196 results on '"Braun DA"'
Search Results
2. PRODUÇÃO MASSAL DE Beauveria bassiana: HISTÓRIA E PERSPECTIVAS NO BRASIL E NO MUNDO
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Oliveira, Lorena Resende, primary, Colognese, Leandro, additional, Silva, Thyenny Gleysse Castro, additional, Souza, Manuella Costa, additional, Gomes, Flávia Luane, additional, Gomes, Tamyres Braun da Silva, additional, Luz, Lisandra Lima, additional, Chagas, Lillian França Borges, additional, and Chagas Júnior, Aloísio Freitas, additional
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- 2020
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- View/download PDF
3. O QUE DIZEM OS(AS) DISCENTES DA UNIVERSIDADE FEDERAL DO PAMPA ACERCA DO HIV/AIDS?
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Fabiane Ferreira da Silva, Ricardo Silva Simões Etchegaray, and Raquel Cristina Braun da Silva
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General Medicine - Abstract
Este trabalho objetivou investigar as percepções dos(as) acadêmicos(as) da Universidade Federal do Pampa a respeito do HIV/Aids e justifica-se em função do entendimento de que o HIV/Aids configura-se como um grave problema de saúde pública no Brasil, bem como no Rio Grande do Sul que é um dos estados com maior índice de casos de HIV/Aids por habitante do país. Para tanto, foi realizada uma Pesquisa de Opinião com abordagem quantitativa, sendo utilizado para coleta de dados um questionário online totalmente anônimo. Com esse instrumento buscamos conhecer o nível de conhecimento/informação dos(as) participantes sobre o HIV/Aids, sobre as formas de transmissão, as práticas adotadas para prevenção, assim como, verificar se o tema HIV/Aids é abordado nos cursos de graduação e pós-graduação. Obtivemos um total de 1.200 devolutivas e os dados foram analisados através de método de estatística simples. As análises demostram que os(as) participantes da pesquisa em sua maioria são do gênero feminino, autodeclarados(as) de cor/raça branca e solteiros(as). Notadamente apresentam conhecimento geral sobre HIV/Aids, mas necessitam de maior aprofundamento sobre aspectos de transmissão e prevenção. Quanto à discussão do tema HIV/Aids nos cursos de graduação e/ou pós-graduação, aproximadamente 80% dos(as) participantes afirmaram que este tema não foi abordado na universidade, o que revelou a necessidade de uma revisão/intensificação a respeito da abordagem desse tema no contexto universitário. Observamos que ainda persiste no imaginário social mitos, tabus e preconceitos sobre as formas de transmissão e prevenção do HIV/Aids. Para finalizar, destacamos que conhecer as percepções de discentes da universidade sobre o HIV/Aids é fundamental para o desenvolvimento de estratégias pedagógicas para a construção de conhecimentos e mudança de comportamento. Com este estudo esperamos contribuir com o debate sobre esse tema tão importante no cenário atual.
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- 2020
4. Mercado consumidor de carne suína e derivados em Capanema, Pará
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Ysteffani Silva Silva, Gerson Diego Pamplona Albuquerque, Tamyres Braun da Silva Gomes, Ebson Pereira Cândido, and Waldjânio de Oliveira Melo
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Marketing ,Pharmacology ,Organizational Behavior and Human Resource Management ,Strategy and Management ,Drug Discovery ,Pharmaceutical Science - Published
- 2020
5. Efectos de un programa de exergame sobre el equilibrio postural en usuarios de un Centro de Atención Psicosocial (CAPS II)
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Peres, Eduardo Nogueira, Silva, Raquel Cristina Braun da, Castro, Antonio Adolfo Mattos de, Lara, Simone, Cassol, Gustavo, Nogueira, Rodrigo, Fernandes, Renanda Goulart, and Serrão Júnior, Nelson Francisco
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Salud mental ,Virtual reality ,Mental health services ,Postural balance ,Realidad Virtual ,Equilíbrio postural ,Mental health ,Equilibrio postural ,Serviços de saúde mental ,Saúde mental ,Realidade virtual ,Servicios de salud mental - Abstract
Psychosocial Care Centers (CAPS) are health services that offer care to patients with persistent, moderate to severe mental disorders. Thereby, the present study aimed to analyze the effects of a virtual reality program on postural balance in users of CAPS on the west boarder of Rio Grande do Sul. The study is descriptive, cases series, constituted by 05 male adults, evaluated by means of dynamic computerized posturography, using the tests of sensory organization (TOS) divided into six conditions and the value of the composite score (general index of balance), as well as the sensory analysis of each system (visual, vestibular and somatosensory). Still, the patients were later submitted to ten sessions of exergames, using the Xbox 360 video game, equipped with the Kinect sensor. For data analysis descriptive statistics was used, for the balance variables description, mean values and standard deviation were used. Pearson's correlation was used to analyze the correlation between the value of the composite score and the postural control systems. The results indicate an improvement in the composite score and in the use of the visual and vestibular systems of the individuals evaluated, after the virtual reality protocol, although it was not statistical significance. In addition, a positive correlation was observed between the composite score and the visual system, indicating that these variables are related to each other. A positive correlation was also identified regarding the values of the composite score and the visual system, pointing out values with a statistically significant difference. In addition, a positive correlation was observed between the composite and the visual system. We can conclude that the practice of exergames contributes to the improvement of postural balance in users of CAPS, constituting an important tool for this purpose. Los Centros de Atención Psicosocial (CAPS) son servicios de salud que ofrecen atención a pacientes con trastornos mentales persistentes, moderados a graves. Así, el presente estudio tuvo como objetivo analizar los efectos de un programa de realidad virtual sobre el equilibrio postural en usuarios de un CAPS en la frontera occidental de Rio Grande do Sul. Se trata de un estudio descriptivo, una serie de casos, constituida por 05 varones adultos, evaluado mediante posturografía computarizada dinámica, utilizando las pruebas de organización sensorial (TOS) divididas en seis condiciones y el valor de la puntuación compuesta (índice de equilibrio general), así como el análisis sensorial de cada sistema (visual, vestibular y somatosensorial) . Posteriormente, los usuarios se sometieron a diez sesiones de exergames, utilizando el videojuego Xbox 360, equipado con el sensor Kinect. Para el análisis de los datos se utilizó estadística descriptiva, para la descripción de las variables de balance se utilizaron valores medios y desviación estándar. Se utilizó la correlación de Pearson para analizar la correlación entre el valor de la puntuación compuesta y los sistemas de control postural. Entre los resultados de este estudio destaca la mejora en los valores de la puntuación compuesta y el uso de los sistemas visual y vestibular de los individuos evaluados, tras el protocolo de realidad virtual, aunque sin significación estadística. Además, hubo una correlación positiva entre la puntuación compuesta y el sistema visual. Podemos concluir que la práctica de exergames contribuye a la mejora del equilibrio postural en los usuarios de un CAPS, constituyéndose en una herramienta importante para tal fin. Os Centros de Atenção Psicossocial (CAPS) são serviços de saúde que oferecem atendimento aos pacientes com transtornos mentais persistentes, moderados à graves. Assim, o presente trabalho teve como objetivo analisar os efeitos de um programa de realidade virtual sobre o equilíbrio postural em usuários de um CAPS da fronteira oeste do Rio Grande do Sul. Trata-se de um estudo de cunho descritivo, série de casos, constituída por 05 adultos do sexo masculino, avaliados por meio da posturografia dinâmica computadorizada, utilizando os testes de organização sensorial (TOS) dividido em seis condições e o valor do escore composto (índice geral do equilíbrio), bem como a análise sensorial de cada sistema (visual, vestibular e somatossensorial). Posteriormente, os usuários foram submetidos a dez sessões de exergames, utilizando o vídeo game Xbox 360, equipado com o sensor Kinect. Para a análise dos dados foi utilizada a estatística descritiva, para a descrição das variáveis do equilíbrio foram utilizados os valores médios e desvio padrão. Utilizou-se a correlação de Pearson para analisar a correlação entre o valor do escore composto com os sistemas de controle postural. Dentre os resultados deste estudo, destaca-se a melhora nos valores do escore composto e da utilização dos sistemas visual e vestibular dos indivíduos avaliados, após o protocolo de realidade virtual, embora sem significância estatística. Além disso, observou-se uma correlação positiva entre o escore composto e o sistema visual. Podemos concluir que a prática dos exergames contribui para a melhora do equilíbrio postural em usuários de um CAPS, constituindo uma ferramenta importante para essa finalidade.
- Published
- 2021
6. Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice
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Majmundar, AJ, Buerger, F, Forbes, TA, Klambt, V, Schneider, R, Deutsch, K, Kitzler, TM, Howden, SE, Scurr, M, Tan, KS, Krzeminski, M, Widmeier, E, Braun, DA, Lai, E, Ullah, I, Amar, A, Kolb, A, Eddy, K, Chen, CH, Salmanullah, D, Dai, R, Nakayama, M, Ottlewski, I, Kolvenbach, CM, Onuchic-Whitford, AC, Mao, Y, Mann, N, Nabhan, MM, Rosen, S, Forman-Kay, JD, Soliman, NA, Heilos, A, Kain, R, Aufricht, C, Mane, S, Lifton, RP, Shril, S, Little, MH, Hildebrandt, F, Majmundar, AJ, Buerger, F, Forbes, TA, Klambt, V, Schneider, R, Deutsch, K, Kitzler, TM, Howden, SE, Scurr, M, Tan, KS, Krzeminski, M, Widmeier, E, Braun, DA, Lai, E, Ullah, I, Amar, A, Kolb, A, Eddy, K, Chen, CH, Salmanullah, D, Dai, R, Nakayama, M, Ottlewski, I, Kolvenbach, CM, Onuchic-Whitford, AC, Mao, Y, Mann, N, Nabhan, MM, Rosen, S, Forman-Kay, JD, Soliman, NA, Heilos, A, Kain, R, Aufricht, C, Mane, S, Lifton, RP, Shril, S, Little, MH, and Hildebrandt, F
- Abstract
Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive NOS1AP variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) NOS1AP, but not cDNA constructs bearing patient variants, increased active CDC42 and promoted filopodia and podosome formation. Pharmacologic inhibition of CDC42 or its effectors, formin proteins, reduced NOS1AP-induced filopodia formation. NOS1AP knockdown reduced podocyte migration rate (PMR), which was rescued by overexpression of WT Nos1ap but not by constructs bearing patient variants. PMR in NOS1AP knockdown podocytes was also rescued by constitutively active CDC42Q61L or the formin DIAPH3 Modeling a NOS1AP patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. Nos1apEx3-/Ex3- mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis. These findings demonstrate that recessive NOS1AP variants impair CDC42/DIAPH-dependent actin remodeling, cause aberrant organoid glomerulogenesis, and lead to a glomerulopathy in humans and mice.
