Cancer Screening by Systemic Administration of a Gene Delivery Vector Encoding Tumor-Selective Secretable Biomarker Expression

Cancer biomarkers facilitate screening and early detection but are known for only a few cancer types. We demonstrated the principle of inducing tumors to secrete a serum biomarker using a systemically administered gene delivery vector that targets tumors for selective expression of an engineered cassette. We exploited tumor-selective replication of a conditionally replicative Herpes simplex virus (HSV) combined with a replication-dependent late viral promoter to achieve tumor-selective biomarker expression as an example gene delivery vector. Virus replication, cytotoxicity and biomarker production were low in quiescent normal human foreskin keratinocytes and high in cancer cells in vitro. Following intravenous injection of virus >90% of tumor-bearing mice exhibited higher levels of biomarker than non-tumor-bearing mice and upon necropsy, we detected virus exclusively in tumors. Our strategy of forcing tumors to secrete a serum biomarker could be useful for cancer screening in high-risk patients, and possibly for monitoring response to therapy. In addition, because oncolytic vectors for tumor specific gene delivery are cytotoxic, they may supplement our screening strategy as a “theragnostic” agent. The cancer screening approach presented in this work introduces a paradigm shift in the utility of gene delivery which we foresee being improved by alternative vectors targeting gene delivery and expression to tumors. Refining this approach will usher a new era for clinical cancer screening that may be implemented in the developed and undeveloped world

An Efficient Targeted Drug Delivery through Apotransferrin Loaded Nanoparticles

BACKGROUND: Cancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin. METHODOLOGY/PRINCIPAL FINDINGS: Apotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano) have diameters of 25-50 etam, which increase to 60-80 etam upon direct loading of drug (direct-nano), and showed further increase in dimension (75-95 etam) in conjugated nanoparticles (conj-nano). The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a) localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus) (b) pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c) the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in regression of hepatocellular carcinoma with negligible toxicity to kidney and liver. CONCLUSIONS: The present study thus demonstrates that the direct-nano is highly efficacious in delivery of drug in a target specific manner with lower toxicity to heart, liver and kidney

Measurement of the W+W- production cross section in p(p)over-bar collisions at root s=1.96 TeV using dilepton events

We present a measurement of the W+W- production cross section using 184 pb(-1) of p (p) over bar collisions at a center-of-mass energy of 1.96 TeV collected with the Collider Detector at Fermilab. Using the dilepton decay channel W+W-→ l(+)ν l(-)(ν) over bar, where the charged leptons can be either electrons or muons, we find 17 candidate events compared to an expected background of 5.0(-0.8)(+2.2) events. The resulting W+W- production cross-section measurement of σ(p (p) over bar → W+W-)=14.6(-5.1)(+5.8)(stat)(-3.0)(+1.8)(syst)± 0.9(lum) pb agrees well with the standard model expectation

Combined Forward-Backward Asymmetry Measurements in Top-Antitop Quark Production at the Tevatron

The CDF and D0 experiments at the Fermilab Tevatron have measured the asymmetry between yields of forward- and backward-produced top and antitop quarks based on their rapidity difference and the asymmetry between their decay leptons. These measurements use the full data sets collected in proton-antiproton collisions at a center-of-mass energy of $\sqrt s =1.96$ TeV. We report the results of combinations of the inclusive asymmetries and their differential dependencies on relevant kinematic quantities. The combined inclusive asymmetry is $A_{\mathrm{FB}}^{t\bar{t}} = 0.128 \pm 0.025$. The combined inclusive and differential asymmetries are consistent with recent standard model predictions

Immunoglobulin G Antibody-Mediated Enhancement of Measles Virus Infection Can Bypass the Protective Antiviral Immune Response

Antibodies to viral surface glycoproteins play a crucial role in immunity to measles by blocking both virus attachment and subsequent fusion with the host cell membrane. Here, we demonstrate that certain immunoglobulin G (IgG) antibodies can also enhance the entry of measles virus (MV) into monocytes and macrophages. Antibody-dependent enhancement of infectivity was observed in mouse and human macrophages using virions opsonized by a murine monoclonal antibody against the MV hemagglutinin (H) glycoprotein, polyclonal mouse anti-MV IgG, or diluted measles-immune human sera. Neither H-specific Fab fragments nor H-specific IgM could enhance MV entry in monocytes or macrophages, indicating involvement of a Fc γ receptor (FcγR)-mediated mechanism. Preincubation with an anti-fusion protein (anti-F) monoclonal antibody or a fusion-inhibitory peptide blocked infection, indicating that a functional F protein was required for viral internalization. Classical complement pathway activation did not promote infection through complement receptors and inhibited anti-H IgG-mediated enhancement. In vivo, antibody-enhanced infection allowed MV to overcome a highly protective systemic immune response in preimmunized IfnarKo-Ge46 transgenic mice. These data demonstrate a previously unidentified mechanism that may contribute to morbillivirus pathogenesis where H-specific IgG antibodies promote the spread of MV infection among FcγR-expressing host cells. The findings point to a new model for the pathogenesis of atypical MV infection observed after immunization with formalin-inactivated MV vaccine and underscore the importance of the anti-F response after vaccination

