Who\u27s the Fairest of Them All? Defining and Subverting the Female Beauty Ideal in Fairy Tale Narratives and Films through Grotesque Aesthetics

This thesis seeks to explore the ways in which women and beauty are depicted in the fairy tales of Giambattista Basile, the Grimm Brothers, and 21st century fairy tale films. A dominant beauty ideal in the genre has established a splitting of female characters into strict dichotomies that reinforce beauty and good moral behaviour while also propagating antagonistic female relationships. The use of spectacle to highlight the physical rewards of beauty and the violent punishments of ugly women have created a stable pattern in the genre that is maintained regardless of time period or context. It is the aim of this thesis to pursue an aesthetic approach to the tales that focuses on the beauty ideal, anxiety, spectacle, and the grotesque, to explore the ways in which this seemingly static genre has been able to challenge the impossible ideals of beauty it overtly emphasizes

The Molecular Mechanisms Underlying the Cancer Killing Effect of Interleukin-24

Interleukin-24 (IL-24) is an immunomodulatory cytokine that also displays specific anti-tumor effects across many cancer cell types. The tumor suppressor activities of IL-24 include inhibition of angiogenesis, metastasis, toxic autophagy, cancer-specific apoptosis, and sensitization to traditional cancer treatments like chemotherapy and radiation. Overexpression of IL-24 can selectively induce apoptosis in various cancer cells while having no adverse effects on normal cells. Due to this favorable killing effect, IL-24 is currently in phase II clinical trials. There is accumulating evidence that IL-24’s anti-cancer activity is primarily through the endoplasmic reticulum (ER) stress pathway but other pathways leading to cell death are also exploited by IL-24 depending on the cell type. In this work, in vitrostudies were performed to understand the downstream effects of IL-24-mediated ER stress such as eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation, which leads to ternary complex depletion and translation initiation inhibition. We also uncover a novel mechanism of IL-24-mediated ER stress involving the protein kinase A pathway and extrinsic apoptosis in breast cancer cell lines. Finally, we show for the first time that endogenous IL-24 mRNA expression is affected by the differential expression of microRNA-4719 and microRNA-6756-5p incastration-resistant prostate cancer cell lines compared to normal or indolent prostate cancer cell lines. Each chapter of this work uncovers a new mechanism of action that can be applied to the development of anti-cancer therapeutics involving IL-24. Understanding the intricacies of IL-24-mediated apoptosis in different cancer cell line types will contribute to the development of personalized gene therapies that can target tumors in a more safe and non-toxic approach

Transportation Barriers to Healthcare in Adults 65+ in the Greater Burlington Area

Introduction. Missed appointments often lead to poorer health care outcomes for patients and pose a major economic burden on medical centers. Transportation is an obstacle to accessing medical care for elderly patients in Vermont and results in delayed medical appointments. Methods. We surveyed senior citizens in Chittenden county to determine both the type of transportation barriers and medical care missed due to the lack of transpor- tation. An original survey assessing the impact of transportation to health care was distributed in person and through an online platform. Participants were asked to identify the following in the past year: how often transportation was an issue for healthcare, specific barriers to transportation, and which specific health care appointments were missed due to lack of transportation. Ninety-six surveys out of a total of 251 collected were included in the analysis. Respondents were grouped into either having high transportation barriers, n=43, (always, often, sometimes had issues in the past year), or low transportation barriers, n=53, (rarely had issues). Results. The high barriers group reported more missed appointments, with eye appointments being the most frequent, and depended more on other modes of trans- portation. The low barriers group was able to drive themselves to their appointments more often. Conclusion. The results suggest a trend between barriers to transportation and a lack of access to healthcare appointments. Although more than half of the survey respondents indicated that they do not currently experience transportation barriers, many expressed concern about the transportation difficulties they could encounter in the future.https://scholarworks.uvm.edu/comphp_gallery/1263/thumbnail.jp