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- 2021
7. Efeitos de um programa de exergames sobre o equilíbrio postural em usuários de um Centro de Atenção Psicossocial (CAPS II)
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Peres, Eduardo Nogueira, primary, Silva, Raquel Cristina Braun da, additional, Castro, Antonio Adolfo Mattos de, additional, Lara, Simone, additional, Cassol, Gustavo, additional, Nogueira, Rodrigo, additional, Fernandes, Renanda Goulart, additional, and Serrão Júnior, Nelson Francisco, additional
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- 2021
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8. SELEÇÃO DE MEIO DE CULTURA PARA PRODUÇÃO DE BACTÉRIAS EM MEIO LÍQUIDO COM APLICABILIDADE NA AGRICULTURA
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Rodrigo Silva de Oliveira, Aloisio Freitas Chagas Junior, Manuella Costa Souza, Albert Lennon Lima Martins, Flávia Luane Gomes, Lillian França Borges Chagas, Fernanda Pereira Rodrigues Lemos, and Tamyres Braun da Silva Gomes
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- 2020
9. PRODUÇÃO MASSAL DE Beauveria bassiana: HISTÓRIA E PERSPECTIVAS NO BRASIL E NO MUNDO
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Lisandra Lima Luz, Flávia Luane Gomes, Aloisio Freitas Chagas Junior, Tamyres Braun da Silva Gomes, Leandro Colognese, Lillian França Borges Chagas, Thyenny Gleysse Castro Silva, Manuella Costa Souza, and Lorena Resende Oliveira
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- 2020
10. O QUE DIZEM OS(AS) DISCENTES DA UNIVERSIDADE FEDERAL DO PAMPA ACERCA DO HIV/AIDS?
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Etchegaray, Ricardo Silva Simões, primary, Silva, Raquel Cristina Braun da, additional, and Silva, Fabiane Ferreira da, additional
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- 2020
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11. Wiederauffinden der Lokalisation in der Koloskopie - Einsatz von Deep Learning mit Hilfe von synthetischen Daten und Lernen ohne manuelle Annotation
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Mehlhase, N, additional, Götze, S, additional, Walter, B, additional, Braun, DA, additional, and Hann, A, additional
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- 2020
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12. Mercado consumidor de carne suína e derivados em Capanema, Pará
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Albuquerque, Gerson Diego Pamplona, primary, Melo, Waldjânio de Oliveira, additional, Gomes, Tamyres Braun da Silva, additional, Silva, Ysteffani Silva, additional, and Cândido, Ebson Pereira, additional
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- 2020
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13. Efeitos de um programa de exergames sobre o equilíbrio postural em usuários de um Centro de Atenção Psicossocial (CAPS II)
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Antonio Adolfo Mattos de Castro, Raquel Cristina Braun da Silva, Eduardo Nogueira Peres, Nelson Francisco Serrão Júnior, Simone Lara, Rodrigo Nogueira, Renanda Goulart Fernandes, and Gustavo Cassol
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03 medical and health sciences ,0302 clinical medicine ,General Earth and Planetary Sciences ,030229 sport sciences ,Psychology ,Humanities ,030217 neurology & neurosurgery ,General Environmental Science - Abstract
Os Centros de Atenção Psicossocial (CAPS) são serviços de saúde que oferecem atendimento aos pacientes com transtornos mentais persistentes, moderados à graves. Assim, o presente trabalho teve como objetivo analisar os efeitos de um programa de realidade virtual sobre o equilíbrio postural em usuários de um CAPS da fronteira oeste do Rio Grande do Sul. Trata-se de um estudo de cunho descritivo, série de casos, constituída por 05 adultos do sexo masculino, avaliados por meio da posturografia dinâmica computadorizada, utilizando os testes de organização sensorial (TOS) dividido em seis condições e o valor do escore composto (índice geral do equilíbrio), bem como a análise sensorial de cada sistema (visual, vestibular e somatossensorial). Posteriormente, os usuários foram submetidos a dez sessões de exergames, utilizando o vídeo game Xbox 360, equipado com o sensor Kinect. Para a análise dos dados foi utilizada a estatística descritiva, para a descrição das variáveis do equilíbrio foram utilizados os valores médios e desvio padrão. Utilizou-se a correlação de Pearson para analisar a correlação entre o valor do escore composto com os sistemas de controle postural. Dentre os resultados deste estudo, destaca-se a melhora nos valores do escore composto e da utilização dos sistemas visual e vestibular dos indivíduos avaliados, após o protocolo de realidade virtual, embora sem significância estatística. Além disso, observou-se uma correlação positiva entre o escore composto e o sistema visual. Podemos concluir que a prática dos exergames contribui para a melhora do equilíbrio postural em usuários de um CAPS, constituindo uma ferramenta importante para essa finalidade.
- Published
- 2021
14. EDUCAÇÃO FÍSICA E SAÚDE MENTAL: ATUAÇÃO PROFISSIONAL NOS CENTROS DE ATENÇÃO PSICOSSOCIAL
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Franciele Machado dos Santos, Susane Graup, Helter Luiz da Rosa Oliveira, Phillip Vilanova Ilha, Tatiane Motta da Costa e Silva, and Raquel Cristina Braun da Silva
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Educação Física ,Trabalhadores ,Serviços de Saúde Mental - Abstract
O objetivo do estudo foi analisar a atuação dos profissionais de Educação Física (PEF) nos Centros de Atenção Psicossocial (CAPS) dos municípios que compõe a 10ª Coordenadoria Regional de Saúde – RS. A coleta de dados se deu por meio de um questionário composto de perguntas abertas e fechadas. A amostra foi composta por 6 PEF. Os resultados indicam que os PEF não receberam em sua graduação nenhuma formação relacionada a saúde mental. A atuação dos PEF envolve práticas variadas como atividades esportivas, recreativas, entre outras, ministradas nas dependências dos CAPS e em espaços públicos. Frente ao que é exposto, sugere-se mudanças, iniciando pela grade curricular dos cursos de graduação e no investimento em capacitações, de modo, a ampliar o conhecimento dos profissionais.
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- 2017
15. EDUCAÇÃO FÍSICA E SAÚDE MENTAL: ATUAÇÃO PROFISSIONAL NOS CENTROS DE ATENÇÃO PSICOSSOCIAL
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Motta da Costa e Silva, Tatiane, primary, Machado dos Santos, Franciele, additional, Braun da Silva, Raquel Cristina, additional, Da Rosa Oliveira, Helter Luiz, additional, Vilanova Ilha, Phillip, additional, and Graup, Susane, additional
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- 2017
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16. Estudo comparativo de carcaças de suínos dos diferentes gupos genéticos produzidos na regiao Centro-Sul do Paraná
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Silva, Telio Braun da, Universidade Federal do Paraná. Setor de Ciencias Agrárias. Programa de Pós-Graduaçao em Ciencias Veterinárias, and Fedalto, Luiz Mario
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Resumo: Com objetivo de avaliar o rendimento de carne magra dos diferentes grupos genéticos de suínos produzidos na região Centro-Sul do Estado do Paraná, foram medidas 5.490 carcaças, com pistola com sonda de refletância de luz HENNESSY GP4, na linha de abate da Cooperativa Central de Laticínios do Paraná Ltda, sendo estas pertencentes a oito genótipos diferentes, oriundos de sete granjas comerciais. Os animais abatidos foram alimentados ad libitum desde a fase inicial à terminação, com ração de mesmo padrão nutricional. As demais condições ambientais foram semelhantes. Os resultados foram submetidos à análise de variância pelo Método dos Quadrados Mínimos e as médias dos tratamentos comparadas pelo teste de Newman Keuls a 1 e 5 %. Os rendimentos de carne magra por grupo genético foram: 57,50 ± 3,28 %, 56,95 ± 3,09 %, 55,51 ± 2,83 %, 55,49 ± 3,32 %, 55,16 ± 3,69 %, 54,63 ± 3,70 %, 54,27 ± 3,56 % e 54,17 ± 3,69 % para AGPIC AGxDAL, DALLAND, FxJSR, JSR, FxSAD, FxDAL e F1000 respectivamente; sendo encontradas diferenças estatísticas altamente significativas entre genótipos (P
- Published
- 2012
17. Bump evolution driven by the x-ray ablation Richtmyer-Meshkov effect in plastic inertial confinement fusion Ablators
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Loomis Eric, Braun Dave, Batha Steven H., and Landen Otto L.
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Physics ,QC1-999 - Abstract
Growth of hydrodynamic instabilities at the interfaces of inertial confinement fusion capsules (ICF) due to ablator and fuel non-uniformities are a primary concern for the ICF program. Recently, observed jetting and parasitic mix into the fuel were attributed to isolated defects on the outer surface of the capsule. Strategies for mitigation of these defects exist, however, they require reduced uncertainties in Equation of State (EOS) models prior to invoking them. In light of this, we have begun a campaign to measure the growth of isolated defects (bumps) due to x-ray ablation Richtmyer-Meshkov in plastic ablators to validate these models. Experiments used hohlraums with radiation temperatures near 70 eV driven by 15 beams from the Omega laser (Laboratory for Laser Energetics, University of Rochester, NY), which sent a ∼1.25Mbar shock into a planar CH target placed over one laser entrance hole. Targets consisted of 2-D arrays of quasi-gaussian bumps (10 microns tall, 34 microns FWHM) deposited on the surface facing into the hohlraum. On-axis radiography with a saran (Cl Heα − 2.76keV) backlighter was used to measure bump evolution prior to shock breakout. Shock speed measurements were also performed to determine target conditions. Simulations using the LEOS 5310 and SESAME 7592 models required the simulated laser power be turned down to 80 and 88%, respectively to match observed shock speeds. Both LEOS 5310 and SESAME 7592 simulations agreed with measured bump areal densities out to 6 ns where ablative RM oscillations were observed in previous laser-driven experiments, but did not occur in the x-ray driven case. The QEOS model, conversely, over predicted shock speeds and under predicted areal density in the bump.
