Translational research : the journal of laboratory and clinical medicine
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Case Reports
Development of Strategies for Community Engaged Research Dissemination by Basic Scientists: A Case Study.
As depicted in the translational research continuum, dissemination of research findings to past research participants and the community-at-large is integral to improving health outcomes. Blocks in translation exist in which poor dissemination is a major contributor. Limited progress has been made on how to engage basic scientists at T1 and T2 phases to meaningfully disseminate study findings to community. ⋯ Finally, we provide competencies, informed by basic scientists, needed to engage in effective, community-engaged research dissemination. The activities, reflections, and competencies can be used by basic scientists and academic institutions as models to guide their community engaged research dissemination activities. This work supports the goal to bridge the translational research gap.
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KRAS mutation is a common driver in solid tumors, and KRAS-mutated tumors are relatively resistant to radiotherapy. Therefore, we investigated the combined effect of radiation and KRAS-MEK inhibitors (AMG510 and trametinib) in KRAS-mutated tumors. The expression of programmed death-ligand 1 (PD-L1), major histocompatibility complex (MHC) class I molecules, and cytokines in KRAS-mutated cell lines was assessed using flow cytometry, western blot analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. ⋯ The combination of trametinib and radiation controlled tumor growth and induced more infiltration of CD4+ and CD8+ T cells in vivo, wherein tumor inhibition function and the survival period of mice could be reduced by CD8+ and/or CD4+ T cell depletion. The expression levels of immune-related genes also increased in the combination therapy group. Our results indicate that KRAS-MEK inhibitors in combination with radiotherapy can enhance antitumor immunity, providing new therapeutic strategies for KRAS-mutated tumors.
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Thrombomodulin (TM) functions in coagulation, fibrinolysis and inflammation by its cofactor activity for protein C, thrombin-activatable fibrinolysis inhibitor (TAFI) activation and high mobility group box 1 (HMGB1) degradation induced by thrombin. It has been widely reported that mutations in TM are related to thromboembolic diseases but hardly in lectin domain. Here we report our findings about the functional deficiencies in TM caused by substitution of aspartate with tyrosine at residue 126. ⋯ And the study with thrombosis models of mice suggested the decreased inhibition of thrombus development of the mutant. Together the results showed deleterious changes on TM function caused by this mutation, which may explain the thrombophilia tendency of the patients. This work provided supportive evidence that mutation in lectin domain of TM might be related to thrombotic diseases and may help us better understand the physiological roles of TM.
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Inflammasomes are multiprotein complexes of the innate immune response that recognize a diverse range of intracellular sensors of infection or cell damage and recruit the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) into an inflammasome signaling complex. The recruitment, polymerization and cross-linking of ASC is upstream of caspase-1 activation and interleukin-1β release. Here we provide evidence that IC 100, a humanized IgG4κ monoclonal antibody against ASC, is internalized into the cell and localizes with endosomes, while another part is recycled and redistributed out of the cell. ⋯ In A549 WT and TRIM21 KO cells treated with either IC 100 or IgG4κ isotype control, the levels of intracellular IC 100 were higher than in the IgG4κ-treated controls at 2 hours, 1 day and 3 days after administration, indicating that IC 100 escapes degradation by the proteasome. Lastly, electron microscopy studies demonstrate that IC 100 binds to ASC filaments and alters the architecture of ASC filaments. Thus, IC 100 readily penetrates a variety of cell types, and it binds to intracellular ASC, but it is not degraded by the TRIM21 antibody-dependent intracellular neutralization pathway.
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After an attack of pancreatitis, individuals may develop metabolic sequelae (eg, new-onset diabetes) and/or pancreatic cancer. These new-onset morbidities are, at least in part, driven by low-grade inflammation. The aim was to study the profiles of cytokines/chemokines in individuals after an attack of pancreatitis. ⋯ Pancreatitis-related factors, body composition, and other studied parameters did not differ significantly between the 2 endotypes. Individuals with a similar phenotype and clinical course of pancreatitis have differing cytokine/chemokine profiles after clinical resolution of the disease. People with the inflammatory endotype have distinct changes in the pancreatic and gut hormones known to be involved in the pathogenesis of new-onset morbidities after an attack of pancreatitis.