Cancer gene therapy – state-of-the-art

A number of gene therapy clinical trials are being carried out the world over. Gene therapy is being applied in (I) cancer diseases, involving the largest number of patients, (II) monogenic diseases, (III) infectious diseases, (IV) vascular diseases, (V) autoimmune diseases and others. In the last decade, several strategies of cancer gene therapy have emerged due to a rapid development of gene delivery systems, both viral (recombinant retroviruses, adenoviruses, AAVs, herpes viruses) and nonviral (liposomes, gene guns, electroporation). To date four main strategies of cancer gene therapy have been evaluated in clinical trials: (I) immunogene therapy, (II) suicide gene therapy, (III) antiangiogenic gene therapy, (IV) and administration of tumour suppressor genes.These strategies mostly involve: malignant melanoma, prostate cancer, renal cell cancer, colon cancer, breast and ovarian cancers, lung cancers, neoplastic diseases of the blood and brain tumours.At the Department of Cancer Immunology at the GreatPoland Cancer Center Gene Modified Tumour Vaccine has been tested in malignant melanoma patients for more than six years. Due to encouraging results from phase I and II of clinical trials a phase III was designed and will be started in 2003

Phase Transition in Sexual Reproduction and Biological Evolution

Using Monte Carlo model of biological evolution we have discovered that populations can switch between two different strategies of their genomes' evolution; Darwinian purifying selection and complementing the haplotypes. The first one is exploited in the large panmictic populations while the second one in the small highly inbred populations. The choice depends on the crossover frequency. There is a power law relation between the critical value of crossover frequency and the size of panmictic population. Under the constant inbreeding this critical value of crossover does not depend on the population size and has a character of phase transition. Close to this value sympatric speciation is observed.Comment: 13 pages, 8 figure

Optimised Spherical Sampling of the Object Colour Solid

We propose a new method for approximating object colour solids, which we call Optimised Spherical Sampling. We compare our new method to the previously described methods based on 1) the two-transition conjecture of Schrodinger and 2) Random Spherical Sampling. The proposed method is based on the approximation of the OCS local error at every face of the volume and its subsequent optimisation. We find that the new method produces a significantly less error for the same number of samples than the two prior art methods

Definition of prominent thermal mechanisms associated with the buoyancy-induced transport of hafnium-carbide within a solidifying uranium-hafnium alloy

Environmental concerns over uranium wastes generated interest in using existing uranium stockpiles as feed materials. One obstacle to recycling is accumulation of carbon that can degrade as-cast mechanical properties. A program was begun to develop a casting procedure capable of reducing the C content in components made from recycled uranium to levels comparable with virgin feed stock. Trace amounts of Hf are added to form low-density Hf C, which floats to the top of the casting, and can be removed at a later time. Developing this procedure requires modeling carbide transport within solidifying uranium, and this necessitates solving a coupled, nonlinear fluid dynamics, heat transfer, and solution thermodynamics problem. The heat transfer facet was addressed first. Steady-state and transient thermal performance of a laboratory-scale casting assembly was characterized to identify those mechanisms that have a prominent influence on modeling uranium melt solidification. The analysis showed that (1) at least first-order accurate definitions for all thermal mechanisms were required to obtain meaningful agreement with experimental data; (2) prominent mechanisms were thermal contact resistances, liquid uranium natural convection, and internal heat generation; and (3) accurately modeling assembly geometry and enclosure radiation heat transfer would also improve agreement. It was recommended that a second-generation thermal model should be constructed which would include each of these elements

Bodybuilders' accounts of synthol use: The construction of lay expertise online.

Synthol is an injectable oil used by bodybuilders to make muscles appear bigger. Widely available on the Internet, it is reported to carry a wide range of health risks and side effects such as localised skin problems, nerve damage and oil-filled cysts, as well as muscle damage and the development of scar tissue. Given the tension between health risk and quick muscle enlargement, how lay users explain and justify their synthol intake becomes an important question. Drawing on discourse analysis, we focus on how lay expertise is worked up by users in the absence of available specialist knowledge by invoking medical and pharmaceutical discourses as legitimation, providing novices with support, gaining trust through positive personal narratives and thus gaining credibility as experts. Results have clear implications for health promotion interventions with bodybuilders

