Targeting of mesenchymal stem cells to ovarian tumors via an artificial receptor

<p>Abstract</p> <p>Background</p> <p>Mesenchymal Progenitor/Stem Cells (MSC) respond to homing cues providing an important mechanism to deliver therapeutics to sites of injury and tumors. This property has been confirmed by many investigators, however, the efficiency of tumor homing needs to be improved for effective therapeutic delivery. We investigated the feasibility of enhancing MSC tumor targeting by expressing an artificial tumor-binding receptor on the MSC surface.</p> <p>Methods</p> <p>Human MSC expressing an artificial receptor that binds to erbB2, a tumor cell marker, were obtained by transduction with genetically modified adenoviral vectors encoding an artificial receptor (MSC-AR). MSC-AR properties were tested <it>in vitro </it>in cell binding assays and <it>in vivo </it>using two model systems: transient transgenic mice that express human erbB2 in the lungs and ovarian xenograft tumor model. The levels of luciferase-labeled MSCs in erbB2-expressing targeted sites were evaluated by measuring luciferase activity using luciferase assay and imaging.</p> <p>Results</p> <p>The expression of AR enhanced binding of MSC-AR to erbB2-expressing cells <it>in vitro</it>, compared to unmodified MSCs. Furthermore, we have tested the properties of erbB2-targeted MSCs <it>in vivo </it>and demonstrated an increased retention of MSC-AR in lungs expressing erbB2. We have also confirmed increased numbers of erbB2-targeted MSCs in ovarian tumors, compared to unmodified MSC. The kinetic of tumor targeting by ip injected MSC was also investigated.</p> <p>Conclusion</p> <p>These data demonstrate that targeting abilities of MSCs can be enhanced via introduction of artificial receptors. The application of this strategy for tumor cell-based delivery could increase a number of cell carriers in tumors and enhance efficacy of cell-based therapy.</p

Peculiarities of the function of cardiomyocytes in patients with ischemic heart disease associated with diabetes mellitus type 2

The functional activity of myocardium in patients with type 2 diabetes mellitus(T2DM) and coronary heart disease (CAD) was studied. The study included patients with CAD with T2DM as representatives of the main group, the comparison group consisted of patients with univariant course of ischemic heart disease without violation of carbohydrate metabolism. Contractile activity of the myocardium was evaluated by the inotroic reaction of isolated trabeculae of patients according to the Protocol tests "Post-rest" and "Ekstrasistoliei test". As a result, it was found that rhythm-inotropic myocardial response in patients with comorbid pathology persists to a greater extent than in the one-dimensional flow of CAD

The SEGUE Stellar Parameter Pipeline. III. Comparison with High-Resolution Spectroscopy of SDSS/SEGUE Field Stars

We report high-resolution spectroscopy of 125 field stars previously observed as part of the Sloan Digital Sky Survey and its program for Galactic studies, the Sloan Extension for Galactic Understanding and Exploration (SEGUE). These spectra are used to measure radial velocities and to derive atmospheric parameters, which we compare with those reported by the SEGUE Stellar Parameter Pipeline (SSPP). The SSPP obtains estimates of these quantities based on SDSS ugriz photometry and low-resolution (R = 2000) spectroscopy. For F- and G-type stars observed with high signal-to-noise ratios (S/N), we empirically determine the typical random uncertainties in the radial velocities, effective temperatures, surface gravities, and metallicities delivered by the SSPP to be 2.4 km/s, 130 K (2.2%), 0.21 dex, and 0.11 dex, respectively, with systematic uncertainties of a similar magnitude in the effective temperatures and metallicities. We estimate random errors for lower S/N spectra based on numerical simulations.Comment: 37 pages, 6 tables, 6 figures, submitted to the Astronomical Journa

A tumor-stroma targeted oncolytic adenovirus replicated in human ovary cancer samples and inhibited growth of disseminated solid tumors in mice

