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Scherer, Joanna Cohan. "Horace Poolaw: Photographer of American Indian Modernity (Smith)". Museum Anthropology Review 11, n.º 1-2 (23 de maio de 2017): 42–44. http://dx.doi.org/10.14434/mar.v11i1.23551.
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Halper, Donna L. "Indian Sound Cultures, Indian Sound Citizenship, Laura Brueck, Jacob Smith and Neil Verma (eds) (2020)". Radio Journal:International Studies in Broadcast & Audio Media 19, n.º 2 (1 de outubro de 2021): 327–29. http://dx.doi.org/10.1386/rjao_00050_5.
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Review of: Indian Sound Cultures, Indian Sound Citizenship, Laura Brueck, Jacob Smith and Neil Verma (eds) (2020)Ann Arbor, MI: University of Michigan Press, 338 pp.,ISBN 978-0-47205-434-3, p/bk, USD 44.95
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BAKER, D. B. "Pfeiffer, Wallace, Allen and Smith: the discovery of the Hymenoptera of the Malay Archipelago". Archives of Natural History 23, n.º 2 (junho de 1996): 153–200. http://dx.doi.org/10.3366/anh.1996.23.2.153.
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The travels of Mme Ida Laura Pfeiffer, Alfred Russel Wallace and Charles Allen in the Malay Archipelago between the years 1851 and 1862 are summarized with a view to establishing more precise data for their collections; details of the disposal of their entomological collections are given and collection data amplified; and the publication of their Hymenoptera by Frederick Smith is outlined. Short lives of Mme Pfeiffer, of Charles Allen, and of Frederick Smith are given.
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McBride, Laura, e Mariko Smith. "The Unsettled exhibition: Laura McBride and Mariko Smith in conversation". Aboriginal History Journal 46 (4 de julho de 2023): 77–107. http://dx.doi.org/10.22459/ah.46.2022.04.
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Hauser, Katherine. "Horace Poolaw: Photographer of American Indian Modernity by Laura E. Smith". Great Plains Quarterly 37, n.º 2 (2017): 151–52. http://dx.doi.org/10.1353/gpq.2017.0028.
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Tiya Miles. "“Shall Woman's Voice Be Hushed?”: Laura Smith Haviland in Abolitionist Women's History". Michigan Historical Review 39, n.º 2 (2013): 1. http://dx.doi.org/10.5342/michhistrevi.39.2.0001.
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Tiya Miles. ""Shall Woman's Voice Be Hushed?": Laura Smith Haviland in Abolitionist Women's History". Michigan Historical Review 39, n.º 2 (2013): 1–20. http://dx.doi.org/10.1353/mhr.2013.0040.
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Smith, Laura. "“Simply what my work has told me:” An Interview with Richard Tuttle". Brock Review 11, n.º 1 (22 de março de 2010): 63–69. http://dx.doi.org/10.26522/br.v11i1.106.
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Artist Richard Tuttle sits down with Laura Lake Smith in Maine to chat about his recent work and what he has learned during his career as an artist. Tuttle speaks about perseverance in the art world, his contributions to art, making an art for everyone, and how art should create “value.” He also discusses why he recently threw out an entire year’s worth of work and why not being a mega art star is alright with him.
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Silvers, Penny, Priya M. Shah e Sarah Fox Sparber. "Professional Reading for Middle Level Educators". Voices from the Middle 18, n.º 3 (1 de março de 2011): 65–67. http://dx.doi.org/10.58680/vm201113573.
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Reviewed are books that present ways to use the many and varied literacies of reading, writing, music, art, and digital technologies to engage our students in powerful learning: Adolescents and Digital Literacies: Learning Alongside Our Students by Sara Kajder; The Socially Networked Classroom: Teaching in the New Media Age by William Kist; Fresh Takes on Teaching Literary Elements: How to Teach What Really Matters about Character, Setting, Point of View, and Theme by Michael W. Smith and Jeffrey D. Wilhelm; The Magic of Middle School Musicals by Victor Bobetsky; Teaching Middle School Writers: What Every English Teacher Needs to Know by Laura Robb.
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Viding, Essi, Pasco Fearon, Tom Wu, Alex Lloyd, Laura Lucas, Roslyn Law e Jaime Smith. "Building resilience: Key to protecting adolescent mental health". Open Access Government 41, n.º 1 (22 de janeiro de 2024): 184–85. http://dx.doi.org/10.56367/oag-041-11194.
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Building resilience: Key to protecting adolescent mental health Essi Viding, Pasco Fearon, Tom Wu, Alexander Lloyd, Laura Lucas, Roslyn Law, and Jaime Smith discuss new approaches to preventing adolescent mental health problems from emerging. Adolescence is a period of heightened vulnerability to developing mental health problems. Rates of mental health disorder among adolescents have increased in the last decade(1). In light of the vast associated interpersonal and economic costs(2,3) , it is striking how few resources have been invested in advancing our understanding of how to effectively prevent mental health problems developing before they become entrenched, particularly in adolescents who are at high risk.
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Sumpf, Alexandre. "Laura Engelstein, Russia in Flames. War, Revolution, Civil War, 1914–1921 | Steve A. Smith, Russi". Cahiers du monde russe 59, n.º 4 (1 de outubro de 2018): 631–35. http://dx.doi.org/10.4000/monderusse.10687.
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Helbrecht, Ilse. "Emotion, Place and Culture - Edited by Mick Smith, Joyce Davidson, Laura Cameron and Liz Bondi". International Journal of Urban and Regional Research 35, n.º 3 (12 de abril de 2011): 678–80. http://dx.doi.org/10.1111/j.1468-2427.2011.01060_2.x.
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Schueler, G. F. "How Can Reason Be Practical?" Crítica (México D. F. En línea) 28, n.º 84 (8 de janeiro de 1996): 41–62. http://dx.doi.org/10.22201/iifs.18704905e.1996.1045.
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En The Moral Problem, Michael Smith ofrece una solución al enigma de cómo puede la razón ser práctica. Éste es un enigma espinoso para un humeano como Smith, quien cree que toda acción tiene que estar motivada por un deseo, pues, desde el punto de vista humeano, los deseos escapan en gran parte a la crítica racional. La solución de Smith supone distinguir entre razones para la acción “motivantes” y “normativas” y luego argüir que si bien una interpretación humeana (o deseo-creencia) funciona para las razones motivantes, se tiene que ofrecer una interpretación “antihumeana” diferente para las razones normativas. De modo que hay por lo menos cuatro cuestiones por examinar: si la distinción entre motivante y normativo es convincente; si la explicación humeana que da Smith de las razones motivantes funciona; si su explicación antihumeana de las razones normativas tiene éxito; y si estos puntos de vista juntos realmente resuelven “el problema moral”, esto es, si explican cómo la razón puede ser práctica. Este artículo insiste en que la respuesta de cada una de estas preguntas es negativa. Aunque pretende trazar el mapa de la distinción ordinaria entre razones del agente y razones que justifican, la distinción entre motivante y normativo choca con la interpretación que el propio Smith ofrece de las explicaciones “deliberativas” de las acciones —una interpretación convincente que, sin embargo, no puede hacer uso ni de las razones “motivantes” ni de las “normativas”, tal como Smith las explica. La interpretación humeana que da Smith de las razones motivantes tropieza con el mismo problema. Bien considerado, su explicación antihumeana de las razones normativas adolece, en puntos cruciales, de una incapacidad para distinguir “una razón” de lo que es razonable. Finalmente, aun si dejásemos todo esto de lado, ya que Smith piensa que la creencia que alguien tiene acerca de lo que tiene mejor razón para hacer provoca que lo quiera hacer (si ese alguien es racional), la solución que propone para el problema de cómo la razón puede ser práctica da “un deseo de más” justo en el tipo de caso que debería ser el más sencillo para un humeano: el tipo de caso en el que uno cree que es el deseo inmotivado que uno tiene de hacer algo lo que le da una razón para hacerlo. [Traducción: Laura Manríquez]
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Hay, John. "The American Sonnet: An Anthology of Poems and Essays, eds. Dora Malech and Laura T. Smith, eds". American Literary History 36, n.º 1 (1 de fevereiro de 2024): 270–73. http://dx.doi.org/10.1093/alh/ajad194.
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Dorlin, Elsa. "Revolução do feminismo negro!" Revista Ártemis 27, n.º 1 (11 de julho de 2019): 63–88. http://dx.doi.org/10.22478/ufpb.1807-8214.2019v27n1.46699.
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Este texto, que serviu de introdução a uma coletânea de textos fundadores do feminismo negro estadunidense, faz um percurso historiográfico das diversas etapas desse movimento, as chamadas “ondas”, desde a primeira delas, surgida na década de 1850 e promovida pelos movimentos de abolição da escravatura nos Estados Unidos, passando pela segunda, representada pelas grandes correntes ativistas e teóricas da década de 1970, até a atual “terceira onda”, em que se faz um questionamento crítico da heteronormatividade ainda muito presente nas primeiras fases do feminismo que foram, essencialmente, feminismos brancos. A autora faz uma detalhada análise crítica da terminologia que, desde sempre, tem sido empregada para qualificar ou, antes, desqualificar a mulher negra na sociedade estadunidense, com a criação de pesados estereótipos a respeito da sexualidade supostamente exacerbada, não só do homem negro, mas principalmente da mulher negra. Elsa Dorlin passa em revista as importantes contribuições do coletivo Combahee e de autoras como Laura Alexandra Harris, Beverly Guy-Shefall, Patricia Hill Collins, Kimberly Springer, Michele Wallace, Barbara Smith, Audre Lorde, Hazel Carby, Angela Davis e bell hooks.
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Adler, K. H. "Vichy Specificities: Repositioning the French Past". Contemporary European History 9, n.º 3 (novembro de 2000): 475–88. http://dx.doi.org/10.1017/s0960777300003106.
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Michèle and Jean-Paul Cointet, eds., Dictionnaire historique de la France sous l'Occupation (Paris: Tallandier, 2000), 732pp., FF 290, ISBN 2-235-02234-0. Hanna Diamond, Women and the Second World War in France 1939–1948: Choices and Constraints (Harlow: Longman, 1999), 231pp., £45.00 (hb), £14.99 (pb), ISBN 0-582-29909-8. Sarah Fishman, Laura Lee Downs, Ioannis Sinanoglou, Leonard V. Smith, Robert Zaretsky, eds., France at War: Vichy and the Historians (Oxford and New York: Berg, 2000), 336pp., £45.00, ISBN 1-859-73299-2. Bertram M. Gordon, ed., Historical Dictionary of World War II France: The Occupation, Vichy, and the Resistance, 1938–1946 (Westport: Greenwood Press, 1998), 433pp., £73.95, ISBN 0-313-29421-6. Miranda Pollard, Reign of Virtue: Mobilizing Gender in Vichy France (Chicago and London: University of Chicago Press, 1998), 285pp., £31.50 (hb), £14.00 (pb), ISBN 0-226-67349-9 and 0-226-67350-2. Lynne Taylor, Between Resistance and Collaboration: Popular Protest in Northern France, 1940–45 (Basingstoke: Macmillan; New York: St. Martin's Press, 2000), 195pp., £40.00, ISBN 0-333-73640-0.
