120 results on '"Elizabeth A. Chavez"'
Search Results
2. Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia
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Manabu Kusakabe, Ann Chong Sun, Kateryna Tyshchenko, Rachel Wong, Aastha Nanda, Claire Shanna, Samuel Gusscott, Elizabeth A. Chavez, Alireza Lorzadeh, Alice Zhu, Ainsleigh Hill, Stacy Hung, Scott Brown, Artem Babaian, Xuehai Wang, Robert A. Holt, Christian Steidl, Aly Karsan, R. Keith Humphries, Connie J. Eaves, Martin Hirst, and Andrew P. Weng
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Science - Abstract
Studies with patient derived xenografts are hampered by factors such as genetic variability and sample availability. Here, the authors generate a leukemia mouse model by lentiviral transduction of normal human cord blood and show an oncogenic role of HOXB genes.
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- 2019
- Full Text
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3. Noncanonical β-catenin interactions promote leukemia-initiating activity in early T-cell acute lymphoblastic leukemia
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Patrizio Panelli, Elisabetta De Santis, Mattia Colucci, Francesco Tamiro, Francesca Sansico, Mattia Miroballo, Emanuele Murgo, Costanzo Padovano, Sam Gusscott, Michele Ciavarella, Elizabeth A. Chavez, Fabrizio Bianchi, Giovanni Rossi, Angelo M. Carella, Christian Steidl, Andrew P. Weng, and Vincenzo Giambra
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a T-cell malignancy characterized by cell subsets and enriched with leukemia-initiating cells (LICs). β-Catenin modulates LIC activity in T-ALL. However, its role in maintaining established leukemia stem cells remains largely unknown. To identify functionally relevant protein interactions of β-catenin in T-ALL, we performed coimmunoprecipitation followed by liquid chromatography–mass spectrometry. Here, we report that a noncanonical functional interaction of β-catenin with the Forkhead box O3 (FOXO3) transcription factor positively regulates LIC-related genes, including the cyclin-dependent kinase 4, which is a crucial modulator of cell cycle and tumor maintenance. We also confirm the relevance of these findings using stably integrated fluorescent reporters of β-catenin and FOXO3 activity in patient-derived xenografts, which identify minor subpopulations with enriched LIC activity. In addition, gene expression data at the single-cell level of leukemic cells of primary patients at the time of diagnosis and minimal residual disease (MRD) up to 30 days after the standard treatments reveal that the expression of β-catenin– and FOXO3-dependent genes is present in the CD82+CD117+ cell fraction, which is substantially enriched with LICs in MRD as well as in early T-cell precursor ALL. These findings highlight key functional roles for β-catenin and FOXO3 and suggest novel therapeutic strategies to eradicate aggressive cell subsets in T-ALL.
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- 2023
4. Intervención del Psicólogo Clínico frente al femicidio en la ciudad de Portoviejo
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Blanca Maritza Vera García, Betty Elizabeth Alarcón Chavez, and Ericka Alexandra Menéndez Moreira
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Special aspects of education ,LC8-6691 ,Social sciences (General) ,H1-99 - Abstract
El Psicólogo Clínico posee un escenario extenso para su desarrollo profesional, en el presente trabajo se destaca al mismo en el campo judicial y más específicamente con casos de femicidio; es así como la Psicología Clínica es aplicada al derecho. El Propósito de este ensayo consiste en investigar el modo de intervención de este profesional para identificar las principales funciones en su práctica; se ejecutó un estudio bibliográfico centrado en la selección de información relevante, así como una entrevista al profesional de esta área en la Fiscalía General del Estado del Cantón Portoviejo – Ecuador, lo que permitió determinar que uno de los roles principales del Psicólogo Clínico en estos casos, consiste en la evaluación del victimario cuando un juez competente lo determina o para la defensa del mismo, además su rol está relacionado con la autopsia psicológica la cual es útil para obtener información y esclarecer muertes dudosas y sospechas de criminalidad, y evalúa a su vez casos de tentativa de femicidio, así el Psicólogo Clínico se convierte en auxiliar de la justicia, respondiendo con su labor especifica al deber de investigar. Abstrac The Clinical Psychologist has an extensive stage for his professional development, in the present work he stands out in the judicial field and more specifically with cases of femicide; this is how Clinical Psychology is applied to the law. The purpose of this essay is to investigate the mode of intervention of this professional to identify the main functions in his practice; a bibliographic study focused on the selection of relevant information was carried out, as well as an interview to the professional of this area in the Prosecutor General of the State of the Canton Portoviejo - Ecuador, which allowed to determine that one of the main roles of the Clinical Psychologist in these cases , consists of the evaluation of the victimizer when a competent judge determines it or for the defense of the same, in addition its role is related to the psychological autopsy which is useful to obtain information and clarify doubtful deaths and suspicions of criminality, and evaluates in turn cases of attempted femicide, so the Clinical Psychologist becomes an auxiliary of justice, responding with his specific work to the duty to investigate.
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- 2018
5. Physical properties of the soil in different agricultural systems in the province of Los Ríos, Ecuador
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Indira Dayanara Novillo Espinoza, Manuel Danilo Carrillo Zenteno, Jessica Elizabeth Cargua Chavez, Virginia Nabel Moreira, Karla Estefania Albán Solarte, and Fátima Lourdes Morales Intriago
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clay dispersed in water ,degree of flocculation ,organic matter index ,erosion ,soil uses ,Agriculture - Abstract
Monoculture systems degrade the soil, affecting its physical and chemical properties, and its regeneration is very slow. With the objective of knowing changes in the physical properties of the Pichilingue Tropical Experimental Station, due to the use effect, a randomized complete block design with three replications was used in native forest soils and corn monocultures (30 years ), cacao (50 years), pasture (4 years) and oil palm (26 years) at different depths every 0.10 m to 0.6 m. were evaluated physical properties such as hydraulic conductivity, bulk density, real density, total porosity, aeration porosity, volumetric moisture, texture, clay dispersed in water, degree of flocculation, organic matter and organic matter / silt + clay index, The data were statistically analyzed and Separation test Tukey (P≤0.05). It was found that corn, oil palm and grass caused significant statistical increases in the apparent density of the soil without exceeding the critical levels of 1390 kg m-3 and not significant in reducing the total porosity in the depth of 0.1-0.2 m. Also, there was a high concentration of clays in the first depths of the soils under monoculture that caused susceptibility to water erosion processes, concluding that the soil under oil palm cultivation showed greater statistical differences due to the texture, negatively affecting the apparent density of the soil , hydraulic conductivity, clay dispersed in water, which in sum contribute to decrease the stability of aggregates.
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- 2018
- Full Text
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6. Proceso del cuidado aplicado en adulto mayor con hipertensión arterial
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Geraldine Ruby Báez Rentera, Levi Rebeca Morales Miranda, Tamara Angela Ortega Albornoz, Chanell Sthefany Rafaile Bada, Milagros Lizbeth Uturunco Vera, and Petronila Elizabeth Alvarado Chavez
- Abstract
Objetivo: Brindar intervenciones de enfermería que ayuden a mejorar la ansiedad y modificar los pensamientos y emociones negativas. Caso clínico: Proceso de cuidado enfermero aplicado durante 3 días a adulto mayor de iniciales A. M. B. de 73 años, de sexo femenino, con antecedentes de 2 años post COVID. Hace 7 días ingresó por emergencia a la clínica Robles, dónde se le diagnosticó embolia cerebral por arritmia cardíaca. Presenta irritabilidad, preocupación, tristeza, frustración, inquietud, ojos ojerosos, desesperación, voz temblorosa, temperatura de 36 °C, FC: 110 lpm, PA: 140/110 mmHg, FR: 26 xm, pupilas irritadas, abdomen normal y confusión para hablar. Método: El método de estudio fue de caso único y de enfoque cualitativo, cuyo caso clínico se realizó en domicilio del paciente en el mes de abril, utilizando el marco teórico de valoración de Marjory Gordon y taxonomía NANDA-NOC-NIC. Resultados: La evolución de la paciente fue favorable, con los ejercicios, terapias y apoyo emocional que se le brindó en domicilio. Conclusiones: En el primer diagnóstico enfermero, disminución de la tolerancia a la actividad, su puntuación de cambio fue +3. En el segundo diagnóstico, ansiedad, su puntuación de cambio fue +3. En el tercer diagnóstico enfermero, deterioro de la movilidad física, su puntuación de cambio fue +2. En el cuarto diagnóstico enfermero, insomnio, su puntuación de cambio fue +3. En el quinto diagnóstico enfermero, aflicción crónica, su puntuación de cambio fue +3 y en el sexto diagnóstico enfermero, riesgo de deterioro de la función cardiovascular, su puntuación de cambio fue +3.
- Published
- 2022
7. Proceso del cuidado de enfermería aplicado en adulto joven con diabetes mellitus tipo 2
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Adriana Jasmin Diaz Areche, Alessandra Katherine Romero Scotty, Lucia Marilu Alvarado Tayca, Vanessa Portillo Jimenez, and Petronila Elizabeth Alvarado Chavez
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Objetivo: Brindar intervenciones de enfermería para el control de glucosa en la sangre. Caso clínico: Adulto joven de 49 años, irritado, con visión borrosa, muy cansado, con antecedentes de dolor en el hombro cuando hace movimientos bruscos, ya que tuvo una cirugía en el hombro años atrás, con incontinencia urinaria, también se le observa sudoración y abdomen hinchado por la presencia de gases en los intestinos, con análisis de sangre donde se pudo evidenciar que presentaba un nivel de glucosa muy alto. Métodos: El estudio es de enfoque cualitativo y de método caso único, se ejecutó en su domicilio en el mes de abril, utilizando el marco teórico de valoración de Marjory Gordon y la taxonomía NANDA-NOC-NIC. Resultados: Los resultados obtenidos quedan reflejados en taxonomía NOC, resultados con una sola escala de medición, taxonomía de intervenciones NIC dominio 1 apoyo nutricional, con un control de glucosa dentro de los valores normales, se le sugirió realizar actividad física regular, tratamiento con medicamentos e insulina. Conclusiones: En el primer diagnóstico, incontinencia urinaria de urgencia, la puntuación de cambio fue +4. En el segundo diagnóstico, motilidad gastrointestinal disfuncional, la puntuación de cambio fue +3. En el tercer diagnóstico, hipertermia, la puntuación de cambio fue +4. En el cuarto diagnóstico, riesgo de nivel de glucemia inestable, la puntuación de cambio fue +3. Finalmente, en el quinto diagnóstico, dolor agudo, la puntuación de cambio fue +1.
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- 2022
8. Valoración por 14 necesidades y cuidado enfermero en adulto con tuberculosis pulmonar, en Lima, Perú
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Carla Arcos Ramos, Joel Oros Sicha, Diana Rojas Huamán, Daniela Vergara Mariñas, and Petronila Elizabeth Alvarado Chavez
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Objetivo: Brindar intervenciones de enfermería para corregir la sintomatología causada por tuberculosis pulmonar. Caso clínico: Paciente de 42 años, presentó debilidad leve en los músculos que le impiden realizar las actividades diarias, alérgica a la penicilina, presenta gastritis, operación quirúrgica de apéndice hace 15 años, fractura de fémur hace 26 años y retiro de placa en fémur hace 4 años, al examen físico presenta temperatura de 39 °C, SaO2 de 91 %, FR: 11, PA: 120/80 mmHg, peso de 63 kg, talla de 165 cm y IMC de 18,4. Método: Estudio de caso único de enfoque cualitativo, se utilizó el marco de valoración de Virginia Henderson y la taxonomía de NANDA-NOC-NIC. Resultados: La evolución del paciente adulto medio fue favorable; las intervenciones fueron dadas en un 100 % según los planes didácticos. Conclusiones: En el primer diagnóstico, patrón respiratorio ineficaz, la puntuación de cambio más importante fue de +3. En el segundo diagnóstico, hipertermia, su puntuación de cambio más importante fue +2. En el tercer diagnóstico, desequilibrio nutricional, ingesta inferior a las necesidades, su puntuación de cambio fue +1. En el cuarto diagnóstico, deterioro a la ambulación, su puntuación de cambio fue +1. En el quinto diagnóstico, disminución de la tolerancia a la actividad, su puntuación de cambio fue +2.
