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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Merkel cell polyomavirus (MCPyV) accounts for 80% of all Merkel cell carcinoma (MCC) cases through expression of two viral oncoproteins: the truncated large T antigen (LT-t) and small T antigen (ST). MCPyV ST is thought to be the main driver of cellular transformation and has also been shown to increase LT protein levels through the activity of its Large-T Stabilization…
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The presence of disseminated tumour cells (DTCs) in bone marrow is predictive of poor metastasis-free survival of patients with breast cancer with localized disease. DTCs persist in distant tissues despite systemic administration of adjuvant chemotherapy. Many assume that this is because the majority of DTCs are quiescent. Here, we challenge this notion and provide evidence that the microenvironment of DTCs…
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In order to provide a comprehensive resource for human structural variants (SVs), we generated long-read sequence data and analyzed SVs for fifteen human genomes. We sequence resolved 99,604 insertions, deletions, and inversions including 2,238 (1.6 Mbp) that are shared among all discovery genomes with an additional 13,053 (6.9 Mbp) present in the majority, indicating minor alleles or errors in the…
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Our publication in Nature Immunology revealed how a rare group of white blood cells called basophils play an important role in the immune response to a bacterial infection, preventing the development of sepsis. Specifically, our studies showed that basophils were one of the first types of immune cell to appear at the sepsis infection site. The presence of basophils not only enhanced inflammation at the early stages of an immune response to infection and improved survival in mice, but did this in part by releasing an...
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