MicroRNA-4719 and microRNA-6756-5p Correlate with Castration-Resistant Prostate Cancer Progression through Interleukin-24 Regulation

Prostate cancer (PCa) is the second leading cause of cancer death in the United States. The five-year survival rate for men diagnosed with localized PCa is nearly 100%, yet for those diagnosed with aggressive PCa, it is less than 30%. The pleiotropic cytokine Interleukin-24 (IL-24) has been shown to specifically kill PCa cells compared to normal cells when overexpressed in both in vitro and in vivo studies. Despite this, the mechanisms regulating IL-24 in PCa are not well understood. Since specific microRNAs (miRNAs) are dysregulated in PCa, we used miRNA target prediction algorithm tools to identify miR-4719 and miR-6556-5p as putative regulators of IL-24. This study elucidates the expression profile and role of miR-4719 and miR-6756-5p as regulators of IL-24 in PCa. qRT-PCR analysis shows miR-4719 and miR-6756-5p overexpression significantly decreases the expression of IL-24 in PCa cells compared to the negative control. Compared to the indolent PCa and normal prostate epithelial cells, miR-4719 and miR-6756-5p are significantly overexpressed in castration-resistant prostate cancer (CRPC) cell lines, indicating that their gain may be an early event in PCa progression. Moreover, miR-4719 and miR-6756-5p are significantly overexpressed in the CRPC cell line of African-American males (E006AA-hT) compared to CRPC cell lines of Caucasian males (PC-3 and DU-145), indicating that miR-4719 and miR-6756-5p may also play a role in racial disparity. Lastly, the inhibition of expression of miR-4719 and miR-6756-5p significantly increases IL-24 expression and inhibits proliferation and migration of CRPC cell lines. Our findings indicate that miR-4719 and miR-6756-5p may regulate CRPC progression through the targeting of IL-24 expression and may be biomarkers that differentiate between indolent and CRPC. Strategies to inhibit miR-4719 and miR-6756-5p expression to increase IL-24 in PCa may have therapeutic efficacy in aggressive PCa

Translation Control by p53

The translation of mRNAs plays a critical role in the regulation of gene expression and therefore, in the regulation of cell proliferation, differentiation and apoptosis. Unrestricted initiation of translation causes malignant transformation and plays a key role in the maintenance and progression of cancers. Translation initiation is regulated by the ternary complex and the eukaryotic initiation factor 4F (eIF4F) complex. The p53 tumor suppressor protein is the most well studied mammalian transcription factor that mediates a variety of anti-proliferative processes. Post-transcriptional mechanisms of gene expression in general and those of translation in particular play a major role in shaping the protein composition of the cell. The p53 protein regulates transcription and controls eIF4F, the ternary complex and the synthesis of ribosomal components, including the down-regulation of rRNA genes. In summary, the induction of p53 regulates protein synthesis and translational control to inhibit cell growth

Mechanism of Action and Applications of Interleukin 24 in Immunotherapy

Interleukin 24 (IL-24) is an important pleiotropic immunoregulatory cytokine, whose gene is located in human chromosome 1q32-33. IL-24’s signaling pathways have diverse biological functions related to cell differentiation, proliferation, development, apoptosis, and inflammation, placing it at the center of an active area of research. IL-24 is well known for its apoptotic effect in cancer cells while having no such effect on normal cells. IL-24 can also be secreted by both immune and non-immune cells. Downstream effects of IL-24, after binding to the IL-20 receptor, can occur dependently or independently of the JAK/STAT signal transduction pathway, which is classically involved in cytokine-mediated activities. After exogenous addition of IL-24, apoptosis is induced in tumor cells independently of the JAK/STAT pathway. We have shown that IL-24 binds to Sigma 1 Receptor and this event induces endoplasmic reticulum stress, calcium mobilization, reactive oxygen species generation, p38MAPK activity, and ceramide production. Here we review IL-24’s role in autoimmunity, infectious disease response, wound repair, and vascular disease. Detailed understanding of the pleiotropic roles of IL-24 signaling can assist in the selection of more accurate therapeutic approaches, as well as targeting of appropriate cell types in treatment strategy development, and ultimately achieve desired therapeutic effects

