Despite the success of immune checkpoint blockade against melanoma, many "cold" tumors like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent across preclinical prostate cancer and resisted T cell infiltration even in the context of CTLA-4 and PD-1 blockade. We demonstrated that the hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia in these tumors. Combination therapy with this hypoxia-prodrug and checkpoint blockade cooperated to cure more than 80% of tumors in the transgenic adenocarcinoma of the mouse prostate-derived (TRAMP-derived) TRAMP-C2 model. Immunofluorescence imaging showed that TH-302 drives an influx of T cells into hypoxic zones, which were expanded by checkpoint blockade. Further, combination therapy reduced myeloid-derived suppressor cell density by more than 50%, and durably reduced the capacity of the tumor to replenish the granulocytic subset. Spontaneous prostate tumors in TRAMP transgenic mice, which completely resist checkpoint blockade, showed minimal adenocarcinoma tumor burden at 36 weeks of age and no evidence of neuroendocrine tumors with combination therapy. Survival of Pb-Cre4, Ptenpc-/-Smad4pc-/- mice with aggressive prostate adenocarcinoma was also significantly extended by this combination of hypoxia-prodrug and checkpoint blockade. Hypoxia disruption and T cell checkpoint blockade may sensitize some of the most therapeutically resistant cancers to immunotherapy.

Thermal runaway is a well-known safety concern in Li-ion cells. Methods to predict and prevent thermal runaway are critically needed for enhanced safety and performance. While much work has been done on understanding the kinetics of various heat generation processes during thermal runaway, relatively lesser work exists on understanding how heat removal from the cell influences thermal runaway. Through a unified analysis of heat generation and heat removal, this paper derives and experimentally validates a non-dimensional parameter whose value governs whether or not thermal runaway will occur in a Li-ion cell. The parameter comprises contributions from thermal transport within and outside the cell, as well as the temperature dependence of heat generation rate. Experimental data using a 26650 thermal test cell are in good agreement with the model, and demonstrate the dependence of thermal runaway on various thermal transport and heat generation parameters. This parameter is used to predict the thermal design space in which the cell will or will not experience thermal runaway. By combining all thermal processes contributing to thermal runaway in a single parameter, this work contributes

Mesenchymal stem cells (MSCs) although used for bone tissue engineering are limited by the requirement of isolation and culture prior to transplantation. Our recent studies have shown that biomaterial implants can be engineered to facilitate the recruitment of MSCs. In this study, we explore the ability of these implants to direct the recruitment and the differentiation of MSCs in the setting of a bone defect. We initially determined that both stromal derived factor-1alpha (SDF-1α) and erythropoietin (Epo) prompted different degrees of MSC recruitment. Additionally, we found that Epo and bone morphogenetic protein-2 (BMP-2), but not SDF-1α, triggered the osteogenic differentiation of MSCs in vitro. We then investigated the possibility of directing autologous MSC-mediated bone regeneration using a murine calvaria model. Consistent with our in vitro observations, Epo-releasing scaffolds were found to be more potent in bridging the defect than BMP-2 loaded scaffolds, as determined by Computed Tomography (CT) scanning, fluorescent imaging and histological analyses. These results demonstrate the tremendous potential, directing the recruitment and differentiation of autologous MSCs has in the field of tissue regeneration.

Key Points A CD34-selected, T-cell–depleted alternative donor graft after a reduced conditioning regimen resulted in engraftment in patients with sickle cell. This approach was associated with a low incidence of acute and chronic graft-versus-host disease and very good survival.

While Li-ion cells offer excellent energy conversion and storage capabilities for multiple applications, including electric vehicles, heat removal from a Li-ion cell remains a serious technological challenge that directly limits performance, and poses serious safety concerns. Due to poor thermal conductivity of Li-ion cells, traditional cooling methods like air cooling on the cell surface do not effectively access and cool the core. This may lead to overheating of the cell core. This paper investigates the cooling of Li-ion cells using an annular channel through the axis of the cell. Air flow through this channel and heat pipe insertion are both shown to result in effective cooling. A temperature reduction of 18-20 °C in the cell core is observed in heat pipe experiments, depending on heat pipe size, for 1.62W heat dissipation. Similar effect is observed when a thin metal rod is used instead of a heat pipe. Experimental measurements are within 10% of finite-element simulation results. Experiments demonstrate that a heat pipe successfully prevents overheating in case of sudden increase in heat generation due to malfunction such as 3 cell shorting. This paper illustrates fundamental thermal-electrochemical trade-offs, and facilitates the development of novel and effective cooling techniques for Li-ion cells.

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In this retrospective cohort study, physostigmine administration to reverse anticholinergic delirium had a good safety profile, and often improved or resolved anticholinergic delirium when administered in doses less than 2 mg.

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