Improving adenoviral vectors and strategies for prostate cancer gene therapy

Gene therapy has been evaluated for the treatment of prostate cancer and includes the application of adenoviral vectors encoding a suicide gene or oncolytic adenoviruses that may be armed with a functional transgene. In parallel, versions of adenoviral vector expressing the p53 gene (Ad-p53) have been tested as treatments for head and neck squamous cell carcinoma and non-small cell lung cancer. Although Ad-p53 gene therapy has yielded some interesting results when applied to prostate cancer, it has not been widely explored, perhaps due to current limitations of the approach. To achieve better functionality, improvements in the gene transfer system and the therapeutic regimen may be required. We have developed adenoviral vectors whose transgene expression is controlled by a p53-responsive promoter, which creates a positive feedback mechanism when used to drive the expression of p53. Together with improvements that permit efficient transduction, this new approach was more effective than the use of traditional versions of Ad-p53 in killing prostate cancer cell lines and inhibiting tumor progression. Even so, gene therapy is not expected to replace traditional chemotherapy but should complement the standard of care. In fact, chemotherapy has been shown to assist in viral transduction and transgene expression. The cooperation between gene therapy and chemotherapy is expected to effectively kill tumor cells while permitting the use of reduced chemotherapy drug concentrations and, thus, lowering side effects. Therefore, the combination of gene therapy and chemotherapy may prove essential for the success of both approaches

S6Ks isoforms contribute to viability, migration, docetaxel resistance and tumor formation of prostate cancer cells

Background: The S6 Kinase (S6K) proteins are some of the main downstream effectors of the mammalian Target Of Rapamycin (mTOR) and act as key regulators of protein synthesis and cell growth. S6K is overexpressed in a variety of human tumors and is correlated to poor prognosis in prostate cancer. Due to the current urgency to identify factors involved in prostate cancer progression, we aimed to reveal the cellular functions of three S6K isoforms-p70-S6K1, p85-S6K1 and p54-S6K2-in prostate cancer, as well as their potential as therapeutic targets. Methods: In this study we performed S6K knockdown and overexpression and investigated its role in prostate cancer cell proliferation, colony formation, viability, migration and resistance to docetaxel treatment. In addition, we measured tumor growth in Nude mice injected with PC3 cells overexpressing S6K isoforms and tested the efficacy of a new available S6K1 inhibitor in vitro. Results: S6Ks overexpression enhanced PC3-luc cell line viability, migration, resistance to docetaxel and tumor formation in Nude mice. Only S6K2 knockdown rendered prostate cancer cells more sensitive to docetaxel. S6K1 inhibitor PF-4708671 was particularly effective for reducing migration and proliferation of PC3 cell line. Conclusions: These findings demonstrate that S6Ks play an important role in prostate cancer progression, enhancing cell viability, migration and chemotherapy resistance, and place both S6K1 and S6K2 as a potential targets in advanced prostate cancer. We also provide evidence that S6K1 inhibitor PF-4708671 may be considered as a potential drug for prostate cancer treatment16CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informação2012/13558-

Potentiation of combined p19Arf and interferon-beta cancer gene therapy through its association with doxorubicin chemotherapy

Balancing safety and efficacy is a major consideration for cancer treatments, especially when combining cancer immunotherapy with other treatment modalities such as chemotherapy. Approaches that induce immunogenic cell death (ICD) are expected to eliminate cancer cells by direct cell killing as well as activation of an antitumor immune response. We have developed a gene therapy approach based on p19Arf and interferon-β gene transfer that, similar to conventional inducers of ICD, results in the release of DAMPS and immune activation. Here, aiming to potentiate this response, we explore whether association between our approach and treatment with doxorubicin (Dox), a known inducer of ICD, could further potentiate treatment efficacy without inducing cardiotoxicity, a critical side effect of Dox. Using central composite rotational design analysis, we show that cooperation between gene transfer and chemotherapy killed MCA205 and B16F10 cells and permitted the application of reduced viral and drug doses. The treatments also cooperated to induce elevated levels of ICD markers in MCA205, which correlated with improved efficacy of immunotherapy in vivo. Treatment of subcutaneous MCA205 tumors associating gene transfer and low dose (10 mg/kg) chemotherapy resulted in inhibition of tumor progression. Moreover, the reduced dose did not cause cardiotoxicity as compared to the therapeutic dose of Dox (20 mg/kg). The association of p19Arf/interferon-β gene transfer and Dox chemotherapy potentiated antitumor response and minimized cardiotoxicity

