Rl Roudebush Veterans Affairs Medical Center

Indianapolis, IN, United States

Rl Roudebush Veterans Affairs Medical Center

Indianapolis, IN, United States
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Slee R.B.,Indiana University | Grimes B.R.,Indiana University | Grimes B.R.,Center for Pancreatic Cancer Research | Victorino J.,California State University, Dominguez Hills | And 8 more authors.
Molecular Cancer Therapeutics | Year: 2014

Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMSP715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome.We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy. Mol Cancer Ther; 13(2); 307-15. © 2014 American Association for Cancer Research.

Jun Hong S.,Indiana University | Jun Hong S.,Indiana Center for Vascular Biology and Medicine | Jun Hong S.,Rl Roudebush Veterans Affairs Medical Center | Jun Hong S.,Korea University | And 31 more authors.
Catheterization and Cardiovascular Interventions | Year: 2015

Objectives The potential for beneficial effects of adipose-derived stem cells (ASCs) on myocardial perfusion and left ventricular dysfunction in myocardial ischemia (MI) has not been tested following intravenous delivery. Methods Surviving pigs following induction of MI were randomly assigned to 1 of 3 different groups: the placebo group (n-=-7), the single bolus group (SB) (n-=-7, 15 × 107 ASCs), or the divided dose group (DD) (n-=-7, 5 × 107 ASCs/day for three consecutive days). Myocardial perfusion defect area and coronary flow reserve (CFR) were compared during the 28-day follow-up. Also, serial changes in the absolute number of circulating CD4+T and CD8+T cells were measured. Results The increases in ejection fraction were significantly greater in both the SB and the DD groups compared to the placebo group (5.4-±-0.9%, 3.7-±-0.7%, and -0.4-±-0.6%, respectively), and the decrease in the perfusion defect area was significantly greater in the SB group than the placebo group (-36.3-±-1.8 and -11.5-±-2.8). CFR increased to a greater degree in the SB and the DD groups than in the placebo group (0.9-±-0.2, 0.8-±-0.1, and 0.2-±-0.2, respectively). The circulating number of CD8+T cells was significantly greater in the SB and DD groups than the placebo group at day 7 (3,687-±-317/μL, 3,454-±-787/μL, and 1,928-±-457/μL, respectively). The numbers of small vessels were significantly greater in the SB and the DD groups than the placebo group in the peri-infarct area. Conclusions Both intravenous SB and DD delivery of ASCs are effective modalities for the treatment of MI in swine. Intravenous delivery of ASCs, with its immunomodulatory and angiogenic effects, is an attractive noninvasive approach for myocardial rescue. © 2014 Wiley Periodicals, Inc.

Hong S.J.,Krannert Institute of Cardiology | Hong S.J.,Indiana Center for Vascular Biology and Medicine | Hong S.J.,Indiana University | Hong S.J.,Korea University | And 7 more authors.
Current Opinion in Organ Transplantation | Year: 2010

Purpose of review: Adipose-derived stem cells (ASCs) are readily available from autologous adipose tissue and have been demonstrated to provide significant potential for tissue rescue from, or repair of, damage in multiple animal models. These include models of myocardial infarction, heart failure, hind limb ischemia, and inflammatory conditions. Early clinical studies have now extended testing of the effects of ASC into patients. This review highlights some of the key reports underlining the potential of ASCs, focusing particularly on diseases involving the cardiovascular system, vascular growth, and tissue repair. Recent findings: Clinical applications of ASCs have begun to show early safety results and promising possibility of efficacy in patients with a range of diseases, including acute myocardial infarction, peripheral vascular disease, and soft and bony tissue defects including cranial bone loss, Crohn's-related fistula, and skin wounds. These effects are importantly based on the secretion of trophic and survival factors by these cells and by their participations in the growth and remodeling of blood vessels. These results suggest that ASCs could be a valuable therapeutic option in vascular growth and tissue repair in various clinical settings. Summary: ASCs may ultimately represent a valuable therapeutic option in tissue rescue and repair based on their ready availability, proangiogenesis and antiapoptotic factor secretion, immunomodulatory effects, and capacity for multilineage differentiation and ready expansion. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Hong S.J.,Krannert Institute of Cardiology | Hong S.J.,Indiana Center for Vascular Biology and Medicine | Hong S.J.,Indiana University | Hong S.J.,Korea University | And 17 more authors.
Catheterization and Cardiovascular Interventions | Year: 2014

