Browsing by Subject "Sirolimus"

Now showing 1 - 5 of 5
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    ItemOpen Access
    Clinical and angiographic outcomes with everolimus eluting stents for the treatment of cardiac allograft vasculopathy.
    (Journal of interventional cardiology, 2014-02) Azarbal, Babak; Arbit, Boris; Ramaraj, Radhakrishnan; Kittleson, Michelle; Young, Amelia; Czer, Lawrence; Rafiei, Matthew; Currier, Jesse; Makkar, Raj; Kobashigawa, Jon
    OBJECTIVES: This study aimed to examine clinical efficacy, safety, and intermediate clinical outcomes with everolimus-eluting stents (EESs) in patients with transplant coronary artery disease (TCAD). BACKGROUND: TCAD is a major cause of mortality in patients following orthotopic heart transplantation (OHT). Systemic everolimus in OHT patients has been shown to reduce TCAD. The safety and efficacy of an EES, the Xience V, have not been evaluated in this population. METHODS: Patients post-OHT with hemodynamically significant CAD who underwent percutaneous coronary intervention (PCI) with EES were included. Participants were maintained on dual antiplatelet therapy for 1-year post-PCI. We examined procedural success, in-hospital and 1-year mortality, stent thrombosis, angiographic restenosis, and myocardial infarction rates. All patients had follow-up angiography 1-year after PCI. Target vessel revascularization (TVR), target lesion revascularization (TLR), in-segment restenosis, target vessel failure (TVF), and lumen late loss were noted. RESULTS: PCI was performed in 34 de novo lesions in 21 patients, and 40 EES were placed. Procedural success rate was 100%. Average stent was 16.5 ± 5.1 mm long and 3.0 ± 0.6 mm in diameter. All patients had angiographic follow-up (409 ± 201 days). There was no stent thrombosis, deaths, or myocardial infarctions during follow-up. Two patients had focal in-stent restenosis. TLR rate was 5.9% (2/34), and TVR rate was 11.1% (3/27). Quantitative coronary angiography (QCA) showed stenosis diameter to be 19.98 ± 17.57%. CONCLUSIONS: Use of an EES is associated with a low incidence of TVR and TLR in patients with TCAD. Further studies are needed to determine whether PCI with EES changes long-term outcomes.
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    ItemOpen Access
    Cytocidal amino acid starvation of Saccharomyces cerevisiae and Candida albicans acetolactate synthase (ilv2{Delta}) mutants is influenced by the carbon source and rapamycin.
    (Microbiology, 2010-03) Kingsbury, Joanne M; McCusker, John H
    The isoleucine and valine biosynthetic enzyme acetolactate synthase (Ilv2p) is an attractive antifungal drug target, since the isoleucine and valine biosynthetic pathway is not present in mammals, Saccharomyces cerevisiae ilv2Delta mutants do not survive in vivo, Cryptococcus neoformans ilv2 mutants are avirulent, and both S. cerevisiae and Cr. neoformans ilv2 mutants die upon isoleucine and valine starvation. To further explore the potential of Ilv2p as an antifungal drug target, we disrupted Candida albicans ILV2, and demonstrated that Ca. albicans ilv2Delta mutants were significantly attenuated in virulence, and were also profoundly starvation-cidal, with a greater than 100-fold reduction in viability after only 4 h of isoleucine and valine starvation. As fungicidal starvation would be advantageous for drug design, we explored the basis of the starvation-cidal phenotype in both S. cerevisiae and Ca. albicans ilv2Delta mutants. Since the mutation of ILV1, required for the first step of isoleucine biosynthesis, did not suppress the ilv2Delta starvation-cidal defects in either species, the cidal phenotype was not due to alpha-ketobutyrate accumulation. We found that starvation for isoleucine alone was more deleterious in Ca. albicans than in S. cerevisiae, and starvation for valine was more deleterious than for isoleucine in both species. Interestingly, while the target of rapamycin (TOR) pathway inhibitor rapamycin further reduced S. cerevisiae ilv2Delta starvation viability, it increased Ca. albicans ilv1Delta and ilv2Delta viability. Furthermore, the recovery from starvation was dependent on the carbon source present during recovery for S. cerevisiae ilv2Delta mutants, reminiscent of isoleucine and valine starvation inducing a viable but non-culturable-like state in this species, while Ca. albicans ilv1Delta and ilv2 Delta viability was influenced by the carbon source present during starvation, supporting a role for glucose wasting in the Ca. albicans cidal phenotype.
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    ItemOpen Access
    Modulation of Xenogeneic T-cell Proliferation by B7 and mTOR Blockade of T Cells and Porcine Endothelial Cells.
    (Transplantation, 2022-05) Li, Shu; Xu, He; Kirk, Allan D

