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The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAFamp) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment. The evolutionary selection of BRAFamp was determined by the fitness threshold, the barrier that subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for inhibitors of ERK signaling, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of the RAF, MEK and ERK kinases, however, imposed a sufficiently high fitness threshold to prevent the propagation of subclones with high-level BRAFamp. When administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11 PDXs of lung cancer or melanoma without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and, thus, merit testing in patients.

Orbital pseudotumor is a rare, idiopathic, inflammatory process within the orbit. Early diagnosis is essential to prevent corneal, retinal and extraocular muscle damage. This article describes the presentation and clinical course of a 3-year-old male with bilateral orbital pseudotumor.

Cancer therapy by entrapment Mutations in the KRAS oncogene occur at high frequency in several of the most lethal human cancers, including lung and pancreatic cancer. Substantial effort has thus been directed toward developing KRAS inhibitors. KRAS encodes an enzyme that binds the nucleotide GTP and hydrolyzes it to GDP. It had been thought that oncogenic mutations disable this hydrolytic activity, locking KRAS in the GTP-bound, active state. Surprisingly, Lito et al. found that a certain KRAS mutant (G12C) retains hydrolytic activity and continues to cycle between its active and inactive states. They describe a compound that inhibits KRAS(G12C) signaling and tumor cell growth by binding to the GDPbound form of KRAS, trapping it in its inactive state. Science , this issue p. 604

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The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAF

Tumors evolve as they adapt to environmental cues. The principles governing evolution of tumors under the selective pressure of targeted therapy are not well understood. We aimed to evaluate the evolution of resistance and to identify therapeutic modalities that prevent this process in BRAFV600E-mutant tumors. We modeled the selection and propagation of BRAFV600E amplification (BRAFamp) in patient-derived tumor xenografts (PDX) treated with a direct ERK inhibitor. Single-cell sequencing and multiplex-fluorescence in situ hybridization mapped the emergence of extra-chromosomal amplification in multiple subclones of the same tumor shortly after treatment. The evolutionary selection of BRAFamp is determined by the fitness threshold, the barrier subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for ERK signaling inhibitors, and single-cell sequencing of a melanoma PDX model showed that drugs of the same pathway do not necessarily select for the same subclones. These data suggest that sequential monotherapy is not optimal, but concurrent targeting of RAF, MEK, and ERK, however, imposes a sufficiently high fitness threshold to prevent the propagation of subclones with high-level amplification. Administered on an intermittent schedule, this treatment inhibited tumor growth without apparent toxicity in 11/11-lung cancer and melanoma PDX models with various additional alterations. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose a high fitness threshold, such as our intermittent triple therapy, will likely prevent the evolution of resistance-causing alterations and merit testing in patients. Citation Format: Yaohua Xue, Luciano Martelotto, Timour Baslan, Alberto Vides, Martha Solomon, Kalyani Chadalavada, Elisa DeStanchina, Gouri Nanjangud, Michael Berger, Scott Lowe, Jorge S. Reis-Filho, Neal Rosen, Piro Lito. An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B015.

Just then they came in sight of thirty or forty windmills that rise from that plain. And no sooner did Don Quixote see them that he said to his squire, “Fortune is guiding our affairs better than w...

By July 1994, Politically Correct Bedtime Stories had appeared for the third time on the New York Times bestseller list with sales exceeding 100,000 copies. One year later, there were almost 1.5 million copies of Politically Correct Bedtime Stories in print as it continued to excite public commentary. This popular book is an ideal case study for exploring the benefits and limits of satiric humor, the book's primary rhetorical strategy and the focus of this essay. We argue that because of its polyvalent nature, the use of ironic satire as a rhetorical strategy to debunk a position is unpredictable. In fact, as this essay demonstrates, some forms of humor may facilitate audience acceptance of the very ideas the satirist intends to disparage. In this case, Garner's use of satiric humor may have facilitated acceptance of moderate forms of political correctness.

Oncogenic mutations impair the GTPase activity of RAS, causing it to accumulate in the activated, GTP-bound conformation. Here we describe the mechanism of action of a novel compound that binds to KRASG12C to selectively inhibit proliferation and induce apoptosis in cancer cells with this mutation. The inhibitor interacted preferentially with the GDP-bound form of the protein, yet it reduced the level of GTP-bound KRASG12C. This suggested that GTPase activity is required for inhibition, which turned out to be the case. The inhibitor traps GDP-bound KRASG12C and prevents nucleotide exchange to the GTP-bound form. Genetic experiments revealed that mutants completely lacking GTPase activity, and those promoting exchange, reduced the potency of the drug. In contrast, mutants with diminished exchange were more susceptible to inhibition. In agreement with these findings, targeting receptor signaling potentiated KRASG12C inhibition, whereas its activation had the opposite effect. This mechanism reveals that KRASG12C undergoes nucleotide cycle in cancer cells and provides a basis for the development of effective combination therapies to treat KRASG12C-driven cancers. Citation Format: Piro Lito, Martha Solomon, Rasmus Hansen, Lian-Sheng Li, Neal Rosen. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-071.