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Lasa Álvarez, María Begoña. "Women Artists and Activism in Ellen Clayton's "English Female Artists" (1876)". Oceánide 12 (9 de fevereiro de 2020): 37–44. http://dx.doi.org/10.37668/oceanide.v12i.23.
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In her biographical compilation English Female Artists (1876), Ellen Clayton documented the lives of many talented and hard-working women as a means of bringing to light and celebrating their role in the history of art. Moreover, she also explored these artists’ biographies in order to problematize more general issues, thus entering into one of the most significant initiatives of the period: the movement for women’s rights, with proposals including the improvement of women’s education, their access to art academies, and the amelioration of laws regarding marriage, family and employment. Of particular interest are the lives of celebrated artists who were also leading activists in the period, such as Laura Herford, Eliza Bridell-Fox and Barbara Leigh Smith Bodichon. Therefore, this study aims to explore not only Clayton’s approach to female artists within the specific domain of art, but also the incursions that they made into broad social and political issues regarding women. Finally, the presence in various biographies of the term “sisters” is particularly revealing in that Clayton, through her text, could be said to be assembling as many women as possible, not just artists, as a means of fighting for their rights together as sisters.
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Puchmüller, Andrea. "Expresiones literarias sobre la pandemia por covid-19: Irrupciones de la otredad en “The Wuhan I Know” (Laura Gao) y “You Clap for me Now” (Darren Smith)". Atenea (Concepción), n.º 526 (2022): 245–67. http://dx.doi.org/10.29393/at526-11elap10011.
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En el devenir de la pandemia por covid-19, la literatura constituye una de las tantas formas de agencia para resignificar una emergente cosmovisión gestada a raíz de la megacrisis. Esta dejó al descubierto cambios profundos en las interacciones humanas y sociales, entre ellos, se acentuaron los procesos de otrorización y segregación hacia los inmigrantes y ciudadanos de minorías étnicas. A partir de la relación otredad/pan-demia, este trabajo propone el análisis de dos textos: “You Clap for Me Now”, poema de Darren Smith, y “The Wuhan I know”, autobiografía gráfica de Laura Gao. Partimos de la hipótesis de que en ambos textos, la condición de ser otro emerge como parte del complejo entramado de la crisis pandémica, revelando la tensión entre la perdurable dicotomía de la modernidad “mismidad y otredad”. Concluimos que “The Wuhan I know” humaniza y construye una dimensión identitaria de Wuhan, contraponiéndose a la retórica racista de los regímenes dominantes de representación que surgieron du-rante la pandemia. En tanto, “You Clap for Me Now” edifica un marco social en el que la figura del extranjero se deconstruye a partir de una plataforma metafórica compartida con el virus pandémico.
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da Silva Diefenthaeler, Samantha, e Carla Cerqueira. "Reflections Around Comic Gaze: From the Female Gaze in the early years of Cinema to the Performance Servitudes, By Jesper Just". International Journal of Film and Media Arts 7, n.º 1 (3 de outubro de 2022): 75–93. http://dx.doi.org/10.24140/ijfma.v7.n1.04.
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This article has as its main objective to reflect on the influences of the female defiant gaze in the early years of cinema history in order to prove its contemporary influence. From the analysis of three irreverent visual gags present in the early years of cinema, in which the woman breaks with the power of the camera by looking directly at the device - Subject for the Rogue ‘s Gallery (A.E. Weed, 1904), Mary Jane’s Mishap [Don’t Fool with the Paraffin] (George Albert Smith, 1903), and One Week (Buster Keaton, Edward F. Cline, 1920) -, we propose a theoretical reflection that allows us to define a concept that we call Comic Gaze. This is related to the concerns and proposals of the challenge imposed by the gaze of a woman directly at the camera. We base this problematization on Laura Mulvey’s proposal on the Male Gaze (1975) and bell hooks’ on the Oppositional Gaze (1992), which allow us to advance that this direct gaze of the woman to the cinematographic camera ends up destabilizing the authority of the male perspective on their bodies and works as a logic of visual resistance. Therefore, the central objective of this article is to investigate and contrast this irreverent gaze in order to finally understand if it is still present in contemporary performance Servitudes (Jesper Just), connecting these distinct works despite the temporal distance between them.
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Moore, Sarah. "Case C-167/97, R v. Secretary of State for Employment, ex parte Nicole Seymour-Smith and Laura Perez. Judgment of 9 February 1999, nyr". Common Market Law Review 37, Issue 1 (1 de fevereiro de 2000): 153–61. http://dx.doi.org/10.54648/253290.
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Green, Anna. "Overcoming Depression for Dummies Elaine Iljon Foreman, Laura L. Smith and Charles H. Elliott Chichester: John Wiley & Sons, 2008. pp. 384. £15.99 (pb). ISBN: 0-470-694-305." Behavioural and Cognitive Psychotherapy 37, n.º 4 (4 de junho de 2009): 481–82. http://dx.doi.org/10.1017/s1352465809990142.
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Lima, Hyanameyka E. de, Elizanilda R. do Rêgo, Gilcianny P. Cavalcante, Mailson M. do Rêgo e Luciano V. Cota. "Reação em campo à murcha bacteriana de cultivares de tomate em Roraima". Horticultura Brasileira 28, n.º 2 (junho de 2010): 227–31. http://dx.doi.org/10.1590/s0102-05362010000200016.
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A murcha bacteriana causada por Ralstonia solanacearum (Smith) é a doença bacteriana mais importante do tomateiro na Região Norte do Brasil. Os objetivos deste trabalho foram avaliar o nível de resistência de cultivares de tomate, avaliar o progresso da murcha bacteriana nesses genótipos a fim de conhecer o comportamento da doença nos diferentes estádios de desenvolvimento da cultura, para auxiliar no manejo da epidemia, e determinar a época crítica para o desenvolvimento da doença nessas cultivares nas condições de Roraima. Os experimentos foram conduzidos em um campo naturalmente infestado com a biovar 1 de Rasltonia solanacearum, por dois anos. A área tinha um histórico de quatro anos de plantios sucessivos com plantas de tomate suscetíveis à murcha bacteriana, e as perdas alcançando até 100%. Para condução do experimento foram utilizadas mudas das cultivares Majestade, Nemonetta, Carmen, Liliane, Santa Clara, Sensação, San Vito, Gaúcho Melhorado, Hector e Laura. Foram feitas seis avaliações do número de tomateiros que apresentavam murcha irreversível e/ou morte durante o ciclo da cultura. Foram determinadas as variáveis área abaixo da curva de progresso da doença (AACPD) e a taxa de progresso da doença (r), incidência média (Y50), incidência máxima (Ymáx) e a incidência final da doença. Os valores de AACPD e da variável r para a cultivar Majestade foram menores que para as demais, demonstrando que houve menor incidência de plantas doentes nesta cultivar, indicando resistência. Embora o nível de resistência apresentado por esta cultivar não seja muito elevado, o cultivo da mesma é recomendável e viável para o plantio no Estado de Roraima, especialmente considerando-se os altos preços do tomate, que são adquiridos de outras regiões produtoras no país, embora somente esta resistência não garanta, sozinha, o controle adequado da doença, sendo necessárias outras medidas de controle associadas.
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Vegar, Laura, Ruth Aranda, Laura Waters, Krystal Moya, Allan Hebbert, Christopher S. Smith, Jill Hallin et al. "Abstract 2778: A novel MTA-cooperative PRMT5 inhibitor, MRTX1719, stabilizes the ternary MTA-PRMT5 complex and leads to synthetic lethality in MTAP deleted cancers". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 2778. http://dx.doi.org/10.1158/1538-7445.am2023-2778.
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Abstract Previous studies have shown that cancer cell lines with homozygous deletion of the MTAP gene (MTAP del), are selectively sensitive to shRNA-mediated PRMT5 inhibition or MTA-cooperative PRMT5 inhibitors. PRMT5 is a methyltransferase that adds symmetric dimethyl arginine marks to various proteins essential for cell viability whereas MTAP is responsible for metabolizing MTA as part of the methionine salvage pathway. In MTAP del cells, MTA accumulates and partially inhibits PRMT5 activity by directly competing with SAM, the universal methyl donor and PRMT5 substrate. Thus, the deletion of MTAP leads to the formation of the PRMT5-MTA complex and functions as a synthetic lethal target. In this capacity, MTA-cooperative PRMT5 inhibitors are hypothesized to exhibit an increased therapeutic index compared to first generation PRMT5 inhibitors by preferentially inhibiting PRMT5 in MTAP del cancer cells while sparing normal cells. First generation PRMT5 inhibitors target either apo-PRMT5 or the PMRT5-SAM complex, while MRTX1719 preferentially binds the PRMT5-MTA complex, stabilizing the complex in an inactive state. Thermal shift analysis demonstrated rapid and complete binding of MRTX1719 to MTA-bound PRMT5 whereas binding to SAM-bound PRMT5 was delayed and incomplete after prolonged incubation. First generation clinical-stage PRMT5 inhibitors showed either preferential binding to the PRMT5-SAM complex or no selectivity between the PRMT5-MTA complex, the PMRT5-SAM complex, or apo-PRMT5 in the thermal shift assay, suggesting first generation inhibitors do not recapitulate the synthetic lethal phenotype in MTAP del cancers. In vitro, MRTX1719 exhibits a durable pharmacodynamic effect in MTAP del cells or MTAP WT cells incubated with MTA following drug washout in agreement with the long target residence time suggested by the thermal shift data. Moreover, in vivo time course studies confirm MRTX1719 exhibits potent and durable inhibition of PRMT5-dependent symmetric dimethyl arginine (SDMA) in MTAP del tumor xenografts. HemaTox™ viability assays were used to determine potency against human MTAP WT erythroid and myeloid cells where MRTX1719 was ~45-fold less potent compared to the MTAP del HCT116 cancer cell line. In contrast, first generation PRMT5 inhibitors were similarly potent against the HCT116 isogenic cell lines and human hematopoietic cells, irrespective of MTAP status. These data demonstrate MRTX1719 preferentially and potently binds PRMT5 in the presence of MTA and selectively inhibits MTAP del cancer cell lines. Moreover, the kinetic properties and selectivity profile suggest MRTX1719 will exhibit a significantly improved therapeutic window for the treatment of MTAP del cancer patients. Citation Format: Laura Vegar, Ruth Aranda, Laura Waters, Krystal Moya, Allan Hebbert, Christopher S. Smith, Jill Hallin, Briere M. David, Lars D. Engstrom, Darin Vanderpool, Matthew M. Marx, James G. Christensen, Peter A. Olson. A novel MTA-cooperative PRMT5 inhibitor, MRTX1719, stabilizes the ternary MTA-PRMT5 complex and leads to synthetic lethality in MTAP deleted cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2778.