Rectal Cancer: the Role of the Surgical Treatment of the Primary Tumor in Advanced Inoperable Liver Metastases

The aim of the study was to determine the role of the surgical resection of the primary tumor in patients with rectal cancer and liver metastases who are not suitable for surgical treatment as part of their complex therapy.Materials and Methods: 74 patients who have undergone a rectal cancer surgery and had unresectable liver metastases were followed during a period of 10 years. Initially, all patients underwent radical resection of the primary tumor and then postoperative chemotherapy for treatment of the liver metastases. The participants were divided into two groups: the first group with survival of up to 8 months (median survival - 6 months) and the second group with survival longer than 8 months (median survival - 12 months). The following factors were analyzed: age, grading of the tumor, infiltration of the tumor into the wall of the rectum into the mesorectum, number of the metastases, localisation of the tumor into the rectum, type of the surgical intervention, as well as their influence over the survival.Results: The role of the surgical treatment of the primary tumor in patients with rectal cancer and inoperable liver metastases depends on the individual response of the patient to the postoperative chemotherapy. It is indicated by vital indications, young age and by the response to the preoperative chemotherapy. When there is lack of response to the preoperative chemotherapy the survival is the same with and without surgical treatment of the primary tumor

Engineered measles virus as a novel oncolytic therapy against prostate cancer

BACKGROUND. No curative therapy is currently available for locally advanced or metastatic prostate cancer. Oncolytic viruses represent a novel class of therapeutic agents that demonstrates no cross-resistance with existing approaches and can therefore be combined with conventional treatment modalities. Measles virus strains deriving from the Edmonston (MV-Edm) vaccine strain have shown considerable oncolytic activity against a variety of solid tumers and hematologic malignancies. In this study, we investigated the antitumor potential of recombinant MV-Edm derivatives as novel oncolytic agents against prostate cancer. METHODS. The susceptibility of prostate cancer cell lines (PC-3, DU-145, and LNCaP) to measles virus infection was demonstrated using an MV-Edm derivative expressing green fluorescent protein (GFP). MV-Edm replication in prostate cancer cell lines was assessed by one step viral growth curves. The oncolytic effect of an MV-Edm strain engineered to express the human carcinoembryonic antigen (CEA) was demonstrated in vitro by MTT assays and in vivo in subcutaneous PC-3 xenografts. CEA levels were quantitated in cell supernatants and mouse serum samples. RESULTS. Recombinant MV-Edm strains can effectively infect, replicate in and kill prostate cancer cells. Intratumoral administration of MV-CEA at a total dose of 6 x 106 TCID50 resulted in statistically significant tumor growth delay (P - 0.004) and prolongation of survival (P - 0.001) in a subcutaneous PC-3 xenograft model. Viral growth kinetics paralleled CEA production. CONCLUSIONS. MV-CEA has potent antitumor activity against prostate cancer cell lines and xenografts. Viral gene expression during treatment can be determined by monitoring of CEA levels in the serum; the latter could allow dose optimization and tailoring of individualized treatment protocols. © 2008 Wiley-Liss, Inc

Noninvasive imaging and radiovirotherapy of prostate cancer using an oncolytic measles virus expressing the sodium iodide symporter

Prostate cancer cells overexpress the measles virus (MV) receptor CD46. Herein, we evaluated the antitumor activity of an oncolytic derivative of the MV Edmonston (MV-Edm) vaccine strain engineered to express the human sodium iodide symporter (NIS; MV-NIS virus). MV-NIS showed significant cytopathic effect (CPE) against prostate cancer cell lines in vitro. Infected cells effectively concentrated radioiodide isotopes as measured in vitro by Iodide-125 ( 125I) uptake assays. Virus localization and spread in vivo could be effectively followed by imaging of 123 I uptake. In vivo administration of MV-NIS either locally or systemically (total dose of 9 × 106 TCID50) resulted in significant tumor regression (P<0.05) and prolongation of survival (P<0.01). Administration of 131 I further enhanced the antitumor effect of MV-NIS virotherapy (P 0.05). In conclusion, MV-NIS is an oncolytic vector with significant antitumor activity against prostate cancer, which can be further enhanced by 131 I administration. The NIS transgene allows viral localization and monitoring by noninvasive imaging which can facilitate dose optimization in a clinical setting. © The American Society of Gene & Cell Therapy