A designer hyper interleukin 11 (H11) is a biologically active cytokine

<p>Abstract</p> <p>Background</p> <p>Interleukin 11 (IL-11) is a pleiotropic cytokine with anti-apoptotic, anti-inflammatory and hematopoietic potential. The IL-11 activity is determined by the expression of the IL-11R receptor alpha (IL-11Rα) and the signal transducing subunit β (gp130) on the cell membrane. A recombinant soluble form of the IL-11Rα (sIL-11Rα) in combination with IL-11 acts as an agonist on cells expressing the gp130 molecule. We constructed a designer cytokine Hyper IL-11 (H11), which is exclusively composed of naturally existing components. It contains the full length sIL-11Rα connected with the mature IL-11 protein using their natural sequences only. Such a construct has two major advantages: (i) its components are as close as possible to the natural forms of both proteins and (ii) it lacks an artificial linker what should avoid induction of antibody production.</p> <p>Results</p> <p>The H11 construct was generated, the protein was produced in a baculovirus expression system and was then purified by using ion exchange chromatography. The H11 protein displayed activity in three independent bioassays, (i) it induced acute phase proteins production in HepG2 cells expressing IL-11, IL-11Rα and gp130, (ii) it stimulated the proliferation of B9 cells (cells expressing IL-11Rα and gp130) and (iii) proliferation of Baf/3-gp130 cells (cells not expressing IL-11 and IL-11Rα but gp130). Moreover, the preliminary data indicated that H11 was functionally distinct from Hyper-IL-6, a molecule which utilizes the same homodimer of signal transducing receptor (gp130).</p> <p>Conclusions</p> <p>The biologically active H11 may be potentially useful for treatment of thrombocytopenia, infertility, multiple sclerosis, cardiovascular diseases or inflammatory disorders.</p

Phase transition in the genome evolution favours non-random distribution of genes on chromosomes

We have used the Monte Carlo based computer models to show that selection pressure could affect the distribution of recombination hotspots along the chromosome. Close to critical crossover rate, where genomes may switch between the Darwinian purifying selection or complementation of haplotypes, the distribution of recombination events and the force of selection exerted on genes affect the structure of chromosomes. The order of expression of gene s and their location on chromosome may decide about the extinction or survival of competing populations.Comment: 13 pages, 7 figures, publicatio

Effect of irradiation on interleukin 6 and soluble interleukin 6 receptor modified melanoma genetic vaccine

We have designed phase I/II human melanoma gene therapy clinical protocol. The aim of the study was to actively immunize HLA-A1 and/or HLA-A2-positive patients with melanoma with an admixture of irradiated autologous tumor cells and allogeneic melanoma cells genetically engineered to secrete IL-6 and sIL-6R in order to elicit or enhance specific and nonspecific anti-melanoma immune responses to autologous tumor cells to eradicate distant melanoma lesions. Irradiation of autologous and allogeneic tumor cells is a key step in preparation of cellular vaccine because of two major reasons, (i) it inhibits cell proliferation which is crucial in the case of autologous cells which may form a tumor; (ii) it increases melanoma vaccine immunogenicity. The aim of the study was to estimate the optimal dose of ionizing radiation which will provide sterilization of both autologous and allogeneic melanoma cells and will ensure cytokine secretion.Human melanoma cells (Mich-1) were transduced with IL-6 and sIL-6R cDNA using double copy bicistronic retroviral vector. Parental and transduced cells were seeded at in six-well tissue culture plates and were irradiated with 10, 50, 100 and 200 Gy. Secretion of both recombinant proteins into culture was analyzed before and 24, 48, 72, 96 h and 6, 7, 10 and 12 days following irradiation. At the same time adherent cells were enumerated, evaluated for viability and proliferation. At 24, 48, 72 and 96 h postirradiation specific IL-6 and sIL-6R mRNA levels were analyzed.Irradiation of gene modified cells inhibited their proliferation in the dose dependant manner. Dose of 50 Gy sufficiently affected cell proliferation, however, for safety reasons we decided to use the dose of 100 Gy for vaccine preparation. Irradiation did not inhibit secretion of IL-6 and sIL-6R. In contrary, on a per cell basis it significantly increased their secretion which lasted 12 days postirradiation. Interestingly, we did not observe dose or time dependent differences in specific mRNA cellular levels suggesting that increased secretion of both proteins is regulated not on the transcriptional but rather on the posttranscriptional level. Taking all these facts into account we concluded that irradiation of tumor cells may provide an effective and safe approach for gene-modified vaccine preparation