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LECAMWASAM, Menaka I. "The Legal Protection of Refugees with Disabilities: Forgotten and Invisible? by Mary CROCK, Laura SMITH-KHAN, Ron MCCALLUM, and Ben SAUL. Cheltenham, UK/Northampton, MA: Edward Elgar Publishing, 2017. xviii + 314 pp. Hardcover: £90." Asian Journal of International Law 10, n.º 2 (julho de 2020): 419–20. http://dx.doi.org/10.1017/s2044251320000156.
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Schlegel, Alice. "Daughters of the Dreaming. Diane BellWomen and Community in Oman. Christine EickelmanWomen, Power, and Economic Change: The Nandi of Kenya. Regina Smith ObolerCapitalism and Confrontation in Sumatra's Plantation Belt, 1870-1979. Ann Laura Stoler". Signs: Journal of Women in Culture and Society 12, n.º 4 (julho de 1987): 824–27. http://dx.doi.org/10.1086/494379.
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Roseman, Nicole, Laura Tucker, Francesco Criscuolo, Lynette Lewis, Li Liu, Tyler Buit, Jasmeen Mandair, Zachary Smith e Calvin Cortes. "Abstract 263: Automating next generation sequencing workflows for custom hyb panels: high quality library preparation and target enrichment on the Biomek NGeniuS System". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 263. http://dx.doi.org/10.1158/1538-7445.am2023-263.
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Abstract This study investigates a custom 2Mb xGen Hyb panel designed against mutated gene targets implicated in several cancers using an end-to-end assay workflow on the Biomek NGeniuS platform. Automation in laboratories is advantageous to generate reproducible next generation sequencing (NGS) sample libraries, however, assay automation differs from instrument vendor to vendor but also from lab to lab with different deck layouts of the same instrument. These differences require a significant amount of optimization to design the workflow and begin generating NGS libraries. In addition to this optimization, some research, e.g., cancer research utilizes low input and/or degraded samples such as cfDNA from plasma or FFPE biopsies. Integrated DNA Technologies (IDT) and Beckman Coulter - Life Sciences together provide a walk away NGS automation solution for these research samples directly upon instrument installation with no optimization required by combining Beckman Coulter’s Biomek NGeniuS with IDT’s xGen cfDNA & FFPE DNA Library Prep kit and xGen Hybridization Capture. This trio provides a solution for laboratories to minimize technician hands-on time, error reduction, and rework while improving flexibility. IDT’s xGen cfDNA & FFPE DNA Library Prep kit utilizes novel chemistry to maximize sample input conversion, suppress adapter-dimer formation, and facilitate consensus analysis. IDT’s xGen Hybridization Capture products maintain high library diversity, obtain high on-target, and provide consistent and uniform sequencing coverage regardless of panel size. We demonstrate performance of this complete workflow with a custom 2Mb xGen Hyb panel yielding high library complexity, high on-target coverage, and capture uniformity. The combination of IDT’s xGen library preparation solutions on the NGeniuS Biomek platform provides a reliable and consistent solution that can be instantly downloaded from the portal straight to analysis of precious low input and degraded samples. Citation Format: Nicole Roseman, Laura Tucker, Francesco Criscuolo, Lynette Lewis, Li Liu, Tyler Buit, Jasmeen Mandair, Zachary Smith, Calvin Cortes. Automating next generation sequencing workflows for custom hyb panels: high quality library preparation and target enrichment on the Biomek NGeniuS System [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 263.
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Pham, Phong Huy, e Hoa Thi Dang. "NEW RECORD OF THE GENUS LARRA FABRICIUS, 1793 (HYMENOPTERA, CRABRONIDAE) FROM VIETNAM". Bulletin of the Iraq Natural History Museum 16, n.º 4 (20 de dezembro de 2021): 535–45. http://dx.doi.org/10.26842/binhm.7.2021.16.4.0535.
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The genus Larra Fabricius, 1793 (Hymenoptera: Crabronidae) is recorded for the first time from Vietnam. Three species and two subspecies belonging to this genus as follows: L. amplipennis (F. Smith, 1873); L. carbonaria (F. Smith, 1858); L. fenchihuensis Tsuneki, 1967; L. polita polita (F. Smith, 1858) and L. polita luzonensis Rohwer, 1919 are presented. Keys to both sexes of the three species and two subspecies reported here are provided.
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Hirth, Kenneth. "Origins of the Ñuu: Archaeology in the Mixteca Alta, Mexico. Stephen A. Kowalewski , Andrew K. Ballansky , Laura R. Stiver Walsh , Thomas J. Pluckhahn , John F. Chamblee , Verónica Pérez Rodríguez , Verenice Y. Heredia Espinoza , Charlotte A. Smith". Journal of Anthropological Research 67, n.º 1 (abril de 2011): 116–17. http://dx.doi.org/10.1086/jar.67.1.41304130.
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Helwani, Z., e Martunus Martunus. "Kesetimbangan Sistim Palm Kernel Oil (PKO) – Asam Laurat - Metanol". REAKTOR 10, n.º 1 (12 de junho de 2017): 37. http://dx.doi.org/10.14710/reaktor.10.1.37-41.
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Meminimasi kandungan asam lemak bebas (asam laurat) di dalam minyak inti sawit (PKO) dapat dilakukan dengan proses ekstraksi menggunakan pelarut methanol. Penggunaan proses ekstraksi untuk keperluan tersebut memerlukan ketersediaan data keseimbangan sistem PKO- asam laurat – methanol. Tujuan penelitian ini adalah untuk menentukan data kesetimbangan sistem PKO- asam laurat- methanol pada suhu 30 sampai 45 0C. Penentuan kondisi jenuh fasa rafinat dan ekstrak dilakukan dalam sel Smith-Bonner. Hasil penelitian menunjukkan luas daerah dua fasa akan makin mengecil dengan naiknya suhu dalam diagram sistem tiga komponen. Kata kunci : kesetimbangan cair-cair, PKO, asam laurat, methanol.
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King, Stacie M. "Origins of the Ñuu: Archaeology in the Mixteca Alta, Mexico - by Kowalewski, Stephen A., Balkansky, Andrew K., Stiver Walsh, Laura R., Pluckhahn, Thomas J., Chamblee, John F., Rodríguez, Verónica P., Heredia Espinoza, Verenice Y., and Smith, Charlotte A." Bulletin of Latin American Research 29, n.º 4 (1 de setembro de 2010): 541–43. http://dx.doi.org/10.1111/j.1470-9856.2010.00430.x.
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Yang, Yu C., Severin Thompson, David Montgomery, Antonio J. Quiñones, Xing Wei, Benjamin Madej, Aidan Tomlinson et al. "Abstract 1598: RM-046, a first-in-class, mutant-selective, and oral KRASQ61H(ON) inhibitor that drives tumor regression in preclinical models and validates KRASQ61H as a therapeutic target". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 1598. http://dx.doi.org/10.1158/1538-7445.am2023-1598.
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Abstract KRASQ61H mutant cancers represent a significant unmet medical need and include common solid tumor histotypes such as non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC). Currently, there are no targeted inhibitors of KRASQ61H in clinical development. Mutant RAS proteins exist predominantly in the GTP-bound active RAS(ON) state, leading to excessive downstream signaling via interaction with effectors such as RAF kinases. The properties of the intrinsic GTPase cycle of KRASQ61H should lead to accumulation of the active ON state. RM-046 is a potent, selective, and oral tri-complex inhibitor of KRASQ61H(ON). RM-046 binds to the abundant intracellular chaperone protein cyclophilin A (CypA) with high affinity to form a binary complex that then non-covalently and selectively engages the active ON state of KRASQ61H. The resulting tri-complex sterically blocks KRASQ61H binding to its effectors, thereby inhibiting its downstream signaling. RM-046 potently suppressed ERK phosphorylation and proliferation in KRASQ61H mutant cancer cells with sub-nanomolar EC50 and IC50 values while displaying selectivity over cancer cells with wildtype KRAS. RM-046 showed no evidence of off-target interactions based on in vitro GTPase, kinome, and safety panels. As a single agent, RM-046 induced dose-dependent, deep, and durable suppression of RAS pathway signaling in preclinical xenograft models in vivo. Daily oral administration of RM-046 demonstrated dose-dependent anti-tumor activity and drove deep tumor regressions across several preclinical xenograft models of human KRASQ61H tumors, including NSCLC and PDAC. All treatment regimens tested with RM-046 were tolerated in vivo. As far as we are aware, RM-046 is the first oral and mutant-selective inhibitor of KRASQ61H(ON). It also represents an example of a non-covalent, mutant-selective tri-complex inhibitor of a KRAS oncogenic driver mutation. Citation Format: Yu C. Yang, Severin Thompson, David Montgomery, Antonio J. Quiñones, Xing Wei, Benjamin Madej, Aidan Tomlinson, Nataliya T. Shifrin, Alexander McNamara, Ethan Ahler, Laura L. McDowell, Michael Flagella, John Setser, Stephanie Chang, Zhican Wang, Zhengping Wang, Jun Huang, Steve Ballmer, Shaong li, Andreas Buckl, Elena Koltun, Adrian Gill, Jingjing Jiang, Mallika Singh, Jacqueline A. Smith. RM-046, a first-in-class, mutant-selective, and oral KRASQ61H(ON) inhibitor that drives tumor regression in preclinical models and validates KRASQ61H as a therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1598.
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Mohanty, Suchismita, Jeremy Chen, Alma Gomez, Angela Boroughs, Irene Scarfo, Laura Lim, Kevin Dang et al. "Abstract 38: AB-2100, a PSMA-inducible CA9-specific CAR T cell product for the treatment of ccRCC provides long-term tumor responses in preclinical mouse model". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 38. http://dx.doi.org/10.1158/1538-7445.am2024-38.
