Kettering University

About: Kettering University is a education organization based out in Flint, Michigan, United States. It is known for research contribution in the topics: RNA & Antigen. The organization has 6842 authors who have published 7689 publications receiving 337503 citations. The organization is also known as: GMI Engineering & Management Institute & General Motors Institute.

Defining an Optimal Dual-Targeted CAR T-cell Therapy Approach Simultaneously Targeting BCMA and GPRC5D to Prevent BCMA Escape-Driven Relapse in Multiple Myeloma.

Abstract: CAR T-cell therapy for multiple myeloma (MM) targeting B-cell maturation antigen (TNFRSF17; BCMA) induces high overall response rates; however, relapse occurs commonly. Implicated in relapse is a reservoir of MM if cells lacking sufficient BCMA surface expression (antigen escape). We demonstrate that simultaneous targeting of an additional antigen-here, G protein-coupled receptor class-C group-5 member-D (GPRC5D)-can prevent BCMA escape-mediated relapse in a model of MM. To identify an optimal approach, we compare subtherapeutic doses of different forms of dual-targeted cellular therapy. These include (1) parallel-produced and pooled mono-targeted CAR T-cells, (2) bicistronic constructs expressing distinct CARs from a single vector, and (3) a dual-scFv "single-stalk" CAR design. When targeting BCMA-negative disease, bicistronic and pooled approaches had the highest efficacy, whereas for dual-antigen-expressing disease, the bicistronic approach was more efficacious than the pooled approach. Mechanistically, expressing two CARs on a single cell enhanced the strength of CAR T-cell/target cell interactions.

Unscheduled incorporation of thymidine in ultraviolet-irradiated human lymphocytes.

Abstract: The nature, degree, and kinetics of unscheduled thymidine incorporation previously shown to occur in 90% of irradiated lymphocytes was studied. The incorporation was severely depressed in the presence of 10-4 M acriflavine and by low temperature, but was unaffected by 10-3 M hydroxyurea or caffeine. Over a dose range of 25 to $400\ {\rm ergs}/{\rm mm}^{2}$, the uptake of thymidine was increased by a factor of only 1.6, although the survival of lymphocytes, measured 5 days after irradiation, decreased by almost two orders of magnitude. (The survival curve suggests that 90% of the lymphocytes have a $D_{0}\ \text{of}\ 35\ {\rm ergs}/{\rm mm}^{2}$ and 10% have a D0 of $250\ {\rm ergs}/{\rm mm}^{2}$.) After exposure to $25\ {\rm ergs}/{\rm mm}^{2}$, over 70% of the cells survived for 5 days in culture; moreover, cells which had been stimulated by this dose to incorporate thymidine transformed and divided after exposure to phytohemaglutinin. The final uptake of thymidine was significantly greater when a total ...

Incorporation of Unnatural Pyrimidine Bases into Deoxyribonucleic Acid of Mammalian Cells

Abstract: When a mammalian cell strain was incubated with 5-iododeoxyuridine and 5-bromodeoxyuridine, DNA thymine was partially replaced by the halogen-containing pyrimidines. The extent of incorporation of the unnatural bases increased when amethopterin and hypoxanthine were added to the medium. It is thus evident that the replacement of DNA thymine by selected structural analogs, a phenomenon previously reported for bacterial systems, is applicable to cells of higher organisms.