    Background

    Activation of porcine endothelial cells (PECs) is the mechanistic centerpiece of xenograft rejection. This study sought to characterize the immuno-phenotype of human T cells in response to PECs and to explore the immuno-modulation of B7 and mammalian target of rapamycin blockade of T cells and/or PECs during xeno-responses.

    Methods

    Rapid memory T-cell (TM) responses to PECs were assessed by an intracellular cytokine staining. T-cell proliferation to PEC with or without belatacept or rapamycin was evaluated by a mixed lymphocyte-endothelial cell reaction (MLER). Additionally, rapamycin-pretreated PECs were used in MLER. Cell phenotypes were analyzed by flow cytometry.

    Results

    Tumor necrosis factor-α/interferon-γ producers were detected in CD8+ cells stimulated by human endothelium but not PECs. MLER showed proliferation of CD4+ and CD8+ cells with predominantly memory subsets. Purified memory and naive cells proliferated following PEC stimulation with an increased frequency of TM in PEC-stimulated naive cells. Proliferating cells upregulated programmed cell death-1 (PD-1) and CD2 expression. Belatacept partially inhibited T-cell proliferation with reduced CD2 expression and frequency of the CD8+CD2highCD28- subset. Rapamycin dramatically inhibited PEC-induced T-cell proliferation, and rapamycin-preconditioned PECs failed to induce T-cell proliferation. PD-1 blockade did not restore T-cell proliferation to rapamycin-preconditioned PECs.

    Conclusions

    Humans lack rapid TM-mediated responses to PECs but induce T-cell proliferative responses characterized largely as TM with increasing CD2 and PD-1 expression. B7-CD28 and mammalian target of rapamycin blockade of T cells exhibit dramatic inhibitory effects in altering xeno-proliferating cells. Rapamycin alters PEC xeno-immunogenicity leading to inhibition of xeno-specific T-cell proliferation independent of PD-1-PD ligand interaction.
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    ItemOpen Access
    MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy.
    (Cancer Res, 2009-10-01) Balakumaran, Bala S; Porrello, Alessandro; Hsu, David S; Glover, Wayne; Foye, Adam; Leung, Janet Y; Sullivan, Beth A; Hahn, William C; Loda, Massimo; Febbo, Phillip G
    Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycin-induced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E-binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy.
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    Preclinical Development of New Therapy for Glycogen Storage Diseases.
    (Curr Gene Ther, 2015) Sun, Baodong; Brooks, Elizabeth D; Koeberl, Dwight D
    Glycogen storage disease (GSD) consists of more than 10 discrete conditions for which the biochemical and genetic bases have been determined, and new therapies have been under development for several of these conditions. Gene therapy research has generated proof-of-concept for GSD types I (von Gierke disease) and II (Pompe disease). Key features of these gene therapy strategies include the choice of vector and regulatory cassette, and recently adeno-associated virus (AAV) vectors containing tissue-specific promoters have achieved a high degree of efficacy. Efficacy of gene therapy for Pompe disease depend upon the induction of immune tolerance to the therapeutic enzyme. Efficacy of von Gierke disease is transient, waning gradually over the months following vector administration. Small molecule therapies have been evaluated with the goal of improving standard of care therapy or ameliorating the cellular abnormalities associated with specific GSDs. The receptor-mediated uptake of the therapeutic enzyme in Pompe disease was enhanced by administration of β2 agonists. Rapamycin reduced the liver fibrosis observed in GSD III. Further development of gene therapy could provide curative therapy for patients with GSD, if efficacy from preclinical research is observed in future clinical trials and these treatments become clinically available.