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- 2013
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18. Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: a double-blind, placebo-controlled, randomized pilot study
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MacConell Leigh, Bruce Simon, Burger Jude, Hoogwerf Byron J, Gill Anne, Yan Ping, Braun Daniel, Giaconia Joseph, and Malone James
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Background Cardiovascular effects of glucose-lowering agents are of increasing interest. Our aim was to assess the effects of the glucagon-like peptide-1 receptor agonist exenatide on heart rate (HR) and blood pressure (BP) in subjects with type 2 diabetes mellitus (T2DM). Methods In this double-blind, placebo-controlled trial, subjects with T2DM on metformin and/or a thiazolidinedione were randomized to receive exenatide (5 μg for 4 weeks followed by 10 μg) or placebo BID for 12 weeks. Heart rate and BP were assessed with 24-hour ambulatory BP monitoring. The primary measure was change from baseline in mean 24-hour HR. Results Fifty-four subjects (28 exenatide, 26 placebo) were randomized and comprised the intent-to-treat population. Baseline values (exenatide and placebo) were (mean ± SE) 74.4 ± 2.1 and 74.5 ± 1.9 beats/minute for HR, 126.4 ± 3.2 and 119.9 ± 2.8 mm Hg for systolic BP (SBP), and 75.2 ± 2.1 and 70.5 ± 2.0 mm Hg for diastolic BP (DBP). At 12 weeks, no significant change from baseline in 24-hour HR was observed with exenatide or placebo (LS mean ± SE, 2.1 ± 1.4 versus -0.7 ± 1.4 beats/minute, respectively; between treatments, p = 0.16). Exenatide therapy was associated with trends toward lower 24-hour, daytime, and nighttime SBP; changes in DBP were similar between groups. No changes in daytime or nighttime rate pressure product were observed. With exenatide, body weight decreased from baseline by -1.8 ± 0.4 kg (p < 0.0001; treatment difference -1.5 ± 0.6 kg, p < 0.05). The most frequently reported adverse event with exenatide was mild to moderate nausea. Conclusions Exenatide demonstrated no clinically meaningful effects on HR over 12 weeks of treatment in subjects with T2DM. The observed trends toward lower SBP with exenatide warrant future investigation. Trial registration NCT00516074
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- 2010
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19. Bounded Rational Decision Networks with Belief Propagation.
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Schmid G, Gottwald S, and Braun DA
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Complex information processing systems that are capable of a wide variety of tasks, such as the human brain, are composed of specialized units that collaborate and communicate with each other. An important property of such information processing networks is locality: there is no single global unit controlling the modules, but information is exchanged locally. Here, we consider a decision-theoretic approach to study networks of bounded rational decision makers that are allowed to specialize and communicate with each other. In contrast to previous work that has focused on feedforward communication between decision-making agents, we consider cyclical information processing paths allowing for back-and-forth communication. We adapt message-passing algorithms to suit this purpose, essentially allowing for local information flow between units and thus enabling circular dependency structures. We provide examples that show how repeated communication can increase performance given that each unit's information processing capability is limited and that decision-making systems with too few or too many connections and feedback loops achieve suboptimal utility., (© 2024 Massachusetts Institute of Technology. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)
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- 2024
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20. Rechallenging with anti-PD-1 therapy in advanced renal cell carcinoma.
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Yochum ZA and Braun DA
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- Humans, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms drug therapy, Immune Checkpoint Inhibitors therapeutic use, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Competing Interests: DAB reports share options in Elephas (a company involved in diagnostic tumour testing to assess ex-vivo responses to immunotherapy); consulting or personal fees from Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post and Harborside, Targeted Oncology, Merck, Pfizer, MedScape, Accolade 2nd MD, DLA Piper, AbbVie, Compugen, Link Cell Therapies, Scholar Rock, NeoMorph, Exelixis, AVEO, Eisai, and Elephas; and research support from Exelixis and AstraZeneca, outside of the submitted work. DAB has collaborated with Toni K Choueiri, Laurence Albiges, Rana R McKay, Hans Hammers, Daniel Y C Heng, Bradley A McGregor, and Robert J Motzer, but not in relation to the trial discussed here. DAB acknowledges support from the Department of Defence (KC190128/W81XWH-20-1-0882 and KC220016/HT9425-23-1-0735), the National Institutes of Health and the National Cancer Institute (1R37CA279822-01), the Louis Goodman and Alfred Gilman Yale Scholar Fund, and the Yale Cancer Center (supported by a National Institutes of Health and National Cancer Institute research grant P30CA016359). ZAY declares no competing interests.
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- 2024
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21. Clinical Implications of Basic Research: Exploring the Transformative Potential of Spatial 'Omics in Uro-oncology.
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Figiel S, Bates A, Braun DA, Eapen R, Eckstein M, Manley BJ, Milowsky MI, Mitchell TJ, Bryant RJ, Sfakianos JP, and Lamb AD
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New spatial molecular technologies are poised to transform our understanding and treatment of urological cancers. By mapping the spatial molecular architecture of tumours, these platforms uncover the complex heterogeneity within and around individual malignancies, offering novel insights into disease development, progression, diagnosis, and treatment. They enable tracking of clonal phylogenetics in situ and immune-cell interactions in the tumour microenvironment. A whole transcriptome/genome/proteome-level spatial analysis is hypothesis generating, particularly in the areas of risk stratification and precision medicine. Current challenges include reagent costs, harmonisation of protocols, and computational demands. Nonetheless, the evolving landscape of the technology and evolving machine learning applications have the potential to overcome these barriers, pushing towards a future of personalised cancer therapy, leveraging detailed spatial cellular and molecular data. PATIENT SUMMARY: Tumours are complex and contain many different components. Although we have been able to observe some of these differences visually under the microscope, until recently, we have not been able to observe the genetic changes that underpin cancer development. Scientists are now able to explore molecular/genetic differences using approaches such as "spatial transcriptomics" and "spatial proteomics", which allow them to see genetic and cellular variation across a region of normal and cancerous tissue without destroying the tissue architecture. Currently, these technologies are limited by high associated costs, and a need for powerful and complex computational analysis workflows. Future advancements and results through these new technologies may assist patients and their doctors as they make decisions about treating their cancer., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2024
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22. Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation.
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Cieri N, Hookeri N, Stromhaug K, Li L, Keating J, Díaz-Fernández P, Gómez-García de Soria V, Stevens J, Kfuri-Rubens R, Shao Y, Kooshesh KA, Powell K, Ji H, Hernandez GM, Abelin J, Klaeger S, Forman C, Clauser KR, Sarkizova S, Braun DA, Penter L, Kim HT, Lane WJ, Oliveira G, Kean LS, Li S, Livak KJ, Carr SA, Keskin DB, Muñoz-Calleja C, Ho VT, Ritz J, Soiffer RJ, Neuberg D, Stewart C, Getz G, and Wu CJ
- Abstract
T cell alloreactivity against minor histocompatibility antigens (mHAgs)-polymorphic peptides resulting from donor-recipient (D-R) disparity at sites of genetic polymorphisms-is at the core of the therapeutic effect of allogeneic hematopoietic cell transplantation (allo-HCT). Despite the crucial role of mHAgs in graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD) reactions, it remains challenging to consistently link patient-specific mHAg repertoires to clinical outcomes. Here we devise an analytic framework to systematically identify mHAgs, including their detection on HLA class I ligandomes and functional verification of their immunogenicity. The method relies on the integration of polymorphism detection by whole-exome sequencing of germline DNA from D-R pairs with organ-specific transcriptional- and proteome-level expression. Application of this pipeline to 220 HLA-matched allo-HCT D-R pairs demonstrated that total and organ-specific mHAg load could independently predict the occurrence of acute GvHD and chronic pulmonary GvHD, respectively, and defined promising GvL targets, confirmed in a validation cohort of 58 D-R pairs, for the prevention or treatment of post-transplant disease recurrence., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2024
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23. First-line Systemic Therapy Following Adjuvant Immunotherapy in Renal Cell Carcinoma: An International Multicenter Study.
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El Zarif T, Semaan K, Xie W, Eid M, Zarba M, Issa W, Zhang T, Nguyen CB, Alva A, Fahey CC, Beckermann KE, Karam JA, Campbell MT, Procopio G, Stellato M, Buti S, Zemankova A, Melichar B, Massari F, Mollica V, Venugopal B, Ebrahimi H, de Velasco G, Gurney HP, De Giorgi U, Parikh O, Winquist E, Master V, Garcia AR, Cutuli HJ, Ferguson TR, Gross-Goupil M, Baca SC, Pal SK, Braun DA, McKay RR, Heng DYC, and Choueiri TK
- Abstract
Background and Objective: Adjuvant pembrolizumab significantly improved overall survival (OS) in renal cell carcinoma (RCC), but real-world data on sequential treatment are scarce. We sought to evaluate the clinical outcomes of first-line (1L) systemic therapy following adjuvant immune oncology (IO)-based regimens., Methods: A retrospective study including patients with recurrent RCC following adjuvant IO across 29 international institutions was conducted. The primary endpoint was progression-free survival (PFS) on 1L systemic therapy estimated using the Kaplan-Meier method. Preplanned subanalyses of clinical outcomes by type of 1L systemic therapy, recurrence timing, and International Metastatic RCC Database Consortium (IMDC) risk groups were performed. Treatment-related adverse events leading to treatment discontinuation, dose reduction, or corticosteroid use were assessed., Key Findings and Limitations: A total of 94 patients were included. Most received adjuvant pembrolizumab (n = 37, 39%), atezolizumab (n = 28, 30%), or nivolumab + ipilimumab (n = 15, 16%). The cohort included 49 (52%) patients who had recurrence within 3 mo of the last adjuvant IO dose, whereas 45 (48%) recurred beyond 3 mo. Bone metastases were significantly higher in tumors recurring at <3 mo (10/49, 20%) than those recurring at >3 mo (1/45, 2.2%; p = 0.008). Most patients received 1L vascular endothelial growth factor-targeted therapy (VEGF-TT; n = 37, 39%), IO + VEGF-TT (n = 26, 28%), or IO + IO (n = 12, 13%). The remaining underwent local therapy. The median follow-up for the 1L systemic therapy cohort was 15 mo. The 18-mo PFS and OS rates were 45% (95% confidence interval [CI]: 34-60) and 85% (95% CI: 75-95), respectively. Treatment-related adverse events occurred in 32 (42%) patients and included skin toxicity (n = 7, 9.2%), fatigue (n = 6, 7.9%), and diarrhea/colitis (n = 4, 5.3%). Limitations included selecting patients from large academic centers and the short follow-up period., Conclusions and Clinical Implications: A subset of patients with recurrent RCC following adjuvant IO respond to systemic therapies, including VEGF-TT and IO-based regimens. Notably, patients with favorable-risk disease may derive more benefit from VEGF-TT than from IO therapies in this setting. Future approaches utilizing radiographic tools and biomarker-based liquid biopsies are warranted to detect occult metastatic disease and identify candidate patients for adjuvant IO therapy., Patient Summary: Adjuvant pembrolizumab significantly improved overall survival in renal cell carcinoma (RCC). There are limited data on clinical outcomes after the recurrence of RCC tumors following adjuvant immunotherapy. In this study, we find that patients respond to subsequent systemic therapies across different treatment options., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
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- 2024
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24. TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3.