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- 2022
9. Single-cell spatial analysis of tumor immune architecture in diffuse large B-cell lymphoma
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Anthony R. Colombo, Monirath Hav, Mohan Singh, Alexander Xu, Alicia Gamboa, Tucker Lemos, Erik Gerdtsson, Denaly Chen, Jane Houldsworth, Rita Shaknovich, Tomohiro Aoki, Lauren Chong, Katsuyoshi Takata, Elizabeth A. Chavez, Christian Steidl, James Hicks, Peter Kuhn, Imran Siddiqi, and Akil Merchant
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Spatial Analysis ,Tumor Microenvironment ,Humans ,Lymphoma, Large B-Cell, Diffuse ,Hematology ,Hepatitis A Virus Cellular Receptor 2 ,Hodgkin Disease - Abstract
Multiplexed immune cell profiling of the tumor microenvironment (TME) in cancer has improved our understanding of cancer immunology, but complex spatial analyses of tumor-immune interactions in lymphoma are lacking. Here, we used imaging mass cytometry (IMC) on 33 cases of diffuse large B-cell lymphoma (DLBCL) to characterize tumor and immune cell architecture and correlate it to clinicopathological features such as cell of origin, gene mutations, and responsiveness to chemotherapy. To understand the poor response of DLBCL to immune checkpoint inhibitors (ICI), we compared our results to IMC data from Hodgkin lymphoma, a cancer highly responsive to ICI, and observed differences in the expression of PD-L1, PD-1, and TIM-3. We created a spatial classification of tumor cells and identified tumor-centric subregions of immune activation, immune suppression, and immune exclusion within the topology of DLBCL. Finally, the spatial analysis allowed us to identify markers such as CXCR3, which are associated with penetration of immune cells into immune desert regions, with important implications for engineered cellular therapies. This is the first study to integrate tumor mutational profiling, cell of origin classification, and multiplexed immuno-phenotyping of the TME into a spatial analysis of DLBCL at the single-cell level. We demonstrate that, far from being histopathologically monotonous, DLBCL has a complex tumor architecture, and that changes in tumor topology can be correlated with clinically relevant features. This analysis identifies candidate biomarkers and therapeutic targets such as TIM-3, CCR4, and CXCR3 that are relevant for combination treatment strategies in immuno-oncology and cellular therapies.
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- 2022
10. Data from Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma
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Christian Steidl, Sohrab P. Shah, Akil Merchant, Anja Mottok, Brad H. Nelson, Gerald Krystal, David W. Scott, Kerry J. Savage, Andrew P. Weng, Pedro Farinha, Jiarui Ding, Saeed Saberi, Jubin Kim, Allen W. Zhang, Johanna Veldman, Talia Goodyear, Daniel Kos, Chanel Ghesquiere, Shannon Healy, Michael Y. Li, Adèle Telenius, Bruce W. Woolcock, Elena Viganò, Vivian Lam, Tomoko Miyata-Takata, Xuehai Wang, Michael Nissen, Elizabeth A. Chavez, Anthony Colombo, Monirath Hav, Katy Milne, Katsuyoshi Takata, Lauren C. Chong, and Tomohiro Aoki
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Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma–specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma–associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class II–deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma.Significance:We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell–like immunosuppressive subset of LAG3+ T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints.See related commentary by Fisher and Oh, p. 342.This article is highlighted in the In This Issue feature, p. 327
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- 2023
11. Supplementary Data from Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma
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Christian Steidl, Sohrab P. Shah, Akil Merchant, Anja Mottok, Brad H. Nelson, Gerald Krystal, David W. Scott, Kerry J. Savage, Andrew P. Weng, Pedro Farinha, Jiarui Ding, Saeed Saberi, Jubin Kim, Allen W. Zhang, Johanna Veldman, Talia Goodyear, Daniel Kos, Chanel Ghesquiere, Shannon Healy, Michael Y. Li, Adèle Telenius, Bruce W. Woolcock, Elena Viganò, Vivian Lam, Tomoko Miyata-Takata, Xuehai Wang, Michael Nissen, Elizabeth A. Chavez, Anthony Colombo, Monirath Hav, Katy Milne, Katsuyoshi Takata, Lauren C. Chong, and Tomohiro Aoki
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Supplementary Methods, Supplementary Figures 1-19, Supplementary References
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- 2023
12. Supplementary Figure S14 from Single-cell Profiles and Prognostic Impact of Tumor-Infiltrating Lymphocytes Coexpressing CD39, CD103, and PD-1 in Ovarian Cancer
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Brad H. Nelson, Christian Steidl, John R. Webb, Katy Milne, Shelby Thornton, Lauren C. Chong, Elizabeth A. Chavez, Nicole S. Gierc, Julian Smazynski, Maartje C.A. Wouters, and Céline M. Laumont
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Supplementary Figure S14 shows the extent of TCR overlap between T-cell subsets isolated from primary HGSC tumor samples.
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- 2023
13. Supplemental Figures 1-8 from The Prognostic Impact of CD163-Positive Macrophages in Follicular Lymphoma: A Study from the BC Cancer Agency and the Lymphoma Study Association
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Gilles Salles, Randy D. Gascoyne, Christian Steidl, Laurie H. Sehn, Joseph M. Connors, Corinne Haioun, Andrew I. Minchinton, Graham W. Slack, Bettina Fabiani, Ashley D. Sanders, David W. Scott, Alastair H. Kyle, Elizabeth A. Chavez, Pauline Brice, Alden A. Moccia, Sami Boussetta, Pedro Farinha, Danielle Canioni, Ayesha Vawda, Pierre Feugier, King Tan, Bénédicte Gelas-Dore, Luc Xerri, and Robert Kridel
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Supplemental Figures 1-8. Suppl. Fig 1. Consort flow diagram. Shown are patient numbers throughout the study. The BCCA TMA was built as duplicate 1.5mm cores whereas the PRIMA TMA was built as triplicate 1.0mm cores. Strict QC criteria were applied to each sample to increase accuracy of point estimates for macrophage infiltration. We required each sample to be represented by more than 1 core, to be unequivocally attributable to a patient and the relative standard error to be less than 33.33%. Suppl. Fig 2. Correlation between Aperio and manual scoring in the BCCA cohort for CD68 (left) and CD163 (right). Suppl. Fig 3. Representative microscopy images in low power magnification. (A) Immunohistochemistry using anti-human CD68 (clone KP1) and anti-human CD163 (clone 10D6) for case FL124 (average number of macrophages). (B) Similar images for case FL136 (elevated number of macrophages). Suppl. Fig 4. (A) Distribution of CD68 and CD163 scores in the BCCA and PRIMA cohorts. (B) Double immunofluorescence on formalin-fixed and paraffin-embedded tissue using antibodies against CD68 and CD163. Shown is case FL148 (22.64% CD68 positive pixels and 4.39% CD163 positive pixels by Aperio). Suppl. Fig 5. Distribution of CD68 and CD163 in the BCCA and PRIMA cohorts. Suppl. Fig 6. Correlation between CD68 and CD163 in the BCCA (left) and PRIMA cohorts (right). Suppl. Fig 7. Outcome correlation for CD68 in the BCCA cohort. The most significant cut-off of 2.94% was defined for progression-free survival (PFS) in the training cohort and carried forward into the overall survival (OS) analysis and validation cohorts. PFS and OS are calculated from date of initiation of R-CVP. Suppl. Fig 8. Outcome correlation for CD68 in the PRIMA cohort. The optimal cut-off of 1.41 was defined for progression-free survival (PFS) in the training cohort and carried forward into the overall survival (OS) analysis and validation cohorts. PFS and OS are calculated from date of registration in the trial.
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- 2023
14. Table S1 from Combined EZH2 Inhibition and IKAROS Degradation Leads to Enhanced Antitumor Activity in Diffuse Large B-cell Lymphoma
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Robert Kridel, Christian Steidl, David W. Scott, Merrill Boyle, Lauren C. Chong, Elizabeth A. Chavez, Rodger E. Tiedemann, Housheng Hansen He, Gilbert G. Privé, Maria C. Xu, Anjali Silva, Jesse Joynt, Michael Y. He, Tracy Lackraj, Mehran Bakhtiari, Keren Isaev, Sharon Yoon, and Kit I. Tong
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Results from CRISPR/Cas9 knockout screen in SU-DHL-4 cells.
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- 2023
15. Supplementary Table S4 from Single-cell Profiles and Prognostic Impact of Tumor-Infiltrating Lymphocytes Coexpressing CD39, CD103, and PD-1 in Ovarian Cancer
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Brad H. Nelson, Christian Steidl, John R. Webb, Katy Milne, Shelby Thornton, Lauren C. Chong, Elizabeth A. Chavez, Nicole S. Gierc, Julian Smazynski, Maartje C.A. Wouters, and Céline M. Laumont
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Supplementary Table S4 presents the list of differentially expressed genes identified between triple-positive and triple-negative Tregs and between triple-positive and other Tregs.
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- 2023
16. Supplementary Data from Single-cell Profiles and Prognostic Impact of Tumor-Infiltrating Lymphocytes Coexpressing CD39, CD103, and PD-1 in Ovarian Cancer
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Brad H. Nelson, Christian Steidl, John R. Webb, Katy Milne, Shelby Thornton, Lauren C. Chong, Elizabeth A. Chavez, Nicole S. Gierc, Julian Smazynski, Maartje C.A. Wouters, and Céline M. Laumont
- Abstract
List of Supplementary Figures and Tables, Supplementary Methods, and Supplementary References
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- 2023
17. Data from Combined EZH2 Inhibition and IKAROS Degradation Leads to Enhanced Antitumor Activity in Diffuse Large B-cell Lymphoma
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Robert Kridel, Christian Steidl, David W. Scott, Merrill Boyle, Lauren C. Chong, Elizabeth A. Chavez, Rodger E. Tiedemann, Housheng Hansen He, Gilbert G. Privé, Maria C. Xu, Anjali Silva, Jesse Joynt, Michael Y. He, Tracy Lackraj, Mehran Bakhtiari, Keren Isaev, Sharon Yoon, and Kit I. Tong
- Abstract
Purpose:The efficacy of EZH2 inhibition has been modest in the initial clinical exploration of diffuse large B-cell lymphoma (DLBCL), yet EZH2 inhibitors are well tolerated. Herein, we aimed to uncover genetic and pharmacologic opportunities to enhance the clinical efficacy of EZH2 inhibitors in DLBCL.Experimental Design:We conducted a genome-wide sensitizing CRISPR/Cas9 screen with tazemetostat, a catalytic inhibitor of EZH2. The sensitizing effect of IKZF1 loss of function was then validated and leveraged for combination treatment with lenalidomide. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing analyses were performed to elucidate transcriptomic and epigenetic changes underlying synergy.Results:We identified IKZF1 knockout as the top candidate for sensitizing DLBCL cells to tazemetostat. Treating cells with tazemetostat and lenalidomide, an immunomodulatory drug that selectively degrades IKAROS and AIOLOS, phenocopied the effects of the CRISPR/Cas9 screen. The combined drug treatment triggered either cell-cycle arrest or apoptosis in a broad range of DLBCL cell lines, regardless of EZH2 mutational status. Cell-line–based xenografts also showed slower tumor growth and prolonged survival in the combination treatment group. RNA-seq analysis revealed strong upregulation of interferon signaling and antiviral immune response signatures. Gene expression of key immune response factors such as IRF7 and DDX58 were induced in cells treated with lenalidomide and tazemetostat, with a concomitant increase of H3K27 acetylation at their promoters. Furthermore, transcriptome analysis demonstrated derepression of endogenous retroviruses after combination treatment.Conclusions:Our data underscore the synergistic interplay between IKAROS degradation and EZH2 inhibition on modulating epigenetic changes and ultimately enhancing antitumor effects in DLBCL.