Coenzyme Q(10) (CoQ(10)) deficiency has been associated with 5 major clinical phenotypes: encephalomyopathy, severe infantile multisystemic disease, nephropathy, cerebellar ataxia, and isolated myopathy. Primary CoQ(10) deficiency is due to defects in CoQ(10) biosynthesis, while secondary forms are due to other causes. A review of 149 cases, including our cohort of 76 patients, confirms that CoQ(10) deficiency is a clinically and genetically heterogeneous syndrome that mainly begins in childhood and predominantly manifests as cerebellar ataxia. Coenzyme Q(10) measurement in muscle is the gold standard for diagnosis. Identification of CoQ(10) deficiency is important because the condition frequently responds to treatment. Causative mutations have been identified in a small proportion of patients.

This essay explores potential political and social implications of filmic adaptations using Spielberg's adaptation of Alice Walker's The Color Purple as a case study. Besides enjoying a strong popular response at the box office, suggesting powerful resonance with viewers, the film “The Color Purple” touched on two issues salient in American society: sexism and racism. We explore the relationships among Spielberg's film as text, the novel as work, and the American viewing public. Adapting Kenneth Burke's language, we argue that Spielberg's film becomes a “terministic screen “for Walker's novel; it selects out and reflects certain elements in that work, but it also deflects our attention from other themes and aspects. While Walker's story is that of a woman's empowerment and liberation through her own self‐discovery, Spielberg's adaptation reframes her story through the lens of comforting American mythologies.

Approaching Places in the Heart as a text “open” to divergent ideological interpretations, this essay argues that the director's skillful manipulation of the romantic formula enhances the film's appeal to a broad audience. In particular, the essay suggests that the film offers complex messages about feminism and the farm crisis. These ambivalent messages sustain, rather than resolve, the tensions in viewers between the moralistic and materialistic dimension of the American Dream.

Using the life stories of two leaders of the woman's suffrage movement, Elizabeth Cady Stanton and Anna Howard Shaw, this essay explores the role of autobiographies in social movements. Theoretically, the essay argues that as sustained narratives, autobiographies offer two distinctive rhetorical resources for their authors: the potential to depict the emergence of belief s from experiences and the ability to enact the doctrine. Second, the essay argues that the characteristic features of autobiography enhance the persuasive force of this depiction and enactment. In essence, the essay suggests that autobiographies can complement and supplement formal public arguments for a movement in distinctive ways.

MEK inhibitors are clinically active in BRAF V600E melanomas, but only marginally so in KRAS-mutant tumors. While MEK inhibitor treatment resulted in sustained inhibition of ERK phopshorylation in BRAF V600E tumors, it was associated with a rebound in ERK phosphorylation after prolonged exposure in KRAS mutant tumors. To understand this phenomenon, we performed an RNAi screen in a KRAS-mutant model and found that CRAF knockdown enhanced the antiproliferative effects of MEK inhibition both in vivo and in vitro. In agreement with previous findings, MEK inhibitor treatment in KRAS mutant cells resulted in CRAF reactivation and induction of MEK phosphorylation. However, MEK activated by CRAF was less susceptible to traditional MEK inhibitors, such as PD0325901, compared to when activated by BRAF V600E. Consistent with this observation, the rebound in ERK phosphorylation following MEK inhibitor treatment in KRAS mutant tumors was dependent on intact CRAF expression. Furthermore, traditional MEK inhibitors induced RAF-MEK complexes in KRAS mutant models, and disrupting these complexes enhanced the inhibition of CRAF-dependent ERK signaling. In an effort to identify more effective compounds we found that newer MEK inhibitors, such as trametinib and CH5126766, do not only target the catalytic activity of MEK, but in addition, they also impair its reactivation by CRAF. This occurs through two distinct mechanisms: trametinib disrupts RAF-MEK complex formation, as evidenced by co-immunoprecipitation of endogenous proteins and surface plasmon resonance assays with purified enzymes. Instead, CH512676 induces the interaction of MEK with RAF, yet it prevents the phosphorylation of MEK in this complex. To elucidate the mechanism responsible for the latter property, we determined the ternary structure of CH512676-bound MEK1. CH5126766 interacts with Asn 221 and Ser 222 residues in MEK1 to displace the activation segment and disrupt RAF-mediated phosphorylation. These data provide a blueprint for developing better MEK inhibitors that effectively inhibit ERK signaling in KRAS mutant tumors. Citation Format: Piro Lito, Anna Saborowski, Jingyin Yue, Martha Solomon, Eric Joseph, Christof Fellman, Kazuhiro Ohara, Kenji Morikami, Takaaki Miura, Christine Lucas, Nobuya Ishii, Scott Lowe, Neal Rosen. Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4758. doi:10.1158/1538-7445.AM2014-4758