Objectives: To examine the comparative fate of adipose-derived stem cells (ASCs) as well as their impact on coronary microcirculation following either retrograde coronary venous (RCV) or arterial delivery. Background: Local delivery of ASCs to the heart has been proposed as a practical approach to limiting the extent of myocardial infarction. Mouse models of mesenchymal stem cell effects on the heart have also demonstrated significant benefits from systemic (intravenous) delivery, prompting a question about the advantage of local delivery. There has been no study addressing the extent of myocardial vs. systemic disposition of ASCs in large animal models following local delivery to the myocardium. Methods: In an initial experiment, dose-dependent effects of ASC delivery on coronary circulation in normal swine were evaluated to establish a tolerable ASC dosing range for intracoronary (IC) delivery. In a set of subsequent experiments, an anterior acute myocardial infarction (AMI) was created by balloon occlusion of the proximal left anterior descending (LAD) artery, followed by either IC or RCV infusion of 107 111Indium- labeled autologous ASCs 6 days following AMI. Indices of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured before sacrifices to collect tissues for analysis at 1 or 24 hr after cell delivery. Results: IC delivery of porcine ASCs to normal myocardium was well tolerated up to a cumulative dose of 14 × 106 cells (approximately 0.5 × 106 cells/kg). There was evidence suggesting microcirculatory trapping of ASC: at unit doses of 50 × 106 ASCs, IMR and CFR were found to be persistently altered in the target LAD distribution at 7 days following delivery, whereas at 10 × 106 ASCs, only CFR was altered. In the context of recent MI, a significantly higher percentage of ASCs was retained at 1 hr with IC delivery compared with RCV delivery (57.2 ± 12.7% vs. 17.9 ± 1.6%, P = 0.037) but this initial difference was not apparent at 24 hr (22.6 ± 5.5% vs. 18.7 ± 8.6%; P = 0.722). In both approaches, most ASC redistributed to the pulmonary circulation by 24 hr postdelivery. There were no significant differences in CFR or IMR following ASC delivery to infarcted tissue by either route. Conclusions: Selective intravascular delivery of ASC by coronary arterial and venous routes leads to similarly limited myocardial cell retention with predominant redistribution of cells to the lungs. IC arterial delivery of ASC leads to only transiently greater myocardial retention, which is accompanied by obstruction of normal regions of coronary microcirculation at higher doses. The predominant intrapulmonary localization of cells following local delivery via both methods prompts the notion that systemic delivery of ASC might provide similarly beneficial outcomes while avoiding risks of inadvertent microcirculatory compromise. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

Green L.A.,Indiana University | Green L.A.,Rl Roudebush Veterans Affairs Medical Center | Petrusca D.,Indiana University | Rajashekhar G.,Indiana University | And 8 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2012

Endothelial monocyte-activating polypeptide II (EMAP II) and interferon-inducible protein (IP)-10 are proinflammatory mediators, which in addition to their chemokine activities, selectively induce apoptosis in endothelial cells and are up-regulated in the lungs of cigarette smoke-exposed humans. Previously, we showed that EMAP II is an essential mediator of cigarette smoke-induced lung emphysema in mice linking endothelial cell apoptosis with inflammation. Here we addressed the role of the CXCR3 receptor in EMAP II-induced and IP-10-induced apoptosis in endothelial cells and its regulation by cigarette smoke. We found that both neutralizing antibodies and small inhibitory RNA to CXCR3 abrogated EMAP II-induced and IP-10-induced endothelial caspase-3 activation and DNA fragmentation. CXCR3 receptor surface expression in human lung microvascular endothelial cells and in lung tissue endothelium was up-regulated by exposure to cigarette smoke. In tissue culture conditions, EMAP II-induced and IP-10-induced apoptosis was enhanced by preincubation with cigarette smoke extract. Interestingly, serum starvation also induced CXCR3 up-regulation and enhanced EMAP II-induced endothelial apoptosis. Signal transduction via p38 mitogen-activated protein kinase activation was essential for CXCR3-induced cell death, but not for CXCR3 receptor up-regulation by cigarette smoke. In turn, protein nitration was required for CXCR3 receptor up-regulation by cigarette smoke and consequently for subsequent CXCR3-induced cell death. In conclusion, the concerted up-regulation of proinflammatory EMAP II, IP-10, and CXCR3 by cigarette smoke could sustain a cascade of cell death that may promote the alveolar tissue loss noted in human emphysema. Copyright © 2012 by the American Thoracic Society.

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