Academic literature on the topic 'Sleeping Beauty adaptations'

Abstract BRAF/MEK inhibition remains an important treatment option for patients with BRAF V600 mutant melanoma who show disease progression on immunotherapy; however, the majority of patients treated with BRAF/MEK (MAPKi) therapy develop MAPKi-resistant disease within two years of initiating treatment. Genomic analysis of drug-resistant melanomas has identified somatic mutations associated with resistance, including BRAF amplification or truncation and RAS mutation. In addition, other forms of acquired resistance involving adaptation and reprogramming have been described, with different studies identifying different drivers in different melanoma cell lines and patient-derived xenografts. The heterogeneity of acquired resistance mechanisms presents a major clinical challenge for identifying novel drug combinations with potential activity in significant subsets of patients. To enable the rapid identification of context-dependent drivers of MAPKi resistance, we adapted our Sleeping Beauty (SB) transposon mutagenesis for use in cell culture. SB mutagenesis in this setting identifies predominantly gain-of-function mechanisms and thus has the ability to identify both genetic mutations (such as expression of truncated proteins) and genes within alternative acquired resistance pathways whose upregulated expression drives MAPKi resistance. Validating our approach, our screen identified N-terminal truncation of BRAF—a known mechanism of vemurafenib resistance. In addition, we identified DBL family guanine exchange factors (GEFs), MCF2 and VAV1, as drivers of MAPKi resistance that we have functionally validated in multiple BRAF V600E mutant melanoma cell lines. Crucially, many DBL family GEFs are well known to be regulated by Src family kinases (SFKs), and our data indicate that GEF-driven MAPKi resistance can be blocked by combination treatment with vemurafenib and saracatinib, a selective SFK inhibitor. Expansion of resistant cells in the presence of vemurafenib or vemurafenib with cobimetinib can be reversed by switching to vemurafenib plus saracatinib. Consistently, we find that adding saracatinib converts MAPKi-mediated cytostasis into cell killing and blocks spontaneous MAPKi resistance in responsive melanoma cell lines. The GEFs signal downstream to a RAC1-PAK kinase module that is required for GEF-driven resistance. Importantly, the potential utility of both SFK inhibitors and PAK inhibitors for overcoming MAPKi resistance has been proposed, but the connection between SFK-dependent and PAK-dependent resistance mechanisms had not been obvious. We show that combined BRAF/SFK inhibition is effective in cell lines in which the GEF-driven mechanism operates, but not in cell lines in which the GEFs do not drive resistance. Our SB mutagenesis system has the ability to rapidly survey the context-dependent landscape of MAPKi resistance in any transfectable cell system, with the potential to reveal connections between seemingly disparate resistance mechanisms. This abstract is also being presented as Poster B04. Citation Format: Charlotte R. Feddersen, Jacob Schillo, Afshin Varzavand, Hayley Vaughn, Andrew Voight, Eliot Zhu, Jesse D Riordan, Christopher S. Stipp, Adam J. Dupuy. Sleeping Beauty mutagenesis reveals a Src-dependent DBL GEF family signaling mechanism driving MAPK inhibitor resistance in BRAF mutant melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR17.

Abstract Abstract SCI-25 Iron-derived reactive oxygen species (ROS) are involved in the pathogenesis of numerous vascular disorders. Heme-derived iron plays an instrumental role in the pathology of intravascular hemolytic diseases including malaria, sickle cell anemia, transfusion reactions, DIC and PNH. Heme catalyzed oxidative stress promotes a pro-inflammatory/prothrombogenic endothelium, diminution of bio-available nitric oxide (NO) and attraction of leukocytes and platelets. The vasculature is protected against heme-catalyzed injury by plasma proteins including haptoglobin, hemopexin, albumin, alpha-1-microglobulin and by scavenger receptors for heme complexes including CD163 and CD91. Heme and its concomitant oxidative stress induces the cytoprotective and rate-limiting enzyme in heme catabolism, heme oxygenase-1 (HO-1). In the process, HO-1 releases three enzymatic byproducts: carbon monoxide (CO), biliverdin/bilirubin, and iron, which stimulates ferritin synthesis. These HO-1 by-products have established anti-oxidant and anti-inflammatory properties. Human patients and mouse models elevate HO-1 in response to chronic hemolysis. Of all sites in the body, the endothelium may be at greatest risk of exposure to heme. Heme greatly potentiates endothelial cell killing mediated by leukocytes and other sources of ROS. As a defense against heme, endothelial cells upregulate HO-1 and ferritin. If cultured endothelial cells are briefly pulsed with heme and are then incubated for a prolonged period (16 h), the cells become highly resistant to oxidant-mediated injury and to the accumulation of endothelial lipid peroxidation products. This protection is associated with induction of both HO-1 and ferritin. H-ferritin with its ferroxidase activity is especially cytoprotective. In animal models, increased expression of HO-1 has been shown to protect tissues against ischemia-reperfusion injury, oxidative stress, inflammation, transplant rejection, apoptosis, and cell proliferation. Conversely, HO-1 null mice (hmox-1−/−) and human patients deficient in HO-1 are especially prone to oxidative stress and inflammation. Sickle cell anemia is an archetypal example of heme-induced oxidative stress and cytoprotective adaptation. The sickle patient and sickle mouse models defend and adapt to hemolysis by increasing their defenses against heme. HO-1 plays an essential role in the inhibition and resolution of vaso-occlusion in sickle cell anemia. HO-1 and its products, carbon monoxide and biliverdin, modulate vaso-occlusion through multiple mechanisms including reducing oxidative stress, inhibiting NF-kB, down-regulating endothelial cell adhesion molecules, decreasing red blood cell hemolysis and altering vascular tone. However, sickle cell patients often have adaptive increases in HO-1 activity which are insufficient to completely handle the excessive heme burden, particularly during acute bouts of hemolysis. HO-1 gene therapy in sickle mice using Sleeping Beauty-mediated transposition of an HO-1 transgene provides a promising non-viral approach to significantly enhance HO-1 expression in sickle cell anemia. Strategies to minimize heme-iron activation of the vasculature including increasing HO-1 and its products, anti-oxidants, iron chelators, increasing haptoglobin, hemopexin and/or their receptors CD163/CD91 should be explored in hemolytic disease states. Disclosures: Vercellotti: Sangart: Consultancy, Research Funding. Belcher:Sangart: Research Funding.

