Key Points• EPHB4 promotes leukemia survival via AKT activation.• EPHB4 can be therapeutically targeted in AML with monoclonal antibodies.EPHB4, an ephrin type B receptor, is implicated in the growth of several epithelial tumors and is a promising target in cancer therapy; however, little is known about its role in hematologic malignancies. In this article, we show that EPHB4 is highly expressed in ;30% of acute myeloid leukemia (AML) samples. In an unbiased RNA interference screen of primary leukemia samples, we found that EPHB4 drives survival in a subset of AML cases.Knockdown of EPHB4 inhibits phosphatidylinositol 3-kinase/AKT signaling, and this is accompanied by a reduction in cell viability, which can be rescued by a constitutively active form of AKT. Finally, targeting EPHB4 with a highly specific monoclonal antibody (MAb131) is effective against AML in vitro and in vivo. EPHB4 is therefore a potential target in AML with high EPHB4 expression.
Cellular heterogeneity is a major cause of treatment resistance in cancer. Despite recent advances in single-cell genomic and transcriptomic sequencing, it remains difficult to relate measured molecular profiles to the cellular activities underlying cancer. Here, we present an integrated experimental system that connects single cell gene expression to heterogeneous cancer cell growth, metastasis, and treatment response. Our system integrates single cell transcriptome profiling with DNA barcode based clonal tracking in patient-derived xenograft models. We show that leukemia cells exhibiting unique gene expression respond to different chemotherapies in distinct but consistent manners across multiple mice. In addition, we uncover a form of leukemia expansion that is spatially confined to the bone marrow of single anatomical sites and driven by cells with distinct gene expression. Our integrated experimental system can interrogate the molecular and cellular basis of the intratumoral heterogeneity underlying disease progression and treatment resistance.
Aim The aim of this study is to describe safety culture as experienced by medical–surgical nurse leaders. Background Safety culture remains a barrier in safer patient care. Nurse leaders play an important role in creating and supporting a safety culture. Methods We used an inductive qualitative descriptive study using semistructured interviews, document review and observations in a Midwestern community hospital in the United States. Results Results of the study are as follows: making sure nurses are keeping patients safe, making sure nurses have nursing interventions in place, expecting nurses to stop unsafe acts or escalate when they feel uncomfortable, making sure nurses have what they need to provide safe care, organization prioritizes patient safety and making sure nurses are learning and growing emerged as themes describing safety culture. Conclusions Nurse leaders made sure patients were safe by making sure everyone was doing their best to provide safe care. Insufficient time, too many priorities, insufficient resources, poor physician behaviours and lack of respect for their role emerged as barriers to leading a safety culture. Implications for Nursing Management Organizations must remove barriers for nurse leaders to develop and lead a safety culture. Nurse leaders must learn to advocate successfully for safe nursing care and professional work environments.
Cellular heterogeneity is a major cause of treatment resistance in cancer. Despite recent advances in single-cell genomic and transcriptomic sequencing, it remains difficult to relate measured molecular profiles to the cellular activities underlying cancer. Here, we present an integrated experimental system that connects single cell gene expression to heterogeneous cancer cell growth, metastasis, and treatment response. Our system integrates single cell transcriptome profiling with DNA barcode based clonal tracking in patient-derived xenograft models. We show that leukemia cells exhibiting unique gene expression signatures respond to different chemotherapies in distinct but consistent manners across multiple mice. In addition, we uncover an unexpected yet common form of leukemia expansion that is spatially confined to the bone marrow of single anatomical sites and driven by cells with distinct gene expression signatures. Our integrated system directly and effectively interrogates the molecular and cellular basis of the intratumoral heterogeneity underlying disease progression and treatment resistance.
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