Translational research : the journal of laboratory and clinical medicine
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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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Overactive inflammatory responses are central to the pathophysiology of many hemolytic conditions including sickle cell disease. Excessive hemolysis leads to elevated serum levels of heme due to saturation of heme scavenging mechanisms. Extracellular heme has been shown to activate the NLRP3 inflammasome, leading to activation of caspase-1 and release of pro-inflammatory cytokines IL-1β and IL-18. ⋯ Some clinical studies indicate there is a benefit to blocking the NLRP3 inflammasome pathway in patients with sickle cell disease and other hemolytic conditions. However, a thorough understanding of the mechanisms of heme-induced inflammasome activation is needed to fully leverage this pathway for clinical benefit. This review will explore the mechanisms of heme-induced NLRP3 inflammasome activation and the role of this pathway in hemolytic conditions including sickle cell disease.
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Despite significant advances and the continuous development of novel, effective therapies to treat a variety of malignancies, cancer therapy-induced cardiotoxicity has been identified as a prominent cause of morbidity and mortality, closely competing with secondary malignancies. This unfortunate limitation has prompted the inception of the field of cardio-oncology with its purpose to provide the necessary knowledge and key information on mechanisms that support the use of the most efficacious cancer therapy with minimal or no interruption while paying close attention to preventing cardiovascular related morbidity and mortality. ⋯ In this review, we focus on describing the principal mechanisms for different classes of cancer therapies that lead to cardiotoxicity involving the NLRP3 inflammasome. We also summarize current evidence of cardio-protection with inflammasome inhibitors in the context of heart disease in general, and further highlight the potential application of this evidence for clinical translation in at risk patients for the purpose of preventing cancer therapy associated cardiovascular morbidity and mortality.
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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.