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Perales O, Jilaveanu L, Adeniran A, Su DG, Hurwitz M, Braun DA, Kluger HM, and Schoenfeld DA
- Subjects
- Humans, T-Lymphocytes immunology, T-Lymphocytes metabolism, Female, Male, Biomarkers, Tumor metabolism, Carcinoma, Renal Cell immunology, Carcinoma, Renal Cell pathology, Carcinoma, Renal Cell metabolism, Receptors, Immunologic metabolism, Lymphocyte Activation Gene 3 Protein, Kidney Neoplasms immunology, Kidney Neoplasms pathology, Kidney Neoplasms metabolism, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Programmed Cell Death 1 Receptor metabolism, Antigens, CD metabolism
- Abstract
Purpose: Immune checkpoint inhibitors have revolutionized the treatment of renal cell carcinoma (RCC), but many patients do not respond to therapy and the majority develop resistant disease over time. Thus, there is increasing need for alternative immunomodulating agents. The co-inhibitory molecule T-cell immunoglobulin and ITIM domain (TIGIT) may play a role in resistance to approved immune checkpoint inhibitors and is being investigated as a potential therapeutic target. The purpose of this study was to quantify TIGIT positivity in tumor-infiltrating T cells in RCC., Methods: We employed tissue microarrays containing specimens from primary RCC tumors, adjacent normal renal tissue, and RCC metastases to quantify TIGIT within tumor-infiltrating CD3
+ T cells using quantitative immunofluorescent analysis. We also compared these results to TIGIT+ CD3+ levels in four other tumor types (melanoma, non-small cell lung, cervical, and head and neck cancers)., Results: We did not observe significant differences in TIGIT positivity between primary RCC tumors and patient-matched metastatic samples. We found that the degree of TIGIT positivity in RCC is comparable to that in lung cancer but lower than that in melanoma, cervical, and head and neck cancers. Correlation analysis comparing TIGIT positivity to previously published, patient-matched spatial proteomic data by our group revealed a negative association between TIGIT and the checkpoint proteins PD-1 and LAG3., Conclusion: Our findings support careful evaluation of TIGIT expression on T cells in primary or metastatic RCC specimens for patients who may be treated with TIGIT-targeting antibodies, as increased TIGIT positivity might be associated with a greater likelihood of response to therapy., (© 2024. The Author(s).)- Published
- 2024
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25. Unveiling systemic responses in kidney transplantation: interplay between the allograft transcriptome and serum proteins.
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Buscher K, Rixen R, Schütz P, Van Marck V, Heitplatz B, Gabriels G, Jehn U, Braun DA, Pavenstädt H, and Reuter S
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- Humans, Female, Male, Middle Aged, Adult, Biomarkers blood, Graft Rejection immunology, Graft Rejection genetics, Graft Rejection blood, Proteome, Aged, Gene Expression Profiling, Gene Regulatory Networks, Kidney metabolism, Kidney immunology, Kidney pathology, Kidney Transplantation adverse effects, Transcriptome, Blood Proteins genetics, Blood Proteins metabolism, Allografts immunology, Proteomics methods
- Abstract
Immunity, as defined by systems biology, encompasses a holistic response throughout the body, characterized by intricate connections with various tissues and compartments. However, this concept has been rarely explored in kidney transplantation. In this proof-of-concept study, we investigated a direct association between the allograft phenotype and serum protein signatures. Time-matched samples of graft biopsies and blood serum were collected in a heterogeneous cohort of kidney-transplanted patients ( n = 15) for bulk RNA sequencing and proteomics, respectively. RNA transcripts exhibit distinct and reproducible, coregulated gene networks with specific functional profiles. We measured 159 serum proteins and investigated correlations with gene expression networks. Two opposing axes-one related to metabolism and the other to inflammation-were identified. They may represent a biological continuum between the allograft and the serum and correlate with allograft function, but not with interstitial fibrosis or proteinuria. For signature validation, we used two independent proteomic data sets ( n = 21). Our findings establish a biological link between the allograft transcriptome and the blood serum proteome, highlighting systemic immune effects in kidney transplantation and offering a promising framework for developing allograft-linked biomarkers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Buscher, Rixen, Schütz, Van Marck, Heitplatz, Gabriels, Jehn, Braun, Pavenstädt and Reuter.)
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- 2024
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26. PAK4-targeted PROTACs in clear cell renal cell carcinoma: a two-for-one targeted and immune therapy?
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Bakouny Z, Braun DA, Reznik E, and Hakimi AA
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- Humans, p21-Activated Kinases metabolism, p21-Activated Kinases genetics, p21-Activated Kinases antagonists & inhibitors, Immunotherapy methods, Proteolysis Targeting Chimera, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell metabolism, Carcinoma, Renal Cell pathology, Kidney Neoplasms drug therapy, Kidney Neoplasms metabolism, Kidney Neoplasms pathology, Molecular Targeted Therapy
- Abstract
Competing Interests: Declaration of interests The following authors report competing interests (all outside of the submitted work): Z.B.: Honoraria from UpToDate; Associate Editor at Journal of Clinical Oncology Clinical Cancer Informatics (JCO CCI); co-chair of the American Society of Clinical Oncology's International Medical Graduate Community of Practice (ASCO IMG CoP); co-founder of the IMG Oncologists nonprofit non-governmental organization. D.A.B.: advisory board fees from Exelixis, AVEO, Eisai, and Elephas, equity in Elephas, Fortress Biotech (subsidiary) and CurIOS Therapeutics, consulting/personal fees from Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, Merck, Pfizer, MedScape, Accolade 2nd MD, DLA Piper, AbbVie, Compugen, Link Cell Therapies, Scholar Rock, and research support from Exelixis and AstraZeneca, outside of the submitted work. E.R.: Consulting/personal fees from Xontogeny, llc, outside of the submitted work. A.A.H.: research funding from Merck, outside of the submitted work.
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- 2024
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27. Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma.
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El Zarif T, Semaan K, Eid M, Seo JH, Garinet S, Davidsohn MP, Sahgal P, Fortunato B, Canniff J, Nassar AH, Abou Alaiwi S, Bakouny Z, Lakshminarayanan G, Savignano H, Lyons K, Matar S, Ali A, Saad E, Saliby RM, Cordeiro P, Zhang Z, El Ahmar N, Laimon YN, Labaki C, Shah V, Freeman D, O'Toole J, Lee GM, Hwang J, Pomerantz M, Signoretti S, Van Allen EM, Xie W, Berchuck JE, Viswanathan SR, Braun DA, Choueiri TK, Freedman ML, and Baca SC
- Subjects
- Humans, DNA Methylation genetics, Cell Differentiation, Gene Expression Regulation, Neoplastic, Male, Female, Epigenesis, Genetic, Middle Aged, Proto-Oncogene Proteins c-fos, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell pathology, Carcinoma, Renal Cell metabolism, Kidney Neoplasms genetics, Kidney Neoplasms pathology, Kidney Neoplasms metabolism, Epigenomics methods
- Abstract
Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy., Competing Interests: Declaration of interests S.R.V. reports consulting (current or past 3 years) for Jnana Therapeutics, research support from Bayer, and that their spouse is an employee of and holds equity in Kojin Therapeutics. D.A.B. reports honoraria from LM Education/Exchange Services; advisory board fees from Exelixis and AVEO; consulting fees from Merck, Pfizer, and Elephas; equity in Elephas, Fortress Biotech (subsidiary), and CurIOS Therapeutics; personal fees from Schlesinger Associates, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, Accolade 2nd.MD, DLA Piper, AbbVie, Compugen, Link Cell Therapies, and Scholar Rock; and research support from Exelixis and AstraZeneca, outside of the submitted work. S.C.B., T.K.C., and M.L.F. are co-founders and shareholders of Precede Biosciences., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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28. Emerging Novel Functional Imaging and Immunotherapy in Renal Cell Carcinoma and Current Treatment Sequencing Strategies After Immunotherapy.
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Ali M, Eid M, Saliby RM, Choi S, McKay RR, Siva S, Braun DA, and Chen YW
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- Humans, Immune Checkpoint Inhibitors therapeutic use, Carcinoma, Renal Cell therapy, Immunotherapy methods, Kidney Neoplasms therapy
- Abstract
The management of renal cell carcinoma (RCC) has advanced significantly in the past two decades. Many promising functional imaging modalities such as radiolabeled tracer targeting carbonic anhydrase IX and prostate-specific membrane antigen are under development to detect primary kidney tumors, stage systemic disease, and assess treatment response in RCC. Immune checkpoint inhibitors targeting PD-1 and cytotoxic T-cell lymphocyte-4 have changed the treatment paradigm in advanced RCC. Trials investigating novel mechanisms such as LAG-3 immune checkpoint inhibition, chimeric antigen receptor T-cell therapies, and T-cell engagers targeting RCC-associated antigens are currently ongoing. With the rapidly changing treatment landscape of RCC, the treatment sequence strategies will continue to evolve. Familiarity with the toxicities associated with the therapeutic agents and how to manage them are essential to achieve optimal patient outcomes. This review summarizes the recent developments of functional imaging and immunotherapy strategies in RCC, and the evidence supports treatment sequencing.
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- 2024
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29. Impact of renal cell carcinoma molecular subtypes on immunotherapy and targeted therapy outcomes.