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- 2023
18. Supplementary Data from Combined EZH2 Inhibition and IKAROS Degradation Leads to Enhanced Antitumor Activity in Diffuse Large B-cell Lymphoma
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Robert Kridel, Christian Steidl, David W. Scott, Merrill Boyle, Lauren C. Chong, Elizabeth A. Chavez, Rodger E. Tiedemann, Housheng Hansen He, Gilbert G. Privé, Maria C. Xu, Anjali Silva, Jesse Joynt, Michael Y. He, Tracy Lackraj, Mehran Bakhtiari, Keren Isaev, Sharon Yoon, and Kit I. Tong
- Abstract
Supplementary Data
- Published
- 2023
19. The invisible impacts of violence and crime on biodiversity and communities in Mexican natural protected areas
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Laura Elizabeth Vallejo Chavez
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Global and Planetary Change ,Ecology ,Nature and Landscape Conservation - Published
- 2022
20. Single-cell Profiles and Prognostic Impact of Tumor-Infiltrating Lymphocytes Coexpressing CD39, CD103, and PD-1 in Ovarian Cancer
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Julian Smazynski, Katy Milne, Céline M. Laumont, Shelby Thornton, Lauren C. Chong, Christian Steidl, Nicole S. Gierc, Brad H. Nelson, Maartje C.A. Wouters, Elizabeth A. Chavez, and John R. Webb
- Subjects
Cancer Research ,Programmed Cell Death 1 Receptor ,chemical and pharmacologic phenomena ,Biology ,Flow cytometry ,Lymphocytes, Tumor-Infiltrating ,Immune system ,TIGIT ,Antigens, CD ,medicine ,Humans ,Ovarian Neoplasms ,medicine.diagnostic_test ,Tumor-infiltrating lymphocytes ,Apyrase ,T-cell receptor ,hemic and immune systems ,Prognosis ,medicine.disease ,Phenotype ,Cystadenocarcinoma, Serous ,Oncology ,Cancer research ,Female ,Ovarian cancer ,Integrin alpha Chains ,CD8 - Abstract
Purpose: Tumor-infiltrating lymphocytes (TIL) are strongly associated with survival in most cancers; however, the tumor-reactive subset that drives this prognostic effect remains poorly defined. CD39, CD103, and PD-1 have been independently proposed as markers of tumor-reactive CD8+ TIL in various cancers. We evaluated the phenotype, clonality, and prognostic significance of TIL expressing various combinations of these markers in high-grade serous ovarian cancer (HGSC), a malignancy in need of more effective immunotherapeutic approaches. Experimental Design: Expression of CD39, CD103, PD-1, and other immune markers was assessed by high-dimensional flow cytometry, single-cell sequencing, and multiplex immunofluorescence of primary and matched pre/post-chemotherapy HGSC specimens. Results: Coexpression of CD39, CD103, and PD-1 (“triple-positive” phenotype) demarcated subsets of CD8+ TIL and CD4+ regulatory T cells (Treg) with a highly activated/exhausted phenotype. Triple-positive CD8+ TIL exhibited reduced T-cell receptor (TCR) diversity and expressed genes involved in both cytolytic and humoral immunity. Triple-positive Tregs exhibited higher TCR diversity and a tumor-resident phenotype. Triple-positive TIL showed superior prognostic impact relative to TIL expressing other combinations of these markers. TIGIT was uniquely upregulated on triple-positive CD8+ effector cells relative to their CD4+ Treg counterparts. Conclusions: Coexpression of CD39, CD103, and PD-1 demarcates highly activated CD8+ and CD4+ TIL with inferred roles in cytolytic, humoral, and regulatory immune functions. Triple-positive TIL demonstrate exceptional prognostic significance and express compelling targets for combination immunotherapy, including PD-1, CD39, and TIGIT.
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- 2021
21. Hepatic and gastrointestinal manifestations in Mexican patients with juvenile systemic lupus erythematosus
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Elizabeth Hernández Chavez, José María Alarid Coronel, and Myriam Mendez Nuñez
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skin and connective tissue diseases - Abstract
Background: Systemic lupus erythematosus (SLE) is a multisystem disorder which can affect the gastrointestinal system (GI), symptoms can manifest in 50% of patients with systemic lupus erythematosus (SLE), these have barely been reviewed due to difficulty in identifying different causes [1]. The causes of abdominal pain in SLE patients are diverse, including lupus-related and non–lupus-related etiologies, as well as infections and medication side effects [2]. Children more often have lupus-related causes such as lupus mesenteric vasculitis, ascites peritonitis, and pancreatitis [2,3]. Liver manifestations, generally mild elevations in liver transaminases, have been reported in approximately 25-57.9% in paediatric-onset SLE (pSLE).Methods: Retrospective study, with review of 63 medical records of patients diagnosed with paediatric-onset SLE (pSLE) according to ACR 1997 criteria treated at the UMAE Hospital Pediatría CMNO, during the period from 2018 to 2020. Results: 63 patients were included, 49 (77.8%) girls and 14 (22.2%) boys, age range 5-17 years, mean 14 years (DS±2.9). Gastrointestinal involvement was recorded in 50.8% (n= 32) children. Lupus hepatitis, the most frequent digestive disorder (12.7%). Elevation of liver enzymes was detected in 31.7% with a higher elevation in patients with digestive disorders, in the case of AST (p= 0.001) and ALT (p= 0.024) Abdominal pain was the most frequent symptom, present in 38.1% (n= 24) patients, especially related to multiple medication 46% (n= 29), pancreatitis 7.9% (n=5), lupus enteritis 3.2% (n=2), intestinal pseud occlusion 1.6% (n=1) and ascites 1.6% (n= 1). A significant association was found (p= 0.03), among those patients with gastrointestinal affection and management with 4 or more drugs. Azathioprine was the drug most associated with abdominal pain (p= 0.07). Pancreatitis was associated with higher levels of disease activity by MEX SLEDAI score (p= 0.016). Of the manifestations not related to SLE, gastritis was the most frequent in 7.9% which was associated with a longer disease evolution time (p= 0.01).The decrease in C4 was the only immunological parameter significantly associated in patients with lupus and digestive disorders (P = 0.033). Conclusions: Gastrointestinal manifestations are common in paediatric-onset SLE (pSLE), but most of them are mild and due to adverse reactions to medications. Moderate elevation of liver enzymes occurred in 31.7% with significantly higher mean values of ALT and AST in patients with digestive disorders.
- Published
- 2022
22. Gene expression profiling of gray zone lymphoma
- Author
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Thierry Jo Molina, Kerry J. Savage, Gerben Duns, Tomoko Miyata-Takata, Christiane Copie-Bergman, Adele Telenius, Anja Mottok, Graham W. Slack, Camille Laurent, Katsuyoshi Takata, Gilles Salles, David Scott, Pedro Farinha, Clémentine Sarkozy, Christian Steidl, Diane Damotte, Elizabeth A. Chavez, Lauren Chong, Alexandra Traverse-Glehen, and Merrill Boyle
- Subjects
Male ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Tumor microenvironment ,Lymphoid Neoplasia ,Differential expression analysis ,Gene Expression Profiling ,Hematology ,Middle Aged ,Cell cycle ,Biology ,medicine.disease ,Hodgkin Disease ,Phenotype ,Gray zone lymphoma ,Lymphoma ,Gene expression profiling ,hemic and lymphatic diseases ,Tumor Microenvironment ,Cancer research ,medicine ,Humans ,Female ,Lymphoma, Large B-Cell, Diffuse ,Gene - Abstract
Gray zone lymphoma (GZL), a B-cell lymphoma with features intermediate between large B-cell lymphoma (LBCL) and classic Hodgkin lymphoma (cHL), is a rare and poorly defined entity. Alongside GZL, a subset of Epstein-Barr virus (EBV)–positive diffuse large B-cell lymphoma (DLBCL) has been described with polymorphic/GZL-like morphology (polymorphic-EBV-L). To fill the important gap in our understanding of the pathogenic process underlying these entities, we performed a gene expression study of a large international cohort of GZL and polymorphic-EBV-L, combined with cHL and primary mediastinal large B-cell lymphoma (PMBCL) cases. In an unsupervised principal component analysis, GZL cases presented with intermediate scores in a spectrum between cHL and PMBCL, whereas polymorphic-EBV-L clustered distinctly. The main biological pathways underlying the GZL spectrum were related to cell cycle, reflecting tumor cell content, and extracellular matrix signatures related to the cellular tumor microenvironment. Differential expression analysis and phenotypic characterization of the tumor microenvironment highlighted the predominance of regulatory macrophages in GZL compared with cHL and PMBCL. Two distinct subtypes of GZL were distinguishable that were phenotypically reminiscent of PMBCL and DLBCL, and we observed an association of PMBCL-type GZL with clinical presentation in the “thymic” anatomic niche. In summary, gene expression profiling (GEP) enabled us to add precision to the GZL spectrum, describe the biological distinction compared with polymorphic-EBV-L, and distinguish cases with and without thymic involvement as 2 subgroups of GZL, namely PMBCL-like and DLBCL-like GZL.
- Published
- 2020
23. Modular treatment approach for drinking water and wastewater
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A. Dalila Larios-Martínez, Christell Barrales-Fernández, P. Elizabeth Alvarez-Chavez, Carlos Méndez-Carreto, Fabiola Sandoval-Salas, Nora Ruiz-Colorado, Stéphane Godbout, Sébastien Fournel, and Antonio Avalos-Ramírez
- Published
- 2022
24. Contributors
- Author
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Ubhat Ali, P. Elizabeth Alvarez-Chavez, Antonio Avalos-Ramírez, L. Barman, Christell Barrales-Fernández, G.D. Bhowmick, Kamalpreet Kaur Brar, Satinder Kaur Brar, Pritha Chatterjee, M. Chaudhary, VR Sankar Cheela, Agnieszka Cuprys, Seyyed Mohammadreza Davoodi, Brajesh K. Dubey, Sébastien Fournel, Javad Ghanei, Partha Sarathi Ghosal, Stéphane Godbout, Ashok Kumar Gupta, N. Jain, Mohammad Hossein Karimi Darvanjooghi, Pratishtha Khurana, Kaivalya Kulkarni, Pratik Kumar, A. Dalila Larios-Martínez, Fernando Jorge Magalhães Filho, Sara Magdouli, Abhradeep Majumder, Carlos Méndez-Carreto, Saba Miri, Carlos Saul Osorio-Gonzalez, Paula Paulo, Rama Pulicharla, Waseem Raja, Hayat Raza, Nora Ruiz-Colorado, Rahul Saini, Fabiola Sandoval-Salas, Joseph Sebastian, Xuhan Shu, Guruprasad V. Talekar, and Bikash R. Tiwari
- Published
- 2022
25. P105 PREVENTION OF INCISIONAL HERNIA WITH A REINFORCED TENSION LINE (RTL) VS PRIMARY SUTURE ONLY IN MIDLINE LAPAROTOMIES: 3 YEARS FOLLOW UP
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Edgard Efren Lozada Hernandez, Leticia Hernández Villegas, and Elizabeth Escamilla Chavez
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Primary suture ,medicine.medical_specialty ,business.industry ,Tension (physics) ,Incisional hernia ,Medicine ,Surgery ,Line (text file) ,business ,medicine.disease - Abstract
Aim “Incisional hernia (IH) has an incidence of 10–23%, which can increase to 38% in specific risk groups. The objective of this study is to report the results at 3 years of follow-up of the use of the reinforced tension line (RTL) technique compared with primary suture only (PSO) closure in the prevention of IH in high-risk patients undergoing laparotomy.” Material and Methods “Open randomized controlled clinical trial. Included were patients older than 18 years who underwent midline laparotomy, emergency or scheduled, who were considered high risk, and who completed 3-year follow-up. The patients were randomized 1:1 to the RTL technique or to PSO. The objective was to report the incidence of IH and the complications associated with the closure method. Intention-to-treat analysis and Cox regression were performed.” Results “A total of 124 patients were randomized; 51 patients from the RTL group and 53 patients from the PSO group finished the 3-year follow-up. The incidence of IH was higher in the PSO group (15/53, 28.3%) than the RTL group (5/51, 9.8%) (p = 0.016, OR 0.35, 95% CI 0.14–0.88, number needed to treat 5.4, log-rank test p = 0.017). The groups were similar in the rates of surgical site infection, hematoma, seroma, and postoperative pain during follow-up.” Conclusions “The RTL technique is useful in the prevention of IH when compared with PSO in high-risk midline laparotomy patients, and it is not associated with a higher percentage of complications. Clinical trials NCT02136628, retrospectively registered”
- Published
- 2021
26. Engineering sperm-binding IgG antibodies for the development of an effective nonhormonal female contraception
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Samuel K. Lai, Yong Zhu, Jamal I. Saada, Elizabeth C. Chavez, Kathleen L. Vincent, Timothy M. Jacobs, Gabriela Baldeon Vaca, Bhawana Shrestha, Thomas R. Moench, Alison Schaefer, Stuart S. Omsted, and Carlos A. Cruz-Teran
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Male ,medicine.drug_class ,Monoclonal antibody ,Article ,Immunoglobulin G ,Andrology ,Immunoglobulin Fab Fragments ,Antigen ,Pregnancy ,Animals ,Humans ,Medicine ,Sperm motility ,Sheep ,biology ,business.industry ,General Medicine ,Spermatozoa ,Mucus ,Sperm ,Contraception ,Sperm Motility ,biology.protein ,Female ,Antibody ,business - Abstract
Many women risk unintended pregnancy because of medical contraindications or dissatisfaction with contraceptive methods, including real and perceived side effects associated with the use of exogenous hormones. We pursued direct vaginal delivery of sperm-binding monoclonal antibodies (mAbs) that can limit progressive sperm motility in the female reproductive tract as a strategy for effective nonhormonal contraception. Here, motivated by the greater agglutination potencies of polyvalent immunoglobulins but the bioprocessing ease and stability of immunoglobulin G (IgG), we engineered a panel of sperm-binding IgGs with 6 to 10 antigen-binding fragments (Fabs), isolated from a healthy immune-infertile woman against a unique surface antigen universally present on human sperm. These highly multivalent IgGs (HM-IgGs) were at least 10- to 16-fold more potent and faster at agglutinating sperm than the parent IgG while preserving the crystallizable fragment (Fc) of IgG that mediates trapping of individual spermatozoa in mucus. The increased potencies translated into effective (>99.9%) reduction of progressively motile sperm in the sheep vagina using as little as 33 μg of the 10-Fab HM-IgG. HM-IgGs were produced at comparable yields and had identical thermal stability to the parent IgG, with greater homogeneity. HM-IgGs represent not only promising biologics for nonhormonal contraception but also a promising platform for engineering potent multivalent mAbs for other biomedical applications.
