Simple Bioparticle Filtration Device Based on an Ultralow-Fouling Zwitterionic Polyurethane Membrane for Rapid Large-Volume Separation of Plasma and Viruses from Whole Blood.

Plasma separation from whole blood is oftent required as an essential first step when performing blood tests with a viral assay. However, developing a point-of-care plasma extraction device with a large output and high virus recovery remains a significant obstacle to the success of on-site viral load tests. Here, we report a portable, easy-to-use, cost-efficient, membrane-filtration-based plasma separation device that enables rapid large-volume plasma extraction from whole blood, designed for point-of-care virus assays.

CD47 Receptor Globally Regulates Metabolic Pathways That Control Resistance to Ionizing Radiation.

Modulating tissue responses to stress is an important therapeutic objective. Oxidative and genotoxic stresses caused by ionizing radiation are detrimental to healthy tissues but beneficial for treatment of cancer. CD47 is a signaling receptor for thrombospondin-1 and an attractive therapeutic target because blocking CD47 signaling protects normal tissues while sensitizing tumors to ionizing radiation.

NOS Inhibition Modulates Immune Polarization and Improves Radiation-Induced Tumor Growth Delay.

Nitric oxide synthases (NOS) are important mediators of progrowth signaling in tumor cells, as they regulate angiogenesis, immune response, and immune-mediated wound healing. Ionizing radiation (IR) is also an immune modulator and inducer of wound response. We hypothesized that radiation therapeutic efficacy could be improved by targeting NOS following tumor irradiation.

Radiation Enhancement of Head and Neck Squamous Cell Carcinoma by the Dual PI3K/mTOR Inhibitor PF-05212384.

Purpose: Radiation remains a mainstay for the treatment of nonmetastatic head and neck squamous cell carcinoma (HNSCC), a malignancy characterized by a high rate of PI3K/mTOR signaling axis activation. We investigated the ATP-competitive dual PI3K/mTOR inhibitor, PF-05212384, as a radiosensitizer in preclinical HNSCC models.

Experimental Design: Extent of radiation enhancement of two HNSCC cell lines (UMSCC1-wtP53 and UMSCC46-mtP53) and normal human fibroblast (1522) was assessed by in vitro clonogenic assay with appropriate target inhibition verified by immunoblotting.

CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy.

Although significant advances in radiotherapy have increased its effectiveness in many cancer settings, general strategies to widen the therapeutic window between normal tissue toxicity and malignant tumor destruction would still offer great value. CD47 blockade has been found to confer radioprotection to normal tissues while enhancing tumor radiosensitivity. Here, we report that CD47 blockade directly enhances tumor immunosurveillance by CD8(+) T cells.

Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated prodrug TH-302.

Background: TH-302 is a hypoxia-activated prodrug (HAP) of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302.

Targeting HIF2α translation with Tempol in VHL-deficient clear cell renal cell carcinoma.

The tumor suppressor gene, Von Hippel-Lindau (VHL), is frequently mutated in the most common form of kidney cancer, clear cell renal cell carcinoma (CCRCC). In hypoxic conditions, or when there is a VHL mutation, the hypoxia inducible factors, HIF1α and HIF2α, are stabilized and transcribe a panel of genes associated with cancer such as vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor (PDGF), and glucose transporter 1 (GLUT1). Recent studies in clear cell kidney cancer have suggested that HIF2α, but not HIF1α, is the critical oncoprotein in the VHL pathway.

CD47 deficiency confers cell and tissue radioprotection by activation of autophagy.

Accidental or therapeutic exposure to ionizing radiation has severe physiological consequences and can result in cell death. We previously demonstrated that deficiency or blockade of the ubiquitously expressed receptor CD47 results in remarkable cell and tissue protection against ischemic and radiation stress. Antagonists of CD47 or its ligand THBS1/thrombospondin 1 enhance cell survival and preserve their proliferative capacity.

The effects of resveratrol and selected metabolites on the radiation and antioxidant response.

Excess reactive oxygen species (ROS) generated from ionizing radiation (IR) or endogenous sources like cellular respiration and inflammation produce cytotoxic effects that can lead to carcinogenesis. Resveratrol (RSV), a polyphenol with antioxidant and anticarcinogenic capabilities, has shown promise as a potential radiation modifier. The present study focuses on examining the effects of RSV or RSV metabolites as a radiation modifier in normal tissue.

