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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The Akilesh laboratory studies genome organization and function in the kidney. The kidney filter (glomerulus) is an important structure that is affected in numerous diseases such as diabetes. This study generates the first reported maps of genome structure and function in the kidney glomerulus. Using integrative analysis methods, it identifies novel target genes and pathways for human kidney disease...
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Anti-HIV broadly neutralizing antibodies (bnAbs) have revealed vaccine targets on the virus’s envelope (Env) protein and are themselves promising immunotherapies. The efficacy of bnAb-based therapies and vaccines depends in part on how readily the virus can escape neutralization. Although structural studies can define contacts between bnAbs and Env, only functional studies can define mutations that confer escape. Here, we mapped…
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Our lab in the Department of Pathology at UW is interested in how cells deal with "genetic entropy", defined as the progressive accumulation of mutations. This can occur during aging or during prolonged expression of a "mutator phenotype". Mutator phenotypes commonly arise in cancers due to mutations that compromise the fidelity of DNA replication or DNA repair. While mutators initially enjoy a more rapid evolution, they run up against a progressive loss of fitness due to the accumulation of deleterious mutations....
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Celiac disease is the most common food-induced enteropathy in humans, with a prevalence of approximately 1% worldwide. It is induced by digestion-resistant, proline- and glutamine-rich seed storage proteins, collectively referred to as “gluten,” found in wheat (Triticum aestivum). Related prolamins are present in barley (Hordeum vulgare) and rye (Secale cereale). The incidence of both celiac disease and a related condition…
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