The observation that enhanced mitochondrial transmembrane potential is a prevalent tumor cell phenotype has provided the conceptual basis for the development of mitochondrial targeting as a novel therapeutic strategy for both chemo- and photochemotherapy of neoplastic diseases. Because the plasma transmembrane potential is negative on the inner side of the cell and the mitochondrial transmembrane potential is negative on the inner side of this organelle, extensively conjugated cationic molecules (dyes) displaying appropriate structural features are driven electrophoretically through these membranes and tend to accumulate inside energized mitochondria. As a result of the higher mitochondrial transmembrane potential typical of tumor cells, a number of cationic dyes preferentially accrue and are retained for longer periods in the mitochondria of these cells compared to normal cells. This differential in both drug loading and retention brings about the opportunity to attack and destroy tumor cells with a high degree of selectivity. Only a small subset of the cationic dyes known to accumulate in energized mitochondria mediate the destruction of tumor cells with a high degree of selectivity, and the lack of a reliable model to describe the structural determinants of this tumor specificity has prevented mitochondrial targeting from becoming a more reliable therapeutic strategy. We describe here a systematic study of how the molecular structure of closely related cationic triarylmethanes affects the selectivity with which these dyes mediate the photochemical destruction of tumor cells. Based on our observations of how the lipophilic/hydrophilic character of these dyes affects tumor selectivity, we propose a simple model to assist in the design of new drugs tailored specifically for imaging and selective destruction of neoplastic tissue via mitochondrial targeting.
RATIONALE: In infancy, rhinovirus illnesses and severe RSV bronchiolitis indicate increased risk for recurrent wheezing and asthma, but there is less information about other viruses. We evaluated the frequency and severity of metapneumovirus (HMPV) and coronavirus (HCV) infections in a high-risk group of infants. METHODS: Nasal lavage samples were obtained in the first year of life during scheduled study visits and symptomatic respiratory illnesses as part of the Childhood Origins of Asthma Project (COAST). Samples (n 5 567) were analyzed by Respiratory Multicode Assay (RMA) for HMPV, HCV-229E, HCV-OC43, HCV-NL63 and HCV-SARS. RESULTS: HMPV was isolated in 10.7% of samples during illnesses (n 5 291), and also occurred with other respiratory viruses (4.8%). 47.8% of HMPV illnesses included wheezing. HCV were isolated in 19.2% of the samples during illnesses and included HCV-OC43 (10.0%) and HCV-NL63 (9.6%). In addition, HCV was commonly detected together with other respiratory viruses (6.5%). Of all HCV illnesses (n 5 42), 33.3% included wheezing; however, HCV-NL63 had a significantly higher wheezing rate compared to HCV-OC43 (37.5% vs. 4.5%, p 5 0.028). Children who had at least one HCV-NL63 illness during infancy were significantly more likely to have asthma at age 6 compared to those without HCV-NL63 illnesses (52.2% vs. 25.0%, p 5 0.007). Having either HCV-OC43 or HMPV was not a risk factor for asthma at age 6. CONCLUSIONS: Improvements in viral diagnostics has allowed for identification of viruses that are difficult to culture. In infancy, HCV-NL63, HCV-OC43 and HMPV were significant causes of wheezing illnesses, however, only HCV-NL63 was significantly associated with asthma development at age six.
ADJ induces inflammasome activation in DCs, but deficiency for NLRP3, ASC or caspase 1 did not affect ADJ-mediated cross-presentationNext, we examined the effects of ADJ on the expression profiles of cytokines, chemokines and canonical cell surface markers of DC activation. Compared to untreated DCs, ADJ-treated DCs showed statistically significant, yet modest increases in expression of CD40, CD80, and CD86; no significant differences in expression were observed for MHC-I, MHC-II, or CCR7 (Fig. 1C).ADJ-treated DCs produced higher levels of IL-12 (p70), TNF-, IL-1, CCL3, CCL4, CXCL1, and RANTES, as compared to untreated DCs; no significant differences in expression were observed for IL-6, IL-10, and IFN- (Fig. 1D). Particularly, ADJ-stimulated DCs also produced significantly elevated levels of IL-1 and IL-18 (Fig. 1D), which is suggestive of inflammasome activation. Since inflammasome activation has been implicated in modulation of antigen presentation by DCs (Sokolovska et al., 2013, Li et al., 2019, we performed B3Z assays using DCs deficient in NLRP3, ASC, or caspase 1 to interrogate whether inflammasome activation is required for ADJ-induced cross-presentation in BMDCs. Surprisingly, loss of NLRP3, ASC or caspase 1 activity did not affect ADJ-induced cross-presentation by DCs, in vitro (Fig. 1E). To validate whether caspase 1 is required for cross-presentation in vivo, we immunized cohorts of wild type (WT) and caspase 1-deficient mice with ADJ+OVA, and quantified OVA SIINFEKLspecific CD8 T cells in spleens using MHC I tetramers at day 8 after immunization. Consistent with our results from B3Z assays, caspase 1 deficiency did not significantly affect the activation of SIINFEKL-specific CD8 T cells in spleens (Fig. 1F), suggesting that caspase 1 is not essential for ADJ-driven cross-presentation to CD8 T cells in vivo.
RATIONALE: In infancy, rhinovirus illnesses and severe RSV bronchiolitis indicate increased risk for recurrent wheezing and asthma, but there is less information about other viruses. We evaluated the frequency and severity of metapneumovirus (HMPV) and coronavirus (HCV) infections in a high-risk group of infants. METHODS: Nasal lavage samples were obtained in the first year of life during scheduled study visits and symptomatic respiratory illnesses as part of the Childhood Origins of Asthma Project (COAST). Samples (n 5 567) were analyzed by Respiratory Multicode Assay (RMA) for HMPV, HCV-229E, HCV-OC43, HCV-NL63 and HCV-SARS. RESULTS: HMPV was isolated in 10.7% of samples during illnesses (n 5 291), and also occurred with other respiratory viruses (4.8%). 47.8% of HMPV illnesses included wheezing. HCV were isolated in 19.2% of the samples during illnesses and included HCV-OC43 (10.0%) and HCV-NL63 (9.6%). In addition, HCV was commonly detected together with other respiratory viruses (6.5%). Of all HCV illnesses (n 5 42), 33.3% included wheezing; however, HCV-NL63 had a significantly higher wheezing rate compared to HCV-OC43 (37.5% vs. 4.5%, p 5 0.028). Children who had at least one HCV-NL63 illness during infancy were significantly more likely to have asthma at age 6 compared to those without HCV-NL63 illnesses (52.2% vs. 25.0%, p 5 0.007). Having either HCV-OC43 or HMPV was not a risk factor for asthma at age 6. CONCLUSIONS: Improvements in viral diagnostics has allowed for identification of viruses that are difficult to culture. In infancy, HCV-NL63, HCV-OC43 and HMPV were significant causes of wheezing illnesses, however, only HCV-NL63 was significantly associated with asthma development at age six.
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