Development of targeted therapy for ovarian cancer mediated by a plasmid expressing diphtheria toxin under the control of H19 regulatory sequences

<p>Abstract</p> <p>Background</p> <p>Ovarian cancer ascites fluid (OCAF), contains malignant cells, is usually present in women with an advanced stage disease and currently has no effective therapy. Hence, we developed a new therapy strategy to target the expression of diphtheria toxin gene under the control of H19 regulatory sequences in ovarian tumor cells. H19 RNA is present at high levels in human cancer tissues (including ovarian cancer), while existing at a nearly undetectable level in the surrounding normal tissue.</p> <p>Methods</p> <p>H19 gene expression was tested in cells from OCAF by the in-situ hybridization technique (ISH) using an H19 RNA probe. The therapeutic potential of the toxin vector DTA-H19 was tested in ovarian carcinoma cell lines and in a heterotopic animal model for ovarian cancer.</p> <p>Results</p> <p>H19 RNA was detected in 90% of patients with OCAF as determined by ISH. Intratumoral injection of DTA-H19 into ectopically developed tumors caused 40% inhibition of tumor growth.</p> <p>Conclusion</p> <p>These observations may be the first step towards a major breakthrough in the treatment of human OCAF, while the effect in solid tumors required further investigation. It should enable us to identify likely non-responders in advance, and to treat patients who are resistant to all known therapies, thereby avoiding treatment failure.</p

Evaluation of myocardial ischemia using a rest metabolism/stress perfusion protocol with fluorine-18 deoxyglucose/technetium-99m MIBI and dual-isotope simultaneous-acquisition single-photon emission computed tomography

Objectives.This study sought to develop a dual-isotope single-acquisition single-photon emission computed tomographic (SPECT) protocol using a multihead SPECT camera equipped with an ultra-high energy collimator to evaluate rest metabolism/stress perfusion simultaneously with fluorine-18 (F-18) deoxyglucose/technetium-99m (Tc-99m) 2-hexakis-2-methoxy-2-methylpropyl isonitrile (MIBI).Background.The most accurate and logistic method of identifying injured but viable myocardium remains a diagnostic challenge.Methods.Sixty-five patients were given 25 to 50 g of glucose and, after ∼60 min, an injection of 370 MBq (10 mCi) of F-18 fluorodeoxyglucose. After a 35-min distribution phase, patients underwent exercise or pharmacologic stress followed by administration of 925 MBq (25 mCi) of Tc-99m MIBI. Five patients underwent F-18 fluorodeoxyglucose positron emission tomography before dualisotope SPECT.Results.With a window of 20% for both photopeaks and a technetium-99m/fluorine-18 concentration of 3.2: 1, the “spillover” from fluorine-18 into the technetium-99m window is <6% of the total counts in the window in patients with a normal distribution of both radiopharmaceuticals. Phantom images clearly demonstrated cardiac defects measuring 2 × 1 and 2 × 0.5 cm. There was no significant difference in the images of the five patients who underwent both positron emission tomography and SPECT. Fifty-seven patients (mean [±SD] age 55 ± 15 years, range 25 to 83; 38 men, 19 women) had satisfactory images and were included in the study. Twenty-one patients had normal study results; 15 had mismatched defects; 14 had matched defects; and 7 had both matched and mismatched defects. Twenty-three patients (mean age 54 ± 6 years, range 30 to 83; 14 men, 9 women) underwent coronary angiography within 3 months of dual-isotope SPECT. There were seven normal studies, eight with mismatched defects, one with a matched defect and seven with matched and mismatched defects. When stenosis >70% was used as the criterion for a diagnosis of coronary artery disease, dual-isotope SPECT had a sensitivity of 100%, specificity of 88%, positive predictive value of 93%, negative predictive value of 100% and an accuracy of 96%.Conclusions.Dual-isotope SPECT may provide an alternative, accurate, cost-effective method to nitrogen-13 ammonia/F-18 fluorodeoxyglucose positron emission tomography or thallium-201 reinjection for identifying injured or dysfunctional but viable myocardium

ORB5: a global electromagnetic gyrokinetic code using the PIC approach in toroidal geometry