Cellular stress induced alterations in microRNA let-7a and let-7b expression are dependent on p53.

Genotoxic stressors, such as radiation, induce cellular damage that activates pre-programmed repair pathways, some of which involve microRNAs (miRNA) that alter gene expression. The let-7 family of miRNA regulates multiple cellular processes including cell division and DNA repair pathways. However, the role and mechanism underlying regulation of let-7 genes in response to stress have yet to be elucidated.

A novel nitroxide is an effective brain redox imaging contrast agent and in vivo radioprotector.

Individuals are exposed to ionizing radiation during medical procedures and nuclear disasters, and this exposure can be carcinogenic, toxic, and sometimes fatal. Drugs that protect individuals from the adverse effects of radiation may therefore be valuable countermeasures against the health risks of exposure. In the current study, the LD(50/30) (the dose resulting in 50% of exposed mice surviving 30 days after exposure) was determined in control C3H mice and mice treated with the nitroxide radioprotectors Tempol, 3-CP, 16c, 22c, and 23c.

Guggulsterone-mediated enhancement of radiosensitivity in human tumor cell lines.

Purpose: To observe the effect of guggulsterone (GS) on the radiation response in human cancer cell lines.

Materials And Methods: The radiation response of cancer cells treated with GS was observed by cell survival studies, cell growth assay, NF-κB activity assay, western blotting of some key growth promoting receptors, the DNA repair protein γH2AX, and flow cytometry for DNA analyses.

Results: GS inhibited radiation induced NF-κB activation and enhanced radiosensitivity in the pancreatic cell line, PC-Sw.

Inhibition of adipogenesis by Tempol in 3T3-L1 cells.

Obesity is highly associated with an increased risk of serious health conditions including hypertension, cardiovascular disease, diabetes, and cancer. Changes in redox status with increased oxidative stress have been linked with obesity. Previous studies have shown that administration of the antioxidant Tempol in the food of mice prevents obesity, causing significant weight loss without toxicity.

Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling.

Radiation-induced damage of normal tissues restricts the therapeutic doses of ionizing radiation that can be delivered to tumors and thereby limits the effectiveness of radiotherapy. Thrombospondin-1 signaling through its cell surface receptor CD47 limits recovery from several types of stress, and mice lacking either gene are profoundly resistant to radiation injury. We describe strategies to protect normal tissues from radiation damage using CD47 or thrombospondin-1 antibodies, a CD47-binding peptide, or antisense suppression of CD47.

Loratadine dysregulates cell cycle progression and enhances the effect of radiation in human tumor cell lines.

Background: The histamine receptor-1 (H1)-antagonist, loratadine has been shown to inhibit growth of human colon cancer xenografts in part due to cell cycle arrest in G2/M. Since this is a radiation sensitive phase of the cell cycle, we sought to determine if loratadine modifies radiosensitivity in several human tumor cell lines with emphasis on human colon carcinoma (HT29).

Methods: Cells were treated with several doses of loratadine at several time points before and after exposure to radiation.

Enhancement of 5-Aminolevulinic acid-induced oxidative stress on two cancer cell lines by gold nanoparticles.

5-Aminolevulinic acid (5-ALA) and its methyl ester (5-ALA-Me) at mM concentration levels induce oxidative stress via the production of reactive oxygen species (ROS). Human cancer cell lines (MCF-7 and HepG2) incubated in the dark in the simultaneous presence of 5.0 mM or more 5-ALA or 5-ALA-Me (for MCF-7) and 7 microg/mL of 15 nm citrate capped gold nanoparticles (AuNPs) were damaged more seriously compared to those in the presence of the levulinic acid alone.

Halofuginone enhances the radiation sensitivity of human tumor cell lines.

Transforming growth factor beta (TGF-beta) is implicated in radiation-induced fibrosis of normal tissues in patients receiving radiotherapy. Inhibiting the TGF-beta signaling pathway by various means has been shown to reduce radiation-induced fibrosis in pre-clinical studies. The present study evaluated the effects of interfering with the TGF-beta signaling pathway on the radiosensitivity of selected human tumor cell lines using the plant-derived alkaloid, halofuginone.

