98 research outputs found
Cloning and characterization of an adenoviral vector for highly efficient and doxycycline – suppressible expression of bioactive human single – chain interleukin 12 in colon cancer
BACKGROUND: Interleukin-12 (IL-12) is well characterized to induce cellular antitumoral immunity by activation of NK-cells and T-lymphocytes. However, systemic administration of recombinant human IL-12 resulted in severe toxicity without perceptible therapeutic benefit. Even though intratumoral expression of IL-12 leads to tumor regression and long-term survival in a variety of animal models, clinical trials have not yet shown a significant therapeutic benefit. One major obstacle in the treatment with IL-12 is to overcome the relatively low expression of the therapeutic gene without compromising the safety of such an approach. Our objective was to generate an adenoviral vector system enabling the regulated expression of very high levels of bioactive, human IL-12. RESULTS: High gene expression was obtained utilizing the VP16 herpes simplex transactivator. Strong regulation of gene expression was realized by fusion of the VP16 to a tetracycline repressor with binding of the fusion protein to a flanking tetracycline operator and further enhanced by auto-regulated expression of its fusion gene within a bicistronic promoter construct. Infection of human colon cancer cells (HT29) at a multiplicity of infection (m.o.i.) of 10 resulted in the production of up to 8000 ng/10(6 )cells in 48 h, thus exceeding any published vector system so far. Doxycycline concentrations as low as 30 ng/ml resulted in up to 5000-fold suppression, enabling significant reduction of gene expression in a possible clinical setting. Bioactivity of the human single-chain IL-12 was similar to purified human heterodimeric IL-12. Frozen sections of human colon cancer showed high expression of the coxsackie adenovirus receptor with significant production of human single chain IL-12 in colon cancer biopsies after infection with 3*10(7 )p.f.u. Ad.3r-scIL12. Doxycycline mediated suppression of gene expression was up to 9000-fold in the infected colon cancer tissue. CONCLUSION: VP16 transactivator-mediated and doxycycline-regulated expression of the human interleukin-12 gene enables highly efficient and tightly controlled cytokine expression in human cancer. These data illustrate the potential of the described adenoviral vector system for the safe and superior expression of therapeutic genes in the treatment of colorectal cancer and other malignancies
Spectroscopic perspective on the interplay between electronic and magnetic properties of magnetically doped topological insulators
We combine low energy muon spin rotation (LE-SR) and soft-X-ray
angle-resolved photoemission spectroscopy (SX-ARPES) to study the magnetic and
electronic properties of magnetically doped topological insulators,
(Bi,Sb)Te. We find that one achieves a full magnetic volume fraction in
samples of (V/Cr)(Bi,Sb)Te at doping levels x 0.16.
The observed magnetic transition is not sharp in temperature indicating a
gradual magnetic ordering. We find that the evolution of magnetic ordering is
consistent with formation of ferromagnetic islands which increase in number
and/or volume with decreasing temperature. Resonant ARPES at the V edge
reveals a nondispersing impurity band close to the Fermi level as well as V
weight integrated into the host band structure. Calculations within the
coherent potential approximation of the V contribution to the spectral function
confirm that this impurity band is caused by V in substitutional sites. The
implications of our results on the observation of the quantum anomalous Hall
effect at mK temperatures are discussed
Autoantikörpernachweis mittels indirekter Immunfluoreszenz an HEp-2-Zellen
Systemic autoimmune diseases are characterized by the presence of antinuclear autoantibodies (ANAs). Diluted patient sera are typically used to screen for the presence of ANAs by immunofluorescence microscopy with fixed HEp-2 cells. Despite high quality test kits, reports of different laboratories frequently present controversial results. This study presents a recommendation for a unified processing and interpretation of HEp-2 based screening for autoantibodies. We provide suggestions for selection of high quality test kits, optimized processing, and diagnostic procedures. For good laboratory practice, in addition to a relevant clinical diagnosis and an experienced laboratory specialist, the following procedure is highly recommended: initial HEp-2 based screening by indirect immunofluorescence, starting with a 1:80 serum dilution and evaluation in a bright fluorescence microscope, pathological values from a titer of 1:160, internal quality checks, and unified interpretation. We aim to improve diagnostics and care for patients with autoimmune diseases as a central focus of the European Autoimmunity Standardization Initiative (EASI)
Proximity-Induced Odd-Frequency Superconductivity in a Topological Insulator
At an interface between a topological insulator (TI) and a conventional
superconductor (SC), superconductivity has been predicted to change
dramatically and exhibit novel correlations. In particular, the induced
superconductivity by an -wave SC in a TI can develop an order parameter with
a -wave component. Here we present experimental evidence for an unexpected
proximity-induced novel superconducting state in a thin layer of the
prototypical TI, BiSe, proximity coupled to Nb. From depth-resolved
