Sensitizing Leukemia Stem Cells to NF-κB Inhibitor Treatment in Vivo by Inactivation of Both TNF and IL-1 Signaling

We previously reported that autocrine TNF-α (TNF) is responsible for JNK pathway activation in a subset of acute myeloid leukemia (AML) patient samples, providing a survival/proliferation signaling parallel to NF-κB in AML stem cells (LSCs). In this study, we report that most TNF-expressing AML cells (LCs) also express another pro-inflammatory cytokine, IL1β, which acts in a parallel manner. TNF was produced primarily by LSCs and leukemic progenitors (LPs), whereas IL1β was mainly produced by partially differentiated leukemic blasts (LBs). IL1β also stimulates an NF-κB-independent pro-survival and proliferation signal through activation of the JNK pathway. We determined that co-inhibition of signaling stimulated by both TNF and IL1β synergizes with NF-κB inhibition in eliminating LSCs both ex vivo and in vivo. Our studies show that such treatments are most effective in M4/5 subtypes of AML

Mechanical properties and joining mechanism of hot isostatic pressing (HIP) diffusion bonded Ni60A-0Cr18Ni10Ti heterogeneous joint

Ni-Cr-B-Si alloys, as alternative alloys for Co-based alloys, are expected to be used in pump in nuclear power plants owing to their excellent wear resistance and lower dose rate. In this work, Ni60A (Ni-Cr-B-Si) hardfacing layer with high hardness (average 898 HV0.2) and excellent bonding strength (ultimate tensile strength 549 MPa) was fabricated onto 0Cr18Ni10Ti (GB/T 1220–2007) austenite steel by hot isostatic pressing (HIP) diffusion bonding technique. The Ni60A-0Cr18Ni10Ti heterogeneous joint was divided into four regions based on the microstructural difference, namely Ni60A hardfacing layer, transition zone, deformation zone and 0Cr18Ni10Ti substrate. The Ni60A hardfacing layer was mainly composed of CrB, Cr7C3, Ni3B, Ni3Si and rarely γ-Ni phases, and the synergistic effects of hard phase contents and fine grain sizes resulted in the high hardness. The transition zone was predominantly composed of equiaxed (Ni, Fe) solid solution ((Fe, Ni)ss), which was attributed to diffusion-induced recrystallization (DIR). The deformation zone exhibited discernible deformation texture, which was induced by the plastic deformation of the substrate during the HIP process. Meanwhile, nano-twins (NTs) and Cr2B borides were observed in the deformation zone near the interface, while Cr-rich carbides were observed in the deformation zone away from the interface. Uniaxial tension results of the joint revealed that the failure initiated on the Ni60A side, approximately 70 μm away from the interface, was attributed to a greater prevalence of Cr7C3 precipitates with notable stacking faults