- Published
- 2021
27. Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma
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Tomoko Miyata-Takata, Merrill Boyle, Adele Telenius, Pedro Farinha, Kerry J. Savage, Andrew P. Weng, Elizabeth A. Chavez, Lauren C. Chong, Ashley Marshall, David W. Scott, Katy Milne, Brad H. Nelson, Tomohiro Aoki, Sohrab P. Shah, Susana Ben-Neriah, Christian Steidl, Doria Unrau, and Katsuyoshi Takata
- Subjects
Receptors, CXCR5 ,PD-L1 ,Lymphocyte ,Programmed Cell Death 1 Receptor ,Fluorescent Antibody Technique ,macromolecular substances ,CXCR5 ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunology and Inflammation ,Nodular sclerosis ,PD-1 ,polycyclic compounds ,medicine ,Tumor Microenvironment ,Humans ,RNA-Seq ,CXCL13 ,Reed-Sternberg Cells ,Lymph node ,030304 developmental biology ,0303 health sciences ,Tumor microenvironment ,B-Lymphocytes ,Multidisciplinary ,biology ,single-cell analyses ,food and beverages ,T-Lymphocytes, Helper-Inducer ,Biological Sciences ,medicine.disease ,Molecular biology ,Chemokine CXCL13 ,Hodgkin Disease ,3. Good health ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Lymph Nodes ,Single-Cell Analysis ,Hodgkin lymphoma - Abstract
Significance Our study provides detailed functional and spatial characteristics of immune cells in the LR-CHL microenvironment at single-cell resolution. We describe detailed T cell subset definitions and importantly identified a unique CD4+PD-1+CXCL13+CXCR5− TFH-like subset that surrounds HRS cells, appears in close proximity to CXCR5+ B cells, and is associated with poor clinical outcome. We also uncovered unique PD-1/PD-L1 axis biology in LR-CHL, namely a negative correlation between PD-L1 genetic alterations on HRS cells and PD-1 protein expression in the tumor microenvironment. Importantly, our findings contribute to a deeper understanding of cellular cross-talk in LR-CHL, which may aid in the development of novel biomarkers and targeted treatment strategies., Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific cross-talk mechanisms between malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironment (TME) of CHL. However, the TME of LR-CHL has not yet been characterized at single-cell resolution. Here, using single-cell RNA sequencing (scRNA-seq), we examined the immune cell profile of 8 cell suspension samples of LR-CHL in comparison to 20 samples of the mixed cellularity (MC, 9 cases) and nodular sclerosis (NS, 11 cases) subtypes of CHL, as well as 5 reactive lymph node controls. We also performed multicolor immunofluorescence (MC-IF) on tissue microarrays from the same patients and an independent validation cohort of 31 pretreatment LR-CHL samples. ScRNA-seq analysis identified a unique CD4+ helper T cell subset in LR-CHL characterized by high expression of Chemokine C-X-C motif ligand 13 (CXCL13) and PD-1. PD-1+CXCL13+ T cells were significantly enriched in LR-CHL compared to other CHL subtypes, and spatial analyses revealed that in 46% of the LR-CHL cases these cells formed rosettes surrounding HRS cells. MC-IF analysis revealed CXCR5+ normal B cells in close proximity to CXCL13+ T cells at significantly higher levels in LR-CHL. Moreover, the abundance of PD-1+CXCL13+ T cells in the TME was significantly associated with shorter progression-free survival in LR-CHL (P = 0.032). Taken together, our findings strongly suggest the pathogenic importance of the CXCL13/CXCR5 axis and PD-1+CXCL13+ T cells as a treatment target in LR-CHL.
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- 2021
28. Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma
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Lauren C. Chong, Andrew J. Mungall, Adele Telenius, Reiner Siebert, Christopher Rushton, David Scott, Anja Mottok, Elena Viganò, Susana Ben-Neriah, Stacy Hung, Barbara Meissner, Kerry J. Savage, Bruce Woolcock, Marco A. Marra, Hisae Nakamura, Randy D. Gascoyne, Clémentine Sarkozy, Christian Steidl, Elizabeth A. Chavez, and Joseph M. Connors
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Immunology ,Cell Biology ,Hematology ,Gene mutation ,Biology ,medicine.disease ,Biochemistry ,Gray zone lymphoma ,Gene expression profiling ,Cancer research ,medicine ,CIITA ,EP300 ,Diffuse large B-cell lymphoma ,Exome sequencing ,IRF4 - Abstract
Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype–phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the Janus kinase-signal transducer and activator of transcription and nuclear factor κB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, and PDCD1LG2). Our analyses highlight the interferon response factor (IRF) pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, and IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB, and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL compared with diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relation between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic evaluation and therapeutic decision-making.
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- 2019
29. Mutational landscape of gray zone lymphoma
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Anja Mottok, Gerben Duns, Lauren C. Chong, Camille Laurent, Katsuyoshi Takata, Susana Ben-Neriah, Adele Telenius, Alexandra Traverse-Glehen, David Scott, Graham W. Slack, Gilles Salles, Kerry J. Savage, Elizabeth A. Chavez, Aixiang Jiang, Tomoko Miyata-Takata, Peggy Dartigues, Stacy Hung, Clémentine Sarkozy, Christian Steidl, Diane Damotte, Tomohiro Aoki, Pedro Farinha, Thierry Jo Molina, René-Olivier Casasnovas, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Male ,Epstein-Barr Virus Infections ,protein p53 ,[SDV]Life Sciences [q-bio] ,medicine.disease_cause ,Biochemistry ,0302 clinical medicine ,chlorambucil ,immune system diseases ,hemic and lymphatic diseases ,B-cell lymphoma ,genes ,Aged, 80 and over ,0303 health sciences ,Mutation ,chile ,Hematology ,Middle Aged ,BCL6 ,Hodgkin Disease ,030220 oncology & carcinogenesis ,Female ,Lymphoma, Large B-Cell, Diffuse ,BLOOD Commentary ,Adult ,Adolescent ,Immunology ,lymphoma ,Thymus Gland ,Biology ,Mediastinal Neoplasms ,Gray zone lymphoma ,Young Adult ,03 medical and health sciences ,medicine ,Humans ,human ,hodgkin's disease ,Aged ,030304 developmental biology ,herpesvirus 4 ,Cell Biology ,medicine.disease ,GNA13 ,NFKBIE ,Lymphoma ,diffuse large b-cell lymphoma ,primary mediastinal large b-cell lymphoma ,Cancer research ,mutation ,Diffuse large B-cell lymphoma - Abstract
The mutational landscape of gray zone lymphoma (GZL) has not yet been established, and differences from related entities are largely unknown. Here, we studied coding sequence mutations of 50 Epstein-Barr virus (EBV)-negative GZLs and 20 polymorphic EBV+ diffuse large B-cell lymphoma (DLBCL) not otherwise specified (poly-EBV-L) in comparison with classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), and DLBCL. Exomes of 21 GZL and 7 poly-EBV-L cases, along with paired constitutional DNA, were analyzed as a discovery cohort, followed by targeted sequencing of 217 genes in an extension cohort of 29 GZL and 13 poly-EBV-L cases. GZL cases with thymic niche involvement (anterior mediastinal mass) exhibited a mutation profile closely resembling cHL and PMBCL, with SOCS1 (45%), B2M (45%), TNFAIP3 (35%), GNA13 (35%), LRRN3 (32%), and NFKBIA (29%) being the most recurrently mutated genes. In contrast, GZL cases without thymic niche involvement (n = 18) had a significantly distinct pattern that was enriched in mutations related to apoptosis defects (TP53 [39%], BCL2 [28%], BIRC6 [22%]) and depleted in GNA13, XPO1, or NF-κB signaling pathway mutations (TNFAIP3, NFKBIE, IKBKB, NFKBIA). They also exhibited more BCL2/BCL6 rearrangements compared with thymic GZL. Poly-EBV-L cases presented a distinct mutational profile, including STAT3 mutations and a significantly lower coding mutation load in comparison with EBV− GZL. Our study highlights characteristic mutational patterns in GZL associated with presentation in the thymic niche, suggesting a common cell of origin and disease evolution overlapping with related anterior mediastinal lymphomas.
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- 2021
30. Single-cell spatial analysis of tumor immune architecture in diffuse large B cell lymphoma
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Erik Gerdtsson, Mohan Singh, James W. Hicks, Denaly Chen, Peter Kuhn, Rita Shaknovich, Lauren Chong, Katsuyoshi Takata, Akil Merchant, Elizabeth A. Chavez, Tomohiro Aoki, Anthony Colombo, Imran Siddiqi, Monirath Hav, Alicia Gamboa, Christian Steidl, Jane Houldsworth, and Alexander Xu
- Subjects
Tumor microenvironment ,Immune system ,medicine ,Cancer research ,Cancer ,Mass cytometry ,Biology ,Gene mutation ,medicine.disease ,Diffuse large B-cell lymphoma ,Lymphoma ,Cancer immunology - Abstract
Multiplexed immune cell profiling of the tumor microenvironment (TME) in cancer has improved our understanding of cancer immunology, but complex spatial analyses of tumor-immune interactions in lymphoma are lacking. Here we used imaging mass cytometry (IMC) on 33 cases of diffuse large B cell lymphoma (DLBCL) to characterize tumor and immune cell architecture and correlate it to clinicopathological features such as cell of origin, gene mutations, and responsiveness to chemotherapy. To understand the poor response of DLBCL to immune check point inhibitors (ICI), we compared our results to IMC data from Hodgkin lymphoma (HL), a cancer highly responsive to ICI, and observed differences in the expression of PD-L1, PD-1, and TIM-3. We created a spatial classification of tumor cells and identified sub-regions of immune activation, immune suppression, and immune exclusion within the topology of DLBCL. Finally, the spatial analysis allowed us to identify markers such as CXCR3, which are associated with penetration of immune cells into immune desert regions, with important implications for engineered cellular therapies.SIGNIFICANCEThis is the first study to integrate tumor mutational profiling, cell of origin classification, and multiplexed immuno-phenotyping of the TME into a spatial analysis of DLBCL at the single cell level. We demonstrate that, far from being histo-pathologically monotonous, DLBCL has a complex tumor architecture, and that changes in tumor topology can be correlated with clinically relevant features. This analysis identifies candidate biomarkers and therapeutic targets such as TIM-3, CCR4, and CXCR3 that are relevant for combination treatment strategies in immuno-oncology and cellular therapies such as CAR-T cells.
