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Kicielinski K.P.,University of Alabama at Birmingham | Chiocca E.A.,Brigham and Womens Hospital | Yu J.S.,Cedars Sinai | Gill G.M.,Oncolytics Biotech | And 2 more authors.
Molecular Therapy | Year: 2014

Reovirus, an oncolytic RNA virus exhibiting antiglioma activity, was shown in a previous single institution phase 1 study found that the inoculation of the virus to be well tolerated in patients with recurrent malignant glioma (MG). The goals of multicenter study reported herein were to determine the dose-limiting toxicity, maximum tolerated dose, and target lesion response rate when reovirus was administered in a novel fashion via intratumoral infusion for 72 hours in patients with recurrent malignant glioma. Fifteen adult patients were treated in a dose escalation study ranging from 1 × 10 8 to 1 × 10 10 tissue culture infectious dose 50, tentimes the dose achieved in the previous trial. Neurological, functional examinations, and imaging studies were completed pre-and postinfusion. There was one grade 3 adverse event (convulsions) felt to be possibly related to treatment, but no grade 4 adverse events considered probably or definitely related to treatment. Dose-limiting toxicity were not identified and a maximum tolerated dose was not reached. Evidence of antiglioma activity was seen in some patients. This first report of intratumoral infusion of reovirus in patients with recurrent malignant glioma demonstrated the approach to be safe and well tolerated, warranting further studies. © 2014 The American Society of Gene and Cell Therapy. Source


Gallagher K.A.,University of Michigan | Joshi A.,University of Michigan | Carson W.F.,University of Michigan | Schaller M.,University of Michigan | And 8 more authors.
Diabetes | Year: 2015

Classically activated (M1) macrophages are known to play a role in the development of chronic inflammation associated with impaired wound healing in type 2 diabetes (T2D); however, the mechanism responsible for the dominant proinflammatory (M1) macrophage phenotype in T2D wounds is unknown. Since epigenetic enzymes can direct macrophage phenotypes, we assessed the role of histone methylation in bone marrow (BM) stem/progenitor cells in the programming of macrophages toward a proinflammatory phenotype. We have found that a repressive histone methylation mark, H3K27me3, is decreased at the promoter of the IL-12 gene in BM progenitors and this epigenetic signature is passed down to wound macrophages in a murine model of glucose intolerance (diet-induced obese). These epigenetically "preprogrammed" macrophages result in poised macrophages in peripheral tissue and negatively impact wound repair. We found that in diabetic conditions the H3K27 demethylase Jmjd3 drives IL- 12 production in macrophages and that IL-12 production can be modulated by inhibiting Jmjd3. Using human T2D tissue and murine models, we have identified a previously unrecognized mechanism by which macrophages are programmed toward a proinflammatory phenotype, establishing a pattern of unrestrained inflammation associated with nonhealing wounds. Hence, histone demethylase inhibitor-based therapy may represent a novel treatment option for diabetic wounds. © 2015 by the American Diabetes Association. Source


Fleshner P.R.,Cedars Sinai | Pezzullo J.C.,Georgetown University | Charlton P.A.,Tranzyme Pharma Inc. | Kosutic G.,Tranzyme Pharma Inc. | Senagore A.J.,Spectrum Health
Diseases of the Colon and Rectum | Year: 2010

Purpose: Ghrelin agonist TZP-101 is a potent prokinetic. This phase 2b study evaluated TZP-101 safety and efficacy in postoperative ileus management. Methods: Adults undergoing open partial colectomy were adaptively randomized to receive 20, 40, 80, 160, 320, 480 or 600 μg/kg TZP-101 (n = 168) or the placebo (n = 68) by 30-minute IV infusion within 1 hour of surgical closure and then daily for up to 7 days. The primary efficacy end point was the time to first bowel movement. Secondary end points included the percentage of patients with return of gastrointestinal function within 72 hours, and the time to readiness for discharge. Results: TZP-101 accelerated the time to first bowel movement in all groups, with Cox proportional hazard ratios of 1.57 (P = .056) for the low-efficacious dose (80 μg/kg) and 1.67 (P = .03) for the most efficacious dose (480μg/kg). Using Kaplan-Meier analysis, the median time to first bowel movement was reduced in all TZP-101 groups by 10 to 22 hours vs. the placebo. A greater number of patients who received TZP-101 achieved recovery (P ≤ .001) by 72 hours postsurgery compared with the placebo. The median time to readiness for hospital discharge was significantly accelerated by 20.4 hours at the 480 μg/kg TZP-101 dose compared with the placebo (hazard ratio = 1.69; P = .03). The most common treatment-emergent adverse events were nausea and vomiting, which were reduced in the TZP-101 group compared with the placebo group. Conclusion: In patients undergoing major abdominal surgery, the first-in-class ghrelin agonist TZP-101 was well-tolerated and accelerated recovery of the upper and lower gastrointestinal tract, with a large proportion of subjects recovering within 72 hours compared with the placebo. © The ASCRS 2010. Source


