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Sökning: WFRF:(Root David E)

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1.
  • Barretina, Jordi, et al. (författare)
  • Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.
  • 2010
  • Ingår i: Nature genetics. - 1546-1718. ; 42:8, s. 715-21
  • Tidskriftsartikel (refereegranskat)abstract
    • Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.
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2.
  • Babbar-Sebens, Meghna, et al. (författare)
  • Training Water Resources Systems Engineers to Communicate : Acting on Observations from On-the-Job Practitioners
  • 2019
  • Ingår i: Journal of professional issues in engineering education and practice. - 1052-3928 .- 1943-5541. ; 145:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Engineers face the ongoing challenge to effectively communicate for diverse purposes and audiences across multiple settings. The authors interviewed 10 practicing water resources systems engineers to collect their lived experiences of the use of water resources systems analysis in their workplaces. Thematic analysis was used to identify three key communications hurdles practitioners face: stakeholder influence over the communication process, engineers as central to communication and decision making, and communication as an opportunity to educate stakeholders and engineers. Practitioners recommended classroom activities to overcome these hurdles and better integrate communications training into curricula. Recommendations include (1) expanding the use of case studies, (2) adding opportunities for role plays and team activities, (3) providing students with more practice on how to hold effective discussions, facilitate teamwork, and resolve conflicts, and (4) providing students with the broader contexts for class problems, including how political/institutional constraints, bureaucracies, and social issues may constrain communication and technical solutions. This study shares 22 example activities as online educational resources in a free, open, searchable repository and shows how activities can serve as a bottom-up approach to integrate communications training into the engineering curriculum.
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3.
  • Järås, Marcus, et al. (författare)
  • Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia
  • 2014
  • Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538. ; 211:4, s. 605-612
  • Tidskriftsartikel (refereegranskat)abstract
    • Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 alpha (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML.
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4.
  • Vu, Ly P., et al. (författare)
  • Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells
  • 2017
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036. ; 49:6, s. 866-875
  • Tidskriftsartikel (refereegranskat)abstract
    • The identity of the RNA-binding proteins (RBPs) that govern cancer stem cells remains poorly characterized. The MSI2 RBP is a central regulator of translation of cancer stem cell programs. Through proteomic analysis of the MSI2-interacting RBP network and functional shRNA screening, we identified 24 genes required for in vivo leukemia. Syncrip was the most differentially required gene between normal and myeloid leukemia cells. SYNCRIP depletion increased apoptosis and differentiation while delaying leukemogenesis. Gene expression profiling of SYNCRIP-depleted cells demonstrated a loss of the MLL and HOXA9 leukemia stem cell program. SYNCRIP and MSI2 interact indirectly though shared mRNA targets. SYNCRIP maintains HOXA9 translation, and MSI2 or HOXA9 overexpression rescued the effects of SYNCRIP depletion. Altogether, our data identify SYNCRIP as a new RBP that controls the myeloid leukemia stem cell program. We propose that targeting these RBP complexes might provide a novel therapeutic strategy in leukemia.
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