magnetic field measurements below the superconducting transition temperature of
Nb, we observe a local enhancement of the magnetic field in BiSe that
exceeds the externally applied field, thus supporting the existence of an
intrinsic paramagnetic Meissner effect arising from an odd-frequency
superconducting state. Our experimental results are complemented by theoretical
calculations supporting the appearance of such a component at the interface
which extends into the TI. This state is topologically distinct from the
conventional Bardeen-Cooper-Schrieffer state it originates from. To the best of
our knowledge, these findings present a first observation of bulk odd-frequency
superconductivity in a TI. We thus reaffirm the potential of the TI-SC
interface as a versatile platform to produce novel superconducting states.Comment: Accepted version for publication in Physical Review Letter
Weyl-fermions, Fermi-arcs, and minority-spin carriers in ferromagnetic CoS2
The pyrite compound CoS2 has been intensively studied in the past due to its
itinerant ferromagnetism and potential for half-metallicity, which make it a
promising material for spintronic applications. However, its electronic
structure remains only poorly understood. Here we use complementary bulk- and
surface-sensitive angle-resolved photoelectron spectroscopy and ab-initio
calculations to provide a complete picture of its band structure. We discover
Weyl-cones at the Fermi-level, which presents CoS2 in a new light as a rare
member of the recently discovered class of magnetic topological metals. We
directly observe the topological Fermi-arc surface states that link the
Weyl-nodes, which will influence the performance of CoS2 as a spin-injector by
modifying its spin-polarization at interfaces. Additionally, we are for the
first time able to directly observe a minority-spin bulk electron pocket in the
corner of the Brillouin zone, which proves that CoS2 cannot be a true
half-metal. Beyond settling the longstanding debate about half-metallicity in
CoS2, our results provide a prime example of how the topology of magnetic
materials can affect their use in spintronic applications
Decreased hydrocortisone sensitivity of T cell function in multiple sclerosis-associated major depression
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS with a high prevalence of depression. Both MS and depression have been linked to elevated cortisol levels and inflammation, indicating disturbed endocrine-immune regulation. An imbalance in mineralocorticoid versus glucocorticoid signaling in the CNS has been proposed as a pathogenetic mechanism of depression. Intriguingly, both receptors are also expressed in lymphocytes, but their role for ‘escape’ of the immune system from endocrine control is unknown. Using steroid sensitivity of T cell function as a read-out system, we here investigate a potential role of mineralocorticoid receptor (MR) versus glucocorticoid receptor (GR) regulation in the immune system as a biological mechanism underlying MS-associated major depression. Twelve female MS patients meeting diagnostic criteria for current major depressive disorder (MDD) were compared to twelve carefully matched MS patients without depression. We performed lymphocyte phenotyping by flow cytometry. In addition, steroid sensitivity of T cell proliferation was tested using hydrocortisone as well as MR (aldosterone) and GR (dexamethasone) agonists. Sensitivity to hydrocortisone was decreased in T cells from depressed MS patients. Experiments with agonists suggested disturbed MR regulation, but intact GR function. Importantly, there were no differences in lymphocyte composition and frequency of T cell subsets, indicating that the differences in steroid sensitivity are unlikely to be secondary to shifts in the immune compartment. To our knowledge, this study provides first evidence for altered steroid sensitivity of T cells from MS patients with comorbid MDD possibly due to MR dysregulation
Активность микрофлоры как показатель токсичности морских донных отложений шельфовой зоны Черного моря и Керченского пролива
Изучена потенциальная активность донной микрофлоры в местах утечки остатков химических токсикантов, затопленных в период Второй Мировой войны ХХ в. Отмечены особенности восстановления жизнедеятельности микрофлоры при различных уровнях загрязнения донных отложений мышьяком и хлорированными органическими сульфидами. Полученные результаты перспективно использовать при оценке экологического состояния донных отложений в загрязненных прибрежных акваториях
European research priorities for intracerebral haemorrhage
Over 2 million people are affected by intracerebral haemorrhage (ICH) worldwide every year, one third of them dying within 1 month, and many survivors being left with permanent disability. Unlike most other stroke types, the incidence, morbidity and mortality of ICH have not declined over time. No standardised diagnostic workup for the detection of the various underlying causes of ICH currently exists, and the evidence for medical or surgical therapeutic interventions remains limited. A dedicated European research programme for ICH is needed to identify ways to reduce the burden of ICH-related death and disability. The European Research Network on Intracerebral Haemorrhage EURONICH is a multidisciplinary academic research collaboration that has been established to define current research priorities and to conduct large clinical studies on all aspects of ICH. Copyright (C) 2011 S. Karger AG, Base
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