Cancer immunotherapy with immune checkpoint inhibitors (CPI) and interleukin (IL)-2 has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune system activation. Here, we addressed this need by targeting both the CPI antibodies anti-cytotoxic T-lymphocyte antigen 4 antibody (αCTLA4) + anti-programmed death-ligand 1 antibody (αPD-L1) and the cytokine IL-2 to tumors via conjugation (for the antibodies) or recombinant fusion (for the cytokine) to a collagen-binding domain (CBD) derived from the blood protein von Willebrand factor (VWF) A3 domain, harnessing the exposure of tumor stroma collagen to blood components due to the leakiness of the tumor vasculature. We show that intravenously (i.v.) administered CBD protein accumulated mainly in tumors. CBD conjugation or fusion decreases the systemic toxicity of both αCTLA4+αPD-L1 combination therapy and IL-2, for example eliminating hepatotoxicity with the CPI molecules and ameliorating pulmonary edema with IL-2. Both CBD-CPI and CBD-IL-2 suppressed tumor growth compared to their unmodified forms in multiple murine cancer models, and both CBD-CPI and CBD-IL-2 increased tumor-infiltrating CD8+ T cells. In an orthotopic breast tumor model, combination treatment with CPI and IL-2 eradicated tumors in 9 of 13 animals with the CBD-modified drugs, whereas it did so in only 1 of 13 animals with the unmodified drugs. Thus, the A3 domain of VWF can be used to improve safety and efficacy of systemically-administered tumor drugs with high translational promise.

This paper presents an experimental and numerical study of the two-phase flow in a particle packed bed, under conditions related to a blast furnace hearth. In these models, drainage velocities, slag ratio, tapping time, and maximum slag level in hearth are studied. The coke free space formed at tap hole level forms a circumference slag flow and significantly improves the hearth drainage efficiency. When the coke free space surround a part of packed bed, the effect is in proportion to the surrounded packed bed size. Such a nonaxisymmetric coke free space causes the imbalances of tap time and slag ratio.

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SUMMARYThe paper under discussion presents a detailed study on the reduction of pounding force on buildings due to expansion joints being filled with rubber. From shake table experiments and numerical simulations, the authors of the paper concluded that the rubber can reduce the maximum pounding force and hence the pounding damage to buildings. However, the writers of this short communication observed some significant issues in the experimental results as well as the numerical simulations. These observations are presented and raise questions about the validity of the results and the subsequent conclusions.

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