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Abstract Common challenges of CAR-T cell therapies in solid tumors, such as clear cell renal cell carcinoma (ccRCC), include insufficient therapeutic potency and lack of tumor specificity. We have developed AB-2100, an autologous integrated circuit T (ICT) cell product, generated via CRISPR-mediated knock-in of a single transgene into a safe-harbor locus. AB-2100 encodes a transcriptionally regulated sequential AND gate that comprises a priming receptor (PrimeR) specific for PSMA and an inducible CAR targeting CA9 antigen, which is widely expressed on local and metastatic lesions. AB-2100’s sequential AND logic-gate confers tumor-specific activity by priming off of PSMA-expressing tumor vasculature to induce CA9 CAR expression. This unique feature of the logic gate is intended to increase the safety profile of AB-2100 given that PSMA and CA9 are predicted to have limited co-expression in normal tissues. Additional functionality includes short-hairpin RNAs (shRNA) against Fas and TGFBR designed to prevent tumor-mediated resistance, and a synthetic pathway activator (SPA) that drives constitutive STAT3 signaling and enhanced T cell cytotoxicity and expansion. Mechanism of action studies demonstrate that AB-2100 can prime off of PSMA-expressing endothelial cells and induce tumor-specific killing of CA9 tumor cells, leading to the eradication of ccRCC targets in vitro. AB-2100 also exhibited selective killing of dual antigen expressing tumors in vivo using a dual-flank subcutaneous xenograft model. Preclinical xenograft studies also demonstrated that TGFBR shRNA and SPA modules enhanced antitumor activity of ICTs. When AB-2100 potency was evaluated in the subcutaneous A498 xenograft model, treatment with AB-2100 resulted in complete and durable anti-tumor responses. In summary, preclinical data demonstrate that AB-2100 selectively targets tumors co-expressing PSMA and CA9, and can overcome multiple suppressive mechanisms in the tumor microenvironment. These results support the evaluation of AB-2100 in the clinic for the treatment of advanced or metastatic ccRCC. Citation Format: Suchismita Mohanty, Jeremy Chen, Alma Gomez, Angela Boroughs, Irene Scarfo, Laura Lim, Kevin Dang, Marvin Chew, Rakesh Sudhakah, Michelle Nguyen, Thomas J. Gardner, Beatriz Millare, James Zhang, Darrian Moskowitz, Stanley Zhou, Neroli H. Xie, Nickolas Attanasio, Amanda Fearon, Ivan Chan, Vibhavari Sail, Vince Thomas, Jennesa Smith, Jennifer McDevitt, Levi Gray-Rupp, Alba Gonzalez, Christopher Murriel, W. Nicholas Haining. AB-2100, a PSMA-inducible CA9-specific CAR T cell product for the treatment of ccRCC provides long-term tumor responses in preclinical mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 38.
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Bernard, Catherine. "LAURA M a LOJO RODRIGUEZ, ed. — Moving across a Century. Women’s Short Fiction from Virginia Woolf to Ali Smith. (Bern : Peter Lang, 2013, 131 pp., 37.50 €.) NICK TURNER. — Post-War British Women Novelists and the Canon . (London: Continuum, 2010, VI + 195 pp., 33.50 €.)". Études anglaises Vol. 67, n.º 3 (9 de dezembro de 2014): 369–70. http://dx.doi.org/10.3917/etan.673.0348n.
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Bustamante-Marin, Ximena, Jenna L. Merlino, Emma J. Grindstaff, Michael F. Coleman, Erika Rezeli, Kristina K. Camp, Laura Smith e Stephen D. Hursting. "Abstract 2388: Role of the primary cilium in the crosstalk between obesity and cancer". Cancer Research 82, n.º 12_Supplement (15 de junho de 2022): 2388. http://dx.doi.org/10.1158/1538-7445.am2022-2388.
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Abstract Background: Defects in primary cilium can lead to a group of disorders termed ciliopathies, with links to both obesity and cancer. Obesity causes inflammation and downregulates anti-tumor immunity generating a protumor microenvironment and increases the risk of breast cancer (BC) development and metastasis. Also, obesity affects cilium length, which could disrupt the essential role of the cilium in detecting extracellular cues, coordinating cell signaling responses, and regulating cell fate and mitochondrial function. However, there is a gap in understanding the effects of obesity on ciliogenesis in cancer cells and in regard to the impact of cilium length and localization on mitochondrial function of tumor cells. We therefore sought to elucidate the impact of obesity on the presence, localization, and function of primary cilium, using murine models of triple-negative breast cancer (TNBC). Methods: We generated mammary tumors by orthotopic transplantation of murine metM-Wntlung or E0771 TNBC cells, and evaluated the impact of obesity on ciliary specific gene sets in tumors using GSEA analysis. We also tested the abundance of cilium in tumor sections using immunofluorescence. Additionally, we developed metM-Wntlung and E0771 expressing the ciliary transmembrane protein Smo fluorescently tagged to pHluorin. Using these cells, we performed in vitro studies to investigate the length and cellular localization of the cilium in cancer cells in 3 compartments; intracellular (in), intermediate, or extracellular (out). Results: Our GSEA analysis results indicated significant upregulation of 18/19 ciliary gene sets in metM-Wntlung mammary tumors from obese mice and 19/19 ciliary gene sets in E0771 mammary tumors from obese mice compared to the corresponding tumors developed in non-obese mice. Ongoing leading-edge analysis will determine the genes driving the enrichment of ciliary-related gene sets in tumors of obese mice. Immunofluorescence analysis showed a significant number of ciliated cells in tumor sections of obese mice and in cultured cells expressing pHluorin-Smo. Ongoing studies will reveal the specific cellular localization of the cilium on cancer cells and the effects on mitochondrial function. Our research is establishing a proof-of-concept that mammary cancer cells express cilium and will elucidate key mechanistic details related to the role of the primary cilium in the crosstalk between obesity and cancer metabolism. This research is supported by R35CA197627 (SDH), AICR Marylin Gentry Fellowship (XBM). Citation Format: Ximena Bustamante-Marin, Jenna L. Merlino, Emma J. Grindstaff, Michael F. Coleman, Erika Rezeli, Kristina K. Camp, Laura Smith, Stephen D. Hursting. Role of the primary cilium in the crosstalk between obesity and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2388.
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Allevato, Michael M., Lisa Chionis, Joshua Smith, Santhoshi Krishnan, Leanne Henry, Tingting Qin, Janice Farlow et al. "Abstract PO-031: Integrated bioinformatics and functional spatial analysis platform for the discovery of predictive biomarkers in oral cancer". Clinical Cancer Research 29, n.º 18_Supplement (15 de setembro de 2023): PO—031—PO—031. http://dx.doi.org/10.1158/1557-3265.aacrahns23-po-031.
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Abstract Background: Oral cavity squamous cell carcinoma (OCSCC) has an unpredictable response to immunotherapy, and standard biomarkers evaluating the tumor immune microenvironment (TIME) lack widespread translational applicability. Defining the TIME is critical to understanding mechanisms and allows the development of reproducible and accurate prognostic and predictive biomarkers based on immune profiles; however, to date, this remains elusive for clinical use. To further study and deconstruct the TIME within OCSCC, we integrated our previously developed computational spatial analysis (CSA) with in-silico deconvolution analyses to comprehensively study the TIME in OCSCC. Methods: We leveraged access to two independent OCSCC cohorts (UM and TCGA) with paired bulk RNASeq, WES, and CSA-immune score data. TMB, neoantigen load, and deconvolution analysis (CIBERSORTx) were performed to generate in silico immune profiles. A previously described CSA evaluates the density and distribution of tumor-infiltrating lymphocytes (TILs) relative to cancer cells to generate immune scores (GCross function [GFx]). GFx scores were then correlated with WES and RNASeq-derived cell-type deconvolution results, immune cell activation expression signatures, and gene expression-based radiosensitivity index scores. Pearson's correlation coefficient and associated p-value were calculated for each comparison. Cox proportional hazards multivariate regression was performed using the entire cohort for survival and recurrence analysis. Results: Here, we better characterize the immunologic tumor environment by objectively measuring the TIL density in spatial relationships with cancer cells. We found that immunoreactive tumors with high GFx scores are highly prognostic for overall survival, with the lowest tiers associated with poor survival. Combining the spatial relationship with immunogenomics (WES and RNASeq immune profiles) increased the prognostic capability of the integrated bioinformatics analysis model. In addition, we further revealed that lymphocyte-infiltrated regions, specifically CD8+ T-cells, are associated with TMB, neoantigen load, and improved overall survival. Conclusion: This study provides an integrated dataset from which to generate future insights and possible immunomodulatory therapies to counteract the poor immunogenicity of OCSCC. We show that integrating computational spatial analysis and in-silico deconvolution analysis is generalizable to multiple patient populations with different demographic compositions and pathology images collected from distinctive digitization methods. Our machine-learning approaches provide clinically actionable predictions that confirm the relevance of these biomarkers with immune cell infiltration and suggest the role of digital pathology profiling in predicting response to immunotherapy which could inform treatments for oral squamous carcinoma patients. Citation Format: Michael M. Allevato, Lisa Chionis, Joshua Smith, Santhoshi Krishnan, Leanne Henry, Tingting Qin, Janice Farlow, Laura Rozek, Jonathan Mchugh, Arvind Rao, Maureen Sartor, Steven B. Chinn. Integrated bioinformatics and functional spatial analysis platform for the discovery of predictive biomarkers in oral cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-031.
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Campbell, Sandra. "E.K. Brown: A Study in Conflict by Laura Smyth Groening". ESC: English Studies in Canada 21, n.º 4 (1995): 473–75. http://dx.doi.org/10.1353/esc.1995.0006.
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Ketcham, John M., Shilpi Khare, Niranjan Sudhakar, David M. Briere, Larry Yan, Jade Laguer, Laura Vegar et al. "Abstract ND02: MRTX0902: A SOS1 inhibitor for therapeutic intervention of KRAS-driven cancers". Cancer Research 82, n.º 12_Supplement (15 de junho de 2022): ND02. http://dx.doi.org/10.1158/1538-7445.am2022-nd02.
