Plos One
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Neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of systemic Lupus erythematosus (SLE), since netting neutrophils release potentially immunogenic autoantigens including histones, LL37, human neutrophil peptide (HNP), and self-DNA. In turn, these NETs activate plasmacytoid dendritic cells resulting in aggravation of inflammation and disease. How suppression of NET formation can be targeted for treatment has not been reported yet. ⋯ Furthermore, NET release by healthy neutrophils exposed to SLE plasma is inhibited by SIRL-1 ligation. Thus, SIRL-1 engagement can dampen spontaneous and anti-neutrophil antibody-induced NET formation in SLE, likely by suppressing NAPDH oxidase and MEK-ERK activity. Together, these findings reveal a regulatory role for SIRL-1 in NET formation, potentially providing a novel therapeutic target to break the pathogenic loop in SLE.
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In hemophilia A, routine prophylaxis with exogenous factor VIII (FVIII) requires frequent intravenous injections and can lead to the development of anti-FVIII alloantibodies (FVIII inhibitors). To overcome these drawbacks, we screened asymmetric bispecific IgG antibodies to factor IXa (FIXa) and factor X (FX), mimicking the FVIII cofactor function. Since the therapeutic potential of the lead bispecific antibody was marginal, FVIII-mimetic activity was improved by modifying its binding properties to FIXa and FX, and the pharmacokinetics was improved by engineering the charge properties of the variable region. ⋯ Furthermore, hBS910 could be purified on a large manufacturing scale and formulated into a subcutaneously injectable liquid formulation for clinical use. These features of hBS910 enable routine prophylaxis by subcutaneous delivery at a long dosing interval without considering the development or presence of FVIII inhibitors. We expect that hBS910 (investigational drug name: ACE910) will provide significant benefit for severe hemophilia A patients.
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An increasing proportion of Canadian induced abortions are performed in large urban areas. For unknown reasons the number of rural abortion providers in Canadian provinces, such as British Columbia (BC), has declined substantially. This study explored the experiences of BC rural and urban physicians providing abortion services. ⋯ This first study of experiences among rural and urban abortion providers in Canada identifies addressable challenges faced by rural physicians. Rural providers expressed a need for increased support from hospital administration and policy. Further challenges identified include a desire for continuing professional education opportunities, and for available replacement providers.
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The role of Pokemon (POK erythroid myeloid ontogenic actor), a recently identified POK transcription factor with proto-oncogenic activity, in hepatocellular carcinogenesis has only been assessed by a few studies. Our previous study revealed that Pokemon is overexpressed in hepatocellular carcinomas (HCC) and promotes HCC cell proliferation and migration via an AKT- and ERK- dependent manner. In the present study, we used the TUNEL assay and FACS analysis to demonstrate that oxaliplatin induced apoptosis was significantly increased in cells with silenced Pokemon. ⋯ Increased activated caspase-8-mediated cleavage and activation of downstream effector caspases such as caspase-9 and caspase-3 was observed in HepG2 si-Pokemon cells as compared to control. Therefore, Pokemon might serve as an important mediator of crosstalk between intrinsic and extrinsic apoptotic pathways in HCC cells. Moreover, our findings suggest that Pokemon could be an attractive therapeutic target gene for human cancer therapy.
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Resting-state functional magnetic resonance imaging (RS-fMRI) has been widely used to investigate temporally correlated fluctuations between distributed brain areas, as well as to characterize local synchronization of low frequency (<0.1 Hz) spontaneous fMRI signal. Regional homogeneity (ReHo) was proposed as a voxel-wise measure of the synchronization of the timecourses of neighboring voxels and has been used in many studies of brain disorders. However, the interpretation of ReHo remains challenging because the effect of high frequency task on ReHo is still not clear. ⋯ In the contralateral sensorimotor cortex, 'Slow' task state showed greater ReHo than 'Rest' in low frequency band (0-0.08Hz) fMRI signal, but lower ReHo in high frequency band (0.08-1.67 Hz); 'Fast' task state showed lower ReHo than 'Rest' in both the low and high frequency band; 'Tonic' state did not show any significant difference compared to 'Rest'. The results in the contralateral sensorimotor cortex suggest that local synchronization of BOLD signal varies with different finger tapping speed. In the ipsilateral sensorimotor cortex, all the three task states had lower ReHo than the 'Rest' state both in the low and high frequency, suggesting a similar effect of fast and slow finger tapping frequencies on local synchronization of BOLD signal in the ipsilateral motor cortex.