- Published
- 2021
31. Impact of MYC and BCL2 structural variants in tumors of DLBCL morphology and mechanisms of false-negative MYC IHC
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Joseph M. Connors, Jeffrey W. Craig, Pedro Farinha, Graham W. Slack, Kerry J. Savage, Brett Collinge, Ryan D. Morin, Diego Villa, Aixiang Jiang, Lauren C. Chong, Tomoko Miyata-Takata, David W. Scott, Elizabeth A. Chavez, Anja Mottok, Daisuke Ennishi, Andrew J. Mungall, Laurie H. Sehn, Randy D. Gascoyne, Susana Ben-Neriah, Barbara Meissner, Marco A. Marra, Ciara L. Freeman, Alina S. Gerrie, Merrill Boyle, and Christian Steidl
- Subjects
Adult ,Male ,0301 basic medicine ,Immunology ,Context (language use) ,In situ hybridization ,Biology ,Polymorphism, Single Nucleotide ,Biochemistry ,Proto-Oncogene Proteins c-myc ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Gene expression ,medicine ,Humans ,Copy-number variation ,Gene ,Aged ,Aged, 80 and over ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,BCL6 ,Immunohistochemistry ,Lymphoma ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Proto-Oncogene Proteins c-bcl-2 ,Cancer research ,Female ,Lymphoma, Large B-Cell, Diffuse ,Transcriptome ,030215 immunology - Abstract
When the World Health Organization defined high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) as a clinical category, rearrangements were the only structural variant (SV) incorporated. An "atypical double-hit" category has been proposed, encompassing tumors with concurrent MYC and BCL2 SVs other than cooccurring translocations (ie, copy number variations [CNVs]). Although the identification of a gene expression signature (DHITsig) shared among tumors harboring MYC and BCL2 rearrangements (HGBL-DH/TH-BCL2) has confirmed a common underlying biology, the biological implication of MYC and BCL2 CNVs requires further elucidation. We performed a comprehensive analysis of MYC and BCL2 SVs, as determined by fluorescent in situ hybridization (FISH), in a cohort of 802 de novo tumors with diffuse large B-cell lymphoma morphology. Although BCL2 CNVs were associated with increased expression, MYC CNVs were not. Furthermore, MYC and BCL2 CNVs, in the context of atypical double-hit, did not confer a similar gene expression profile as HGBL-DH/TH-BCL2. Finally, although MYC immunohistochemistry (IHC) has been proposed as a screening tool for FISH testing, 2 mechanisms were observed that uncoupled MYC rearrangement from IHC positivity: (1) low MYC messenger RNA expression; and (2) false-negative IHC staining mediated by a single-nucleotide polymorphism resulting in an asparagine-to-serine substitution at the 11th amino acid residue of MYC (MYC-N11S). Taken together, these results support the current exclusion of MYC and BCL2 CNVs from HGBL-DH/TH and highlight the ability of a molecular-based classification system to identify tumors with shared biology that FISH and IHC fail to fully capture.
- Published
- 2020
32. Combined EZH2 Inhibition and IKAROS Degradation Leads to Enhanced Antitumor Activity in Diffuse Large B-cell Lymphoma
- Author
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Elizabeth A. Chavez, Maria C. Xu, Sharon Yoon, Lauren C. Chong, Jesse Joynt, Keren Isaev, Merrill Boyle, Tracy Lackraj, Gilbert G. Privé, Christian Steidl, Housheng Hansen He, David Scott, Rodger E. Tiedemann, Kit I. Tong, Anjali Silva, Michael Y. He, Robert Kridel, and Mehran Bakhtiari
- Subjects
Cancer Research ,EZH2 ,Apoptosis ,Cell Cycle Checkpoints ,Biology ,medicine.disease ,3. Good health ,Transcriptome ,Immune system ,Oncology ,Downregulation and upregulation ,Interferon ,Cell Line, Tumor ,medicine ,Cancer research ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Epigenetics ,Lymphoma, Large B-Cell, Diffuse ,Diffuse large B-cell lymphoma ,Lenalidomide ,medicine.drug - Abstract
Purpose:The efficacy of EZH2 inhibition has been modest in the initial clinical exploration of diffuse large B-cell lymphoma (DLBCL), yet EZH2 inhibitors are well tolerated. Herein, we aimed to uncover genetic and pharmacologic opportunities to enhance the clinical efficacy of EZH2 inhibitors in DLBCL.Experimental Design:We conducted a genome-wide sensitizing CRISPR/Cas9 screen with tazemetostat, a catalytic inhibitor of EZH2. The sensitizing effect of IKZF1 loss of function was then validated and leveraged for combination treatment with lenalidomide. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing analyses were performed to elucidate transcriptomic and epigenetic changes underlying synergy.Results:We identified IKZF1 knockout as the top candidate for sensitizing DLBCL cells to tazemetostat. Treating cells with tazemetostat and lenalidomide, an immunomodulatory drug that selectively degrades IKAROS and AIOLOS, phenocopied the effects of the CRISPR/Cas9 screen. The combined drug treatment triggered either cell-cycle arrest or apoptosis in a broad range of DLBCL cell lines, regardless of EZH2 mutational status. Cell-line–based xenografts also showed slower tumor growth and prolonged survival in the combination treatment group. RNA-seq analysis revealed strong upregulation of interferon signaling and antiviral immune response signatures. Gene expression of key immune response factors such as IRF7 and DDX58 were induced in cells treated with lenalidomide and tazemetostat, with a concomitant increase of H3K27 acetylation at their promoters. Furthermore, transcriptome analysis demonstrated derepression of endogenous retroviruses after combination treatment.Conclusions:Our data underscore the synergistic interplay between IKAROS degradation and EZH2 inhibition on modulating epigenetic changes and ultimately enhancing antitumor effects in DLBCL.
- Published
- 2020
33. Activation-induced cytidine deaminase localizes to G-quadruplex motifs at mutation hotspots in lymphoma
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Ying-Zhi Xu, Stacy Hung, Volodymyr Shponka, Piroon Jenjaroenpun, Lisa M. Rimsza, Christian Steidl, Samantha Kendrick, Stephanie D. Byrum, Thidathip Wongsurawat, Shankar Balasubramanian, David Tannahill, Elizabeth A. Chavez, Jenjaroenpun, Piroon [0000-0002-1555-401X], Wongsurawat, Thidathip [0000-0002-3659-2074], Kendrick, Samantha [0000-0002-0281-5815], and Apollo - University of Cambridge Repository
- Subjects
AcademicSubjects/SCI01140 ,0301 basic medicine ,Genome instability ,AcademicSubjects/SCI01060 ,Lymphoma ,AcademicSubjects/SCI00030 ,32 Biomedical and Clinical Sciences ,Standard Article ,AcademicSubjects/SCI01180 ,3101 Biochemistry and Cell Biology ,medicine.disease_cause ,3105 Genetics ,03 medical and health sciences ,chemistry.chemical_compound ,Rare Diseases ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Genetics ,Activation-induced (cytidine) deaminase ,medicine ,2.1 Biological and endogenous factors ,Gene ,Cancer ,2 Aetiology ,Mutation ,biology ,Human Genome ,3 Good Health and Well Being ,Hematology ,Cytidine deaminase ,3211 Oncology and Carcinogenesis ,BCL6 ,medicine.disease ,Molecular biology ,030104 developmental biology ,chemistry ,3201 Cardiovascular Medicine and Haematology ,FOS: Biological sciences ,030220 oncology & carcinogenesis ,biology.protein ,AcademicSubjects/SCI00980 ,DNA ,31 Biological Sciences ,Biotechnology - Abstract
Diffuse large B-cell lymphoma (DLBCL) is a molecularly heterogeneous group of malignancies with frequent genetic abnormalities. G-quadruplex (G4) DNA structures may facilitate this genomic instability through association with activation-induced cytidine deaminase (AID), an antibody diversification enzyme implicated in mutation of oncogenes in B-cell lymphomas. Chromatin immunoprecipitation sequencing analyses in this study revealed that AID hotspots in both activated B cells and lymphoma cells in vitro were highly enriched for G4 elements. A representative set of these targeted sequences was validated for characteristic, stable G4 structure formation including previously unknown G4s in lymphoma-associated genes, CBFA2T3, SPIB, BCL6, HLA-DRB5 and MEF2C, along with the established BCL2 and MYC structures. Frequent genome-wide G4 formation was also detected for the first time in DLBCL patient-derived tissues using BG4, a structure-specific G4 antibody. Tumors with greater staining were more likely to have concurrent BCL2 and MYC oncogene amplification and BCL2 mutations. Ninety-seven percent of the BCL2 mutations occurred within G4 sites that overlapped with AID binding. G4 localization at sites of mutation, and within aggressive DLBCL tumors harboring amplified BCL2 and MYC, supports a role for G4 structures in events that lead to a loss of genomic integrity, a critical step in B-cell lymphomagenesis.
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- 2020
34. Engineering tetravalent IgGs with enhanced agglutination potencies for trapping vigorously motile sperm in mucin matrix
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Alison Schaefer, Samuel K. Lai, Alexander Kopp, Bhawana Shrestha, Elizabeth C. Chavez, Timothy M. Jacobs, and Thomas R. Moench
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Male ,Agglutination ,0206 medical engineering ,Biomedical Engineering ,02 engineering and technology ,Biochemistry ,Antibodies ,Article ,Biomaterials ,Immune system ,Antigen ,Humans ,Molecular Biology ,biology ,Chemistry ,Mucin ,Mucins ,Sperm Agglutination ,General Medicine ,021001 nanoscience & nanotechnology ,020601 biomedical engineering ,Mucus ,Sperm ,Spermatozoa ,Agglutination (biology) ,biology.protein ,Female ,Antibody ,0210 nano-technology ,Biotechnology - Abstract
Multivalent antibodies such as sIgA can crosslink motile entities such as sperm and bacteria, creating agglomerates that are too large to permeate the dense mucin matrix in mucus, a process commonly referred to as immune exclusion. Unfortunately, sIgA remains challenging to produce in large quantities, and easily aggregates, which prevented their use in clinical applications. To develop sIgA-like tetravalent antibodies that are stable and can be easily produced in large quantities, we designed two IgGs possessing 4 identical Fab domains, with the Fabs arranged either in serial or in the diametrically opposite orientation. As a proof-of-concept, we engineered these tetravalent IgG constructs to bind a ubiquitous sperm antigen using a Fab previously isolated from an immune infertile woman. Both constructs possess at least 4-fold greater agglutination potency and induced much more rapid sperm agglutination than the parent IgG, while exhibiting comparable production yields and identical thermostability as the parent IgG. These tetravalent IgGs offer promise for non-hormonal contraception and underscores the multimerization of IgG as a promising strategy to enhance antibody effector functions based on immune exclusion.
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- 2020
35. Engineering Highly Homogenous Tetravalent IgGs with Enhanced Sperm Agglutination Potency
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Sam Lai, Elizabeth C. Chavez, Alexander Kopp, Alison Schaefer, Bhawana Shrestha, Timothy M. Jacobs, and Thomas R. Moench
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0303 health sciences ,030219 obstetrics & reproductive medicine ,biology ,medicine.drug_class ,Chemistry ,Sperm Agglutination ,Monoclonal antibody ,Sperm ,Mucus ,3. Good health ,03 medical and health sciences ,Agglutination (biology) ,0302 clinical medicine ,Immune system ,Immunology ,biology.protein ,medicine ,Potency ,Antibody ,030304 developmental biology - Abstract
Millions of women avoid using available contraceptives and risk unintended pregnancies every year, due to perceived and/or real side-effects associated with the use of exogenous hormones. Naturally occurring anti-sperm antibodies can prevent fertilization in immune infertile women by limiting sperm permeation through mucus, particularly multivalent antibodies such as sIgA that offers robust agglutination potencies. Unfortunately, sIgA remains challenging to produce in large quantities and easily aggregates. Here, we designed two tetravalent anti-sperm IgGs with a Fab domain previously isolated from an immune infertile woman. Both constructs possess at least 4-fold greater agglutination potency and induced much more rapid sperm agglutination than the parent IgG while exhibiting comparable production yields and identical thermostability as the parent IgG. These tetravalent IgGs offer promise for non-hormonal contraception and underscore the multimerization of IgG as a promising strategy to improve existing mAb therapeutics.