Targeting the tumor stroma in addition to the malignant cell compartment is of paramount importance to achieve complete tumor regression. In this work, we modified a previously designed tumor stroma-targeted conditionally replicative adenovirus (CRAd) based on the SPARC promoter by introducing a mutated E1A unable to bind pRB and pseudotyped with a chimeric Ad5/3 fiber (Ad F512v1), and assessed its replication/lytic capacity in ovary cancer in vitro and in vivo. AdF512v1 was able to replicate in fresh samples obtained from patients: (i) with primary human ovary cancer; (ii) that underwent neoadjuvant treatment; (iii) with metastatic disease. In addition, we show that four intraperitoneal (i.p.) injections of 5 × 10(10) v.p. eliminated 50% of xenografted human ovary tumors disseminated in nude mice. Moreover, AdF512v1 replication in tumor models was enhanced 15-40-fold when the tumor contained a mix of malignant and SPARC-expressing stromal cells (fibroblasts and endothelial cells). Contrary to the wild-type virus, AdF512v1 was unable to replicate in normal human ovary samples while the wild-type virus can replicate. This study provides evidence on the lytic capacity of this CRAd and highlights the importance of targeting the stromal tissue in addition to the malignant cell compartment to achieve tumor regression.Fil: Lopez, Maria Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Rivera, Angel A.. University Of Alabama At Birmingahm; Estados UnidosFil: Viale, Diego Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Benedetti, Lorena Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Cuneo, Nicasio. Hospital Municipal de Oncología Marie Curie; ArgentinaFil: Kimball, Kristopher J.. University Of Alabama At Birmingahm; Estados UnidosFil: Wang, Minghui. University Of Alabama At Birmingahm. School Of Medicine. Division Of Human Gene Therapy; Estados UnidosFil: Douglas, Joanne T.. University Of Alabama At Birmingahm. School Of Medicine. Division Of Human Gene Therapy; Estados UnidosFil: Zhu, Zeng B.. University Of Alabama At Birmingahm. School Of Medicine. Division Of Human Gene Therapy; Estados UnidosFil: Bravo, Alicia I.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "eva Peron"; ArgentinaFil: Gidekel, Manuel. Universidad de la Frontera; ChileFil: Alvarez, Ronald D.. University Of Alabama At Birmingahm; Estados UnidosFil: Curiel, David T.. University Of Alabama At Birmingahm. School Of Medicine. Division Of Human Gene Therapy; Estados Unidos. University of Washington; Estados UnidosFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentin

Aparente influencia de la marea terrestre en la actividad hidrotermal del volcán Misti observada en datos de temperatura

En este trabajo se presentan los resultados preliminares del monitoreo de temperatura del suelo a 30 cm de profundidad en el cráter del volcán Misti en el periodo 2004-2011. La posible contribución de las mareas terrestres en el disparo de erupciones volcánicas ha sido observada en ambientes de volcanismo basáltico (Dzurisin, 1980; Van Manen et al., 2010; Sottili & Palladino, 2012), pero no se han reportado tal tipo de fenómeno en volcanes de arco. El volcán Misti es un volcán andesítico activo que no está en erupción pero que presenta, por ciertos lapsos de tiempo, una actividad fumarólica intensa al nivel de su cráter interno y en sus inmediaciones. El objetivo del presente trabajo es mostrar que en el volcán Misti se han observado variaciones de tipo periódico de la temperatura del suelo, y que dichas variaciones podrían tener asociación con las mareas terrestres. Los datos de temperatura provienen de la cúspide del volcán, a inmediaciones de la zona de fumarolas del cráter; los datos de la marea terrestre provienen de cálculos teóricos válidos para la zona donde se ubica el volcán

A phase I clinical trial of Ad5/3-Δ24, a novel serotype-chimeric, infectivity-enhanced, conditionally-replicative adenovirus (CRAd), in patients with recurrent ovarian cancer

The conditionally replicative adenovirus Ad5/3-Δ24 has a type-3 knob incorporated into the type-5 fiber that facilitates enhanced ovarian cancer infectivity. Preclinical studies have shown that Ad5/3-Δ24 achieves significant oncolysis and antitumor activity in ovarian cancer models. The purpose of this study was to evaluate in a Phase I trial the feasibility and safety of intraperitoneal (IP) Ad5/3-Δ24 in recurrent ovarian cancer patients

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

Monitoring of Biodistribution and Persistence of Conditionally Replicative Adenovirus in a Murine Model of Ovarian Cancer Using Capsid-Incorporated mCherry and Expression of Human Somatostatin Receptor Subtype 2 Gene

A significant limiting factor to the human clinical application of conditionally replicative adenovirus (CRAd)-based virotherapy is the inability to noninvasively monitor these agents and their potential persistence. To address this issue, we proposed a novel imaging approach that combines transient expression of the human somatostatin receptor (SSTR) subtype 2 reporter gene with genetic labeling of the viral capsid with mCherry fluorescent protein. To test this dual modality system, we constructed the Ad5/3Δ24pIXcherry/SSTR CRAd and validated its capacity to generate fluorescent and nuclear signals in vitro and following intratumoral injection. Analysis of 64 Cu-CB-TE2A-Y3-TATE biodistribution in mice revealed reduced uptake in tumors injected with the imaging CRAd relative to the replication-incompetent, Ad-expressing SSTR2 but significantly greater uptake compared to the negative CRAd control. Optical imaging demonstrated relative correlation of fluorescent signal with virus replication as determined by viral genome quantification in tumors. Positron emission tomography/computed tomography studies demonstrated that we can visualize radioactive uptake in tumors injected with imaging CRAd and the trend for greater uptake by standardized uptake value analysis compared to control CRAd. In the aggregate, the plasticity of our dual imaging approach should provide the technical basis for monitoring CRAd biodistribution and persistence in preclinical studies while offering potential utility for a range of clinical applications