One of the hallmarks of young adult literature is its focus on adolescent protagonists who struggle to reconcile what they want with what they are supposed to want. Indeed, some of the most enduring works of young adult literature, from L. M. Montgomery’s Anne of Green Gables (2006) to Judy Blume’s Forever (1975), place their young characters at a crossroads between cultural convention and individual desire. Foundational scholarship in the field of young adult fiction has suggested a recurring conflict in novels for young readers in which a protagonist finds himself or herself directly at odds with social expectations (McCallum, 1999; Trites, 2004). Furthermore, critics such as Trites (1997), Wilkie-Stibbs (2003), and Mallan (2009) have noted that many of these works concern an adolescent search for identity that is complicated by issues of gender politics, in which a protagonist’s grappling with conventional notions of masculinity and/or femininity is fundamental to a completed coming of age. In Waking Sleeping Beauty: Feminist Voices in Children’s Literature, Roberta Seelinger Trites (1997) argues that this kind of novel “demonstrate[s] characters ‘turning inward’ in ‘a search for identity’ because some form of environmental pressure has made them aware that they are not upholding socially sanctioned gender roles” (p. 2). In turn, these novels can become cathartic for adolescent readers, who may be facing similar struggles in the throes of real-life adolescence. Relying on the definition of a feminist novel established by Elaine Showalter (1977), Trites (1997) defines a “feminist children’s novel” as one “in which the main character is empowered regardless of gender,” or a novel in which “the child’s sex does not provide a permanent obstacle to her/his development. Although s/he will likely experience some gender-related conflicts, s/he ultimately triumphs over them” (p. 4). Though many novels fit this description, two bestselling young adult novels distinguish their adolescent female protagonists’ search for identity as inspired by the legends of Arthurian literature. Meg Cabot’s Avalon High (2006) and Libba Bray’s A Great and Terrible Beauty (2003) each reference the Arthurian legend of the Lady of Shalott—specifically the version that was retold and adapted by Alfred, Lord Tennyson in his 1842 poem “The Lady of Shalott.” Both novels use the characters, language, and symbolism from Tennyson’s poem to provide their heroines—and by extension, their adolescent readers—with a template through which they can understand, examine, and potentially reject the social codes that attempt to determine their behavior. In capitalizing on the ways in which Tennyson’s “The Lady of Shalott” enhanced and adapted the traditional Arthurian legend for a Victorian audience, Cabot and Bray access what Ann Howey (2007) calls the “constellation of association and meanings” (pp. 89–92) connected to the Lady of Shalott in the medieval and Victorian texts, many of which are distinctly feminist by Trites’s definition. In this article, I will argue that in drawing inspiration specifically from Tennyson’s “The Lady of Shalott,” Cabot’s and Bray’s novels develop their feminism through the framework of a Victorian narrative that is more thematically complex and more politically charged than any earlier, medieval version of the Lady of Shalott legend. Specifically, Cabot’s and Bray’s novels reflect the impact of feminist criticism of Tennyson’s poem found in the works of Victorian scholars Nina Auerbach (e.g., The Woman and the Demon: The Life of a Victorian Myth, 1982) and the team of Sandra Gilbert and Susan Gubar (e.g., Madwoman in the Attic, 1984). This foundational work identifies in Tennyson’s adaptation of the Lady of Shalott a dualistic and subversive set of alternatives that is not present in the medieval sources: her status as both a docile, passive figure who is “powerless in the face of the male” (Gilbert & Gubar, 1984, p. 618) and, simultaneously, as an icon of deviant and potentially powerful feminine desire. To identify the ways in which Cabot’s and Bray’s novels revise the Lady of Shalott narrative and embrace this subversion of traditional gender roles, I will first examine the Lady of Shalott narrative in medieval Arthurian literature and in Tennyson’s poem, focusing on how Tennyson’s enhancements to the tale transformed the Lady of Shalott into an iconic image of Victorian femininity. I will then demonstrate how Cabot and Bray employ revisionist strategies to adapt the gender politics of Tennyson’s poem for a 21st-century young adult readership, creating heroines who reject the passive qualities of the Lady of Shalott in favor of a more autonomous alternative and who, in doing so, model for adolescent readers a search for identity that results in self-identification and empowerment.

This article aims to develop a comparative analysis between the literary narrative Sleeping Beauty of the Grimm Brothers, published in 1812, and the film adaptation Maleficent, by Robert Stromberg, released in 2014. In this sense, we will highlight the most relevant similarities and differences between the two narratives, with regard to the role of Maleficent, the attitudes of the female character (Aurora), the desire for revenge, the kiss of salvation and the main symbolic elements of each narrative. The results in the analysis show that adaptation is a very complex process, which reveals the goals and interpretations of the director, the context of the time and its characteristics, resulting in an aesthetic product with marks of literary origin but with many innovations.
 
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