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Abstract KRAS is the most frequently mutated oncogene in cancer and drives uncontrolled growth through hyperactivation of the MAPK pathway. Significant progress has been made in the past several years to directly target KRASG12C with the FDA approval of sotorasib and the reported clinical activity of adagrasib (MRTX849). Despite these remarkable breakthroughs, additional therapies that enhance the depth and duration of response to KRASG12C inhibitors provide the opportunity to build upon the initial progress. SOS proteins are guanine nucleotide exchange factors (GEFs) that transduce receptor tyrosine kinase (RTK) signaling from the cell surface and facilitate the activation of RAS family proteins. In addition, SOS1 is a target of negative feedback signaling following RAS-mediated activation of the RAF-MEK-ERK cascade. Thus, SOS proteins represent a significant therapeutic node that maintains RAS pathway equilibrium as well as oncogenic signaling dynamics. Here we highlight the discovery and preclinical evaluation of MRTX0902, a potent, selective, and orally bioavailable inhibitor of SOS1 presently in IND-enabling studies. A structure-based approach was used to identify a novel chemical series that disrupts the protein-protein interaction between SOS1 and KRAS, thereby preventing SOS1-mediated GTP-exchange on GDP-bound KRAS. Considering MRTX849 preferentially binds to inactive GDP-bound KRASG12C, targeting SOS1 in this genetic context increases the ability of MRTX849 to bind and inhibit KRASG12C. The combination of MRTX0902 with MRTX849 enhances the depth and durability of an anti-tumor response when compared to MRTX849 alone in pre-clinical KRASG12C tumor models. MRTX0902 augments additional targeted therapies across a variety of RAS-addicted tumors, indicating that SOS1 inhibition is effective against a broad spectrum of mutations within the MAPK pathway. Furthermore, drug-anchored CRISPR experiments with MRTX0902 and MRTX849 uncovered a previously underappreciated functional role of the SOS1 paralog, SOS2, in KRAS-addicted tumors. In addition to aiding in the understanding of SOS and RAS family signaling dynamics, these studies implicate SOS2 as a potential cancer drug target in the context of SOS1/KRASG12C inhibition. In summary, we have used a structure-based approach to discover a SOS1 inhibitor that augments the anti-tumor activity of MRTX849 and additional targeted MAPK pathway inhibitors. We anticipate our findings to translate into the clinic and make an impact in patients with RAS-addicted tumors. Citation Format: John M. Ketcham, Shilpi Khare, Niranjan Sudhakar, David M. Briere, Larry Yan, Jade Laguer, Laura Vegar, Darin Vanderpool, Jill Hallin, Lauren Hargis, Vickie Bowcut, David Lawson, Robin J. Gunn, Anthony Ivetac, Nicole C. Thomas, Barbara Saechao, Natalie Nguyen, Jeffrey Clarine, Lisa Rahbaek, Christopher R. Smith, Aaron C. Burns, Matthew A. Marx, James G. Christensen, Peter Olson, Jacob R. Haling. MRTX0902: A SOS1 inhibitor for therapeutic intervention of KRAS-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND02.
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Herron, David, e Lotta Haglund. "Students and Graduates Learn Library Educational Content from Interactive Multimedia Tutorials". Evidence Based Library and Information Practice 1, n.º 4 (11 de dezembro de 2006): 64. http://dx.doi.org/10.18438/b84k5r.
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A review of:
Markey, Karen, Annie Armstrong, Sandy De Groote, Michael Fosmire, Laura Fuderer, Kelly Garrett, Helen Georgas, Linda Sharp, Cheri Smith, Michael Spaly, and JoniE. Warner. “Testing the Effectiveness of Interactive Multimedia for Library-User Education.” portal: Libraries & the Academy 5.4 (Oct. 2005): 527-54.
Objective –To demonstrate the effectiveness of interactive multimedia tutorials in delivering library educational content, and to evaluate librarian experiences of developing multimedia tutorials, both as part of the LUMENS (Drabenstott) project.
Design – User study (questionnaire and interviews) using pretest-posttest design.
Setting – Four academic libraries in the United States. One library dropped out during the course of the project.
Subjects – Ninety university students from the University of Illinois Chicago (UIC), Purdue University, and the University of Notre Dame participated in the main study to evaluate three of the tutorials: “Doing research an introduction to the concepts of online searching,” “How to read a scientific paper,” and “Hungry for information?” Another group of 15 subjects from UIC, consisting of 10 graduate students, 2 faculty, 2 librarians, and one fellow, assessed a fourth tutorial “Keeping current in your field.” Librarians were interviewed about their experiences producing the interactive multimedia tutorials.
Methods – The 90 students were given a pretest containing questions about library educational content and five demographic questions. The students used the multimedia tutorial for 15-30 minutes and immediately afterward were given a posttest containing comparable questions to the pretest in terms of content and difficulty. The students were also asked to rate their experiences of using the tutorials in various ways on a scale from 0-10. At UIC, the experiences of the subjects using the multimedia tutorial were assessed by personal interviews. Librarians producing the multimedia tutorials were asked about their experiences of developing multimedia tutorials through e-mail, listserv discussion, phone calls, and face-to-face personal and group interviews.
Main results – All three libraries measured a significant increase (using a one sample t-test, p75%) of students were familiar with tutorial content before start. Despite this, most of the students found the tutorials useful and enjoyable, and the majority were fairly likely to recommend the tutorial to a friend. Interviews with subjects at UIC revealed similar experiences, except that the subjects were less familiar with the tutorial content at the beginning, and they were more likely to return to the tutorial for a refresher. The tutorial with the highest amount of interactivity was the most popular. The librarians found it difficult to find time to learn Macromedia Flash and to work within the LUMENS project generally. Eight out of 15 librarians remained with the project over the entire period.
Conclusion – Students learned library educational content by using multimedia tutorials and seemed to enjoy the experience, and educational librarians should lead multi-expert project teams in tutorial production. Finally, the educational value of multimedia tutorials must be offset from the time and effort needed to produce them.
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Khakbaz, Hamid, Mohammad Saeed Khanjani, Seyyed Jallal Younesi, Mohammad Reza Khodaie Ardakani, Mohammad Hadi Safi e Samaneh Hosseinzadeh. "Effectiveness of Cognitive-behavioral Therapy on the Positive and Negative Psychotic Symptoms and Emotion Regulation of Patients With Schizophrenia Spectrum Disorders". Journal of Rehabilitation 24, n.º 1 (23 de maio de 2023): 2–27. http://dx.doi.org/10.32598/rj.24.1.1450.3.
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Objective Schizophrenia is the most debilitating psychiatric disorder with the highest psychiatric ward admission rate. Drug therapy is the first line of treatment. However, it does not result in appropriate therapeutic responses in many patients, and they experience emotional regulation difficulties and psychosis symptoms after initial symptom resolution. Cognitive-behavioral therapy (CBT) is currently an adjuvant treatment besides drug therapy to target the persistent symptoms of psychosis. The present study aims to determine the effectiveness of CBT on the positive and negative symptoms and emotional regulation of those suffering from schizophrenia spectrum disorders. Materials & Methods The research design was single-subject and of the AB type (baseline and intervention) with a follow-up phase. Besides the routine therapy sessions, CBT sessions were held for the study participants. They were patients admitted to Razi Educational and Therapeutic and Research Psychiatric Center in Tehran City, Iran, who were selected based on the inclusion criteria. Thirty patients were selected with convenience sampling, and 5 were randomly placed in the CBT group. They were evaluated with the scales of positive and negative symptoms of Kay, Fiszbein, and Opler (1986) and difficulties in emotional regulation by Gratz and Roemer (2004) in the baseline, intervention, and follow-up phases. The treatment sessions were planned based on the CBT protocol developed by Laura Smith, Paula Nathan, Uta juniper, Patrick Kingsep, and Louella Lim (2003). Non-overlap of all pairs (NAP), percentage of non-overlapping data (PND), percentage of all non-overlapping data (PAND), percentage of data points exceeding the median (PEM), Cohen’s d effect size, and improvement percentages were used to analyze the data, and visual graphs were used for data presentation. Results The outcomes showed that in the intervention phase, compared to the baseline phase, the effect sizes of the positive and negative symptoms in the first to fifth participants were 1.6, 3.1, 3.2, 1.9, and 2.4, respectively. Only the effect sizes of the second and third participants were large. The effect sizes of the emotional regulation factor in the first to fifth participants were 2.8, 1.2, 1.1, 2.2, and 1.9, respectively. The effect size of the second participant was large, and the rest were average. The findings of this study showed that during the post-therapy and follow-up stages, while patients who had received CBT still experienced positive and negative symptoms of psychosis and difficulties in emotional regulation; these symptoms decreased in comparison with the baseline phase. Furthermore, their improvement percentages were not significant. Conclusion Data analysis showed that although CBT is effective in reducing positive and negative psychotic symptoms and improving the emotional regulation of patients, the data obtained from Cohen’s d effect size and recovery indices showed that the results are not clinically significant. In other words, although the patients who received CBT showed a slight improvement in psychotic symptoms and difficulty in emotional regulation, they could not maintain the therapeutic gains in the follow-up phase.
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Pilgrim, Charles, Marty Smith, Ee-Jun Ban, Samantha Ellis, John Zalcberg, Benjamin Markman, Margaret Lashof-Sullivan e Laura Indolfi. "Abstract CT106: First-in-human phase 1 study of paclitaxel-eluting PTM-101 film in subjects with borderline resectable or locally advanced pancreatic cancers". Cancer Research 84, n.º 7_Supplement (5 de abril de 2024): CT106. http://dx.doi.org/10.1158/1538-7445.am2024-ct106.
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Abstract Background Unlike many other types of cancer, improvements in the treatment of pancreatic cancer have been very limited, in part due to the inability to deliver chemotherapy to the tumor at efficacious concentrations for a prolonged time. PTM-101 is a novel biodegradable film containing paclitaxel and is designed to continuously release high concentrations of paclitaxel precisely to the site of a pancreatic tumor over one month. Methods This first in human study was conducted at one center in Australia to assess the safety, toxicity, and surgical feasibility of a single administration of PTM-101 containing 100 mg of paclitaxel. PTM-101 was sutured directly onto the pancreatic surface overlying the tumor by a surgical oncologist using standard laparoscopic equipment during a disease-staging assessment. Approximately 3 weeks after PTM-101 placement, all participants began standard of care therapy which included mFOLFIRINOX. This study enrolled 3 subjects that had treatment naïve, borderline resectable or locally advanced, pancreatic adenocarcinoma. Subjects were monitored closely for local and systemic toxicities, as well as for preliminary signals of efficacy. An independent central imaging lab reviewed CT scans to determine changes in tumor volume. Results PTM-101 was successfully implanted over the tumor site in all three subjects. In all cases, there were no adverse events reported during the procedure. Overall, PTM-101 was well tolerated with a total of five Grade 1 adverse events judged at least possibly related to the procedure or the mFOLFIRINOX. No serious adverse events (SAEs) or deaths occurred. Paclitaxel was undetectable in the circulation at all time points. Subjects were followed for 6 months. Best overall response rate according to RECIST was stable disease (2 subjects) and partial response (1 subject). An independent analysis showed that all tumors had a reduction in size in the anterior/posterior diameter, which was consistent with unidirectional paclitaxel release from PTM-101. Two of the 3 subjects had a >30% tumor volume reduction, importantly, with the initial decrease in tumor size detected prior to mFOLFIRINOX. Conclusion PTM-101 was readily implanted during diagnostic laparoscopy and was well tolerated with no SAEs or deaths reported during 6 months of follow up. This study demonstrated that a PTM-101 implant was surgically feasible, safe, resulted in no systemic paclitaxel exposure, and caused a tumor size reduction in all 3 subjects. Additional studies may demonstrate the potential for PTM-101 to be a first-line adjunct prior to neoadjuvant therapy in treatment naïve, borderline resectable or locally advanced, pancreatic cancer. Citation Format: Charles Pilgrim, Marty Smith, Ee-Jun Ban, Samantha Ellis, John Zalcberg, Benjamin Markman, Margaret Lashof-Sullivan, Laura Indolfi. First-in-human phase 1 study of paclitaxel-eluting PTM-101 film in subjects with borderline resectable or locally advanced pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT106.