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Saliby RM, Labaki C, Jammihal TR, Xie W, Sun M, Shah V, Saad E, Kane MH, Kashima S, Sadak K, El Zarif T, Poduval D, Motzer RJ, Powles T, Rini BI, Albiges L, Pal SK, McGregor BA, McKay RR, Signoretti S, Van Allen EM, Shukla SA, Choueiri TK, and Braun DA
- Subjects
- Humans, Molecular Targeted Therapy methods, Treatment Outcome, Machine Learning, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell immunology, Carcinoma, Renal Cell therapy, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms immunology, Kidney Neoplasms genetics, Kidney Neoplasms therapy, Kidney Neoplasms drug therapy, Immunotherapy methods, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors pharmacology
- Abstract
Saliby et al. show that a machine learning approach can accurately classify clear cell renal cell carcinoma (RCC) into distinct molecular subtypes using transcriptomic data. When applied to tumors biospecimens from the JAVELIN Renal 101 (JR101) trial, a benefit is observed with immune checkpoint inhibitor (ICI)-based therapy across all molecular subtypes., Competing Interests: Declaration of interests C.L. reports research funding from Genentech/imCORE. W.X. reports performing consulting for Convergent Therapeutics, Inc. R.J.M. reports clinical trial support (institutional) from Bristol Myers Squibb (BMS) for this manuscript; advisory board fees from AstraZeneca, AVEO, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer; and fees (institutional) for coordinating principal investigator from AVEO, BMS, Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer. T.P. reports honoraria and consulting/advisory roles with Roche/Genentech, Bristol-Myers Squibb, and Merck; consulting/advisory role with AstraZeneca and Novartis; research funding from AstraZeneca/MedImmune and Roche/Genentech; and other relationships with Ipsen and Bristol-Myers Squibb. B.I.R reports grants or contracts from Pfizer, Hoffman-LaRoche, Incyte, AstraZeneca, Seattle Genetics, Arrowhead Pharmaceuticals, Immunomedics, BMS, Mirati Therapeutics, Merck, Surface Oncology, Aravive, Exelixis, Jannsen, Pionyr, and AVEO; consulting fees from BMS, Pfizer, GNE/Roche, Aveo, Synthorx, Merck, Corvus, Surface Oncology, Aravive, Alkermes, Arrowhead, Shionogi, Eisai, Nikang Therapeutics, EUSA, Athenex, Allogene Therapeutics, and Debiopharm; support for travel from BMS, Pfizer, and Merck; participation on a data safety monitoring board or advisory board (Astra Zeneca); and stock or stock options (PTC Therapeutics). L.A. reports research grants (institutional) from BMS; consulting fees (institutional) from BMS, Ipsen, Roche, Novartis, Pfizer, Astellas Pharma, Merck, MSD, AstraZeneca, Janssen, and Eisai; and travel support from BMS and MSD. S.K.P. reports their institution received grants from or has contracts with Exelixis, Xencor, Pfizer, Allogene Therapeutics, AstraZeneca, Genentech, and CRISPR Therapeutics; reports payment or honoraria for lectures, presentations, or speakers’ bureaus from EMD Serono and Pfizer; and reports meeting or travel support from CRISPR Therapeutics and Roche. B.Mc.G. reports grants or contracts, paid to their institution, from Exelixis, SeaGen, Pfizer, and Bristol Myers Squibb and consulting fees from Astellas, Bristol-Myers Squibb, Calithera, Eisai, Exelixis, Pfizer, and SeaGen. T.P. reports research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; consulting fees from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and support for attending meetings or travel Astra Zeneca, Ipsen, MSD, Pfizer, and Roche. R.R.McK. reports consulting or advisory roles: Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion Therapeutics, Calithera Biosciences, AstraZeneca, Myovant Sciences, Caris Life Sciences, Sorrento Therapeutics, and AVEO; and research funding from Pfizer (Inst), Bayer (Inst), and Tempus (Inst). S.S. reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis, and Novartis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; receives royalties from Biogenex; and mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. E.M.V. reports advisory or consulting roles for Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Riva Therapeutics, and Serinus Bio; research support from Novartis, BMS, and Sanofi; equity at Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics, and Serinus Bio; institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag; and being on the editorial boards of JCO Precision Oncology and Science Advances. S.A.S. reports nonfinancial support from Bristol-Myers Squibb and equity in Agenus Inc., Agios Pharmaceuticals, Breakbio Corp., Bristol-Myers Squibb, and Lumos Pharma. T.K.C. reports research funding, paid to their institution, from AstraZeneca, Aveo, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, and Takeda; consulting fees from AstraZeneca, Aravive, Aveo, Bayer, Bristol-Myers Squibb, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Nuscan, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events; payment or honoraria for lectures, presentations, manuscript writing, or educational events from AstraZeneca, Aravive, Aveo, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, Takeda, Tempest, Up-To-Date, and CME events; support for attending meetings or travel from Eisai, Merck, Exelixis, and Pfizer; patents planned, issued, or pending related to ctDNA and biomarkers of response to immune checkpoint inhibitors (no royalties as of April 12, 2022); participation on a data safety monitoring board or advisory board for Aravive; a leadership or fiduciary role in other board, society, committee, or advocacy group, for KidneyCan (unpaid), committees for American Society of Clinical Oncology, European Society for Medical Oncology, National Comprehensive Cancer Network®, and Genitourinary Steering Committee of the National Cancer Institute; stock or stock options from Pionyr, Tempest, Precede Bio, and Osel; and salary and research support from Dana-Farber and Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School, and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute. D.A.B. reports honoraria from LM Education/Exchange Services; advisory board fees from Exelixis and AVEO; consulting fees from Merck and Elephas; equity in Elephas, Fortress Biotech (subsidiary), and CurIOS Therapeutics; personal fees from Schlesinger Associates, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, AbbVie, Accolade 2nd.MD, DLA Piper, Merck, Link Cell Therapies, and Compugen; and research support from Exelixis and AstraZeneca, outside of the submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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30. A Pooled Analysis of 3 Phase II Trials of Salvage Nivolumab/Ipilimumab After Nivolumab in Renal Cell Carcinoma.
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McKay RR, Leucht K, Xie W, Jegede O, Braun DA, Atkins MB, Grimm MO, and Choueiri TK
- Subjects
- Humans, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Trials, Phase II as Topic, Ipilimumab therapeutic use, Nivolumab therapeutic use, Progression-Free Survival, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell pathology, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology
- Abstract
Background: Nivolumab plus ipilimumab has demonstrated improved survival for treatment-naïve advanced clear cell renal cell carcinoma (RCC). A series of clinical trials evaluated the effect of salvage nivolumab plus ipilimumab in patients without an objective response to nivolumab. Given the size and heterogeneity of these studies, we performed a pooled analysis to better inform the activity of nivolumab plus ipilimumab after nivolumab., Patients and Methods: Eligible patients included those with advanced clear cell RCC having received no prior immunotherapy. The primary objective was confirmed objective response rate (ORR) by investigator-assessment. Secondary objectives included progression-free survival (PFS) and overall survival (OS)., Results: The analysis included 410 patients with clear cell RCC, of whom 340 (82.9%) had IMDC intermediate/poor risk disease, and 137 (33.4%) had prior treatment. The 16-18-week ORR to nivolumab prior to nivolumab plus ipilimumab was 22.7% (n = 93), and best ORR to nivolumab was 25.1% (n = 103). Two hundred and thirty (56.1%) patients treated with nivolumab received nivolumab plus ipilimumab at a median of 16 weeks (IQR 9-19) after initiation of nivolumab [27.0% (n = 62) with stable disease and 73.0% (n = 168) with progressive disease to nivolumab]. The ORR to nivolumab plus ipilimumab was 12.6% (n = 29). Six-month PFS on nivolumab plus ipilimumab was 37% (95% CI, 27-47). Median follow-up was 34.3 months and 3-year OS was 59% (95% CI, 53-64) from nivolumab start., Conclusion: A small subset of patients lacking a response to nivolumab derive benefit from salvage nivolumab plus ipilimumab. When possible, both drugs should be given in concomitantly, rather in an adaptive fashion., (© The Author(s) 2023. Published by Oxford University Press.)
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- 2024
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31. Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma.
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Choueiri TK, Donahue AC, Braun DA, Rini BI, Powles T, Haanen JBAG, Larkin J, Mu XJ, Pu J, Teresi RE, di Pietro A, Robbins PB, and Motzer RJ
- Subjects
- Humans, Sunitinib therapeutic use, Axitinib, Biomarkers, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell genetics, Kidney Neoplasms drug therapy, Kidney Neoplasms genetics
- Abstract
The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and an abundance of innate immune subsets in the A+Ax arm. Treatment with A+Ax led to greater T-cell repertoire modulation and less change in T-cell numbers versus sunitinib. In the A+Ax arm, patients with tumors harboring mutations in ≥2 of 10 previously identified PFS-associated genes (double mutants) had distinct circulating and tumor-infiltrating immunologic profiles versus those with wild-type or single-mutant tumors, suggesting a role for non-T-cell-mediated and non-natural killer cell-mediated mechanisms in double-mutant tumors. We provide evidence for different immunomodulatory mechanisms based on treatment (A+Ax vs. sunitinib) and tumor molecular subtypes., Significance: Our findings provide novel insights into the different immunomodulatory mechanisms governing responses in patients treated with avelumab (PD-L1 inhibitor) + axitinib or sunitinib (both VEGF inhibitors), highlighting the contribution of tumor biology to the complexity of the roles and interactions of infiltrating immune cells in response to these treatment regimens. This article is featured in Selected Articles from This Issue, p. 384., (©2023 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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32. PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients.
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Denize T, Jegede OA, Matar S, El Ahmar N, West DJ, Walton E, Bagheri AS, Savla V, Nabil Laimon Y, Gupta S, Vemula SV, Braun DA, Burke KP, Catalano PJ, Freeman GJ, Motzer RJ, Atkins MB, McDermott DF, Sharpe AH, Choueiri TK, and Signoretti S
- Subjects
- Humans, Nivolumab therapeutic use, T-Lymphocytes, Regulatory metabolism, Hepatitis A Virus Cellular Receptor 2 metabolism, Everolimus therapeutic use, Programmed Cell Death 1 Receptor metabolism, Carcinoma, Renal Cell pathology
- Abstract
Purpose: Programmed cell death protein 1 (PD-1) expression on CD8+TIM-3-LAG-3- tumor-infiltrating cells predicts positive response to PD-1 blockade in metastatic clear-cell renal cell carcinoma (mccRCC). Because inhibition of PD-1 signaling in regulatory T cells (Treg) augments their immunosuppressive function, we hypothesized that PD-1 expression on tumor-infiltrating Tregs would predict resistance to PD-1 inhibitors., Experimental Design: PD-1+ Tregs were phenotyped using multiparametric immunofluorescence in ccRCC tissues from the CheckMate-025 trial (nivolumab: n = 91; everolimus: n = 90). Expression of CD8, PD-1, TIM-3, and LAG-3 was previously determined (Ficial and colleagues, 2021). Clinical endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR)., Results: In the nivolumab (but not everolimus) arm, high percentage of PD-1+ Tregs was associated with shorter PFS (3.19 vs. 5.78 months; P = 0.021), shorter OS (18.1 vs. 27.7 months; P = 0.013) and marginally lower ORR (12.5% vs. 31.3%; P = 0.059). An integrated biomarker (PD-1 Treg/CD8 ratio) was developed by calculating the ratio between percentage of PD-1+Tregs (marker of resistance) and percentage of CD8+PD-1+TIM-3-LAG-3- cells (marker of response). In the nivolumab (but not everolimus) arm, patients with high PD-1 Treg/CD8 ratio experienced shorter PFS (3.48 vs. 9.23 months; P < 0.001), shorter OS (18.14 vs. 38.21 months; P < 0.001), and lower ORR (15.69% vs. 40.00%; P = 0.009). Compared with the individual biomarkers, the PD-1 Treg/CD8 ratio showed improved ability to predict outcomes to nivolumab versus everolimus., Conclusions: PD-1 expression on Tregs is associated with resistance to PD-1 blockade in mccRCC, suggesting that targeting Tregs may synergize with PD-1 inhibition. A model that integrates PD-1 expression on Tregs and CD8+TIM-3-LAG-3- cells has higher predictive value., (©2023 American Association for Cancer Research.)
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- 2024
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33. Reactive and proactive control processes in voluntary task choice.