This paper presents the current state of the global gyrokinetic code ORB5 as an update of the previous reference [Jolliet et al., Comp. Phys. Commun. 177 409 (2007)]. The ORB5 code solves the electromagnetic Vlasov-Maxwell system of equations using a PIC scheme and also includes collisions and strong flows. The code assumes multiple gyrokinetic ion species at all wavelengths for the polarization density and drift-kinetic electrons. Variants of the physical model can be selected for electrons such as assuming an adiabatic response or a ``hybrid'' model in which passing electrons are assumed adiabatic and trapped electrons are drift-kinetic. A Fourier filter as well as various control variates and noise reduction techniques enable simulations with good signal-to-noise ratios at a limited numerical cost. They are completed with different momentum and zonal flow-conserving heat sources allowing for temperature-gradient and flux-driven simulations. The code, which runs on both CPUs and GPUs, is well benchmarked against other similar codes and analytical predictions, and shows good scalability up to thousands of nodes

Arquitetos pioneiros na construção do estado de Roraima: décadas de 1980 e 1990

Este artigo tem por objetivo evidenciar a importância dos arquitetos pioneiros de Roraima, que foram responsáveis pela consolidação da estrutura dos órgãos técnicos no surgimento do estado e que contribuíram para a imagem da arquitetura local, entre o final da década de 1980 e ao longo da década de 1990. Inseridos num segundo momento de influxo desenvolvimentista, estes arquitetos se destacaram pela coordenação e autoria de obras modernas que serviram de alicerce infraestrutural e arranque para o desenvolvimento socioeconômico roraimense, especialmente na década de 1990, com destaque às obras arquitetônicas dos edifícios institucionais, que constituiram um conjunto arquitetônico simbólico para a capital. A necessidade desse registro deve-se à escassez de documentação histórica desse período importante, sendo necessário o registro dessas contribuições, cujas fontes foram pesquisas bibliográficas e análises documentais, como entrevistas com os profissionais da época e registros fotográficos. Desse modo, o trabalho visa destacar como se deu o processo da Arquitetura Moderna tardia em Roraima nesse período, assim como o papel dos arquitetos dos órgãos públicos de infraestrutura como precursores na construção e consolidação do, então, novo estado brasileiro

Use of H19 Gene Regulatory Sequences in DNA-Based Therapy for Pancreatic Cancer

Pancreatic cancer is the eighth most common cause of death from cancer in the world, for which palliative treatments are not effective and frequently accompanied by severe side effects. We propose a DNA-based therapy for pancreatic cancer using a nonviral vector, expressing the diphtheria toxin A chain under the control of the H19 gene regulatory sequences. The H19 gene is an oncofetal RNA expressed during embryo development and in several types of cancer. We tested the expression of H19 gene in patients, and found that 65% of human pancreatic tumors analyzed showed moderated to strong expression of the gene. In vitro experiments showed that the vector was effective in reducing Luciferase protein activity on pancreatic carcinoma cell lines. In vivo experiment results revealed tumor growth arrest in different animal models for pancreatic cancer. Differences in tumor size between control and treated groups reached a 75% in the heterotopic model (P = .037) and 50% in the orthotopic model (P = .007). In addition, no visible metastases were found in the treated group of the orthotopic model. These results indicate that the treatment with the vector DTA-H19 might be a viable new therapeutic option for patients with unresectable pancreatic cancer

Numerical Calculations of the B1g Raman Spectrum of the Two-Dimensional Heisenberg Model

The B1g Raman spectrum of the two-dimensional S=1/2 Heisenberg model is discussed within Loudon-Fleury theory at both zero and finite temperature. The exact T=0 spectrum for lattices with up to 6*6 sites is computed using Lanczos exact diagonalization. A quantum Monte Carlo (QMC) method is used to calculate the corresponding imaginary-time correlation function and its first two derivatives for lattices with up to 16*16 spins. The imaginary-time data is continued to real frequency using the maximum-entropy method, as well as a fit based on spinwave theory. The numerical results are compared with spinwave calculations for finite lattices. There is a surprisingly large change in the exact spectrum going from 4*4 to 6*6 sites. In the former case there is a single dominant two-magnon peak at frequency w/J appr. 3.0, whereas in the latter case there are two approximately equal-sized peaks at w/J appr. 2.7 and 3.9. This is in good qualitative agreement with the spinwave calculations including two-magnon processes on the same lattices. Both the Lanczos and the QMC results indicate that the actual infinite-size two-magnon profile is broader than the narrow peak obtained in spinwave theory, but the positions of the maxima agree to within a few percent. The higher-order contributions present in the numerical results are merged with the two-magnon profile and extend up to frequencies w/J appr. 7. The first three frequency cumulants of the spectrum are in excellent agreement with results previously obtained from a series expansion around the Ising limit. Typical experimental B1g$ spectra for La2CuO4 are only slightly broader than what we obtain here. The exchange constant extracted from the peak position is J appr. 1400K, in good agreement with values obtained from neutron scattering and NMR experiments.Comment: 15 pages, Revtex, 13 PostScript figure