Prime Focus Spectrograph (PFS) for the Subaru Telescope: Overview, recent progress, and future perspectives

PFS (Prime Focus Spectrograph), a next generation facility instrument on the 8.2-meter Subaru Telescope, is a very wide-field, massively multiplexed, optical and near-infrared spectrograph. Exploiting the Subaru prime focus, 2394 reconfigurable fibers will be distributed over the 1.3 deg field of view. The spectrograph has been designed with 3 arms of blue, red, and near-infrared cameras to simultaneously observe spectra from 380nm to 1260nm in one exposure at a resolution of ~1.6-2.7A. An international collaboration is developing this instrument under the initiative of Kavli IPMU. The project is now going into the construction phase aiming at undertaking system integration in 2017-2018 and subsequently carrying out engineering operations in 2018-2019. This article gives an overview of the instrument, current project status and future paths forward.Comment: 17 pages, 10 figures. Proceeding of SPIE Astronomical Telescopes and Instrumentation 201

Prime Focus Spectrograph - Subaru's future -

The Prime Focus Spectrograph (PFS) of the Subaru Measurement of Images and Redshifts (SuMIRe) project has been endorsed by Japanese community as one of the main future instruments of the Subaru 8.2-meter telescope at Mauna Kea, Hawaii. This optical/near-infrared multi-fiber spectrograph targets cosmology with galaxy surveys, Galactic archaeology, and studies of galaxy/AGN evolution. Taking advantage of Subaru's wide field of view, which is further extended with the recently completed Wide Field Corrector, PFS will enable us to carry out multi-fiber spectroscopy of 2400 targets within 1.3 degree diameter. A microlens is attached at each fiber entrance for F-ratio transformation into a larger one so that difficulties of spectrograph design are eased. Fibers are accurately placed onto target positions by positioners, each of which consists of two stages of piezo-electric rotary motors, through iterations by using back-illuminated fiber position measurements with a wide-field metrology camera. Fibers then carry light to a set of four identical fast-Schmidt spectrographs with three color arms each: the wavelength ranges from 0.38 {\mu}m to 1.3 {\mu}m will be simultaneously observed with an average resolving power of 3000. Before and during the era of extremely large telescopes, PFS will provide the unique capability of obtaining spectra of 2400 cosmological/astrophysical targets simultaneously with an 8-10 meter class telescope. The PFS collaboration, led by IPMU, consists of USP/LNA in Brazil, Caltech/JPL, Princeton, & JHU in USA, LAM in France, ASIAA in Taiwan, and NAOJ/Subaru.Comment: 13 pages, 11 figures, submitted to "Ground-based and Airborne Instrumentation for Astronomy IV, Ian S. McLean, Suzanne K. Ramsay, Hideki Takami, Editors, Proc. SPIE 8446 (2012)

Search for New Particles Decaying to Dijets at CDF

We have used 106 pb^-1 of data collected with the Collider Detector at Fermilab to search for new particles decaying to dijets. We exclude at the 95% confidence level models containing the following new particles: axigluons and flavor universal colorons with mass between 200 and 980 GeV/c, excited quarks with mass between 80 and 570 GeV/c^2 and between 580 and 760 GeV/c^2, color octet technirhos with mass between 260 and 480 GeV/c^2, W' bosons with mass between 300 and 420 GeV/c^2, and E_6 diquarks with mass between 290 and 420 GeV/c^2.Comment: 18 pages, 4 figures, 1 table. Submitted to Physical Review D Rapid Communications. Postscript file of paper is also available at http://www-cdf.fnal.gov/physics/pub97/cdf3276_dijet_search_prd_rc.p