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- 2020
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36. Engineering highly multivalent sperm-binding IgG antibodies for potent non-hormonal female contraception
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Alison Schaefer, Thomas R. Moench, Jamal I. Saada, Zhu Yong, Bhawana Shrestha, Timothy M. Jacobs, Stuart S. Omsted, Samuel K. Lai, Kathleen L. Vincent, and Elizabeth C. Chavez
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biology ,Chemistry ,medicine.drug_class ,Non hormonal ,Sperm binding ,Motile sperm ,Monoclonal antibody ,Sperm ,Mucus ,3. Good health ,Antigen ,Immunology ,medicine ,biology.protein ,Antibody - Abstract
Many women risk unintended pregnancy due to dissatisfaction with available hormonal contraceptive methods. This led us to pursue topical sperm-binding monoclonal antibodies as a strategy for safe, non-hormonal contraception. Motivated by the greater agglutination potencies of polymeric immunoglobulins such as IgM and the exceptional bioprocessing ease in manufacturing IgG, we engineered IgGs possessing 6-10 Fabs against a unique surface antigen universally present on human sperm. These highly multivalent IgGs (HM-IgGs) are at least 10- to 16-fold more potent and faster than the parent IgG at agglutinating sperm, while preserving Fc-mediated trapping of individual spermatozoa in mucus. The increased potencies translate to effective (>99.9%) reduction of progressively motile sperm in the sheep vagina using 33 micrograms of the 10 Fab HM-IgG. HM-IgGs produce at comparable yields and possess identical thermal stability to the parent IgG, with greater homogeneity. HM-IgGs represent not only promising biologics for non-hormonal contraception but also a promising platform for generating potent agglutinating mAb for diverse medical applications.
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- 2020
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37. LA TEORÍA DEL CARÁCTER SOCIAL DE ERICH FROMM: CLAVE INTERPRETATIVA DEL PROCESO DE INDUSTRIALIZACIÓN EN MÉXICO, 1957-1974
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Mariana Elizabeth Reyna Chavez and Miguel Ángel Urrego
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La teoría del carácter social, formulada por Erich Fromm en calidad de Director del Departamento de Psicología Social de la Escuela de Fráncfort durante la década 1930, condensa su aportación más relevante al campo de estudio que articula psicoanálisis y marxismo. La primera investigación empírica con base en sus conceptualizaciones tuvo lugar en Alemania, antes de que Hitler llegara al poder. Después de permanecer un período exiliado en Estados Unidos, Fromm recibió la invitación de radicar en México de parte de un prestigioso grupo de psiquiatras vinculado a instancias representativas del Estado posrevolucionario. En este país encontró un terreno propicio para impulsar otras investigaciones sustentadas en su metodología socio-psicoanalítica. El artículo destaca el análisis de una comunidad campesina del Estado de Morelos, realizado entre 1957 y 1964. Así mismo, retomamos las conclusiones un estudio concretado en la ciudad de México, en la Unidad Habitacional Legaria del Instituto Mexicano del Seguro Social (IMSS) a lo largo de la década de 1960. Se ubica la propuesta teórica sobre la salud mental elaborada por Fromm en el debate sobre las políticas públicas necesarias para encauzar a las sociedades latinoamericanas en la vía de la modernización. Veremos que para los especialistas en las disciplinas psi ligados al connotado sociólogo y analista alemán, la teoría del carácter social fue una clave interpretativa de las vicisitudes políticas, culturales y subjetivas que conllevaba el proceso de industrialización en México.
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- 2020
38. Propiedades físicas del suelo en diferentes sistemas agrícolas en la provincia de Los Ríos, Ecuador
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Manuel Danilo Carrillo Zenteno, Jessica Elizabeth Cargua Chavez, Indira Dayanara Novillo Espinoza, Fátima Lourdes Morales Intriago, Karla Estefania Albán Solarte, and Virginia Nabel Moreiral
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chemistry.chemical_classification ,Moisture ,chemistry ,Hydraulic conductivity ,Agronomy ,Soil water ,Environmental science ,Organic matter ,Monoculture ,Silt ,Porosity ,Bulk density - Abstract
Los sistemas de monocultivo degradan el suelo afectando sus propiedades físicas y químicas, y su regeneración es muy lenta. Con el objetivo de conocer cambios en las propiedades físicas del suelo de la Estación Experimental Tropical Pichilingue, por efecto del uso, se empleó un diseño de bloques completos al azar con tres repeticiones, en los suelos de bosque nativo y monocultivos de maíz (30 años), cacao (50 años), pasto (4 años) y palma aceitera (26 años) en diferentes profundidades cada 0,10 m hasta los 0,6 m. Se evaluaron propiedades físicas como conductividad hidráulica, densidad aparente, densidad real, porosidad total, porosidad de aireación, humedad volumétrica, textura, arcilla dispersa en agua, grado de floculación, materia orgánica e índice de materia orgánica/limo+arcilla. Los datos fueron analizados estadísticamente y se realizó la prueba de Tuckey (P≤0,05). Se encontró que maíz, palma aceitera y pasto provocaron incrementos estadísticos significativos en la densidad aparente del suelo sin llegar a sobrepasar los niveles críticos de 1390 kg m-3 y no significativos en reducción de la porosidad total en la profundidad de 0,1-0,2 m. También, hubo alta concentración de arcillas en las primeras profundidades de los suelos cultivados, que provocó susceptibilidad a los procesos de erosión hídrica, concluyendo que el suelo bajo cultivo de palma aceitera mostró mayores diferencias estadísticas debido a la textura, afectando negativamente la densidad aparente del suelo, conductividad hidráulica, arcilla dispersa en agua, que en suma contribuyen a disminuir la estabilidad de agregados.
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- 2018
39. Assessment of Capture and Amplicon-Based Approaches for the Development of a Targeted Next-Generation Sequencing Pipeline to Personalize Lymphoma Management
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Merrill Boyle, Daisuke Ennishi, Stacy Hung, Randy D. Gascoyne, Christian Steidl, Fong Chun Chan, Andrew J. Mungall, Joseph M. Connors, Martin Jones, David W. Scott, Marco A. Marra, Elizabeth A. Chavez, Robert Kridel, Barbara Meissner, Hennady P. Shulha, and Susana Ben-Neriah
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0301 basic medicine ,Biopsy ,Chronic lymphocytic leukemia ,Follicular lymphoma ,Context (language use) ,Computational biology ,Gene mutation ,Biology ,Sensitivity and Specificity ,DNA sequencing ,Pathology and Forensic Medicine ,Cohort Studies ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Gene Frequency ,Formaldehyde ,medicine ,Humans ,Precision Medicine ,Sanger sequencing ,Paraffin Embedding ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,Amplicon ,medicine.disease ,Lymphoproliferative Disorders ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Mutation (genetic algorithm) ,symbols ,Feasibility Studies ,Molecular Medicine ,Genes, Neoplasm - Abstract
Targeted next-generation sequencing panels are increasingly used to assess the value of gene mutations for clinical diagnostic purposes. For assay development, amplicon-based methods have been preferentially used on the basis of short preparation time and small DNA input amounts. However, capture sequencing has emerged as an alternative approach because of high testing accuracy. We compared capture hybridization and amplicon sequencing approaches using fresh-frozen and formalin-fixed, paraffin-embedded tumor samples from eight lymphoma patients. Next, we developed a targeted sequencing pipeline using a 32-gene panel for accurate detection of actionable mutations in formalin-fixed, paraffin-embedded tumor samples of the most common lymphocytic malignancies: chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and follicular lymphoma. We show that hybrid capture is superior to amplicon sequencing by providing deep more uniform coverage and yielding higher sensitivity for variant calling. Sanger sequencing of 588 variants identified specificity limits of thresholds for mutation calling, and orthogonal validation on 66 cases indicated 93% concordance with whole-genome sequencing. The developed pipeline and assay identified at least one actionable mutation in 91% of tumors from 219 lymphoma patients and revealed subtype-specific mutation patterns and frequencies consistent with the literature. This pipeline is an accurate and sensitive method for identifying actionable gene mutations in routinely acquired biopsy materials, suggesting further assessment of capture-based assays in the context of personalized lymphoma management.
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- 2018
40. Immune Profiling of Diagnostic DLBCL Biopsies Dramatically Improves upon Cell-of-Origin Risk Stratification
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Stacy Hung, David Scott, Xuehai Wang, Daisuke Ennishi, Pedro Farinha, Andrew P. Weng, Tomohiro Aoki, Graham W. Slack, Aixiang Jiang, Jeffrey W. Craig, Elizabeth A. Chavez, Michael D. Nissen, Clémentine Sarkozy, and Christian Steidl
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Immune profiling ,business.industry ,Cell of origin ,Immunology ,Risk stratification ,Cancer research ,Medicine ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Background: Diffuse large B cell lymphoma (DLBCL) is an aggressive malignancy of mature B cells. The disease has traditionally been subdivided into cell-of-origin (COO) subtypes - germinal centre B cell-like (GCB) or activated B cell-like (ABC) - as determined by expression profiling or immunohistochemistry of the tumor cells. However the role of the immune microenvironment, and how the tumor and immune system interact to influence patient outcomes, remains to be fully investigated. Methods: In this project, we used mass cytometry (CyTOF) to deeply profile both tumor cell phenotypes and the immune microenvironments, alongside ABC/GCB classification and mutation profiling, in a discovery cohort of 54 DLBCL cases. As well, a validation cohort of 129 DLBCL patients were immunologically profiled by high-dimensional conventional flow cytometry, and their immune profiles alongside ABC/GCB classification, mutation profiling, and RNAseq data, were correlated with patient outcomes as measured by progression-free survival (PFS). Results: Analysis of the CyTOF/discovery cohort demonstrated that DLBCL tumor cells are phenotypically unique to each patient, with a small number of samples displaying distinct sub-clonal structure, often distinguished by differential expression of immune-related proteins like MHC-II. ABC/GCB classifications could be recapitulated based on tumor cell phenotypes, demonstrating that while COO was a robust feature, a great deal of heterogeneity exists within these established subtypes. Immunological profiling of the CyTOF/discovery cohort revealed that DLBCL samples could be divided into three distinct groups which roughly correlated with abundances of naïve, activated, or terminally differentiated T cells, respectively. This profiling schema was extended to the validation cohort of 129 patients which in turn led to identification of a subset of patients with a very high risk of disease progression (5-year PFS; 30% high risk vs. 80% low risk, p This final classifier was based on a combination of ABC-DLBCL designation, combined with the presence of an immune microenvironment dominated by terminally differentiated (CD57+) T cells. We performed a limited series of functional studies using primary DLBCL biopsy samples to characterize further these CD57+ T cells as clonally restricted and incapable of responding to antigenic challenge. Interestingly, traditional immune markers of T cell exhaustion such as PD-1, TIM3, LAG3 and TIGIT were not correlated with patient outcomes. Conclusions: Overall, this study demonstrates the utility of immune profiling in risk stratification based on initial diagnostic biopsy material and highlights a subset of DLBCL patients who may benefit from immune-based therapies to rejuvenate the anti-tumor T cell response. We conclude that T cell senescence, rather than exhaustion, is the more relevant feature in DLBCL disease biology and highlights an alternate target for immunomodulatory therapy. Figure 1 Figure 1. Disclosures Craig: Bayer: Consultancy. Slack: Seagen: Consultancy, Honoraria. Scott: Abbvie: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; Rich/Genentech: Research Funding; Janssen: Consultancy, Research Funding; Incyte: Consultancy. Steidl: Epizyme: Research Funding; Bayer: Consultancy; Curis Inc.: Consultancy; Seattle Genetics: Consultancy; AbbVie: Consultancy; Trillium Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding.