IL-24 Promotes Apoptosis through cAMP-Dependent PKA Pathways in Human Breast Cancer Cells

Interleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces cancer cell-specific apoptosis. We have shown that IL-24 regulates apoptosis through phosphorylated eukaryotic initiation factor 2 alpha (eIF2α) during endoplasmic reticulum (ER) stress in cancer. Although multiple stresses converge on eIF2α phosphorylation, the cellular outcome is not always the same. In particular, ER stress-induced apoptosis is primarily regulated through the extent of eIF2α phosphorylation and activating transcription factor 4 (ATF4) action. Our studies show for the first time that cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation is required for IL-24-induced cell death in a variety of breast cancer cell lines and this event increases ATF4 activity. We demonstrate an undocumented role for PKA in regulating IL-24-induced cell death, whereby PKA stimulates phosphorylation of p38 mitogen-activated protein kinase and upregulates extrinsic apoptotic factors of the Fas/FasL signaling pathway and death receptor 4 expression. We also demonstrate that phosphorylation and nuclear import of tumor suppressor TP53 occurs downstream of IL-24-mediated PKA activation. These discoveries provide the first mechanistic insights into the function of PKA as a key regulator of the extrinsic pathway, ER stress, and TP53 activation triggered by IL-24

Evaluating the Current State of Findability and Accessibility of Microplastics Data

Tia Jenkins1, Bhaleka D. Persaud1, Win Cowger2, Kathy Szigeti3, Dominique G. Roche4,5, Erin Clary6, Stephanie Slowinski1, Benjamin Lei1, Amila Abeynayaka7, Ebenezer S. Nyadjro8,9, Thomas Maes10, Leah Thornton Hampton11, Melanie Bergmann12, Julian Aherne13, Sherri A. Mason14, John F. Honek15, Fereidoun Rezanezhad1, Amy L. Lusher16, Andy M. Booth17, Rodney D. L. Smith15 and Philippe Van Cappellen1. Affiliations: 1 Department of Earth and Environmental Sciences, University of Waterloo, Waterloo, ON, Canada 2 Moore Institute for Plastic Pollution Research, Long Beach, CA, United States 3 Davis Centre Library, University of Waterloo, Waterloo, ON, Canada 4 Department of Biology, Carleton University, Ottawa, ON, Canada 5 Institute of Biology, University of Neuchâtel, Neuchâtel, Switzerland 6 Digital Research Alliance of Canada, Ottawa, ON, Canada 7 Institute for Global Environment Strategies (IGES), Kanagawa, Japan 8 National Oceanic and Atmospheric Administration (NOAA) National Centers for Environmental Information (NCEI), Stennis Space Center, Starkville, MS, United States 9 Northern Gulf Institute, Mississippi State University, Stennis Space Center, Starkville, MS, United States 10 GRID-Arendal, Arendal, Norway 11 Southern California Coastal Water Research Project (SCCWRP), Costa Mesa, CA, United States 12 Alfred-Wegener-Institut Helmholtz-Zentrum für Polar- und Meeresforschung, Bremerhaven, Germany 13 School of Environment, Trent University, Peterborough, ON, Canada 14 The Behrend College, Pennsylvania State University, Erie, PA, United States 15 Department of Chemistry, University of Waterloo, Waterloo, ON, Canada 16 Norwegian Institute for Water Research, Oslo, Norway 17 SINTEF Ocean, Trondheim, NorwayThe rapid growth in microplastic pollution research is influencing funding priorities, environmental policy, and public perceptions of risks to water quality and environmental and human health. Ensuring that environmental microplastics research data are findable, accessible, interoperable, and reusable (FAIR) is essential to inform policy and mitigation strategies. We present a bibliographic analysis of data sharing practices in the environmental microplastics research community, highlighting the state of openness of microplastics data. A stratified (by year) random subset of 785 of 6,608 microplastics articles indexed in Web of Science indicates that, since 2006, less than a third (28.5%) contained a data sharing statement. These statements further show that most often, the data were provided in the articles’ supplementary material (38.8%) and only 13.8% via a data repository. Of the 279 microplastics datasets found in online data repositories, 20.4% presented only metadata with access to the data requiring additional approval. Although increasing, the rate of microplastic data sharing still lags behind that of publication of peer-reviewed articles on environmental microplastics. About a quarter of the repository data originated from North America (12.8%) and Europe (13.4%). Marine and estuarine environments are the most frequently sampled systems (26.2%); sediments (18.8%) and water (15.3%) are the predominant media. Of the available datasets accessible, 15.4% and 18.2% do not have adequate metadata to determine the sampling location and media type, respectively. We discuss five recommendations to strengthen data sharing practices in the environmental microplastic research community. Read more at https://www.frontiersin.org/articles/10.3389/fenvs.2022.912107/fullNSERC/ECCC Alliance Grants - Plastics science for a cleaner future program, Grant ALLRP 558435-20 || The Canada First Research Excellence Fund Global Water Futures Programme || The McPike Zima Charitable || The PoF IV program “Changing Earth - Sustaining our Future” Topic 6.4 of the German Helmholtz Association || The Research Council of Norway projects REVEAL, Grant 301157 || ANDROMEDA, Grant 312262 || MicroLEACH, Grant 295174 || The Early-Career Research Fellowship from the Gulf Research Program of the US National Academies of Sciences, Engineering, and Medicine, Grant 2000012639 || European Union’s Horizon 2020 Coordination and Support Action programme, Grant 101003805 (EUROqCHARM) || The Union Horizon 2020 research and innovation programme under Marie Skłodowska-Curie, Grant 838237-OPTIMISE

