min

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The poor performance of 2014–15 Northern Hemisphere (NH) influenza vaccines was attributed to mismatched H3N2 component with circulating epidemic strains. Using human serum samples collected from 2009–10, 2010–11 and 2014–15 NH influenza vaccine trials, we assessed their cross-reactive hemagglutination inhibition (HAI) antibody responses against recent H3 epidemic isolates. All three populations (children, adults, and older adults) vaccinated with the 2014–15 NH egg- or cell-based vaccine, showed >50% reduction in HAI post-vaccination geometric mean titers against epidemic H3 isolates from those against egg-grown H3 vaccine strain A/Texas/50/2012 (TX/12e). The 2014–15 NH vaccines, regardless of production type, failed to further extend HAI cross-reactivity against H3 epidemic strains from previous seasonal vaccines. Head-to-head comparison between ferret and human antisera derived antigenic maps revealed different antigenic patterns among representative egg- and cell-grown H3 viruses characterized. Molecular modeling indicated that the mutations of epidemic H3 strains were mainly located in antibody-binding sites A and B as compared with TX/12e. To improve vaccine strain selection, human serologic testing on vaccination-induced cross-reactivity need be emphasized along with virus antigenic characterization by ferret model.

Despite the promise of sonodynamic processes in cancer therapy, existing sonosensitizers often fail to regulate the generation of reactive oxygen species (ROS)a gainst tumors, potentially leading to off-target toxicity to normal tissues.W e report at ransformable core-shell nanosonosensitizer (TiO 2 @CaP) that reinvigorates ROSg eneration and dissolves its CaP shell to release Ca 2+ in an acidic tumor microenvironment (TME) under ultrasound activation. Thus,T iO 2 @CaP acts as as mart nanosonosensitizer that specifically induces mitochondrial dysfunction via overloading intracellular Ca 2+ ions to synergize with the sonodynamic process in the TME. TiO 2 @CaP substantially enhances immunogenic cell death, resulting in enhanced T-cell recruitment and infiltration into the immunogenic cold tumor (4T1). In conjunction with checkpointb lockade therapy( anti-PD 1), TiO 2 @CaP-mediated sonodynamic therapyelicits systemic antitumor immunity, leading to regression of non-treated distant tumors and inhibition of lung metastasis.T his work paves the way to development of "smart" TME-activatable sonosensitizers with temporospatial control over antitumor responses.

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In atherosclerosis-prone mice, PAI-1 promotes neointima formation after oxidative vascular injury. The apparent hyperlipidemia-dependent effect of PAI-1 may be mediated by its capacity to inhibit the clearance of platelet-fibrin thrombi that can deliver growth factors to the blood vessel wall or be incorporated into developing vascular lesions. Alternatively, hyperlipidemia may alter the pattern of gene expression in the blood vessel wall to enhance potential effects of PAI-1 on antiproliferative processes, such as transforming growth factor-beta activation and apoptosis.