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Background: Glioblastoma (GBM) is an aggressive brain tumor giving a poor prognosis with the current treatment options. The advent of chimeric antigen receptor (CAR) T-cell therapy revolutionized the field of immunotherapy and has provided a new set of therapeutic options for refractory blood cancers. In an effort to apply this therapeutic approach to solid tumors, various immune cell types and CAR constructs are being studied. Notably, macrophages have recently emerged as potential candidates for targeting solid tumors, attributed to their inherent tumorinfiltrating capacity and abundant presence in the tumor microenvironment. Materials and methods: In this study, we developed a chemically defined differentiation protocol to generate macrophages from human pluripotent stem cells (hPSCs). A GBM-specific CAR was genetically incorporated into hPSCs to generate CAR hPSC-derived macrophages. Results: The CAR hPSC-derived macrophages exhibited potent anticancer activity against GBM cells in vitro. Conclusion: Our findings demonstrate the feasibility of generating functional CAR-macrophages from hPSCs for adoptive immunotherapy, thereby opening new avenues for the treatment of solid tumors, particularly GBM. 

Mutations in theTP53tumor suppressor gene occur in >80% of the triple-negative or basal-like breast cancer. To test whether neomorphic functions of specificTP53missense mutations contribute to phenotypic heterogeneity, we characterized phenotypes of non-transformed MCF10A-derived cell lines expressing the ten most common missense mutant p53 proteins and observed a wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell migration, invasion and 3D mammosphere architecture. The p53 mutants R248W, R273C, R248Q, and Y220C are the most aggressive while G245S and Y234C are the least, which correlates with survival rates of basal-like breast cancer patients. Interestingly, a crucial amino acid difference at one position—R273C vs. R273H—has drastic changes on cellular phenotype. RNA-Seq and ChIP-Seq analyses show distinct DNA binding properties of different p53 mutants, yielding heterogeneous transcriptomics profiles, and MD simulation provided structural basis of differential DNA binding of different p53 mutants. Integrative statistical and machine-learning-based pathway analysis on gene expression profiles with phenotype vectors across the mutant cell lines identifies quantitative association of multiple pathways including the Hippo/YAP/TAZ pathway with phenotypic aggressiveness. Further, comparative analyses of large transcriptomics datasets on breast cancer cell lines and tumors suggest that dysregulation of the Hippo/YAP/TAZ pathway plays a key role in driving the cellular phenotypes towards basal-like in the presence of more aggressive p53 mutants. Overall, our study describes distinct gain-of-function impacts on protein functions, transcriptional profiles, and cellular behaviors of different p53 missense mutants, which contribute to clinical phenotypic heterogeneity of triple-negative breast tumors.

 

There is an imminent need to remedy the ‘skills gaps’ in the digital manufacturing (DM) sector as evident from the Bureau of Labor Statistics projections pointing to a decline in traditional manufacturing jobs accompanied by marked growth in digital- and computer-driven manufacturing jobs. With proven advantages such as cost benefits, material conservation, minimized labor, and enhanced precision, manufacturing industries worldwide are adapting to digital manufacturing standards on a large scale. In an effort to remedy the lack of well-defined DM career pathways and instructional framework, our NSF ATE (Advanced Technological Education) project MANEUVER (Manufacturing Education Using Virtual Environment Resources) is developing an innovative pedagogical approach using virtual reality (VR). This multimodal VR framework DM instruction targeted at 2-year and 4-year manufacturing programs, facilitates the development of VR modules for multiple modes such as desktop VR, Augmented VR, and Immersive VR. The advantages of the virtual reality framework for digital manufacturing education include: significant cost reduction, reduction in equipment and maintenance costs, ability to pre-visualize the product before manufacturing. This paper introduces the design and development process of VR education tool to simulate three different additive manufacturing machines, e.g., LutzBot™, FormLabs™, and UPrint™ and different 3D printing technologies e.g., fused deposition modeling, and selective laser sintering to allow the students experience the materials and equipment needed to create the same part using different types of equipment and different types of technology.