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Activation of apoptosis in malignant cells is an established strategy for controlling cancer and is potentially curative. To assess the impact of concurrently inducing the extrinsic and intrinsic apoptosis-signaling pathways in acute myeloid leukemia (AML), we evaluated activity of the TRAIL receptor agonistic fusion protein eftozanermin alfa (eftoza; ABBV-621) in combination with the B-cell lymphoma protein-2 selective inhibitor venetoclax in preclinical models and human patients. Simultaneously stimulating intrinsic and extrinsic apoptosis-signaling pathways with venetoclax and eftoza, respectively, enhanced their activities in AML cell lines and patient-derived ex vivo/in vivo models. Eftoza activity alone or plus venetoclax required death receptor 4/5 (DR4/DR5) expression on the plasma membrane but was independent of TP53 or FLT3-ITD status. The safety/tolerability of eftoza as monotherapy and in combination with venetoclax was demonstrated in patients with relapsed/refractory AML in a phase 1 clinical trial. Treatment-related adverse events were reported in 2 of 4 (50%) patients treated with eftoza monotherapy and 18 of 23 (78%) treated with eftoza plus venetoclax. An overall response rate of 30% (7/23; 4 complete responses [CRs], 2 CRs with incomplete hematologic recovery, and 1 morphologic leukemia-free state) was reported in patients who received treatment with eftoza plus venetoclax and 67% (4/6) in patients with myoblasts positive for DR4/DR5 expression; no tumor responses were observed with eftoza monotherapy. These data indicate that combination therapy with eftoza plus venetoclax to simultaneously activate the extrinsic and intrinsic apoptosis-signaling pathways may improve clinical benefit compared with venetoclax monotherapy in relapsed/refractory AML with an acceptable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT03082209.

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The two key aspects of water infrastructure – engineered and human – in mid-nineteenth-century Rio de Janeiro are the foci of this article. On the one hand, gravity flow engineering brought fresh water from the Tijuca Forest to the fountains in the city, but on the other, hundreds of slaves carried heavy jugs of water from the fountains though the streets to residences. Using the account of Thomas Ewbank (1856), georeferenced historical maps and a field study, this article first reconstructs the route of the Carioca Aqueduct, then, using the accounts of Ewbank and other travellers, turns to the delivery of water in the city by enslaved water carriers.

PCR primers and conditions. Figure S1. MCL-1 protein expression in parental cell lines and venetoclax-resistant populations. MCL-1 protein expression was measured using an assay developed based on the Luminex technology [19]. In brief, MCL-1 capture antibody (Santa Cruz Biotechnology Inc., Santa Cruz, CA) was custom-conjugated to Luminex carboxyl beads (bead region 9) by Millipore (St. Charles, MO, USA). MCL-1 detection antibody (Santa Cruz Biotechnology Inc.) was also conjugated to biotin through a custom service provided by Millipore. Cells were lysed in MILLIPLEX MAP lysis buffer 1 (Millipore Cat. no. 43-040, Danvers, MA, USA) containing protease inhibitor cocktail (Sigma). Data are presented as median fluorescent intensity (MFI). Equivalent amounts of protein from whole cell lysates generated from parental cell lines and their venetoclax-resistant versions were assessed. The signal was read using a Luminex FlexMap 3D system (Luminex, Austin, TX). Asterisks denote p < 0.05. (PPTX 79 kb)

This essay stresses the importance of the humoural medical tradition and its lay reiterations in popular eighteenth-century British works on slavery, abolition and illness. In particular, it examines the popular medical concept of ‘seasoning’ and how contemporaries applied it to enslaved African bodies. Seasoning became a common talking point during the British abolition debate as both sides stressed different aspects of humoural theory to make their arguments. While numerous historians have used seasoning as an analytical term to explore the impact of movement on the enslaved, this essay rehabilitates its historical medical meaning and traces how abolition politics affected that meaning.