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: Cancer & RNA. 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.

GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells

Abstract: Early clinical results of chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) appear promising, but relapses associated with residual low-to-negative BCMA-expressing MM cells have been reported, necessitating identification of additional targets. The orphan G protein–coupled receptor, class C group 5 member D (GPRC5D), normally expressed only in the hair follicle, was previously identified as expressed by mRNA in marrow aspirates from patients with MM, but confirmation of protein expression remained elusive. Using quantitative immunofluorescence, we determined that GPRC5D protein is expressed on CD138+ MM cells from primary marrow samples with a distribution that was similar to, but independent of, BCMA. Panning a human B cell–derived phage display library identified seven GPRC5D-specific single-chain variable fragments (scFvs). Incorporation of these into multiple CAR formats yielded 42 different constructs, which were screened for antigen-specific and antigen-independent (tonic) signaling using a Nur77-based reporter system. Nur77 reporter screen results were confirmed in vivo using a marrow-tropic MM xenograft in mice. CAR T cells incorporating GPRC5D-targeted scFv clone 109 eradicated MM and enabled long-term survival, including in a BCMA antigen escape model. GPRC5D(109) is specific for GPRC5D and resulted in MM cell line and primary MM cytotoxicity, cytokine release, and in vivo activity comparable to anti-BCMA CAR T cells. Murine and cynomolgus cross-reactive CAR T cells did not cause alopecia or other signs of GPRC5D-mediated toxicity in these species. Thus, GPRC5D(109) CAR T cell therapy shows potential for the treatment of advanced MM irrespective of previous BCMA-targeted therapy.

Native chemical ligation at valine: a contribution to peptide and glycopeptide synthesis.

Abstract: Our laboratory has been pursuing the total synthesis of naturally occurring glycoproteins bearing multiple oligosaccharide domains. Specifically, efforts are well underway to accomplish a de novo total synthesis of erythropoietin alpha (EPO), in homogeneous form.[1] Although a variety of peptide ligation strategies have been developed to facilitate the merger of large, complex peptide and glycopeptide fragments,[2–9] the need for highly efficient methodology continues to motivate the chemical community to develop more powerful strategies. Our pursuit of the total synthesis of homogeneous erythropoietin (EPO) as well as other biologically active glycopeptides has inspired new glycopeptide ligations.[10] To achieve our most complex goals, we must learn how to overcome the serious obstacles in joining glycopeptides in an iterative fashion.

Breast cancer during pregnancy

Abstract: Ten to 20% of the 178,700 new cases of breast cancer occurring yearly (1998 estimates) are found in women of childbearing age (1). The issue of pregnancy-associated breast cancer is very important, particularly as more women delay childbearing for personal or professional reasons. The delay in childbearing to the 30s or 40s occurs concordantly with an increasing incidence of breast cancer in those ages. Pregnancy-associated breast cancer has been traditionally defined as the diagnosis of breast cancer made during pregnancy or within 1 year afterward. It is estimated to have an incidence of 0.2–3.8% (2) and is reported to occur in 1/10,000–1/3000 pregnancies (3,4).

Chromosomal double-strand break repair in Ku80-deficient cells.

Abstract: The x-ray sensitive hamster cell line xrs-6 is deficient in DNA double-strand break (DSB) repair and exhibits impaired V(D)J recombination. The molecular defect in this line is in the 80-kDa subunit of the Ku autoantigen, a protein that binds to DNA ends and recruits the DNA-dependent protein kinase to DNA. Using an I-SceI endonuclease expression system, chromosomal DSB repair was examined in xrs-6 and parental CHO-K1 cell lines. A DSB in chromosomal DNA increased the yield of recombinants several thousand-fold above background in both the xrs-6 and CHO-K1 cells, with recombinational repair of DSBs occurring in as many as 1 of 100 cells electroporated with the endonuclease expression vector. Thus, recombinational repair of chromosomal DSBs can occur at substantial levels in mammalian cells and it is not grossly affected in our assay by a deficiency of the Ku autoantigen. Rejoining of broken chromosome ends (end-joining) near the site of the DSB was also examined. In contrast to recombinational repair, end-joining was found to be severely impaired in the xrs-6 cells. Thus, the Ku protein appears to play a critical role in only one of the chromosomal DSB repair pathways.

A Double-Scale, Particle-Filtering, Energy State Prediction Algorithm for Lithium-Ion Batteries

Abstract: In order for the battery management system (BMS) in an electric vehicle to function properly, accurate and robust indication of the energy state of the lithium-ion batteries is necessary. This robustness requires that the energy state can be estimated accurately even when the working conditions of batteries change dramatically. This paper implements battery remaining available energy prediction and state-of-charge (SOC) estimation against testing temperature uncertainties, as well as inaccurate initial SOC values. A double-scale particle filtering method has been developed to estimate or predict the system state and parameters on two different time scales. The developed method considers the slow time-varying characteristics of the battery parameter set and the quick time-varying characteristics of the battery state set. In order to select the preferred battery model, the Akaike information criterion (AIC) is used to make a tradeoff between the model prediction accuracy and complexity. To validate the developed double-scale particle filtering method, two different kinds of lithium-ion batteries were tested at three temperatures. The experimental results show that, with 20% initial SOC deviation, the maximum remaining available energy prediction and SOC estimation errors are both within 2%, even when the wrong temperature is indicated. In this case, the developed double-scale particle filtering method is expected to be robust in practice.