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Mittelstädt V, Mackenzie IG, Braun DA, and Arrington CM
- Subjects
- Humans, Time Factors, Reaction Time physiology, Choice Behavior, Memory, Short-Term, Motivation
- Abstract
Deciding which task to perform when multiple tasks are available can be influenced by external influences in the environment. In the present study, we demonstrate that such external biases on task-choice behavior reflect reactive control adjustments instead of a failure in control to internally select a task goal. Specifically, in two experiments we delayed the onset of one of two task stimuli by a short (50 ms), medium (300 ms), or long (1,000 ms) stimulus-onset asynchrony (SOA) within blocks while also varying the relative frequencies of short versus long SOAs across blocks (i.e., short SOA frequent vs. long SOA frequent). Participants' task choices were increasingly biased towards selecting the task associated with the first stimulus with increasing SOAs. Critically, both experiments also revealed that the short-to-medium SOA bias was larger in blocks with more frequent long SOAs when participants had limited time to prepare for an upcoming trial. When time to select an upcoming task was extended in Experiment 2, this interaction was not significant, suggesting that the extent to which people rely on reactive control adjustments is additionally modulated by proactive control processes. Thus, the present findings also suggest that voluntary task choices are jointly guided by both proactive and reactive processes, which are likely to adjust the relative activation of different task goals in working memory., (© 2023. The Author(s).)
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- 2024
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34. Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model.
- Author
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Wang Y, Cho JW, Kastrunes G, Buck A, Razimbaud C, Culhane AC, Sun J, Braun DA, Choueiri TK, Wu CJ, Jones K, Nguyen QD, Zhu Z, Wei K, Zhu Q, Signoretti S, Freeman GJ, Hemberg M, and Marasco WA
- Abstract
One of the major barriers that have restricted successful use of chimeric antigen receptor (CAR) T cells in the treatment of solid tumors is an unfavorable tumor microenvironment (TME). We engineered CAR-T cells targeting carbonic anhydrase IX (CAIX) to secrete anti-PD-L1 monoclonal antibody (mAb), termed immune-restoring (IR) CAR G36-PDL1. We tested CAR-T cells in a humanized clear cell renal cell carcinoma (ccRCC) orthotopic mouse model with reconstituted human leukocyte antigen (HLA) partially matched human leukocytes derived from fetal CD34
+ hematopoietic stem cells (HSCs) and bearing human ccRCC skrc-59 cells under the kidney capsule. G36-PDL1 CAR-T cells, haploidentical to the tumor cells, had a potent antitumor effect compared to those without immune-restoring effect. Analysis of the TME revealed that G36-PDL1 CAR-T cells restored active antitumor immunity by promoting tumor-killing cytotoxicity, reducing immunosuppressive cell components such as M2 macrophages and exhausted CD8+ T cells, and enhancing T follicular helper (Tfh)-B cell crosstalk., Competing Interests: W.A.M. has patents in the PD-1/PDL1 field. G.J.F. has patents/pending royalties on the PD-1/PD-L1 pathway from Roche, Merck MSD, Bristol-Myers-Squibb, Merck KGA, Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, Eli Lilly, and Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, NextPoint, IgM, Jubilant, Trillium, IOME, GV20, Invaria, and Geode. G.J.F. has equity in NextPoint, Triursus, Xios, iTeos, IgM, GV20, Invaria, and Geode. M.H. is a co-founder of Neomer Diagnostics where he is also on the advisory board. K.W. received a sponsored-research agreement from Gilead Sciences. K.W. served as a consultant for Gilead Sciences and Horizon Therapeutics. D.A.B. reports nonfinancial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and AVEO, personal fees from Charles River Associates, Schlesinger Associates, Imprint Science, Insight Strategy, Trinity Group, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, and AbbVie, and research support from Exelixis and AstraZeneca, outside of the submitted work. C.J.W. holds equity in BioNTech, Inc., and receives research funding from Pharmacyclics. S.S. reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis, and Novartis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; receives royalties from Biogenex; and mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. T.K.C. reports institutional and personal, paid and unpaid support for research, advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH, and others), outside the submitted work. T.K.C. has institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA. T.K.C. has equity in Tempest, Pionyr, Osel, and Precede Bio. T.K.C. has served on committees for NCCN, GU Steering Committee, ASCO/ESMO, ACCRU, and KidneyCan. T.K.C. has medical writing and editorial assistance support may have been funded by Communications companies in part. T.K.C. has mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter., (© 2024.)- Published
- 2024
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35. Update on Biomarkers in Renal Cell Carcinoma.
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Saliby RM, Saad E, Kashima S, Schoenfeld DA, and Braun DA
- Subjects
- Humans, Biomarkers, Gene Expression Profiling, Carcinoma, Renal Cell diagnosis, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell genetics, Kidney Neoplasms diagnosis, Kidney Neoplasms genetics, Kidney Neoplasms therapy, Biomedical Research
- Abstract
Immune checkpoint inhibitors have significantly transformed the treatment paradigm for metastatic renal cell carcinoma (RCC), offering prolonged overall survival and achieving remarkable deep and durable responses. However, given the multiple ICI-containing, standard-of-care regimens approved for RCC, identifying biomarkers that predict therapeutic response and resistance is of critical importance. Although tumor-intrinsic features such as pathological characteristics, genomic alterations, and transcriptional signatures have been extensively investigated, they have yet to provide definitive, robust predictive biomarkers. Current research is exploring host factors through in-depth characterization of the immune system. Additionally, innovative technological approaches are being developed to overcome challenges presented by existing techniques, such as tumor heterogeneity. Promising avenues in biomarker discovery include the study of the microbiome, radiomics, and spatial transcriptomics.
- Published
- 2024
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36. Plasma protein signatures reflect systemic immunity and allograft function in kidney transplantation.
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Buscher K, Rixen R, Schütz P, Hüchtmann B, Van Marck V, Heitplatz B, Jehn U, Braun DA, Gabriëls G, Pavenstädt H, and Reuter S
- Subjects
- Humans, Kidney, Blood Proteins, Biomarkers, Allografts, Graft Rejection, Kidney Transplantation
- Abstract
Kidney transplantation causes large perturbations of the immune system. While many studies focus on the allograft, insights into systemic effects are largely missing. Here, we analyzed the systemic immune response in 3 cohorts of kidney transplanted patients. Using serum proteomics, laboratory values, mass cytometry, histological and clinical parameters, inter-patient heterogeneity was leveraged for multi-omic co-variation analysis. We identified circulating immune modules (CIM) that describe extra-renal signatures of co-regulated plasma proteins. CIM are present in nontransplanted controls, in transplant conditions and during rejection. They are enriched in pathways linked to kidney function, extracellular matrix, signaling, and cellular activation. A complex leukocyte response in the blood during allograft quiescence and rejection is associated with CIM activity and CIM-specific cytokines. CIM activity correlates with kidney function including a 2-month prediction. Together, the data suggest a systemic and multi-layered response of transplant immunity that might be insightful for understanding allograft dysfunction and developing translational biomarkers., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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37. Novel Immune Therapies for Renal Cell Carcinoma: Looking Beyond the Programmed Cell Death Protein 1 and Cytotoxic T-Lymphocyte-Associated Protein 4 Axes.
- Author
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Saad E, Saliby RM, Labaki C, Xu W, Viswanathan SR, Braun DA, and Bakouny Z
- Subjects
- Humans, T-Lymphocytes, Cytotoxic, Programmed Cell Death 1 Receptor, Neoplasm Recurrence, Local, Immunotherapy, Carcinoma, Renal Cell therapy, Kidney Neoplasms therapy
- Abstract
Immunotherapy has revolutionized treatment for patients with advanced and metastatic renal cell carcinoma. Nevertheless, many patients do not benefit or eventually relapse, highlighting the need for novel immune targets to overcome primary and acquired resistance. This review discusses 2 strategies currently being investigated: disabling inhibitory stimuli that maintain immunosuppression ("brakes") and priming the immune system to target tumoral cells ("gas pedals"). We explore each class of novel immunotherapy, including the rationale behind it, supporting preclinical and clinical evidence, and limitations., Competing Interests: Disclosures Conflicts of Interest: E. Saad, R.M. Saliby, C. Labaki: none. W. Xu reports advisory board fees from Exelixis and Jazz Pharmaceuticals, and continuing medical education honoraria from MedNet, Harborside Press, MJH Healthcare Holdings, and Academy for Continued Healthcare Learning. S.R. Viswanathan reports consulting for Jnana Therapeutics, MPM Capital, and Vida Ventures within the last 3 years and research support from Bayer, Germany. Spouse is an employee of and holds equity in Kojin Therapeutics. D.A. Braun reports honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and AVEO, personal fees from Schlesinger Associates, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, AbbVie, and research support from Exelixis and AstraZeneca, outside of the submitted work. Z. Bakouny reports research support from Genentech, United States/imCORE and Bristol Myers Squibb, United States, and honoraria from UpToDate., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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38. Immunobiology and Metabolic Pathways of Renal Cell Carcinoma.
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Braun DA and Chakraborty AA
- Subjects
- Humans, Immune Checkpoint Inhibitors therapeutic use, Metabolic Networks and Pathways, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell therapy, Kidney Neoplasms genetics, Kidney Neoplasms therapy
- Abstract
The treatment of advanced renal cell carcinoma (RCC) has changed dramatically with immune checkpoint inhibitors, yet most patients do not have durable responses. There is consequently a tremendous need for novel therapeutic development. RCC, and particularly the most common histology clear cell RCC, is an immunobiologically and metabolically distinct tumor. An improved understanding of RCC-specific biology will be necessary for the successful identification of new treatment targets for this disease. In this review, we discuss the current understanding of RCC immune pathways and metabolic dysregulation, with a focus on topics important for future clinical development., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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39. Novel Targeted Therapies for Renal Cell Carcinoma: Building on the Successes of Vascular Endothelial Growth Factor and mTOR Inhibition.
- Author
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Saliby RM, Saad E, Labaki C, Xu W, Braun DA, Viswanathan SR, and Bakouny Z
- Subjects
- Humans, Vascular Endothelial Growth Factor A, TOR Serine-Threonine Kinases, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell metabolism, Kidney Neoplasms drug therapy, Kidney Neoplasms metabolism, Kidney Neoplasms pathology
- Abstract
Targeted therapies have revolutionized the treatment of renal cell carcinoma (RCC). The VHL/HIF pathway is responsible for the regulation of oxygen homeostasis and is frequently altered in RCC. Targeting this pathway as well as the mTOR pathway have yielded remarkable advances in the treatment of RCC. Here, we review the most promising novel targeted therapies for the treatment of RCC, including HIF2α, MET, metabolic targeting, and epigenomic reprogramming., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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40. Emerging Biomarkers of Response to Systemic Therapies in Metastatic Clear Cell Renal Cell Carcinoma.
