66 research outputs found

    Phenothiourea Sensitizes Zebrafish Cranial Neural Crest and Extraocular Muscle Development to Changes in Retinoic Acid and IGF Signaling

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    1-phenyl 2-thiourea (PTU) is a tyrosinase inhibitor commonly used to block pigmentation and aid visualization of zebrafish development. At the standard concentration of 0.003% (200 µM), PTU inhibits melanogenesis and reportedly has minimal other effects on zebrafish embryogenesis. We found that 0.003% PTU altered retinoic acid and insulin-like growth factor (IGF) regulation of neural crest and mesodermal components of craniofacial development. Reduction of retinoic acid synthesis by the pan-aldehyde dehydrogenase inhibitor diethylbenzaldehyde, only when combined with 0.003% PTU, resulted in extraocular muscle disorganization. PTU also decreased retinoic acid-induced teratogenic effects on pharyngeal arch and jaw cartilage despite morphologically normal appearing PTU-treated controls. Furthermore, 0.003% PTU in combination with inhibition of IGF signaling through either morpholino knockdown or pharmacologic inhibition of tyrosine kinase receptor phosphorylation, disrupted jaw development and extraocular muscle organization. PTU in and of itself inhibited neural crest development at higher concentrations (0.03%) and had the greatest inhibitory effect when added prior to 22 hours post fertilization (hpf). Addition of 0.003% PTU between 4 and 20 hpf decreased thyroxine (T4) in thyroid follicles in the nasopharynx of 96 hpf embryos. Treatment with exogenous triiodothyronine (T3) and T4 improved, but did not completely rescue, PTU-induced neural crest defects. Thus, PTU should be used with caution when studying zebrafish embryogenesis as it alters the threshold of different signaling pathways important during craniofacial development. The effects of PTU on neural crest development are partially caused by thyroid hormone signaling

    Dual Anti-OX40/IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression

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    The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of OX40 can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, OX40 agonists are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naïve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, the downstream signals that regulate OX40 itself remain unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2 augmented tumor immunotherapy against multiple tumor types. Dual therapy was also able to restore the function of anergic tumor-reactive CD8 T cells in mice with long-term well-established (>5 wks) tumors, leading to increased survival of the tumor-bearing hosts. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 expression and demonstrate a novel means of augmenting cancer immunotherapy by providing dual anti-OX40/common gamma chain cytokine-directed therapy

    Societal-level versus individual-level predictions of ethical behavior: a 48-society study of collectivism and individualism

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    Is the societal-level of analysis sufficient today to understand the values of those in the global workforce? Or are individual-level analyses more appropriate for assessing the influence of values on ethical behaviors across country workforces? Using multi-level analyses for a 48-society sample, we test the utility of both the societal-level and individual-level dimensions of collectivism and individualism values for predicting ethical behaviors of business professionals. Our values-based behavioral analysis indicates that values at the individual-level make a more significant contribution to explaining variance in ethical behaviors than do values at the societal-level. Implicitly, our findings question the soundness of using societal-level values measures. Implications for international business research are discussed

    The role of preclinical SPECT in oncological and neurological research in combination with either CT or MRI

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    Why people do not take their psychotropic drugs as prescribed: results of the 2000 National Psychiatric Morbidity Survey

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    Objective: We examined the prevalence and determinants of the reasons given for non-adherence to psychiatric medication in a representative community survey.Method: We used data for all participants taking oral psychotropic medication (n = 634) from the 2000 British Survey of National Psychiatric Morbidity.Results: Of participants interviewed, 217 (34.2%) reported incomplete adherence to their psychiatric medication. Reasons given included forgetting, losing, running out (37.4%); thinking medication unnecessary (24.6%); reluctance to take drugs (18.9%) and side-effects (14.2%). Those giving forgetfulness or side-effects as reasons were younger. Side-effects were reported more frequently by people with a lower IQ or with psychosis. Those taking Selective Serotonin Reuptake Inhibitors were more likely to forget to take their medication.Conclusion: Two-fifths of people reported that missing their medication was a decision taken because they did not want it or think it necessary. Side-effects are a relatively uncommon reason for under-medication. Our results have implications for interventions to assist adherence
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