GRP78-CAR T cell effector function against solid and brain tumors is controlled by GRP78 expression on T cells.

Lack of targetable antigens is a key limitation for developing successful T cell-based immunotherapies. Members of the unfolded protein response (UPR) represent ideal immunotherapy targets because the UPR regulates the ability of cancer cells to resist cell death, sustain proliferation, and metastasize. Glucose-regulated protein 78 (GRP78) is a key UPR regulator that is overexpressed and translocated to the cell surface of a wide variety of cancers in response to elevated endoplasmic reticulum (ER) stress. We show that GRP78 is highly expressed on the cell surface of multiple solid and brain tumors, making cell surface GRP78 a promising chimeric antigen receptor (CAR) T cell target. We demonstrate that GRP78-CAR T cells can recognize and kill GRP78+ brain and solid tumors in vitro and in vivo. Additionally, our findings demonstrate that GRP78 is upregulated on CAR T cells upon T cell activation; however, this expression is tumor-cell-line specific and results in heterogeneous GRP78-CAR T cell therapeutic response.

Tackling Quality-It's Never a Level Playing Field: Companion Piece to the Neurology Outcome Measure Set.

The American Academy of Neurology (AAN) has recently proposed 3 outcome metrics crafted to be both broadly applicable across neurologic diseases and to function as potential tools to facilitate quality improvement. These measures should be of interest to physicians and payers due to the increasing linkage of reimbursement to quality care. However, the use of quality measures cannot exist in a vacuum as external factors outside of physician control can negatively affect these metrics. The original Centers for Medicare and Medicaid (CMS) value-based programs illustrate the necessity for iterative review and revision of outcome metrics to allow for risk adjustment to avoid unjust penalties. Accordingly, at this time, the Neurology Outcome Measurement Set is not suitable for inclusion in a quality payment program.

Teaching the process of science through COVID-19 pandemic themes.

Several predominant themes have emerged during the COVID-19 global pandemic that intersect with the nature and process of science. This paper identifies three such themes and briefly explores how they can be used as case studies and narrative cornerstones in teaching and learning. The themes include: (1) the understanding that science is cumulative and ever-changing, meaning that new findings may cause us to reconsider previous understandings; (2) the importance of citation tracking in the process of science; and (3) the need for accessible and purposeful science communication.

Superoxide dismutase activity enabled by a redox-active ligand rather than metal.

Reactive oxygen species are integral to many physiological processes. Although their roles are still being elucidated, they seem to be linked to a variety of disorders and may represent promising drug targets. Mimics of superoxide dismutases, which catalyse the decomposition of O2•- to H2O2 and O2, have traditionally used redox-active metals, which are toxic outside of a tightly coordinating ligand. Purely organic antioxidants have also been investigated but generally require stoichiometric, rather than catalytic, doses. Here, we show that a complex of the redox-inactive metal zinc(II) with a hexadentate ligand containing a redox-active quinol can catalytically degrade superoxide, as demonstrated by both reactivity assays and stopped-flow kinetics studies of direct reactions with O2•- and the zinc(II) complex. The observed superoxide dismutase catalysis has an important advantage over previously reported work in that it is hastened, rather than impeded, by the presence of phosphate, the concentration of which is high under physiological conditions.

Adding a Second Quinol to a Redox-Responsive MRI Contrast Agent Improves Its Relaxivity Response to H2O2.

The overproduction of reactive oxygen species has been linked to a wide array of health disorders. The ability to noninvasively monitor oxidative stress in vivo could provide substantial insight into the progression of these conditions and, in turn, could facilitate the development of better diagnosis and treatment options. A mononuclear Mn(II) complex with the redox-active ligand N,N'-bis(2,5-dihydroxybenzyl)-N,N'-bis(2-pyridinylmethyl)-1,2-ethanediamine (H4qtp2) was made and characterized. A previously prepared Mn(II) complex with a ligand containing a single quinol subunit was found to display a modest T1-derived relaxivity response to H2O2. The introduction of a second redox-active quinol both substantially improves the relaxivity response of the complex to H2O2 and reduces the cytotoxicity of the sensor but renders the complex more susceptible to transmetalation. The addition of H2O2 partially oxidizes the quinol subunits to para-quinones, concomitantly increasing the r1 from 5.46 mM-1 s-1 to 7.17 mM-1 s-1. The oxidation of the ligand enables more water molecules to coordinate to the metal ion, providing an explanation for the enhanced relaxivity. That the diquinol complex is only partially oxidized by H2O2 is attributed to its activity as an antioxidant; the complex can both catalytically degrade superoxide and serve as a hydrogen atom donor.