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Wei C.-Y.,Molecular Medicine Program | Wei C.-Y.,Academia Sinica, Taiwan | Wei C.-Y.,National Yang Ming University | Chung W.-H.,National Yang Ming University | And 4 more authors.
Journal of Allergy and Clinical Immunology | Year: 2012

Background: Increasing studies have revealed that HLA alleles are the major genetic determinants of drug hypersensitivity; however, the underlying molecular mechanism remains unclear. Objective: We adopted the HLA-B1502 genetic predisposition to carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) as a model to study the pathologic role of HLA in delayed-type drug hypersensitivity. Methods: We in vitro expanded CBZ-specific cytotoxic T lymphocytes (CTLs) from patients with CBZ-induced SJS/TEN and analyzed the interaction between HLA-B and CBZ analogs based on CTL response, surface plasmon resonance, peptide-binding assay, site-directed mutagenesis, and computer modeling. Results: The endogenous peptide-loaded HLA-B1502 molecule presented CBZ to CTLs without the involvement of intracellular drug metabolism or antigen processing. The HLA-B1502/peptide/ β2-microglobulin protein complex showed binding affinity toward chemicals sharing 5-carboxamide on the tricyclic ring, as with CBZ. However, modifications of the ring structure of CBZ altered HLA-B1502 binding and CTL response. In addition to HLA-B1502, other HLA-B75 family members could also present CBZ to activate CTLs, whereas members of the HLA-B62 and HLA-B72 families could not. Three residues (Asn63, Ile95, and Leu156) in the peptide-binding groove of HLA-B1502 were involved in CBZ presentation and CTL activation. In particular, Asn63 shared by members of the B75 family was the key residue. Computer simulations revealed a preferred molecular conformation of the 5-carboxamide group of CBZ and the side chain of Arg62 on the B pocket of HLA-B1502. Conclusions: This study demonstrates a direct interaction of HLA with drugs, provides a detailed molecular mechanism of HLA-associated drug hypersensitivity, and has clinical correlations for CBZ-related drug-induced SJS/TEN. © 2012 American Academy of Allergy, Asthma & Immunology.

Smith M.C.P.,Molecular Medicine Program | Li D.Y.,Molecular Medicine Program | Li D.Y.,University of Utah | Whitehead K.J.,Molecular Medicine Program
Current Opinion in Hematology | Year: 2010

PURPOSE OF REVIEW: The genetic basis for a variety of vascular malformation syndromes have been described, with an increasing functional understanding of the associated genes. RECENT FINDINGS: Genes responsible for familial vascular malformation syndromes have increasingly been shown to be involved in the control of vascular stability. SUMMARY: Genes involved in vascular stability pathways are good candidates for causing vascular malformation syndromes. Although these findings confirm the biologic importance of the involved pathways, further explanations are required to describe the focal nature of disease. © 2010 Lippincott Williams & Wilkins, Inc.

Bera S.,University of Iowa | Greiner S.,Molecular Medicine Program | Choudhury A.,University of Iowa | Dispenzieri A.,Rochester College | And 3 more authors.
Neoplasia | Year: 2010

Dexamethasone (Dex) and radiation therapy are established modalities in multiple myeloma. In this study, we propose a novel combination of Dex plus radiation that shows superior clonogenic cell killing and apoptosis of myeloma cells and selectively eliminates myeloma cells when cocultured with bone marrow stromal cells (BMSCs). Dex was found to inhibit the release of interleukin-6 from irradiated BMSCs, which is an established myeloma cell proproliferative cytokine. In 5TGM1 model, the combination of Dex with skeletal targeted radiotherapy (153-Sm-EDTMP) prolonged median survival time and inhibited radiation-induced myelosuppression. A two-cycle treatment of Dex plus 153-Sm-EDTMP was well tolerated and further improved median survival time. Mechanistically, Dex increased superoxide and hydrogen peroxide production and augmented radiation-induced oxidative stress and cell death of myeloma cells. In contrast, Dex inhibited radiation-induced increase in pro-oxidant levels and enhanced the clonogenic survival in normal hematopoietic stem and progenitor cells. Treatment with either N-acetylcysteine or the combination of polyethylene glycol (PEG)-conjugated copper, zinc-superoxide dismutase, and PEG-catalase significantly protected myeloma cells from Dex-induced clonogenic death. Overall, these results demonstrate that Dex in combination with radiotherapy enhances the killing of myeloma cells while protecting normal bone marrow hematopoiesis through a mechanism that involves selective increases in oxidative stress. © 2010 Neoplasia Press, Inc. All rights reserved.

Turner E.C.,Center for Research in Vascular Biology | Huang C.-L.,Center for Research in Vascular Biology | Sawhney N.,Center for Research in Vascular Biology | Govindarajan K.,Center for Research in Vascular Biology | And 19 more authors.
Stem Cells | Year: 2016

Abstract: Disorders affecting smooth muscle structure/function may require technologies that can generate large scale, differentiated and contractile smooth muscle cells (SMC) suitable for cell therapy. To date no clonal precursor population that provides large numbers of differentiated SMC in culture has been identified in a rodent. Identification of such cells may also enhance insight into progenitor cell fate decisions and the relationship between smooth muscle precursors and disease states that implicate differentiated SMC. In this study, we used classic clonal expansion techniques to identify novel self-renewing Islet 1 (Isl-1) positive primitive progenitor cells (PPC) within rat bone marrow that exhibited canonical stem cell markers and preferential differentiation towards a smooth muscle-like fate. We subsequently used molecular tagging to select Isl-1 positive clonal populations from expanded and de novo marrow cell populations. We refer to these previously undescribed cells as the PPC given its stem cell marker profile, and robust self-renewal capacity. PPC could be directly converted into induced smooth muscle cells (iSMC) using single transcription factor (Kruppel-like factor 4) knockdown or transactivator (myocardin) overexpression in contrast to three control cells (HEK 293, endothelial cells and mesenchymal stem cells) where such induction was not possible. iSMC exhibited immuno- and cytoskeletal-phenotype, calcium signaling profile and contractile responses similar to bona fide SMC. Passaged iSMC could be expanded to a scale sufficient for large scale tissue replacement. PPC and reprogramed iSMC so derived may offer future opportunities to investigate molecular, structure/function and cell-based replacement therapy approaches to diverse cardiovascular, respiratory, gastrointestinal, and genitourinary diseases that have as their basis smooth muscle cell functional aberrancy or numerical loss. © 2016 AlphaMed Press.

Schubert S.,Molecular Medicine Program | Weyrich A.S.,Molecular Medicine Program | Weyrich A.S.,University of Utah | Rowley J.W.,Molecular Medicine Program | Rowley J.W.,University of Utah
Blood | Year: 2014

The RNA code found within a platelet and alterations of that code continue to shed light onto the mechanistic underpinnings of platelet function and dysfunction. It is now known that features of messenger RNA (mRNA) in platelets mirror those of nucleated cells. This review serves as a tour guide for readers interested in developing a greater understanding of platelet mRNA. The tour provides an in-depth and interactive examination of platelet mRNA, especially in the context of nextgeneration RNA sequencing. At the end of the expedition, the reader will have a better grasp of the topography of platelet mRNA and how it impacts platelet function in health and disease. © 2014 by The American Society of Hematology.

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