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Cheng, Zhao, Hasan B. Mirza, Darren P. Ennis, Philip Smith, Lena Morrill Gavarró, Chishimba Sokota, Gaia Giannone et al. "Abstract 53: The copy number landscape of early stage ovarian high grade serous carcinoma". Cancer Research 82, n.º 12_Supplement (15 de junho de 2022): 53. http://dx.doi.org/10.1158/1538-7445.am2022-53.
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Abstract Background: High grade serous carcinoma (HGSC) is the most common and poorest prognosis subtype of ovarian cancer. The large majority of patients present with advanced (stage IIIC or IV) disease with a median survival of only 3-4 years. By contrast, approximately 10% patients are diagnosed with early stage disease, confined to the ovary/fallopian tube, of whom 90% are cured with surgery and platinum-based chemotherapy. Beyond TP53 mutation, classic activating oncogene mutations are rare in HGSC. Rather, HGSC is marked by extreme copy number (CN) abnormalities, and this complexity has prevented detailed understanding of the mutational processes underpinning outcomes in HGSC. We have used shallow whole genome sequencing (sWGS) to develop novel CN signatures that are able to deconvolute the complexity of HGSC genomes. However, nearly all genomics studies in HGSC have examined advanced stage disease, and little is known about the genomics of early stage HGSC - specifically, it is unclear whether these tumors are identified purely by chance or whether they represent a specific subset that does not metastasize. Hypotheses: We hypothesized that early stage HGSC has a distinct copy number landscape compared to stage IIIC/IV disease. Methods and results: We have identified 43 cases of FIGO stage I-IIA HGSC from the pathology archives of three large London Gynaecological Cancer Centres and 52 late-stage (stage IIIC-IV) cases from BriTROC-1 cohort. Median age at diagnosis was 61.3 years vs 62.3 years respectively. There were no significant differences in mutation rates of TP53 and BRCA1/2, and TP53 mutations were near-universal in both cohorts. We also did not find cohort-specific focal SCNA that could explain biological behavior. However, ploidy was significant higher in late-stage (median 3.0) than early-stage (median 1.9) samples. CN signature exposures were significantly different between early and late stage cohorts. Relative exposure of signature 3 was greater in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. Summary:This project identifed that early stage and late stage HGSC have highly similar patterns of mutation and focal SCNA. However, genome-wide analysis indicates that the abnormalities seen in advanced disease are not present in early stage disease, which may represent a discrete subset with reduced metastatic potential. By identifying and characterizing the copy number signature changes, these data suggest that diagnosis at early-stage might reflect biological differences and not fortuitous chance. These data improve understanding of HGSC biology and may reveal potential new treatment strategies. Citation Format: Zhao Cheng, Hasan B. Mirza, Darren P. Ennis, Philip Smith, Lena Morrill Gavarró, Chishimba Sokota, Gaia Giannone, Teodora Goranova, Thomas Bradley, Anna Piskorz, Michelle Lockley, Baljeet Kaur, Naveena Singh, Laura A. Tookman, Jonathan Krell, Jackie McDermott, Geoff Macintyre, Florian Markowetz, James D. Brenton, Iain A. McNeish. The copy number landscape of early stage ovarian high grade serous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 53.
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Knox, John E., Jingjing Jiang, G. Leslie Burnett, Yang Liu, Caroline E. Weller, Zhican Wang, Laura McDowell et al. "Abstract 3596: RM-036, a first-in-class, orally-bioavailable, Tri-Complex covalent KRASG12D(ON) inhibitor, drives profound anti-tumor activity in KRASG12D mutant tumor models". Cancer Research 82, n.º 12_Supplement (15 de junho de 2022): 3596. http://dx.doi.org/10.1158/1538-7445.am2022-3596.
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Abstract KRASG12D mutant cancers represent a significant unmet medical need with 55,000 new diagnoses annually in the US. The KRASG12D mutation occurs commonly in multiple tumor histotypes, including about 20%, 29% and 17% of KRAS mutant colorectal, pancreatic, and non-small cell lung cancers, respectively. However, there are no directly targeted inhibitors of KRASG12D in clinical development. Mutant RAS proteins exist predominantly in the GTP-bound RAS(ON) state, leading to excessive downstream signaling via interaction with effectors such as RAF kinases. Highly selective inhibitors that covalently target the KRASG12C(OFF) state and inhibit conversion to KRASG12C(ON) have been shown to be active and well tolerated in the clinic, and we have described a novel, covalent tri-complex KRASG12C(ON) inhibitor that has robust anti-tumor activity and is well tolerated in preclinical studies. Developing a covalent inhibitor of KRASG12D presents several challenges. The Asp residue in KRASG12D is significantly less reactive toward electrophiles than is Cys. And most reported covalent chemical warheads capable of reacting with Asp exhibit high nonspecific reactivity. The intrinsic GTP hydrolysis rate of KRASG12D is about 2.6-fold lower than that of KRASG12C, further biasing the cellular KRASG12D pool to the RAS(ON) state and emphasizing the importance of targeting the KRASG12D(ON) state for maximal suppression of this oncogenic driver. Based on these considerations we designed RM-036, a potent, selective, orally bioavailable, covalent KRASG12D(ON) inhibitor with attractive drug-like properties. It forms a tri-complex between the abundant intracellular chaperone cyclophilin A (CypA) and the active state of KRASG12D, positioning the warhead relative to KRASG12D and enabling selective covalent engagement of Asp. In cellular models, RM-036 exhibited efficient and selective covalent binding to KRASG12D, with no detectable reactivity toward the adjacent Asp residue in cells with the KRASG13D mutation. RM-036 showed low off-target reactivity in cell-based proteomic screens. RM-036 potently inhibited growth and induced apoptosis in KRASG12D mutant cancer cells in vitro but not in BRAFV600E-dependent cells. RM-036, as a single agent, produced deep, durable, and dose-dependent suppression of tumor RAS pathway activation with covalent target engagement in vivo following repeat oral administration. Profound tumor regressions, including complete regressions, were observed in various KRASG12D mutant xenograft models upon treatment with RM-036. All treatments regimens tested with RM-036 were well tolerated in vivo. These preclinical findings provide a strong foundation for advancing RM-036 toward clinical evaluation in patients with tumors bearing the KRASG12D mutation. Citation Format: John E. Knox, Jingjing Jiang, G. Leslie Burnett, Yang Liu, Caroline E. Weller, Zhican Wang, Laura McDowell, Shelby L. Steele, Shook Chin, Kang Jye Chou, Fang Wang, Mengqi Zhong, Elena S. Koltun, David Wildes, Mallika Singh, Adrian L. Gill, Jacqueline A. Smith. RM-036, a first-in-class, orally-bioavailable, Tri-Complex covalent KRASG12D(ON) inhibitor, drives profound anti-tumor activity in KRASG12D mutant tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3596.
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Brassil, Kelly J., Alexi Wright, Elizabeth Arthur, Austin Barr, Laura Flora, Barbara Halpenny, Mariah K. Jackson et al. "Abstract 742: Trial in progress: Comprehensive outcomes for after cancer health (COACH), a randomized trial assessing health outcomes following primary cancer therapy". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 742. http://dx.doi.org/10.1158/1538-7445.am2023-742.
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Abstract Purpose: This study evaluates feasibility and acceptability of a digital health coaching intervention for individuals who are within one year of completing primary cancer treatment of any modality, as well as its effect on health self-efficacy. Secondary endpoints evaluate trends in patient-reported outcomes (PRO), including financial toxicity, for which the Economic StraiN and Resilience in Cancer (ENRICh) tool is being validated. Additional endpoints explore associations between patient-reported symptoms, wearable, biomarker, and clinical data. This study seeks to fill a critical knowledge gap as to how health behavioral changes prompted by health coaching may modulate symptoms and physical/psychosocial well-being through the longitudinal tracking of patient reported, clinical, and bioinformatic data. Methods: This randomized, wait-list control trial is being conducted at geographically diverse National Cancer Institute-designated cancer centers. Per site enrollment is <150 participants, aged 18 and older, following completion of primary treatment for breast, ovarian, endometrial, lung, or gastric cancer or population specific (eg, ≥65 years) cohorts. A 6-month coaching intervention utilizing phone calls coupled with supplemental digital content via text, email, or web-based application is delivered during months 1 through 6 (intervention) or months 7 through 12 (wait-list control). PROMIS and other validated questionnaires and activity data are collected over 12 months. Gut microbiome specimens and the Diet History Questionnaire (DHQ) III are collected at enrollment and 6 months. Feasibility (retention rate ≥70%) and acceptability (≤20% scoring “not at all helpful”), are assessed with descriptive statistics. Summary Data: To date, 47 individuals have been enrolled at 3 study sites, Nebraska Medicine (36), Dana-Farber Cancer Institute (10), and The Ohio State University James Cancer Center (1). This includes 1 male and 46 female participants, with an average age of 63.62 (R 33-75), of whom 44 identify as White and 3 as Black or African American, and 47 identify as non-Hispanic. Among participants, 35 have a history of breast, 10 ovarian, 1 endometrial, and 1 gastric cancer. Two additional sites are planned to begin enrollment in 2023, one of which will primarily enroll participants identifying as Black and/or Hispanic. Conclusions: Enrollment is anticipated to complete by December 2023 with site-specific and composite results reported by December 2024. Novel outcomes related to the use of digital health coaching in the context of survivorship, as well as robust data assessing clinical, microbiome, dietary, patient-reported, and wearable data is expected to enhance existing evidence regarding outcomes in patients on both active surveillance and maintenance therapies for diverse tumor types. Citation Format: Kelly J. Brassil, Alexi Wright, Elizabeth Arthur, Austin Barr, Laura Flora, Barbara Halpenny, Mariah K. Jackson, Jessica Krok-Schoen, Robin Lally, Jennifer Loftis, Debra Lynch Kelly, Leorey Saligan, Rachael Schmidt, Grace L. Smith, Angela Starkweather, Anna Tavormina, Gisele Tlusty, Michael Vazquez, Marilyn Hammer. Trial in progress: Comprehensive outcomes for after cancer health (COACH), a randomized trial assessing health outcomes following primary cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 742.
