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.

Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells

Abstract: Chromosomal deletions associated with human diseases, such as cancer, are common, but synteny issues complicate modeling of these deletions in mice. We use cellular reprogramming and genome engineering to functionally dissect the loss of chromosome 7q (del(7q)), a somatic cytogenetic abnormality present in myelodysplastic syndromes (MDS). We derive del(7q)- and isogenic karyotypically normal induced pluripotent stem cells (iPSCs) from hematopoietic cells of MDS patients and show that the del(7q) iPSCs recapitulate disease-associated phenotypes, including impaired hematopoietic differentiation. These disease phenotypes are rescued by spontaneous dosage correction and can be reproduced in karyotypically normal cells by engineering hemizygosity of defined chr7q segments in a 20-Mb region. We use a phenotype-rescue screen to identify candidate haploinsufficient genes that might mediate the del(7q)- hematopoietic defect. Our approach highlights the utility of human iPSCs both for functional mapping of disease-associated large-scale chromosomal deletions and for discovery of haploinsufficient genes.

Immunization of ovarian cancer patients with a synthetic Lewisy-protein conjugate vaccine : A phase 1 trial

Abstract: As the initial step in developing carbohydrate-based vaccines for the treatment of ovarian cancer patients in an adjuvant setting, 25 patients were immunized with a Lewisy pentasaccharide (Ley)-keyhole limpet hemocyanin (KLH)-conjugate vaccine together with the immunological adjuvant QS-21. Four different doses of the vaccine, containing 3, 10, 30, and 60 μg of carbohydrate were administered s.c. at 0, 1, 2, 3, 7, and 19 weeks to groups of 6 patients. Sera taken from the patients at regular intervals were assayed by ELISA for reactivity with naturally occurring forms of Ley (Ley-ceramide and Ley mucin) and by flow cytometry and a complement-dependent cytoxicity assay for reactivity with Ley-expressing tumor cells. The majority of the patients (16/24) produced anti-Ley antibodies as assessed by ELISA, and a proportion of these had strong anti-tumor cell reactivity as assessed by flow cytometry and complement-dependent cytotoxicity. One serum, analyzed in detail, was shown to react with glycolipids but not with glycoproteins or mucins expressed by ovarian cancer cell line OVCAR-3. The vaccine was well tolerated and no gastrointestinal, hematologic, renal, or hepatic toxicity related to the vaccine was observed. On the basis of this study, Ley-KLH should be a suitable component for a polyvalent vaccine under consideration for the therapy of epithelial cancers. Int. J. Cancer 87:79–85, 2000. © 2000 Wiley-Liss, Inc.

Mechanisms of microbubble-facilitated sonoporation for drug and gene delivery.

Abstract: Ultrasound-mediated delivery facilitated by microbubbles provides a novel means for intracellular drug and gene delivery and particularly a noninvasive strategy uniquely suitable for clinical applications. Spatiotemporally controllable application of ultrasound energy combined with microbubbles make it possible for site-specific delivery of therapeutic agents to the region-of-interest with minimal undesirable systemic side effects. By inducing rapid expansion/contraction and/or collapse of microbubbles, ultrasound application can temporarily increase the cell membrane permeability (sonoporation) to create a physical route for impermeable agents to enter the cells. Sonoporation is transient and dynamic, involving complex processes of bubble physics, bubble–cell interactions, and subsequent cellular effects that all affect the ultimate delivery outcome. This review summarizes the studies on the important aspects of the mechanisms of ultrasound-mediated delivery, provides illustrative examples of applications, and discusses the challenges and limitations of the technique. Microbubbles have been used for several decades as a contrast agent for ultrasound imaging [1]. The small size of microbubbles allows them access to well-perfused organs when injected into the vasculature, and their gas core efficiently reflects and scatters the incident ultrasound field, thereby increasing image contrast between the vasculature and the surrounding tissue. Recent developments in microbubble technology have enabled molecular imaging via targeting of the microbubbles to molecular markers of disease expressed on the surface of cells [2]. In addition to imaging, innovation in microbubbles has opened new opportunities for targeted drug and gene delivery. Ultrasound excitation of microbubbles has been exploited to increase vascular and cell membrane permeability and facilitate the passage of therapeutic agents across the vascular barrier and cell membrane into the cytoplasm for drug and gene transfection [3–7]. The ultrasound delivery technique, with the advantage of noninvasive, spatiotemporaly controllable ultrasound application combined with functionalized micro-bubbles, holds great promise to provide new therapeutic strategies. However, even with recent progress in the field, challenges remain, including relatively low delivery efficiency and large variation of delivery outcome. Better understanding of the underlying mechanisms is thus of great importance to optimize this technique and promote its translation towards clinical application. Although the mechanisms of ultrasound- and microbubble-facilitated intracellular delivery have not yet been fully understood, a direct physical route of transport often termed sonoporation is most likely involved [8–10]. The dynamic response of the microbubbles driven by ultrasound as well as the interaction between the microbubbles and the cell membrane are key factors in determining delivery efficiency. Other factors such as the cellular response, the kinetics and metabolism of therapeutic agents in the cytoplasm, also play important roles in the ultimate outcome of ultrasound-mediated delivery. In this review, we first summarize progress in these aspects and then discuss limitations and challenges that the technique currently faces.