- Author
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Labaki C, Saliby RM, Bakouny Z, Saad E, Semaan K, Eid M, Lalani AK, Choueiri TK, and Braun DA
- Subjects
- Humans, Immunotherapy, Biomarkers, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell pathology, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology
- Abstract
Patients with metastatic clear cell renal cell carcinoma (mccRCC) experience highly heterogeneous outcomes when treated with standard-of-care systemic regimens. Therefore, valid biomarkers are needed to predict the clinical response to these therapies and help guide management. In this review, the authors outline relevant and promising biomarkers for patients with mccRCC receiving systemic therapies, with a focus on immunotherapy-based regimens., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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41. Spatially aware deep learning reveals tumor heterogeneity patterns that encode distinct kidney cancer states.
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Nyman J, Denize T, Bakouny Z, Labaki C, Titchen BM, Bi K, Hari SN, Rosenthal J, Mehta N, Jiang B, Sharma B, Felt K, Umeton R, Braun DA, Rodig S, Choueiri TK, Signoretti S, and Van Allen EM
- Subjects
- Humans, Phenotype, Carcinoma, Renal Cell genetics, Deep Learning, Kidney Neoplasms, Carcinoma
- Abstract
Clear cell renal cell carcinoma (ccRCC) is molecularly heterogeneous, immune infiltrated, and selectively sensitive to immune checkpoint inhibition (ICI). However, the joint tumor-immune states that mediate ICI response remain elusive. We develop spatially aware deep-learning models of tumor and immune features to learn representations of ccRCC tumors using diagnostic whole-slide images (WSIs) in untreated and treated contexts (n = 1,102 patients). We identify patterns of grade heterogeneity in WSIs not achievable through human pathologist analysis, and these graph-based "microheterogeneity" structures associate with PBRM1 loss of function and with patient outcomes. Joint analysis of tumor phenotypes and immune infiltration identifies a subpopulation of highly infiltrated, microheterogeneous tumors responsive to ICI. In paired multiplex immunofluorescence images of ccRCC, microheterogeneity associates with greater PD1 activation in CD8
+ lymphocytes and increased tumor-immune interactions. Our work reveals spatially interacting tumor-immune structures underlying ccRCC biology that may also inform selective response to ICI., Competing Interests: Declaration of interests T.K.C. reports institutional and personal paid and unpaid support for research, advisory boards, consultancy, and honoraria from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, UpToDate, and CME events (Peerview, OncLive, MJH, CCO, and others), outside the submitted work; institutional patents filed on molecular alterations and immunotherapy response/toxicity and ctDNA; and equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse, and InnDura. T.K.C. serves on the committees of NCCN, GU Steering Committee, and ASCO/ESMO. Medical writing and editorial assistance support may have been funded by communications companies in part. T.K.C. does not report any speaker’s bureau. T.K.C. has mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies and/or royalties potentially involved in research around the subject matter. E.M.V.A. reports advisory/consulting with Tango Therapeutics, Genome Medical, Invitae, Monte Rosa, Enara Bio, Manifold Bio, Riva Therapeutics, Serinus Bio, and Janssen; research support from Novartis and BMS; equity in Tango Therapeutics, Genome Medical, Syapse, Manifold Bio, Monte Rosa, Enara Bio, Riva Therapeutics, and Serinus Bio; institutional patents filed on chromatin mutations and immunotherapy response and on methods for clinical interpretation; and intermittent legal consulting on patents for Foaley & Hoag. D.A.B. reports personal fees from LM Education and Exchange, Adnovate Strategies, MDedge, Cancer Network, Cancer Expert Now, OncLive, Catenion, and AVEO and grants and personal fees from Exelixis outside the submitted work. C.L. reports research funding from Genentech/imCORE. Z.B. reports research funding from Bristol-Myers Squibb and Genentech/imCORE and honoraria from UpToDate. S.S. reports grants from Exelixis, grants from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from AstraZeneca, personal fees from CRISPR Therapeutics, personal fees from NCI, and personal fees from AACR as well as a patent for Biogenex with royalties paid. K.B. has consulted for Related Sciences (RS) outside of the scope of this work. S.R. receives research funding from Bristol-Myers Squibb and KITE/Gilead and is a member of the SAB for Immunitas Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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42. Cross-hemispheric recruitment during action planning with increasing task demand.
- Author
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Schach S, Braun DA, and Lindner A
- Subjects
- Young Adult, Humans, Prospective Studies, Retrospective Studies, Memory, Short-Term, Brain diagnostic imaging, Cerebellum
- Abstract
The recruitment of cross-hemispheric counterparts of lateralized prefrontal brain regions with increasing processing demand is thought to increase memory performance despite cognitive aging, but was recently reported to be present also in young adults working at their capacity limit. Here we ask if cross-hemispheric recruitment is a general strategy of the adult brain in that executive task demand would modulate bilateral activation beyond prefrontal cortex and across cognitive tasks. We analyzed data sets from two fMRI experiments investigating retrospective working memory maintenance and prospective action planning. We confirmed a cross-hemispheric recruitment of prefrontal cortex across tasks and experiments. Changes in lateralization due to planning further surfaced in the cerebellum, dorsal premotor and posterior parietal cortex. Parietal cortex thereby exhibited cross-hemispheric recruitment also during spatial but not verbal working memory maintenance. Our results confirm a domain-general role of prefrontal cortex in cross-hemispheric recruitment. They further suggest that other task-specific brain regions also recruit their idling cross-hemispheric counterparts to relocate executive processing power., (© 2023. Springer Nature Limited.)
- Published
- 2023
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43. Chromophobe renal cell carcinoma
- Author
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Henske EP, Cheng L, Hakimi AA, Choueiri TK, and Braun DA
- Subjects
- Humans, Immunity, Innate, Lymphocytes metabolism, Oxidative Stress, Biomarkers, Tumor genetics, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell therapy, Kidney Neoplasms genetics, Kidney Neoplasms therapy
- Abstract
Chromophobe renal cell carcinoma (ChRCC) is the second most common variant histology (non-clear cell) RCC. ChRCC is distinct from clear cell RCC (ccRCC) in terms of genetics, genomics, metabolism, cell of origin, and response to targeted and immune therapies. The pathogenesis of ChRCC remains unclear, but current data suggest two potential mechanisms: mTORC1 hyperactivation through PTEN pathway mutations and mitochondrial dysfunction leading to oxidative stress. There are no specific approved treatments for ChRCC, although some responses to tyrosine kinase and mTOR inhibitors have been observed. Response to immunotherapy is generally limited. Targetable pathways involving innate lymphoid cells/IL-15 and cysteine homeostasis/ferroptosis have recently been identified., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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44. Antigenic targets in clear cell renal cell carcinoma.
- Author
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Schindler NR and Braun DA
- Abstract
Immune checkpoint inhibitors (ICIs) have transformed the management of advanced renal cell carcinoma (RCC), but most patients still do not receive a long-term benefit from these therapies, and many experience off-target, immune-related adverse effects. RCC is also different from many other ICI-responsive tumors, as it has only a modest mutation burden, and total neoantigen load does not correlate with ICI response. In order to improve the efficacy and safety of immunotherapies for RCC, it is therefore critical to identify the antigens that are targeted in effective anti-tumor immunity. In this review, we describe the potential classes of target antigens, and provide examples of previous and ongoing efforts to investigate and target antigens in RCC, with a focus on clear cell histology. Ultimately, we believe that a concerted antigen discovery effort in RCC will enable an improved understanding of response and resistance to current therapies, and lay a foundation for the future development of "precision" antigen-directed immunotherapies., Competing Interests: D.A.B. reports honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and AVEO, equity in Fortress Biotech (subsidiary), personal fees from Schlesinger Associates, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, AbbVie, and research support from Exelixis and AstraZeneca, outside of the submitted work. N.R.S has no conflict of interest to report., (© 2023 – The authors. Published by IOS Press.)
- Published
- 2023
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45. Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma.
- Author
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Saliby RM, El Zarif T, Bakouny Z, Shah V, Xie W, Flippot R, Denize T, Kane MH, Madsen KN, Ficial M, Hirsch L, Wei XX, Steinharter JA, Harshman LC, Vaishampayan UN, Severgnini M, McDermott DF, Lee GM, Xu W, Van Allen EM, McGregor BA, Signoretti S, Choueiri TK, McKay RR, and Braun DA
- Subjects
- Humans, Bevacizumab therapeutic use, Vascular Endothelial Growth Factor A, B7-H1 Antigen, Carcinoma, Renal Cell pathology, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology
- Abstract
Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an "inflammatory module" that was increased in International Metastatic RCC Database Consortium poor-risk patients and was associated with worse progression-free survival (PFS; P = 0.028). At baseline, an elevated circulating vascular endothelial growth factor A (VEGF-A) level was associated with a lack of response (P = 0.03) and worse PFS (P = 0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (P = 0.01) and improved overall survival (P = 0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+PD-L1+ [HR, 0.62; 95% confidence interval (CI), 0.49-0.91; P = 0.016] and CD8+PD-L1+ T cells (HR, 0.59; 95% CI, 0.39-0.87; P = 0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (P = 0.028). Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations., (©2023 American Association for Cancer Research.)
- Published
- 2023
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46. Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases.