Since the British produced film “Chariots of Fire”; was extraordinarily appealing to American audiences, this essay explores the rhetorical factors which underlie its popularity. The essay argues that: (1) the central characters symbolize the two contradictory facets of the American Dream described by Fisher, both which are reaffirmed; and, (2) the film depicts multiple romantic quests, all of which end successfully. These two strategies make the film function metaphorically and mythically for an American audience to provide emotional catharsis and psychological reinforcement.

Despite its success and the publicity it has received, the STOP ERA movement, led by Phyllis Schlafly, has received little critical attention. This article examines: (1) the image which the group develops of its opponents; (2) the image it projects of its supporters; (3) the ideological framework indicated by these images; and, (4) the rhetorical implications of (1), (2), and (3). It concludes that, although the movement's ideology is implicitly fatalistic and manipulative, its reaffirmation of traditional perspectives and its appeal to the need for personal security make it extremely effective rhetorically.

This essay examines the rhetoric of the STOP ERA movement. It traces the elements of a divinely ordained order which STOP ERA advocates perceived in women, families, and societies and explores the contrasting anomalies and anomy which STOP ERA supporters perceive in the opposition. The essay also examines the rhetorical function of the vision offered by STOP ERA to its members and assesses the social impact of the message.

The success of Marabel Morgan's Total Woman indicate its rhetorical effectiveness despite its substantive flaws. This article argues that the book's strong appeal to readers stems from: (1) its promise of fulfillment if woman expiate the guilt they bear for marital discord by self sacrifice; (2) its reinforcement of readers perceptions of themselves and their husbands; and (3) its emphasis on the power of “Total Women”; and its encouragement of sexual fantasy and play. These strategies produce a persuasive message which plays on readers’ concerns for their marriages, offers an alternative to the self consciousness urged by feminists and permits women to fulfill comfortable stereotypes yet experience the power and sexual freedom promised by liberationists. For readers with troubled marriages Morgan provides an alluringly simple, emotionally attractive answer to complex questions. Her message is rhetorically effective even if intellectually weak and psychologically misleading.

Using research by Martin Joos and John J. Gumperz to develop a perspective for rhetorical analysis, the article contends that Carter's final remarks in his Playboy interview reflect an ineffective sociolinguistic code shift to a stylistic level inappropriate to Carter as public personality and as presidential candidate.

With malice toward none; with charity to all; with firmness in the right, as God gives us to see the right, let us strive on to finish the work we are in; to bind up the nation's wounds; to care for him who shall have borne the battle, and for his widow, and his orphan; to do all which may achieve and cherish a just, and a lasting peace, among ourselves, and with all nations.

Examining the medical journal reports of the Tuskegee syphilis study, this essay explores the role that rhetoric played in the study's continuation. The essay argues that depicting patients as scen...

This case study of the rhetoric of Emma Goldman explores the relationship between ideology and rhetorical strategies. After tracing Goldman's use of argument by incongruity and embodiment, the essay explains why these strategies were ineffective for an American audience. Finally, the essay argues that these strategies are inherent in anarchist ideology and that, consequently, anarchism could not be rhetorically effective as a social movement within American society.

The continuity motif, a prominent feature in the rhetoric of the Right to Life movement, pervades the group's depiction of human life, western cultural traditions and the group's sustained efforts against abortion. Moreover, the motif colors and intensifies the group's description of the controversy. Rhetorically the motif helps members to justify their substitution of one hierarchy for another, to legitimize their activities, to redefine group and member activities and to provide an effective form of internal and external expiation. The motif functions, thus, as an integrative symbol and goad to action for RTL members.

By drawing its structural pattern from the romantic quest mythoi and developing characterizations of supporters and opponents which reflect elements of Jung's mother archetype, the rhetorical vision of STOP ERA becomes especially potent and appealing to many American women. The impact of such mythical archetypes is both subtle and pervasive.

This essay explores the rhetorical process underlying the outstanding success of Robert Schuller's gospel of possibility thinking. Schuller's amalgamation of secular and spiritual values produces a rhetorically powerful version of American Civil Religion which sanctifies self‐interest and relieves the tension in his audience's minds between competitive private enterprise and Christian brotherhood. However, this blending of two sets of values is potentially harmful to believers and to American society because it blurs the distinction between religious and secular values and removes the healthy tension between religious and other social institutions.