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- 2021
41. Single-Cell Profiling Reveals Clinically Relevant Evolutionary Trajectories and Alternate Biologies in Human Follicular Lymphoma
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Xuehai Wang, Aly Karsan, Deanne Gracias, Michael D. Nissen, Clémentine Sarkozy, Christian Steidl, Rashedul Islam, Sohrab P. Shah, Gerben Duns, Andrew P. Weng, Gabriela Cristina Segat, Guillermo Simkin, Kateryna Tyshchenko, Jeffrey W. Craig, Ryan R. Brinkman, Laurie H. Sehn, Stacy Hung, Ciara L. Freeman, Jubin Kim, David Scott, Elizabeth A. Chavez, Martin Hirst, Manabu Kusakabe, Tomohiro Aoki, Aixiang Jiang, Kerry J. Savage, and Christina M. May
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Profiling (computer programming) ,medicine.anatomical_structure ,Immunology ,Cell ,Follicular lymphoma ,medicine ,Cancer research ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry - Abstract
Follicular lymphoma (FL) is an indolent lymphoma of mature B-cells but may transform to a more aggressive histology, most commonly diffuse large B cell lymphoma. Recurrent mutations associated with transformation have been identified; however, biological predictors to guide initial therapy have remained elusive. We hypothesized that clonal heterogeneity and patient-specific immune responses would contribute to variable clinical outcomes and that understanding the complexity of the entire tumor "ecosystem" would allow more individualized matching of patients with specific therapies. In prior ASH meetings, we presented preliminary analyses of B and T cell-focused phenotypic profiling of 155 newly diagnosed pre-treatment FL biopsy samples at single cell resolution by mass cytometry (CyTOF). These prior analyses unexpectedly revealed two distinct evolutionary trajectories which were independently reflected in both B and T cell compartments. One trajectory expectedly involved germinal center B cells (GCB); however, the other was more related to naïve/memory B-cells (NMB). Interestingly, cluster co-occurrence analysis suggested that the GCB and NMB trajectories were mutually exclusive of another and tended not to be found within the same tumor despite their high prevalences (χ 2 = 29.8, DF=1, p=4.8e-8; χ 2 test). Clustering analysis based on relative abundances of T cell subsets revealed 4 distinct immune patterns: Group 1 was characterized by naive T cells; Group 2 by T follicular helper (Tfh) cells; Group 3 by CD4+ regulatory T (Treg) and CD8 effector memory cells (CD8EM); and Group 4 by a diverse complement of naive, memory, and differentiated effector subsets. We report here further analyses, now incorporating DNA mutational and clinical outcome information. Tumors were parsed into 3 types based on the phenotype of the majority (>50%) of tumor cells present in the diagnostic biopsy: Type A tumors dominated by GCB cells (28% of samples), type B tumors dominated by NMB cells (18% of samples), and type nonA/nonB tumors dominated by neither GCB nor NMB cells (54% of samples). Type A tumors were significantly enriched for mutations in EZH2, TNFRSF14, and MEF2B, while no significant mutational associations were seen in type B and nonA/nonB tumors. Type B was significantly associated with increased risk of transformation, and when combined with a measure of intratumoral phenotypic diversity ("Entropy"), we found that type B tumors with high (above median) Entropy, representing 8.5% of all cases, exhibited a hazard ratio (HR) of 5.9 for transformation risk in comparison to all others combined (log-rank p We also investigated survival outcomes using a sub-cohort of 108 patients who had received bendamustine + rituximab (BR) as their primary therapy. Despite the association of type B tumors with transformation risk, patients with type nonA/nonB tumors exhibited the poorest outcomes as measured by disease-specific survival (DSS; 5yr survival 78% vs 98% for all others combined, log-rank p=0.0241). Combining type nonA/nonB with high Entropy defined 20% of patients with significantly shorter DSS (HR 5.3, log-rank p=0.0019). In multivariate analysis, type nonA/nonB and high risk FLIPI score were significant (p=0.038 and 0.035, respectively), while high Entropy trended with inferior DSS (HR 2.8, 95% CI 0.76-10; p=0.123). Taken together, these data support that CyTOF-defined phenotypic subtypes of FL and intratumoral phenotypic diversity identify clinically significant subgroups at initial diagnosis and compare favorably against FLIPI score in predicting both risk of transformation and inferior DSS. Figure 1 Figure 1. Disclosures Freeman: Incyte: Honoraria; Seattle Genetics: Honoraria; Sanofi: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Amgen: Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Teva: Research Funding; Abbvie: Honoraria; Roche: Research Funding. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Savage: BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Seattle Genetics: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; Takeda: Other: Institutional clinical trial funding; Roche: Research Funding; Servier: Consultancy, Honoraria; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Craig: Bayer: Consultancy. Scott: Abbvie: Consultancy; AstraZeneca: Consultancy; Incyte: Consultancy; Celgene: Consultancy; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; Rich/Genentech: Research Funding; Janssen: Consultancy, Research Funding. Steidl: Trillium Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy; Seattle Genetics: Consultancy; Curis Inc.: Consultancy; Bayer: Consultancy; Epizyme: Research Funding.
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- 2021
42. Single Cell Profiling Reveals Unique CXCL13 Positive T Cell Subsets in the Tumor Microenvironment of Lymphocyte Rich Classic Hodgkin Lymphoma
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Tomohiro Aoki, Katsuyoshi Takata, Adele Telenius, Susana Ben-Neriah, Katy Milne, Sohrab P. Shah, Kerry J. Savage, Elizabeth A. Chavez, Merrill Boyle, Christian Steidl, Tomoko Miyata-Takata, Lauren C. Chong, Pedro Farinha, David W. Scott, Brad H. Nelson, Andrew P. Weng, and Doria Unrau
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Tumor microenvironment ,Cell type ,LAG3 ,T cell ,Lymphocyte ,Immunology ,Naive B cell ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Molecular biology ,Immune system ,medicine.anatomical_structure ,medicine ,CXCL13 - Abstract
Introduction: Classic Hodgkin lymphoma (CHL) features a unique crosstalk between malignant cells and different types of normal immune cells in the tumor-microenvironment (TME). On the basis of histomorphologic and immunophenotypic features of the malignant Hodgkin and Reed-Sternberg (HRS) cells and infiltrating immune cells, four histological subtypes of CHL are recognized: Nodular sclerosing (NS), Mixed cellularity, Lymphocyte-rich (LR) and Lymphocyte-depleted CHL. Recently, our group described the high abundance of various types of immunosuppressive CD4+ T cells including LAG3+ and/or CTLA4+ cells in the TME of CHL using single cell RNA sequencing (scRNAseq). However, the TME of LR-CHL has not been well characterized due to the rarity of the disease. In this study, we aimed at characterizing the immune cell profile of LR-CHL at single cell resolution. METHODS: We performed scRNAseq on cell suspensions collected from lymph nodes of 28 primary CHL patients, including 11 NS, 9 MC and 8 LR samples, with 5 reactive lymph nodes (RLN) serving as normal controls. We merged the expression data from all cells (CHL and RLN) and performed batch correction and normalization. We also performed single- and multi-color immunohistochemistry (IHC) on tissue microarray (TMA) slides from the same patients. In addition, an independent validation cohort of 31 pre-treatment LR-CHL samples assembled on a TMA, were also evaluated by IHC. Results: A total of 23 phenotypic cell clusters were identified using unsupervised clustering (PhenoGraph). We assigned each cluster to a cell type based on the expression of genes described in published transcriptome data of sorted immune cells and known canonical markers. While most immune cell phenotypes were present in all pathological subtypes, we observed a lower abundance of regulatory T cells (Tregs) in LR-CHL in comparison to the other CHL subtypes. Conversely, we found that B cells were enriched in LR-CHL when compared to the other subtypes and specifically, all four naïve B-cell clusters were quantitatively dominated by cells derived from the LR-CHL samples. T follicular helper (TFH) cells support antibody response and differentiation of B cells. Our data show the preferential enrichment of TFH in LR-CHL as compared to other CHL subtypes, but TFH cells were still less frequent compared to RLN. Of note, Chemokine C-X-C motif ligand 13 (CXCL13) was identified as the most up-regulated gene in LR compared to RLN. CXCL13, which is a ligand of C-X-C motif receptor 5 (CXCR5) is well known as a B-cell attractant via the CXCR5-CXCL13 axis. Analyzing co-expression patterns on the single cell level revealed that the majority of CXCL13+ T cells co-expressed PD-1 and ICOS, which is known as a universal TFH marker, but co-expression of CXCR5, another common TFH marker, was variable. Notably, classical TFH cells co-expressing CXCR5 and PD-1 were significantly enriched in RLN, whereas PD-1+ CXCL13+ CXCR5- CD4+ T cells were significantly enriched in LR-CHL. These co-expression patterns were validated using flow cytometry. Moreover, the expression of CXCR5 on naïve B cells in the TME was increased in LR-CHL compared to the other CHL subtypes We next sought to understand the spatial relationship between CXCL13+ T cells and malignant HRS cells. IHC of all cases revealed that CXCL13+ T cells were significantly enriched in the LR-CHL TME compared to other subtypes of CHL, and 46% of the LR-CHL cases showed CXCL13+ T cell rosettes closely surrounding HRS cells. Since PD-1+ T cell rosettes are known as a specific feature of LR-CHL, we confirmed co-expression of PD-1 in the rosetting cells by IHC in these cases. Conclusions: Our results reveal a unique TME composition in LR-CHL. LR-CHL seems to be distinctly characterized among the CHL subtypes by enrichment of CXCR5+ naïve B cells and CD4+ CXCL13+ PD-1+ T cells, indicating the importance of the CXCR5-CXCL13 axis in the pathogenesis of LR-CHL. Figure Disclosures Savage: BeiGene: Other: Steering Committee; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Scott:Janssen: Consultancy, Research Funding; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy. Steidl:AbbVie: Consultancy; Roche: Consultancy; Curis Inc: Consultancy; Juno Therapeutics: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding.
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- 2020
43. TRAF3 Loss Drives Alternative NF-κB Pathway Activation in Diffuse Large B-Cell Lymphoma
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Elena Viganò, Shannon Healy, Adele Telenius, David Scott, Vivian Lam, Michael Y. Li, Gerald Krystal, Bruce Woolcock, Christian Steidl, Elizabeth A. Chavez, and Lauren C. Chong
- Subjects
TRAF3 ,chemistry.chemical_compound ,Chemistry ,Immunology ,Cancer research ,medicine ,NF-κB ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Diffuse large B-cell lymphoma - Abstract
Introduction: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor family that regulates gene expression programs contributing to inflammation and cell survival. NF-κB signaling occurs via two branches: classical and alternative, and is often enriched in somatic mutations of key pathway members in several lymphoid malignancies. Here, we reveal deregulation and constitutive activation of the alternative NF-κB pathway in a subset of DLBCL patients with recurrent genomic loss of the gene encoding tumor necrosis factor receptor-associated factor 3 (TRAF3), a regulator of the NF-κB signaling pathway. Methods and Results: To uncover novel driver mutations of DLBCL pathogenesis and tumor maintenance, we performed Affymetrix SNP6.0 copy number analysis on 347 de novo DLBCL samples from patients uniformly treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). We observed frequent, focal genomic loss of chr:14q32.31-32 which included TRAF3 and RCOR1 (7%, 22/313) in the minimally deleted region and an enrichment of activated B-cell-like (ABC) subtype cases over germinal center B-cell-like (GCB) subtype cases, confirming previously published data (Chan et al, Blood 2014). RNAseq of these DLBCL samples revealed a significant reduction of TRAF3 mRNA in chr:14q32.31-32 deleted cases compared to copy number neutral cases (p=0.002). Next, we focused on characterizing the phenotypic consequences of TRAF3 loss in DLBCL. We used CRISPR/Cas9 gene editing to knock out TRAF3 in 2 GCB-DLBCL (DOHH2, OCI-LY1) and 2 ABC-DLBCL (HBL1, OCI-LY3) cell lines. We performed immunoblotting analysis of NF-κB pathway members on cell fractionated samples of TRAF3 knockout cells and found increased levels of the NF-κB inducing kinase NIK (a direct target of TRAF3-mediated ubiquitin-proteasome degradation) and a concomitant increased nuclear translocation of NF-κB transcription factor complex subunits RelB and p52. Proteasome blockade restored RelB cytoplasmic localization and reduced processed p52 protein in TRAF3 knockout GCB-DLBCL lines only, indicating other factors may contribute to alternative NF-κB activation in ABC-DLBCL. Moreover, classical NF-κB activation remained unaffected, highlighting the specific role of TRAF3 regulation on the alternative NF-κB pathway in DLBCL. Consistent with these findings, TRAF3 knockout cells exhibited NF-κB-dependent transcriptional upregulation by luciferase reporter activity and elevated pro-inflammatory cytokine production (IL-6, TNF-β) by Luminex and ELISA. To study transcriptome changes as a result of TRAF3 loss-of-function, we performed RNAseq and differential gene expression analysis on wildtype and TRAF3 knockout DLBCL cell lines as well as primary DLBCL samples (N=347). We found enrichment of NIK and NF-κB associated pathways in TRAF3 deficient DLBCL and uncovered additional enriched gene sets including those involved in cell cycle regulation, cell division and metabolism, suggesting a potential proliferative and survival advantage. Conclusion: Our findings link TRAF3 loss-of-function to clinical and gene expression phenotypes in DLBCL and highlight alternative NF-κB activation as a pathogenically important pathway in both GCB and ABC subtypes. Future studies will be directed towards comprehensive evaluation of NF-κB inhibitors for effective blockade of constitutive alternative NF-κB activation in DLBCL. Disclosures Scott: NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding. Steidl:Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Consultancy; Curis Inc: Consultancy; Juno Therapeutics: Consultancy; Bayer: Consultancy; AbbVie: Consultancy.