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Jiang, Lingyan, Marie Menard, Caroline Weller, Zhican Wang, Les Burnett, Ida Aronchik, Shelby Steele et al. "Abstract 526: RMC-9805, a first-in-class, mutant-selective, covalent and oral KRASG12D(ON) inhibitor that induces apoptosis and drives tumor regression in preclinical models of KRASG12D cancers". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 526. http://dx.doi.org/10.1158/1538-7445.am2023-526.
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Abstract KRASG12D is the most frequent KRAS mutation in human cancers, with the highest prevalence in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). RMC-9805 is a first-in-class, oral, mutant-selective covalent inhibitor of the GTP-bound and active RAS(ON) form of KRASG12D. The formation of a stable, high affinity tri-complex between RMC-9805, KRASG12D and cyclophilin A results in the suppression of signaling downstream of KRASG12D(ON) by disrupting its interactions with downstream effectors such as RAF kinases. RMC-9805 treatment caused selective and persistent modification of KRASG12D leading to deep and durable suppression of RAS pathway activity, inhibition of cell proliferation, and apoptosis induction in KRASG12D human cancer cell lines in vitro and tumor models in vivo. In a mouse clinical trial with KRASG12D xenograft tumor models, RMC-9805 administered orally as a single agent was well tolerated and induced objective responses in 7 of 9 PDAC PDX and CDX models and 6 of 9 NSCLC PDX models, as assessed by mRECIST. In the few models that exhibited sub-optimal responses to RMC-9805 monotherapy, combination treatment with various RAS Companion Inhibitors improved depth and/or duration of anti-tumor response. In contrast to RASMUTANT NSCLC and PDAC, CRC tumors are less dependent on RAS driver mutations. For example, a more heterogeneous response to KRASG12C inhibitors has been reported in CRC than in NSCLC patients, suggesting combinations will be desired to achieve significant clinical benefit in CRC. Likewise, RMC-9805 monotherapy is less active in CRC models at doses that were highly active in KRASG12D NSCLC and PDAC models. However, combinations of RMC-9805 with vertical or parallel pathway RAS Companion Inhibitors such as SHP2, mTORC1 or RASMULTI(ON) inhibitors, achieved objective response rates up to 60% and delayed the onset of resistance in tumor models in vivo. RMC-9805 also synergized with anti-PD1 therapy in KRASG12D tumors in immune-competent animal models by shaping a favorable tumor immune microenvironment through cytokine modulation. In addition, RMC-9805 engaged the adaptive immune system by increasing presentation and recognition of tumor antigens, promoting a diversification of the TCR repertoire, and inducing immunological memory. Overall, RMC-9805 monotherapy elicited tumor regressions in most preclinical PDAC and NSCLC cancer models harboring KRASG12D. Furthermore, RMC-9805 combination therapies drove regressions in CRC models relatively less responsive to monotherapy. Supported by these findings, RMC-9805 is currently in IND-enabling development to permit clinical evaluation of single agent and combination strategies in patients with KRASG12D tumors. Citation Format: Lingyan Jiang, Marie Menard, Caroline Weller, Zhican Wang, Les Burnett, Ida Aronchik, Shelby Steele, Mike Flagella, Ruiping Zhao, James W W. Evans, Shook Chin, Kang-Jye Chou, Yunming Mu, Michael Longhi, Laura McDowell, John E. Knox, Adrian Gill, Jacqueline A. Smith, Mallika Singh, Elsa Quintana, Jingjing Jiang. RMC-9805, a first-in-class, mutant-selective, covalent and oral KRASG12D(ON) inhibitor that induces apoptosis and drives tumor regression in preclinical models of KRASG12D cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 526.
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Boroughs, Angela C., Irene Scarfo, Nickolas Attanasio, Thomas Gardner, Jenessa B. Smith, Jennifer McDevitt, Laura Lim et al. "Abstract 4088: A neovasculature-inducible CA9 CAR resistant to FASL and TGFb mediated suppression for the treatment of ccRCC". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 4088. http://dx.doi.org/10.1158/1538-7445.am2023-4088.
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Abstract Clinically effective CAR-T cell therapy for solid tumors, such as clear cell renal cell carcinoma (ccRCC), will require substantial T cell engineering to increase their specificity and potency. We have developed an Integrated Circuit T cell (ICT) that encodes multiple synthetic “modules” in order to overcome diverse barriers to efficacy in ccRCC; ICT cells are generated via CRISPR-mediated, targeted knock-in of a single large transgene into the novel GS94 safe-harbor locus. Both primary and metastatic sites of ccRCC are highly vascularized, with the majority of tumor cells expressing elevated levels of carbonic anhydrase IX (CA9), suggesting CA9 may be an excellent CAR target. However, CA9 is also expressed in healthy bile ducts and stomach tissue which has led to on-target, off-tumor toxicities in patients treated with constitutive CA9 CAR T cells. To improve the therapeutic index of CA9 CAR T cells, we developed an “AND” logic gated ICT cell that requires the presence of two antigens to trigger tumor cell killing, thereby enhancing tumor specificity. Induction of the CA9 CAR is gated on the expression of PSMA found on the tumor neovasculature of ccRCC. Importantly, PSMA and CA9 are not co-expressed in normal tissues. When the anti-PSMA priming receptor (PrimeRTM) binds PSMA, PrimeRTM engagement triggers proteolytic release of a chimeric, fully human transcription factor that induces expression of a CA9 CAR. We confirmed the feasibility of vascular priming using a transwell assay where ICTs were primed by a PSMA expressing endothelial cell line and then migrated across the transwell membrane to kill CA9 expressing RCC cells. In addition, a dual flank xenograft model was used to show logic gated circuits selectively kill tumors that express both CA9 and PSMA, and not tumors that express CA9 alone. Transforming growth factor beta (TGFb) is an immunosuppressive cytokine known to be highly expressed in ccRCC. To further increase the potency and persistence of the ICT cells an shRNA cassette was developed targeting both FAS and TGFBR2, a receptor required for TGFB signaling in T cells. Addition of FAS/TGFBR2 shRNA enhanced antitumor activity of PSMAxCA9 logic gate expressing T cells during in vitro chronic stimulation assays conducted in the presence of exogenous TGFb. Furthermore, FAS/TGFBR shRNA containing ICTs demonstrated enhanced antitumor activity in multiple xenograft RCC models. Collectively, these results demonstrate that PSMAxCA9 ICT cells can (i) selectively target antigens that cannot be safely targeted by conventional CARs and (ii) overcome multiple suppressive mechanisms in the tumor microenvironment. Citation Format: Angela C. Boroughs, Irene Scarfo, Nickolas Attanasio, Thomas Gardner, Jenessa B. Smith, Jennifer McDevitt, Laura Lim, Nishant Mehta, Suchismita Mohanty, James Zhang, Eric Cui, Vibhavari Sail, Amanda Fearon, Samuel Williams, Stephen Santoro, W. Nicholas Haining, Levi Gray-Rupp. A neovasculature-inducible CA9 CAR resistant to FASL and TGFb mediated suppression for the treatment of ccRCC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4088.
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Jakubek, Yasminka A., Ying Zhou, Adrienne Stilp, Jason Bacon, Justin Wong, Zuhal Ozcan, Donna Arnett et al. "Abstract 3507: Mosaic chromosomal alterations in blood across ancestries via whole-genome sequencing". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 3507. http://dx.doi.org/10.1158/1538-7445.am2023-3507.
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Abstract Mosaic mutations in blood are common with increasing age and are prognostic markers for cancer, cardiovascular dysfunction and other diseases. This group of acquired mutations include megabase-scale mosaic chromosomal alterations (mCAs). These large mutations have mainly been surveyed using SNP array data from individuals of European (EA) or Japanese genetic ancestry. To gain a better understanding of mCA rates and associated risk factors in genetically diverse populations, we surveyed whole genome sequencing data from 67,390 individuals, including 20,132 individuals of African ancestry (AA), and 7,608 of Hispanic ancestry (HA) with deep (30X) whole genome sequencing data from the NHLBI Trans Omics for Precision Medicine (TOPMed) program. We adapted an existing mCA calling algorithm for application to WGS data, and observed higher sensitivity with WGS data, compared with array-based data, in uncovering mCAs at low mutant cell fractions. As in previous reports, we observed a strong association with age and a non-uniform distribution of mCAs across the genome. The presence of autosomal (but not chromosome X) mCAs was associated with an increased risk of both lymphoid and myeloid malignancies. After adjusting for age, we found that individuals of European ancestry have the highest rates of autosomal mCAs, mirroring the higher rate of leukemia in this group. Our analysis also uncovered higher rates of chromosome X mCAs in AA and HA compared to EA, again after adjusting for age. Germline variants in ATM and MPL showed strong associations with mCAs in cis, including ancestry specific variants. And rare variant gene-burden analysis confirmed the association of putatively protein altering variants in ATM and MPL with mCAs in cis. Individual rare variants in DCPS, ADM17, PPP1R16B, and TET2 were all associated with autosomal mCAs and rare variants in OR4C16 were associated with chromosome X mCAs in females. There was significant enrichment of co-occurrence of CHIP mutations and mCAs both altering cancer associated genes TET2, DNMT3A, JAK2, CUX1, and TP53. Overall, our study demonstrates that rates of mCAs differ across populations and that rare inherited germline variants are strongly associated with mCAs across genetically diverse populations. These results strongly motivate further studies of mCAs in under-represented populations to better understand the causes and consequences of this class of somatic variation. Citation Format: Yasminka A. Jakubek, Ying Zhou, Adrienne Stilp, Jason Bacon, Justin Wong, Zuhal Ozcan, Donna Arnett, Kathleen Barnes, Josh Bis, Eric Boerwinkle, April Carson, Daniel Chasman, Michael Cho, Matthew Conomos, Nancy Cox, Margaret Doyle, Myriam Fornage, Xiuqing Guo, Sharon Kardia, Joshua Lewis, Ruth Loos, Xiaolong Ma, Mitchell Machiela, Taralynn Mack, Rasika Mathias, Braxton Mitchell, Kari North, Nathan Pankratz, Patricia Peyser, Michael Preuss, Bruce Psaty, Laura Raffield, Ramachandran Vasan, Susan Redline, Stephen Rich, Jerome Rotter, Edwin Silverman, Jennifer Smith, Margaret Taub, Jeong Yun, Yun Li, Pinkal Desai, Alexander Bick, Alexander Reiner, Paul Scheet, Paul Auer. Mosaic chromosomal alterations in blood across ancestries via whole-genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3507.