- Author
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Schoenfeld DA, Moutafi M, Martinez S, Djureinovic D, Merkin RD, Adeniran A, Braun DA, Signoretti S, Choueiri TK, Parisi F, Hurwitz M, Rimm DL, Wei W, Jilaveanu L, and Kluger HM
- Subjects
- Humans, Hepatitis A Virus Cellular Receptor 2, Medical Oncology, Tumor Microenvironment, Carcinoma, Renal Cell, Brain Neoplasms, Immune System Diseases, Kidney Neoplasms
- Abstract
Background: The tumor microenvironment (TME) contributes to cancer progression and treatment response to therapy, including in renal cell carcinoma (RCC). Prior profiling studies, including single-cell transcriptomics, often involve limited sample sizes and lack spatial orientation. The TME of RCC brain metastases, a major cause of morbidity, also remains largely uncharacterized., Methods: We performed digital spatial profiling on the NanoString GeoMx platform using 52 validated immuno-oncology markers on RCC tissue microarrays representing progressive stages of RCC, including brain metastases. We profiled 76 primary tumors, 27 adjacent histologically normal kidney samples, and 86 metastases, including 24 brain metastases., Results: We observed lower immune checkpoint (TIM-3 and CTLA-4), cytolytic (GZMA and GZMB), and T cell activation (CD25) protein expression in metastases compared with primary tumors in two separate cohorts. We also identified changes in macrophages in metastases, with brain metastases-susceptible patients showing less M1-like, inflammatory macrophage markers (HLA-DR and CD127) in metastatic samples. A comparison of brain metastases to extracranial metastases revealed higher expression of the anti-apoptotic, BCL-2-family protein BCL-XL and lower expression of the innate immune activator STING in brain metastases. Lower TIM-3 and CD40 in the TME of brain metastases appear to be associated with longer survival, a finding that requires further validation., Conclusions: Compared with primary tumors, RCC metastases, including brain metastases, express lower levels of numerous markers of immune activation and current or investigational therapeutic targets. Our findings may have important implications for designing future biomarker and treatment studies and may aid in development of brain metastases-specific therapies., Competing Interests: Competing interests: HMK has received consulting fees from Iovance, Immunocore, Celldex, Merck, Elevate Bio, Instil Bio, Bristol-Myers Squibb, Clinigen, Shionogi, Chemocentryx, Calithera, Signatero, Gigagen, GI Reviewers, all outside of the submitted work. HMK has also received research grant funding (to Yale University) from Merck, Bristol-Myers Squibb and Apexigen. MH reports—Advisory Boards: Bristol Myer Squibb, CRISPR Therapeutics, Exelixis, Nektar Therapeutics, Janssen, Pliant. Research: Alpine, Achilles Therapeutics, Apexigen, Arrowhead, Astellas, AstraZeneca, Bayer, Bristol Myer Squibb, CRISPR Therapeutics, Corvus, Eli Lilly, Endocyte, Fate Therapeutics, Genentech, Genmab, GSK, Innocrin, Iovance, KSQ, Merck, Nektar Therapeutics, Novartis, Pfizer, Progenics, Sanofi Aventis, Seattle Genetics, Tmunity, Torque, Unum. Other: Arvinas. DLR reports - Advisory boards: Amgen, Astra Zeneca, Cell Signaling Technology, Cepheid, Danaher, Merck, Monopteros, Nanostring, PAIGE.AI, Regeneron, Ventana. Consultant: Immunogen, NextCure, Sanofi, Verily. Research support: Amgen, Cepheid, Navigate BioPharma, NextCure, Konica/Minolta, Akoya. Royalty: Rarecyte. SS reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis and Novartis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; receives royalties from Biogenex; and mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. TKC reports institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy, and honoraria from: Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH and others), outside the submitted work. Institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA. Equity: Tempest, Pionyr, Osel, Precede Bio, CureResponse. Committees: NCCN, GU Steering Committee, ASCO/ESMO, ACCRU, KidneyCan. Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. TKC is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus Fund and Loker Pinard Funds for Kidney Cancer Research at DFCI. DB reports nonfinancial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and AVEO, personal fees from Charles River Associates, Schlesinger Associates, Imprint Science, Insight Strategy, Trinity Group, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, AbbVie, and research support from Exelixis and AstraZeneca, outside of the submitted work. SM is currently an employee at Boehringer Ingelheim, Inc. WW is currently an employee at Takeda. DD reports stock ownership in Atlas Antibodies.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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47. Disruption of the Rab7-Dependent Final Common Pathway of Endosomal and Autophagic Processing Results in a Severe Podocytopathy.
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Vöing K, Michgehl U, Mertens ND, Picciotto C, Maywald ML, Goretzko J, Waimann S, Gilhaus K, Rogg M, Schell C, Klingauf J, Tsytsyura Y, Hansen U, van Marck V, Edinger AL, Vollenbröker B, Rescher U, Braun DA, George B, Weide T, and Pavenstädt H
- Subjects
- Animals, Mice, Humans, Endosomes, Drosophila, Kidney, Mammals, Kidney Glomerulus pathology, Podocytes metabolism
- Abstract
Significance Statement: Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration rates and complex morphology, such as podocytes. To improve our understanding on how disturbances of these trafficking pathways are linked to podocyte depletion and slit diaphragm (SD) injury, the authors explored the role of the small GTPase Rab7, which is linked to endosomal, lysosomal, and autophagic pathways, using as model systems mice and Drosophila with podocyte-specific or nephrocyte-specific loss of Rab7, and a human podocyte cell line depleted for Rab7. Their findings point to maturation and fusion events during endolysosomal and autophagic maturation as key processes for podocyte homeostasis and function and identify altered lysosomal pH values as a putative novel mechanism for podocytopathies., Background: Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration rates, such as podocytes. How disturbances within these trafficking pathways may act as factors in proteinuric glomerular diseases is poorly understood., Methods: To explore how disturbances in trafficking pathways may act as factors in proteinuric glomerular diseases, we focused on Rab7, a highly conserved GTPase that controls the homeostasis of late endolysosomal and autophagic processes. We generated mouse and Drosophila in vivo models lacking Rab7 exclusively in podocytes or nephrocytes, and performed histologic and ultrastructural analyses. To further investigate Rab7 function on lysosomal and autophagic structures, we used immortalized human cell lines depleted for Rab7., Results: Depletion of Rab7 in mice, Drosophila , and immortalized human cell lines resulted in an accumulation of diverse vesicular structures resembling multivesicular bodies, autophagosomes, and autoendolysosomes. Mice lacking Rab7 developed a severe and lethal renal phenotype with early-onset proteinuria and global or focal segmental glomerulosclerosis, accompanied by an altered distribution of slit diaphragm proteins. Remarkably, structures resembling multivesicular bodies began forming within 2 weeks after birth, prior to the glomerular injuries. In Drosophila nephrocytes, Rab7 knockdown resulted in the accumulation of vesicles and reduced slit diaphragms. In vitro , Rab7 knockout led to similar enlarged vesicles and altered lysosomal pH values, accompanied by an accumulation of lysosomal marker proteins., Conclusions: Disruption within the final common pathway of endocytic and autophagic processes may be a novel and insufficiently understood mechanism regulating podocyte health and disease., (Copyright © 2023 by the American Society of Nephrology.)
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- 2023
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48. Leveraging immune resistance archetypes in solid cancer to inform next-generation anticancer therapies.
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Anderson KG, Braun DA, Buqué A, Gitto SB, Guerriero JL, Horton B, Keenan BP, Kim TS, Overacre-Delgoffe A, Ruella M, Triplett TA, Veeranki O, Verma V, and Zhang F
- Subjects
- Humans, Immunotherapy, Tumor Microenvironment, Neoplasms drug therapy, Antibodies, Bispecific pharmacology, Antibodies, Bispecific therapeutic use
- Abstract
Anticancer immunotherapies, such as immune checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T cells, have improved outcomes for patients with a variety of malignancies. However, most patients either do not initially respond or do not exhibit durable responses due to primary or adaptive/acquired immune resistance mechanisms of the tumor microenvironment. These suppressive programs are myriad, different between patients with ostensibly the same cancer type, and can harness multiple cell types to reinforce their stability. Consequently, the overall benefit of monotherapies remains limited. Cutting-edge technologies now allow for extensive tumor profiling, which can be used to define tumor cell intrinsic and extrinsic pathways of primary and/or acquired immune resistance, herein referred to as features or feature sets of immune resistance to current therapies. We propose that cancers can be characterized by immune resistance archetypes, comprised of five feature sets encompassing known immune resistance mechanisms. Archetypes of resistance may inform new therapeutic strategies that concurrently address multiple cell axes and/or suppressive mechanisms, and clinicians may consequently be able to prioritize targeted therapy combinations for individual patients to improve overall efficacy and outcomes., Competing Interests: Competing interests: DB reports nonfinancial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and AVEO, personal fees from Charles River Associates, Schlesinger Associates, Imprint Science, Insight Strategy, Trinity Group, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, AbbVie, and research support from Exelixis and AstraZeneca, outside of the submitted work. BPK reports advisory board fees from Regeneron Pharmaceuticals, travel support from Roche/Genentech, and research funding (to institution) from Partner Therapeutics, outside of this submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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49. The Changing Landscape of Immunotherapy for Advanced Renal Cancer.
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Kashima S and Braun DA
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- Humans, Immunotherapy, Combined Modality Therapy, Carcinoma, Renal Cell pathology, Kidney Neoplasms pathology
- Abstract
The management of advanced renal cell carcinoma has advanced tremendously over the past decade, but most patients still do not receive durable clinical benefit from current therapies. Renal cellcarcinoma is an immunogenic tumor, historically with conventional cytokine therapies, such as interleukin-2 and interferon-α, and contemporarily with the introduction of immune checkpoint inhibitors. Now the central therapeutic strategy in renal cell carcinoma is combination therapies including immunecheckpoint inhibitors. In this Review, we look back on the historical changes in systemic therapy for advanced renal cell carcinoma, and focus on the latest developments and prospects in this field., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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50. The transcription factor ATF4 mediates endoplasmic reticulum stress-related podocyte injury and slit diaphragm defects.
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Krausel V, Pund L, Nüsse H, Bachir H, Ricker A, Klingauf J, Weide T, Pavenstädt H, Krahn MP, and Braun DA
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- Animals, Humans, Transcription Factors genetics, Drosophila melanogaster genetics, Drosophila melanogaster metabolism, Gene Expression Regulation, Endoplasmic Reticulum Stress genetics, Activating Transcription Factor 4 genetics, Activating Transcription Factor 4 metabolism, Podocytes pathology, Kidney Diseases genetics, Kidney Diseases pathology
- Abstract
Mutations in OSGEP and four other genes that encode subunits of the KEOPS complex cause Galloway-Mowat syndrome, a severe, inherited kidney-neurological disease. The complex catalyzes an essential posttranscriptional modification of tRNA and its loss of function induces endoplasmic reticulum (ER) stress. Here, using Drosophila melanogaster garland nephrocytes and cultured human podocytes, we aimed to elucidate the molecular pathogenic mechanisms of KEOPS-related glomerular disease and to test pharmacological inhibition of ER stress-related signaling as a therapeutic principle. We found that ATF4, an ER stress-mediating transcription factor, or its fly orthologue Crc, were upregulated in both fly nephrocytes and human podocytes. Knockdown of Tcs3, a fly orthologue of OSGEP, caused slit diaphragm defects, recapitulating the human kidney phenotype. OSGEP cDNA with mutations found in patients lacked the capacity for rescue. Genetic interaction studies in Tcs3-deficient nephrocytes revealed that Crc mediates not only cell injury, but surprisingly also slit diaphragm defects, and that genetic or pharmacological inhibition of Crc activation attenuates both phenotypes. These findings are conserved in human podocytes where ATF4 inhibition improved the viability of podocytes with OSGEP knockdown, with chemically induced ER stress, and where ATF4 target genes and pro-apoptotic gene clusters are upregulated upon OSGEP knockdown. Thus, our data identify ATF4-mediated signaling as a molecular link among ER stress, slit diaphragm defects, and podocyte injury, and our data suggest that modulation of ATF4 signaling may be a potential therapeutic target for certain podocyte diseases., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
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- 2023
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