Search for charged Higgs decays of the top quark using hadronic tau decays

We present the result of a search for charged Higgs decays of the top quark, produced in $p\bar{p}$ collisions at $\surd s =$ 1.8 TeV. When the charged Higgs is heavy and decays to a tau lepton, which subsequently decays hadronically, the resulting events have a unique signature: large missing transverse energy and the low-charged-multiplicity tau. Data collected in the period 1992-1993 at the Collider Detector at Fermilab, corresponding to 18.7$\pm$0.7~pb$^{-1}$, exclude new regions of combined top quark and charged Higgs mass, in extensions to the standard model with two Higgs doublets.Comment: uuencoded, gzipped tar file of LaTeX and 6 Postscript figures; 11 pp; submitted to Phys. Rev.

Measurement of Dijet Angular Distributions at CDF

We have used 106 pb^-1 of data collected in proton-antiproton collisions at sqrt(s)=1.8 TeV by the Collider Detector at Fermilab to measure jet angular distributions in events with two jets in the final state. The angular distributions agree with next to leading order (NLO) predictions of Quantum Chromodynamics (QCD) in all dijet invariant mass regions. The data exclude at 95% confidence level (CL) a model of quark substructure in which only up and down quarks are composite and the contact interaction scale is Lambda_ud(+) < 1.6 TeV or Lambda_ud(-) < 1.4 TeV. For a model in which all quarks are composite the excluded regions are Lambda(+) < 1.8 TeV and Lambda(-) < 1. 6 TeV.Comment: 16 pages, 2 figures, 2 tables, LaTex, using epsf.sty. Submitted to Physical Review Letters on September 17, 1996. Postscript file of full paper available at http://www-cdf.fnal.gov/physics/pub96/cdf3773_dijet_angle_prl.p

Inclusive jet cross section in pˉp{\bar p p} collisions at s=1.8\sqrt{s}=1.8 TeV

The inclusive jet differential cross section has been measured for jet transverse energies, $E_T$, from 15 to 440 GeV, in the pseudorapidity region 0.1$\leq | \eta| \leq$0.7. The results are based on 19.5 pb$^{-1}$ of data collected by the CDF collaboration at the Fermilab Tevatron collider. The data are compared with QCD predictions for various sets of parton distribution functions. The cross section for jets with $E_T>200$ GeV is significantly higher than current predictions based on O($\alpha_s^3$) perturbative QCD calculations. Various possible explanations for the high-$E_T$ excess are discussed.Comment: 8 pages with 2 eps uu-encoded figures Submitted to Physical Review Letter

IL-33-mediated protection against experimental cerebral malaria is linked to induction of Type 2 innate lymphoid cells, M2 macrophages and regulatory T cells

Author Summary Cerebral malaria (CM) caused by the parasite Plasmodium sp . is a fatal disease, especially in children. Currently there is no effective treatment. We report here our investigation on the role of a recently discovered cytokine IL-33, in treating experimental cerebral malaria (ECM) in the susceptible C57BL/6 mice. IL-33 protects the mice against ECM. The protection is accompanied by a reduction of Th1 response and the enhancement of type 2 cytokine response. We also found that IL-33 mediates its protective effect by inducing a population of type 2 innate lymphoid cells (ILC2), which then polarize macrophages to alternatively-activated phenotypes (M2). M2 in turn expand regulatory T cells (Tregs) which suppress the deleterious Th1 response. Our report therefore reveals hitherto unrecognised mechanisms of the regulation of ECM and provide a novel function of IL-33