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

MicroRNA-4719 and microRNA-6756-5p Correlate with Castration-Resistant Prostate Cancer Progression through Interleukin-24 Regulation

Prostate cancer (PCa) is the second leading cause of cancer death in the United States. The five-year survival rate for men diagnosed with localized PCa is nearly 100%, yet for those diagnosed with aggressive PCa, it is less than 30%. The pleiotropic cytokine Interleukin-24 (IL-24) has been shown to specifically kill PCa cells compared to normal cells when overexpressed in both in vitro and in vivo studies. Despite this, the mechanisms regulating IL-24 in PCa are not well understood. Since specific microRNAs (miRNAs) are dysregulated in PCa, we used miRNA target prediction algorithm tools to identify miR-4719 and miR-6556-5p as putative regulators of IL-24. This study elucidates the expression profile and role of miR-4719 and miR-6756-5p as regulators of IL-24 in PCa. qRT-PCR analysis shows miR-4719 and miR-6756-5p overexpression significantly decreases the expression of IL-24 in PCa cells compared to the negative control. Compared to the indolent PCa and normal prostate epithelial cells, miR-4719 and miR-6756-5p are significantly overexpressed in castration-resistant prostate cancer (CRPC) cell lines, indicating that their gain may be an early event in PCa progression. Moreover, miR-4719 and miR-6756-5p are significantly overexpressed in the CRPC cell line of African-American males (E006AA-hT) compared to CRPC cell lines of Caucasian males (PC-3 and DU-145), indicating that miR-4719 and miR-6756-5p may also play a role in racial disparity. Lastly, the inhibition of expression of miR-4719 and miR-6756-5p significantly increases IL-24 expression and inhibits proliferation and migration of CRPC cell lines. Our findings indicate that miR-4719 and miR-6756-5p may regulate CRPC progression through the targeting of IL-24 expression and may be biomarkers that differentiate between indolent and CRPC. Strategies to inhibit miR-4719 and miR-6756-5p expression to increase IL-24 in PCa may have therapeutic efficacy in aggressive PCa