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Merrill, Nathan M., Aaron Udager, Angel Qin, Kiran Lagisetty, Liwei Bao, Xu Cheng, Hamadi Madhi et al. "Abstract 223: Precision medicine-based platform to guide the treatment of EML4-ALK fusion lung cancers and other NSCLC". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 223. http://dx.doi.org/10.1158/1538-7445.am2024-223.
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Abstract Background: Lung cancer (LC) remains the top cause of cancer-associated mortality worldwide, with a 10-year overall survival rate of only 5%. While most LCs are smoking related, in the US, 25% of non-small cell LC (NSCLC) are diagnosed in patients with little or no smoking history. Fusions involving anaplastic lymphoma kinase (ALK) are the oncogenic driver in ~3-7% of NSCLC. While inhibitors targeting the kinase domain of ALK (TKIs) have proven extremely effective, inevitably, resistance develops with limited effective treatment options. Additionally, NSCLCs without identified molecular alterations have limited treatment options beyond radiation, immunotherapy, chemotherapy, and resection. Methods: We developed a precision medicine-based platform (PMP) to screen patient-derived material (PDM) directly from the operating room with curated panels of drugs. PDM collected during clinically indicated procedures is plated in 3D-culture to generate patient-derived organoids (PDOs) and screened with drugs curated to each tumor type. PDOs are screened at therapeutically relevant doses, drawing from pharmacokinetic data for each drug. We have optimized an assay to rapidly screen for EML4-ALK fusions and can perform next-generation sequencing in real time (~7 days) to integrate with drug screening results. Results: To date, we have screened 83 cases, including 8 EML4-ALK NSCLC. We have demonstrated an ability to produce high quality data from low input samples (biopsies). In one EML4-ALK NSCLC we were able to collect PDM from two distinct anatomic spaces (pleural effusion and peritoneal fluid) and screen with the same panel of drugs, with nearly identical results, highlighting the reproducibility and consistency of our assay. Screening of EML4-ALK tumors which have progressed to second or higher line TKIs, demonstrate sensitivity to earlier generation ALK TKIs, a known phenomenon. Characterization of tumors with unknown clinical drivers identifies ~1/3 tumors with no prioritized variants and particularly poor response to chemotherapies. Our results recapitulate known resistance/progression in samples previously exposed to therapy, demonstrating a strong negative predictive value. Longitudinal assessment will be required to robustly assess positive predictive value (PPV). Conclusions: Our PMP captures robust and reproducible results that are consistent with known clinical pathogenesis. Moving forward, we are collecting longitudinal data from enrolled patients in parallel with clinical trials to demonstrate the PPV of our PMP. We additionally strive to demonstrate reproducibility to obtain Clinical Laboratory Improvement Amendments approval and to deliver results to patients and physicians to help guide clinical care. Citation Format: Nathan M. Merrill, Aaron Udager, Angel Qin, Kiran Lagisetty, Liwei Bao, Xu Cheng, Hamadi Madhi, Ananya Banerjee, Marziyeh Salehi Jahromi, Laura Goo, Varun Kathawate, Bryce Vandenburg, Marisa Aikins, Mark Slayton, Peter Ulintz, Zhaoping Qin, Chia-jen Liu, Habib Serhan, John Jefferies, Muhammad Sajawal Ali, Vishal Navani, Michael Monument, Johannes Kratz, Amber Smith, Andrew Chang, Gregory Kalemkerian, Sunitha Nagrath, Peggy Hsu, Matthew B. Soellner, Sofia D. Merajver. Precision medicine-based platform to guide the treatment of EML4-ALK fusion lung cancers and other NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 223.
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JENNER, MARK S. R. "David L. Smith, Richard Strier and David Bevington (eds.), The theatrical city: culture, theatre and politics in London 1576–1649. (Cambridge: Cambridge University Press, 1995.) Pages xv+288. £40.00. Laura Gowing, Domestic dangers: women, words, and sex in early modern London. (Oxford: Oxford University Press, 1995.) Pages ix+301. £35.00." Continuity and Change 14, n.º 2 (agosto de 1999): 275–314. http://dx.doi.org/10.1017/s0268416099283294.
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Schubel, Laura C., Mandi L. Pratt-Chapman, Teletia Taylor, Robin A. Littlejohn, Andrea J. Lopez, Judith Lee Smith, Susan Sabatino et al. "Abstract B031: Preferences for social risk factor screening among breast and prostate cancer survivors in the Washington DC region: A qualitative study". Cancer Epidemiology, Biomarkers & Prevention 32, n.º 1_Supplement (1 de janeiro de 2023): B031. http://dx.doi.org/10.1158/1538-7755.disp22-b031.
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Abstract Despite improvements in cancer outcomes over time, significant disparities remain between Black and White cancer survivors. Medical care is estimated to account for 10-20% of health outcomes, while other modifiable factors explain as much as 80-90% of outcomes. These disparities may thus be driven by multiple factors including social determinants of health, differences in treatment or follow up, or attitudes and behaviors of care teams. As part of a larger project, we conducted a qualitative study to understand cancer survivor preferences for and experiences with social needs screening and referrals. The results of this assessment will inform the delivery of social risk screening for breast and prostate cancer survivors in the multi-site study. Semi-structured interviews were conducted in English between March and April 2022 with breast and prostate cancer survivors from two cancer institutes in Washington DC. Patients were purposively recruited to ensure diversity in age, race, and cancer stage (I-III). Each interview lasted 60 minutes. Transcripts were reviewed for consensus and preferences for social needs screening. Thirteen survivors participated in the interviews. Participants were mostly breast cancer survivors (n=10), African American (n=6), were equal in stages I and II at time of diagnosis (n=5), and ranged in age from 34 to 81 with a median age of 64. Most patients (n=7) did not report social needs screening during their treatment, though all patients welcomed having these conversations with their care team. The majority of patients (n=9) desired face-to-face conversations as opposed to on paper (n=1) or through the patient portal (n=1). Similarly, most patients (n=7) did not mind who on their care team held the conversations. There was difference in opinion on how often social needs should be discussed, with four participants suggesting every appointment to another patient suggesting once at diagnosis. When asked about the needs patients experienced during treatment, food insecurity and nutrition were most cited (n=6), followed by transportation (n=4) and emotional resources (n=4). Only one patient reported not desiring social needs referrals during treatment. Other avenues for seeking out social resources included self-initiated research online or through books (n=2), and another patient described utilizing their local church (n=1). Finally, patients also spoke about challenges in receiving treatment and transitioning to survivorship due to the COVID-19 pandemic, including hospital staff turnover and care team inconsistency (n=1), bringing loved ones to appointments (n=1), and transportation challenges for individuals who relied on public transport to and from the clinic (n=1). This research reveals important insight to the perspective on social needs screening among a group of breast and prostate cancer survivors in the Washington DC region and highlights the ways in which patients have experienced and desire screening for social needs. In future work we will expand the number of interviews and apply these findings into practice. Citation Format: Laura C. Schubel, Mandi L. Pratt-Chapman, Teletia Taylor, Robin A. Littlejohn, Andrea J. Lopez, Judith Lee Smith, Susan Sabatino, Arica White, Joseph Astorino, Bryan O. Buckley, Christopher King, Hannah Arem. Preferences for social risk factor screening among breast and prostate cancer survivors in the Washington DC region: A qualitative study [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B031.
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De Lima, Dieila Giomo, Mariana Brait, Laura Palmieri, Fernando T. Zamuner, Esther Broner, Kellie N. Smith, Timothy Westlake et al. "Abstract 2121: Saliva TCR repertoire as a tool for head and neck cancer immunophenotype monitoring". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 2121. http://dx.doi.org/10.1158/1538-7445.am2023-2121.
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Abstract Head and neck squamous cell carcinoma (HNSCC) is a global health problem. Successful immunotherapy in HNSCC is currently based on the ability to block the interaction of PD1 and PDL1 and abolish the inhibition of CD8+ T cells, thus enhancing the antitumor activity. T cells recognize peptide antigens in the context of MHC molecules through the clonally distributed T Cell receptor (TCR), which offers the means to detect and track specific T cells. We characterized TCR signatures in unique HNSCC paired samples (including L = Lymphocyte, S = Saliva, T = Tumor) to profile TCR repertoire diversity and clonality in different compartments. A total of 48 HNSCC samples corresponding to 14 patients (2 assayed 2X) were obtained from Johns Hopkins University. DNA samples were submitted for TCR sequencing (TCR-seq) via enrichment of the human TCRB locus using Human-TCRB-PD4bx. CDR3 sequences were downloaded from Adaptive ImmuneAnalyzer. For each sequence, V, D and J regions were extracted and translation to amino acid done on the CDR3 region. 8 paired (T, L, S) samples were submitted for shallow sequencing survey depth and 8 for deep assay depth. In order to better understand the TCR repertoire, we assessed the number of unique immune receptor clonotypes, their relative abundance, repertoire overlap, clonotype tracking and sequence length distribution. As expected, the deep assay revealed more clones than the survey. Using the TCR-seq deep assay, 9 out of 10 S samples harbored at least 10% of the number of clonotypes found in their paired T. As expected, L harbored a greater number and more diverse clones than T and S samples and showed partial overlap with T and S samples. Comparing the overlap between T, L and S based on a shared CDR3.aa repertoire: by shallow survey, 3/5 S samples had at least 1 overlap with the primary T. Using the deep assay, 9 out of 10 patients (90%) showed overlap between the S and paired T. We found top public clonotypes occupying the larger part in HPV negative samples, and surprisingly no known CDR3.aa sequences annotated to HPV in HPV positive samples but annotated to other common viruses (CMV, EBV). Our study demonstrates a robust TCR repertoire in S that corresponds at least partially to the clones observed in T and circulating L. The presence of HPV did not yet yield CDR3.aa specific sequences. Future single-cell transcriptomes may identify signatures of CD8+ and CD4+ neoantigen-reactive tumor-infiltrating L in the paired S samples in addition to the viral or tumor-associated antigens present in bulk assays. Our data need to be further validated in larger well characterized cohorts that include S from cancer-free subjects. These early results support the use of saliva as a potential surrogate for diagnostic immune-profiling of tumors, for early detection and follow-up. We further envision creating a personalized TCR repertoire for individual patients from an initial tumor sample biopsy to monitor their tumor immune dynamics using saliva. Citation Format: Dieila Giomo De Lima, Mariana Brait, Laura Palmieri, Fernando T. Zamuner, Esther Broner, Kellie N. Smith, Timothy Westlake, Or Malca, Sol Efroni, Ido Sloma, David Sidransky. Saliva TCR repertoire as a tool for head and neck cancer immunophenotype monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2121.