Jackson W.C.,University of Michigan | Schipper M.J.,University of Michigan | Johnson S.B.,University of Michigan | Foster C.,University of Michigan | And 5 more authors.
European Urology | Year: 2016

Background Limited data exist to guide the use of androgen deprivation therapy (ADT) for men treated with radiation therapy (RT) after radical prostatectomy (RP). The optimal duration of ADT in this setting is unknown. Objective To determine if the duration of ADT influences clinical outcomes for men receiving post-RP RT. Design, setting, and participants A total of 680 men who received adjuvant radiation therapy (n = 105) or salvage radiation therapy (n = 575) between 1986 and 2010 at a single tertiary care institution were reviewed retrospectively. Median follow-up post-RT was 57.8 mo. Intervention RT was delivered using three-dimensional conformal or intensity-modulated RT in 1.8-Gy fractions. For patients treated with ADT, >80% were treated with a gonadotropin-releasing hormone agonist with or without a nonsteroidal antiandrogen. Outcome measurements and statistical analysis Biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall mortality were assessed using Kaplan-Meier analysis and propensity score analysis. Results and limitations Overall, 144 patients (21%) received ADT with post-RP RT, most of whom had high-risk disease features such as Gleason score 8-10, seminal vesicle invasion, or pre-RT prostate-specific antigen >1 ng/ml. Median ADT duration was 12 mo (interquartile range: 6.0-23.7). Patients who received <12 mo of ADT had an association with increased BF (hazard ratio [HR]: 2.27; p = 0.003) and DM (HR: 2.48; p = 0.03) compared with patients receiving ≥12 mo of ADT. The 5-yr rates of DM were 6.0% and 23% for ≥12 and <12 mo of ADT, respectively. On propensity score analysis controlling for pretreatment and treatment-related factors, each month of ADT was associated with a decreased risk for BF (HR: 0.95; p = 0.0004), DM (HR: 0.88; p = 0.0004), and PCSM (HR: 0.90; p = 0.037). These findings are limited by the retrospective nature of our analysis. Conclusions For men with high-risk disease features receiving ADT with post-RP RT, the duration of ADT is associated with clinical outcomes. Our findings suggest that for these men an extended course of ADT ≥12 mo may be preferable. Validation of our findings is needed. Patient summary We evaluated outcomes for men with high-risk disease features treated with androgen deprivation therapy (ADT) and radiotherapy after radical prostatectomy. Longer durations of ADT resulted in improved patient outcomes. © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved. Source


Guise J.-M.,Oregon Health And Science University | O'Haire C.,Oregon Health And Science University | McPheeters M.,Vanderbilt University | Most C.,Oregon Health And Science University | And 4 more authors.
Journal of Clinical Epidemiology | Year: 2013

Objective: A major goal of patient-centered outcomes and comparative effectiveness research is to increase the involvement of stakeholders throughout the research process to provide relevant and immediately actionable information. In this report, we review the current practices for engaging stakeholders in prioritizing research. Study Design and Setting: To evaluate the range of approaches to stakeholder engagement, we reviewed the relevant literature and conducted semistructured interviews with (1) leading research organizations in the United States, Canada, and the United Kingdom; and (2) eight Evidence-based Practice Centers that engage stakeholders in comparative effectiveness research. Results: We identified 56 articles related to stakeholder engagement in research prioritization. Studies and research organizations interviewed frequently used mixed methods approaches combining in-person venues with structured ranking or voting processes such as Delphi. EPCs similarly used group web/conference calls combined with Delphi ranking or voting. Research organizations reported difficulties engaging the public and policy makers, and EPCs reported challenges engaging federal stakeholders. Conclusion: Explicit and consistent use of terminology about stakeholders was absent. In-person techniques were useful to generate ideas and clarify issues, and quantitative methods were important in the prioritization of research. Recommendations for effective stakeholder engagement and a reporting checklist were developed from the accumulation of findings. © 2013 Elsevier Inc. All rights reserved. Source

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