Russell, Stephen J.

AbstractDisorders 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.

Key Points IV therapy with oncolytic VSV-IFNβ-NIS virus extends survival of immunocompetent mice with AML. The therapeutic outcome of VSV-IFNβ-NIS–treated mice with AML is augmented by anti-PD-L1 immunotherapy.

Over the past decade, use of novel agents, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) has resulted in high response rates and improvement in overall survival (OS) for patients with multiple myeloma (MM); however, the prognostic significance of refractoriness to these agents when used as initial therapy has not been extensively studied. We reviewed the outcomes of 816 consecutive patients treated for MM at our institution since 2006 to evaluate the survival difference between those achieving at least a partial response (PR) to induction therapy and those who were primary refractory. The median OS from start of therapy was significantly shorter for the primary refractory group at 3.6 vs. 7.6 years for the responding patients ( P < 0.001). The difference in median OS persisted when only patients receiving a novel agent as part of induction therapy were considered (3.6 vs. 7.9 years, P < 0.001) and in a 4‐month landmark analysis (4.2 vs. 7.6 years, P < 0.001). The median OS for patients achieving a complete response (CR), very good partial response (VGPR), PR, or less than PR was not reached (NR), 6.1, 6.4, and 4.2 years from the 4‐month landmark, respectively ( P < 0.001). The comparatively poor outcomes of patients refractory to induction therapy in the current era of novel agents suggests that this high‐risk subpopulation must be further studied for predictors of resistance and, when identified, should be targeted for clinical trials. Am. J. Hematol. 90:981–985, 2015. © 2015 Wiley Periodicals, Inc.

The use of soluble cardiac biomarkers such as N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and troponin has revolutionized prognostication for patients with AL amyloidosis. Soluble ST2 (sST2) and galectin‐3 have also been reported to have prognostic value in other cardiac patient populations. We identified 502 patients with AL amyloidosis, who provided a research sample and consent to review their medical records between 1/1/2006‐12/31/2010 within 90 days of their diagnosis. Samples were assayed for sST2 and galectin‐3. Within this AL amyloidosis population, overall survival (OS) was 25.5 months (95% CI 18, 35.7 months). Receiver operating curve analyses were done to detect the best cut‐points for sST2 and galectin‐3 to predict both 1‐ and 5‐year OS. The respective cut points for sST2 were 30 and 29.7 ng/mL, while the median sST2 for the entire population was 31 ng/mL (IQR 19.8, 53.6). The respective cut points for galectin‐3 were 11 and 10.4 ng/mL while the median for the entire population was 16.6 ng/mL (IQR 11.5, 24.0). Although on univariate analysis, both sST2 and galectin‐3 were prognostic, upon multivariate analysis, only sST2 was independent of troponin, NT‐proBNP, serum immunoglobulin free light chain, and blood pressure. Not only did sST2 add to previously reported prognostication systems, but a novel prognostication 5‐point system including sST2 was possible. The addition of sST2 – but not galectin‐3 – to existing prognostication systems for patients with AL amyloidosis strengthens the ability to predict for death. Am. J. Hematol. 90:524–528, 2015. © 2015 Wiley Periodicals, Inc.

Cell transplantation is a potential treatment for the many liver disorders that are currently only curable by organ transplantation. However, one of the major limitations of hepatocyte (HC) transplantation is an inability to monitor cells longitudinally after injection. We hypothesized that the thyroidal sodium iodide symporter (NIS) gene could be used to visualize transplanted HCs in a rodent model of inherited liver disease: hereditary tyrosinemia type 1. Wild‐type C57Bl/6J mouse HCs were transduced ex vivo with a lentiviral vector containing the mouse Slc5a5 (NIS) gene controlled by the thyroxine‐binding globulin promoter. NIS‐transduced cells could robustly concentrate radiolabeled iodine in vitro, with lentiviral transduction efficiencies greater than 80% achieved in the presence of dexamethasone. Next, NIS‐transduced HCs were transplanted into congenic fumarylacetoacetate hydrolase knockout mice, and this resulted in the prevention of liver failure. NIS‐transduced HCs were readily imaged in vivo by single‐photon emission computed tomography, and this demonstrated for the first time noninvasive 3‐dimensional imaging of regenerating tissue in individual animals over time. We also tested the efficacy of primary HC spheroids engrafted in the liver. With the NIS reporter, robust spheroid engraftment and survival could be detected longitudinally after direct parenchymal injection, and this thereby demonstrated a novel strategy for HC transplantation. This work is the first to demonstrate the efficacy of NIS imaging in the field of HC transplantation. We anticipate that NIS labeling will allow noninvasive and longitudinal identification of HCs and stem cells in future studies related to liver regeneration in small and large preclinical animal models. Liver Transpl 21:442–453, 2015. © 2015 AASLD.

Abstract Edmonston vaccine strains of measles virus (MV) have significant antitumor activity in mouse xenograft models of ovarian cancer. MV engineered to express the sodium iodide symporter gene (MV-NIS) facilitates localization of viral gene expression and offers a tool for tumor radiovirotherapy. Here, we report results from a clinical evaluation of MV-NIS in patients with taxol- and platinum-resistant ovarian cancer. MV-NIS was given intraperitoneally every 4 weeks for up to 6 cycles. Treatment was well tolerated and associated with promising median overall survival in these patients with heavily pretreated ovarian cancer; no dose-limiting toxicity was observed in 16 patients treated at high-dose levels (108–109 TCID50), and their median overall survival of 26.5 months compared favorably with other contemporary series. MV receptor CD46 and nectin-4 expression was confirmed by immunohistochemistry in patient tumors. Sodium iodide symporter expression in patient tumors after treatment was confirmed in three patients by 123I uptake on SPECT/CTs and was associated with long progression-free survival. Immune monitoring posttreatment showed an increase in effector T cells recognizing the tumor antigens IGFBP2 and FRα, indicating that MV-NIS treatment triggered cellular immunity against the patients' tumor and suggesting that an immune mechanism mediating the observed antitumor effect. Our findings support further clinical evaluation of MV-NIS as an effective immunovirotherapy. Cancer Res; 75(1); 22–30. ©2014 AACR.