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  • 1
    Publication Date: 2013-06-07
    Description: Immunosuppressive strategies currently used in hematopoietic stem cell transplantation reliably decrease graft-versus-host disease (GVHD) rates, but also impair pathogen-specific immunity. Experimental transplant studies indicate that GVHD-initiating alloreactive T cells reside primarily in naive and central memory T-cell compartments. In contrast, virus-specific T cells comprise a more differentiated memory population. After finding that the rat sarcoma/mitogen-activated protein kinase kinase/extracellular receptor kinase (RAS/MEK/ERK) pathway is preferentially activated in naive and central memory human T cells, we hypothesized that MEK inhibitors would preferentially inhibit alloreactive T cells, while sparing more differentiated virus-specific T cells. Confirming our hypothesis, we found that MEK inhibitors including selumetinib preferentially inhibited cytokine production and alloreactivity mediated by naive and central memory human CD4 + and CD8 + T cells while sparing more differentiated T cells specific for the human herpesviruses cytomegalovirus and Epstein-Barr virus. We then demonstrated that short-term posttransplant administration of selumetinib in a major histocompatibility complex major- and minor-mismatched murine model significantly delayed the onset of GVHD-associated mortality without compromising myeloid engraftment, demonstrating the in vivo potential of MEK inhibitors in the setting of hematopoietic stem cell transplantation. These findings demonstrate that targeting memory-dependent differences in T-cell signaling is a potent and selective approach to inhibition of alloreactivity.
    Keywords: Immunobiology, Transplantation
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2013-10-24
    Description: Purpose: To compare the low-contrast detectability and image quality of computed tomography (CT) at different radiation dose levels reconstructed with iterative reconstruction (IR) and filtered back projection (FBP). Materials and Methods: A custom liver phantom with 12 simulated hypoattenuating tumors (diameters of 5, 10, 15, and 20 mm; tumor-to-liver contrast values of –10, –20, and –40 HU) was designed. The phantom was scanned with a standard abdominal CT protocol with a volume CT dose index of 21.6 mGy (equivalent 100% dose) and four low-dose protocols (20%, 40%, 60%, and 80% of the standard protocol dose). CT data sets were reconstructed with IR and FBP. Image noise was measured, and the tumors’ contrast-to-noise ratios (CNRs) were calculated. Tumor detection was independently assessed by three radiologists who were blinded to the CT technique used. A total of 840 simulated tumors were presented to the radiologists. Statistical analyses included analysis of variance. Results: IR yielded an image noise reduction of 43.9%–63.9% and a CNR increase of 74.1%–180% compared with FBP at the same dose level ( P 〈 .001). The overall sensitivity for tumor detection was 64.7%–85.3% for IR and 66.3%–85.7% for FBP at the 20%–100% doses, respectively. There was no significant difference in the sensitivity for tumor detection between IR and FBP at the same dose level ( P = .99). The sensitivity of the protocol at the 20% dose with FBP and IR was significantly lower than that of the protocol at the 100% dose with FBP and IR ( P = .019). Conclusion: As the radiation dose at CT decreases, the IR algorithm does not preserve the low-contrast detectability. © RSNA, 2013 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122349/-/DC1
    Keywords: Quality Assurance/Quality Improvement, Computed Tomography
    Print ISSN: 0033-8419
    Electronic ISSN: 1527-1315
    Topics: Medicine
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