- Published
- 2020
44. Abstract 1321: CarboCell provides new opportunities for image-guided high-precision intratumoral combinatorial immunotherapy
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Thomas Lars Andresen, Sophie B. Jensen, Holmfridur R. Haldorsdottir, Linda Maria Bruun, Anders Elias Hansen, Elizabeth S. Chavez, Fredrik Melander, Marouschka J. Scheeper, and Jonas Rosager Henriksen
- Subjects
Cancer Research ,Tumor microenvironment ,business.industry ,medicine.medical_treatment ,Necroptosis ,Cancer ,Immunotherapy ,Acquired immune system ,medicine.disease ,medicine.anatomical_structure ,Immune system ,Oncology ,Cancer cell ,Cancer research ,Medicine ,business ,Lymph node - Abstract
Intratumoral immune activating therapy is biologically supported by the cancer immune response being generated in the tumor microenvironment (TME) and draining lymph nodes. Successful intratumoral immune activation is however challenging as the cells in the TME are plastic and reactive, and therefore requires continuous stimulation. This is problematic as drugs are rapidly washed out of tumors, and frequent intratumoral injections limit manageable locations, patient compliance and provides risks for cancer cell dissemination. The CarboCell technology overcomes this by forming a positionally stable drug release depot at the injection site with tailored release profiles of single or multiple drugs. Here we demonstrate the therapeutic performance of a CarboCell formulation releasing a TLR7/8 agonist and a TGFb inhibitor (CarboCell TLR:TGFb). CarboCell provides intratumoral drug retention up to 90% at day 3 and 50% at day 7 after injection in mouse tumors and beyond 14 days in canines. By control of the release kinetics, more than five times the systemically tolerated drug dose was tolerated for intratumoral CarboCell TLR:TGFb even at repeated dosing. CarboCell TLR:TGFb combinatorial therapy provided complete tumor rejection in 71%, 67% and 89% of mice carrying large MC38, EMT-6 and CT26 tumors. The dual drug CarboCell TLR:TGFb formulation was therapeutically superior to single drug CarboCell formulations, which underlines the synergistic value the combinatorial therapy. CarboCell TLR:TGFb was further demonstrated to inhibit lung metastasis in highly metastatic cancer models. Mechanistically, CarboCell TLR:TGFb activated the innate and adaptive immune system. Inflammatory cytokines were rapidly induced and accompanied by cancer cells necroptosis. This was followed by an increased number and activation of central DCs in the tumor draining lymph node and anti-cancer specific T cells in the tumor. CarboCell TLR:TGFb demonstrate potent immune activating properties and overcomes the multifactorial immunosuppressive barriers in the TME. Clinically attractive features of CarboCell further includes intrinsic MR and US visibility and radiographic contrast. This, in combination with full compatibility with high precision thin needle injection technologies, makes image guided injection, therapeutic planning, interpretation and validation of clinical performance possible. Combined, the unprecedented drug release and imaging properties of CarboCell makes the technology highly attractive for clinical advancement. Citation Format: Sophie B. Jensen, Elizabeth S. Chavez, Hólmfridur R. Haldórsdóttir, Fredrik Melander, Marouschka J. Scheeper, Linda M. Bruun, Jonas R. Henriksen, Anders Elias Hansen, Thomas L. Andresen. CarboCell provides new opportunities for image-guided high-precision intratumoral combinatorial immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1321.
- Published
- 2021
45. Real Time Neuromorphic Camera Architecture Implemented with Quadratic Emphasis in an FPGA
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Ruben Ortega-Gonzalez, Polytechnic, Elizabeth Fonseca Chavez, Mario A. Ibarra-Carrillo, and Julio C. Sosa
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Quadratic equation ,Neuromorphic engineering ,Computer science ,business.industry ,020208 electrical & electronic engineering ,Emphasis (telecommunications) ,0202 electrical engineering, electronic engineering, information engineering ,02 engineering and technology ,Architecture ,business ,Field-programmable gate array ,Computer hardware ,020202 computer hardware & architecture - Published
- 2017
46. Bio-inspired for Detection of Moving Objects Using Three Sensors
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Dept. Telecommunications, F.I. Unam, Ciudad de México, Mexico, Mario Alfredo Ibarra Carrillo, and Elizabeth Fonseca Chavez
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0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Computer science ,030217 neurology & neurosurgery - Published
- 2017
47. Bacteriocins of Gram-positive bacteria: Features and biotherapeutic approach
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Tania Elizabeth Velasquez Chavez, David Francisco Lafuente-Rincon, and Norma M de la Fuente-Salcido
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0301 basic medicine ,biology ,medicine.drug_class ,Gram-positive bacteria ,030106 microbiology ,Antibiotics ,Antimicrobial peptides ,food and beverages ,Bacillus ,Plant Science ,biology.organism_classification ,Microbiology ,03 medical and health sciences ,Resistant bacteria ,Infectious Diseases ,Antibiotic resistance ,Bacteriocin ,medicine ,bacteria ,Bacteria - Abstract
Bacteriocins are potent antimicrobial peptides produced by every bacterial and archeal species reported to date. The most studied are bacteriocins produced by lactic acid bacteria (LAB) and many species of Bacillus. Knowledge on the classification, biosynthesis and transport of these peptides is changing continually because the discovery and characterization of new bacteriocins increases, thus, the research reports increase at the same rate. The bacteriocins are considered the most promising molecules with enormous possibilities and realities for the design of improved antibiotics possessing specific characteristics, mostly against antibiotic resistant bacteria. Here, current information on the generalities, classification proposals, biosynthesis and transport systems involved in the bacteriocins secretion is review. Finally, this review will focus on the new approaches for its application in veterinary medicine and human health. Key words: Bacteriocin, biotherapeutic, resistant bacteria, human health.
- Published
- 2016
48. Single Cell Phenotypic Profiling of 27 DLBCL Cases Reveals Marked Intertumoral and Intratumoral Heterogeneity
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Xuehai Wang, Ryan R. Brinkman, Deanne Gracias, Elizabeth A. Chavez, Pedro Farinha, Graham W. Slack, Joseph M. Connors, Michael D. Nissen, Ainsleigh Hill, Christian Steidl, Manabu Kusakabe, Kateryna Tyshchenko, Guillermo Simkin, Andrew P. Weng, Justin Meskas, Stacy Hung, Daisuke Ennishi, Randy D. Gascoyne, Clémentine Sarkozy, David W. Scott, and Tomohiro Aoki
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0301 basic medicine ,Histology ,medicine.diagnostic_test ,Combination chemotherapy ,Cell Biology ,Biology ,medicine.disease ,Phenotype ,Pathology and Forensic Medicine ,Flow cytometry ,Lymphoma ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Biopsy ,Mutation ,medicine ,HLA-DR ,Cancer research ,Humans ,Mass cytometry ,Lymphoma, Large B-Cell, Diffuse ,Cytometry - Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and is notorious for its clinical heterogeneity. Patient outcomes can be predicted by cell-of-origin (COO) classification, demonstrating that the underlying transcriptional signature of malignant B-cells informs biological behavior in the context of standard combination chemotherapy regimens. In the current study, we used mass cytometry (CyTOF) to examine tumor phenotypes at the protein level with single cell resolution in a collection of 27 diagnostic DLBCL biopsy specimens from treatment naive patients. We found that malignant B-cells from each patient occupied unique regions in 37-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Interestingly, variable MHC class II expression was found to be the greatest contributor to phenotypic diversity. Within individual tumors, a subset of cases showed multiple phenotypic subpopulations, and in one case, we were able to demonstrate direct correspondence between protein-level phenotypic subsets and DNA mutation-defined subclones. In summary, CyTOF analysis can resolve both intertumoral and intratumoral heterogeneity among primary samples and reveals that each case of DLBCL is unique and may be comprised of multiple, genetically distinct subclones. © 2019 International Society for Advancement of Cytometry.
- Published
- 2019
49. Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma
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Saeed Saberi, Anthony Colombo, Pedro Farinha, Akil Merchant, Elizabeth A. Chavez, Elena Viganò, Xuehai Wang, Michael D. Nissen, Katy Milne, Christian Steidl, Katsuyoshi Takata, Bruce Woolcock, Sohrab P. Shah, Tomohiro Aoki, Allen W. Zhang, Anja Mottok, Kerry J. Savage, Chanel Ghesquiere, Lauren C. Chong, Daniel Kos, Tomoko Miyata-Takata, Michael Yu Li, David Scott, Jubin Kim, Talia Goodyear, Monirath Hav, Shannon Healy, Gerald Krystal, Jiarui Ding, Adele Telenius, Johanna Veldman, Vivian Lam, Andrew P. Weng, and Brad H. Nelson
- Subjects
0301 basic medicine ,Male ,LAG3 ,T cell ,Population ,T-Lymphocytes, Regulatory ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Single-cell analysis ,immune system diseases ,T-Lymphocyte Subsets ,hemic and lymphatic diseases ,MHC class I ,medicine ,Tumor Microenvironment ,Humans ,education ,education.field_of_study ,Tumor microenvironment ,biology ,Sequence Analysis, RNA ,Gene Expression Profiling ,Hodgkin Disease ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,Single-Cell Analysis ,Transcriptome - Abstract
Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma–specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma–associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class II–deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma. Significance: We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell–like immunosuppressive subset of LAG3+ T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints. See related commentary by Fisher and Oh, p. 342. This article is highlighted in the In This Issue feature, p. 327
- Published
- 2019
50. Variación en la absorción de macronutrientes en híbridos de maíz duro
- Author
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Wuellins Dennis Durango Cabanilla, Manuel Danilo Carrillo Zenteno, Betty Janet Rivadeneira Moreira, Fátima Lourdes Morales Intriago, and Jessica Elizabeth Cargua Chavez
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General Medicine - Abstract
El cultivo de maíz duro tiene importancia a nivel mundial por ser un cereal que forma parte de la canasta básica familiar, además de ser un insumo importante para la industria alimenticia de animales. Los suelos destinados al cultivo, varían en sus condiciones de fertilidad, al igual que los nuevos materiales genéticos en sus requerimientos nutricionales. Por lo antes indicado, en la Estación Experimental Tropical Pichilingue (EETP) del Instituto Nacional de Investigaciones Agropecuarias (INIAP), se realizó esta investigación con el objetivo de conocer las necesidades nutricionales de cuatro híbridos promisorios de maíz, bajo tres niveles de fertilización, las parcelas fueron planteadas en época seca y lluviosa, siguiendo un diseño de bloques completos al azar en parcelas divididas con tres repeticiones y las medias se compararon mediante la prueba de Tukey (p
- Published
- 2019
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