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Insufficient reactivity against cells with low antigen density has emerged as an important cause of chimeric antigen receptor (CAR) T-cell resistance. Little is known about factors that modulate the threshold for antigen recognition. We demonstrate that CD19 CAR activity is dependent upon antigen density and that the CAR construct in axicabtagene ciloleucel (CD19-CD28ζ) outperforms that in tisagenlecleucel (CD19-4-1BBζ) against antigen-low tumors. Enhancing signal strength by including additional immunoreceptor tyrosine-based activation motifs (ITAM) in the CAR enables recognition of low-antigen-density cells, whereas ITAM deletions blunt signal and increase the antigen density threshold. Furthermore, replacement of the CD8 hinge-transmembrane (H/T) region of a 4-1BBζ CAR with a CD28-H/T lowers the threshold for CAR reactivity despite identical signaling molecules. CARs incorporating a CD28-H/T demonstrate a more stable and efficient immunologic synapse. Precise design of CARs can tune the threshold for antigen recognition and endow 4-1BBζ-CARs with enhanced capacity to recognize antigen-low targets while retaining a superior capacity for persistence. SIGNIFICANCE: Optimal CAR T-cell activity is dependent on antigen density, which is variable in many cancers, including lymphoma and solid tumors. CD28ζ-CARs outperform 4-1BBζ-CARs when antigen density is low. However, 4-1BBζ-CARs can be reengineered to enhance activity against low-antigen-density tumors while maintaining their unique capacity for persistence.This article is highlighted in the In This Issue feature, p. 627.

In this paper, we prove a result similar to results of Itoh [J. Algebra 150 (1992), pp. 101–117] and Hong-Ulrich [J. Lond. Math. Soc. (2) 90 (2014), pp. 861–878], proving that integral closure of an ideal is compatible with specialization by a general element of that ideal for ideals of height at least two in a large class of rings. Moreover, we show integral closure of sufficiently large powers of the ideal is compatible with specialization by a general element of the original ideal. In a polynomial ring over an infinite field, we give a class of squarefree monomial ideals for which the integral closure is compatible with specialization by a general linear form. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer.sup.1-3, but dysfunction due to T cell exhaustion is an important barrier to progress.sup.4-6. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion.sup.6. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells.sup.7-10. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents. Chimeric antigen receptor (CAR) T cells engineered to overexpress the canonical AP-1 transcription factor c-Jun are resistant to T cell exhaustion, and provide enhanced therapeutic benefit in mouse tumour models., Author(s): Rachel C. Lynn [sup.1] [sup.11] , Evan W. Weber [sup.1] , Elena Sotillo [sup.1] , David Gennert [sup.2] , Peng Xu [sup.1] , Zinaida Good [sup.1] [sup.3] [sup.4] , [...]

In 2009, the city of Detroit proposed a $500.5 million bond referendum to stem the declining enrollment in Detroit Public Schools (DPS) that mirrored the decades-long decline in the city's population. Proposal S was passed in November to fund the construction of 8 new schools, the renovation of 10 more, and the improvement of information technology and security infrastructure district-wide. This funding would help the district reshape a shrinking school system while strategically allocating resources to the schools and their communities. The bond language challenged DPS to maximize the financial resources within a compressed delivery schedule. To help achieve program goals, DPS challenged the joint-venture team to ensure consistency and continuity across all projects through the development of enhanced specifications and the bridging documents that served as the foundation of the modified design-build delivery method, thereby communicating the district's design intent for programs, systems, and finishes. This article discusses how a modified design-build delivery method helped Detroit Public School to maximize financial resources within a compressed delivery schedule.

Abstract Background The small non-coding microRNAs play an important role in development by regulating protein translation, but their involvement in axon guidance is unknown. Here, we investigated the role of microRNA-134 (miR-134) in chemotropic guidance of nerve growth cones. Results We found that miR-134 is highly expressed in the neural tube of Xenopus embryos. Fluorescent in situ hybridization also showed that miR-134 is enriched in the growth cones of Xenopus spinal neurons in culture. Importantly, overexpression of miR-134 mimics or antisense inhibitors blocked protein synthesis (PS)-dependent attractive responses of Xenopus growth cones to a gradient of brain-derived neurotrophic factor (BDNF). However, miR-134 mimics or inhibitors had no effect on PS-independent bidirectional responses of Xenopus growth cones to bone morphogenic protein 7 (BMP7). Our data further showed that Xenopus LIM kinase 1 (Xlimk1) mRNA is a potential target of miR-134 regulation. Conclusions These findings demonstrate a role for miR-134 in translation-dependent guidance of nerve growth cones. Different guidance cues may act through distinct signaling pathways to elicit PS-dependent and -independent mechanisms to steer growth cones in response to a wide array of spatiotemporal cues during development.