Ionizing radiation-induced oxidative stress alters miRNA expression.

Background: MicroRNAs (miRNAs) are small, highly conserved, non-coding RNA that alter protein expression and regulate multiple intracellular processes, including those involved in the response to cellular stress. Alterations in miRNA expression may occur following exposure to several stress-inducing anticancer agents including ionizing radiation, etoposide, and hydrogen peroxide (H(2)O(2)).

Methodology/principal Findings: Normal human fibroblasts were exposed to radiation, H(2)O(2), or etoposide at doses determined by clonogenic cell survival curves.

Detection of free radical reactions in an aqueous sample induced by low linear-energy-transfer irradiation.

Quantitative detection of free radical reactions induced by low linear-energy-transfer (LET) irradiation in an aqueous solution was attempted using nitroxyl radicals. The stability and reactivity of reaction mixtures containing a nitroxyl radical and a hydrogen donor, i.e.

Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury.

Radiation, a primary mode of cancer therapy, acutely damages cellular macromolecules and DNA and elicits stress responses that lead to cell death. The known cytoprotective activity of nitric oxide (NO) is blocked by thrombospondin-1, a potent antagonist of NO/cGMP signaling in ischemic soft tissues, suggesting that thrombospondin-1 signaling via its receptor CD47 could correspondingly increase radiosensitivity. We show here that soft tissues in thrombospondin-1-null mice are remarkably resistant to radiation injury.

PX-478, an inhibitor of hypoxia-inducible factor-1alpha, enhances radiosensitivity of prostate carcinoma cells.

Overexpression of hypoxia-inducible factor-1alpha (HIF-1alpha) in human tumors is associated with poor prognosis and poor outcome to radiation therapy. Inhibition of HIF-1alpha is considered as a promising approach in cancer therapy. The purpose of this study was to test the efficacy of a novel HIF-1alpha inhibitor PX-478 as a radiosensitizer under normoxic and hypoxic conditions in vitro.

Absence of Smad3 confers radioprotection through modulation of ERK-MAPK in primary dermal fibroblasts.

Background: Transforming growth factor-beta1 (TGF-beta1), a key biological mediator following ionizing radiation, plays a role in a complex tissue reaction involved in local radiation-induced pathological damage. Knocking out Smad3 (S3KO), a downstream signaling intermediate in the TGF-beta pathway, in mice protects their skin from radiation damage as demonstrated by decreased epithelial acanthosis and dermal fibrosis as compared to Smad3 wild-type (S3WT) mice.

Objective: The present study was designed to investigate the molecular mechanisms contributing to increased radioprotection in the absence of Smad3.

Gene expression profiling of breast, prostate, and glioma cells following single versus fractionated doses of radiation.

Studies were conducted to determine whether gene expression profiles following a single dose of radiation would yield equivalent profiles following fractionated radiation in different tumor cell lines. MCF7 (breast), DU145 (prostate), and SF539 (gliosarcoma) cells were exposed to a total radiation dose of 10 Gy administered as a single dose (SD) or by daily multifractions (MF) of 5 x 2 Gy. Following radiation treatment, mRNA was isolated at 1, 4, 10, and 24 h and processed for cDNA microarray analysis.

Radiation-induced changes in gene-expression profiles for the SCC VII tumor cells grown in vitro and in vivo.

SCCVII tumor cells that grow in vitro or in vivo as a solid tumor were used to compare and contrast geneexpression profiles with or without exposure to two doses of ionizing radiation. Exponentially growing SCCVII cell cultures and tumors (1 cm diameter) were treated with 0, 2, or 10 Gy, and RNA was collected 1, 3, 6, 12, and 24 h after treatment. Growth under in vitro conditions increased the expression of genes associated with the unfolded protein response (UPR) including ATF4, Ero-1 like, and cystathionase.

Superoxide fluxes limit nitric oxide-induced signaling.

Independently, superoxide (O2-) and nitric oxide (NO) are biologically important signaling molecules. When co-generated, these radicals react rapidly to form powerful oxidizing and nitrating intermediates. Although this reaction was once thought to be solely cytotoxic, herein we demonstrate using MCF7, macrophage, and endothelial cells that when nanomolar levels of NO and O2- were produced concomitantly, the effective NO concentration was established by the relative fluxes of these two radicals.