The Kaushansky Lab in the Center for Global Infectious Disease Research at Seattle Children’s Research Institute focuses on the interactions between pathogens and the humans they infect.  A substantial part of the lab focuses on the malaria parasite (Plasmodium) and its human “host”, as well as the development of host-targeted drugs and other therapeutics. One of the major topics of our work is how the malaria parasite selects, invades and manipulates the host cell(s) within the liver...
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Mechanosensory hair cells of the zebrafish lateral line regenerate rapidly following damage. These renewed hair cells arise from the proliferation of surrounding support cells, which undergo symmetric division to produce two hair cell daughters. Given the continued regenerative capacity of the lateral line, support cells presumably have the ability to replenish themselves. Utilizing novel transgenic lines, we identified support cell…
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Preterm birth (PTB) complications are the leading cause of long-term morbidity and mortality in children. By using whole blood samples, we integrated whole-genome sequencing (WGS), RNA sequencing (RNA-seq), and DNA methylation data for 270 PTB and 521 control families. We analyzed this combined dataset to identify genomic variants associated with PTB and secondary analyses to identify variants associated with very…
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Quantitative modeling is useful for predicting behaviors of a system and for rationally constructing or modifying the system. The predictive power of a model relies on accurate quantification of model parameters. Here, we illustrate challenges in parameter quantification and offer means to overcome these challenges, using a case example in which we quantitatively predict the growth rate of a cooperative…
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In rodent models of type 2 diabetes (T2D), sustained remission of diabetic hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1). To identify the brain area(s) responsible for this effect, we first used immunohistochemistry to map the hypothalamic distribution of phosphoERK (pERK1/2), a marker of MAP kinase-ERK signal transduction downstream of FGF receptor…
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Avoidance of innate threats is often in conflict with motivations to engage in exploratory approach behavior. The neural pathways that mediate this approach-avoidance conflict are not well resolved. Here we isolated a population of dopamine D1 receptor (D1R)-expressing neurons within the posteroventral region of the medial amygdala (MeApv) in mice that are activated either during approach or during avoidance of…
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Metagenomic sequencing is a promising approach for identifying and characterizing organisms and their functional characteristics in complex, polymicrobial infections, such as airway infections in people with cystic fibrosis. These analyses are often hampered, however, by overwhelming quantities of human DNA, yielding only a small proportion of microbial reads for analysis. In addition, many abundant microbes in respiratory samples can produce large…
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Factors associated with durable remission after CD19 chimeric antigen receptor (CAR)-modified T cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors impacting response and progression-free survival (PFS) in aggressive NHL patients treated with cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by 2×106 CD19 CAR-T cells/kg. The best overall response rate (ORR) was 51%,…
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My lab is focused on understanding small cell lung cancer (SCLC), an extremely aggressive and highly metastatic cancer type. We study genes mutated in SCLC to try to understand how these genetic changes contribute to SCLC and we seek to identify new therapeutic approaches. We employ genetically engineered mouse models, patient derived xenograft models and functional screens in our research program. One area of particular interest is in the high number of mutations in genes that regulate...
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Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease-negative complete remission (MRD-negative CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR-T cells have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase I/II clinical trial…
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