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At least 109 records · Page 6Linked to original sources
PubMed2006

Immuno-isolation in cancer gene therapy.

The implantation of genetically-modified non-autologous cells in immuno-protected microcapsules is an alternative to ex vivo gene therapy. Such cells delivering a recombinant therapeutic product are isolated from the host's immune system by being encapsulated within permselective microcapsules. This approach has been successful in pre-clinical animal studies involving delivery of hormone or enzymes to treat dwarfism, lysosomal storage disease, or hemophilia B. Recently, this platform technology has shown promise in the treatment for more complex diseases such as cancer. One of the earliest strategy was to augment the chemotherapeutic effect of a prodrug by implanting encapsulated cells that can metabolise prodrugs into cytotoxic products in close proximity to the cancer cells. More recent approaches include enhancing tumor cell death through immunotherapy, or suppressing tumor cell proliferation through anti-angiogenesis. These can be achieved by delivering single molecules of cytokines or angiostatin, respectively, by implanting microencapsulated cells engineered to secrete these recombinant products. Recent refinements of these approaches include genetic fusion of cytokines or angiostatin to additional functional groups with tumor targeting or tumor cell killing properties, thus enhancing the potency of the recombinant products. Furthermore, a COMBO strategy of implanting microencapsulated cells to deliver multiple products targeted to diverse pathways in tumor suppression also showed much promise. This review will summarise the application of microencapsulation of genetically-modified cells to cancer treatment in animal models, the efficacy of such approaches, and how these studies have led to better understanding of the biology of cancer treatment. The flexibility of this modular system involving molecular engineering, cellular genetic modification, and polymer chemistry provides potentially a huge range of application modalities, and a tremendous multi-disciplinary challenge for the future.

Animals↗
PubMed2003

Pax-6 activates endogenous proglucagon gene expression in the rodent gastrointestinal epithelium.

The proglucagon gene encodes pancreatic glucagon and the glucagon-like peptides, which exert diverse effects on nutrient absorption and assimilation. The therapeutic potential of glucagon-like peptide-1 (GLP-1) has fostered interest in development of cellular engineering approaches to augment endogenous intestinal-derived GLP-1 for the treatment of type 2 diabetes. We have used adenovirus technology to examine the potential roles of the transcription factors Cdx-2/3 and Pax-6 as activators of endogenous proglucagon gene expression in enteroendocrine cell lines and in nontransformed rat intestinal cells. Adenoviral-expressed Cdx-2/3 and Pax-6 activated proglucagon promoter-luciferase activity in baby hamster kidney (BHK) fibroblasts, HEK 293 cells, and enteroendocrine cell lines. Pax-6, but not Cdx-2/3, induced expression of the endogenous proglucagon gene in enteroendocrine cell lines, but not in heterologous fibroblasts. Furthermore, transduction of primary rat intestinal cell cultures in vitro, or the rat colonic epithelium in vivo, with Ad-Pax-6 activated endogenous proglucagon gene expression. These data demonstrate that Pax-6, but not Cdx-2/3, is capable of activating the endogenous proglucagon gene in both immortalized enteroendocrine cells and the nontransformed intestinal epithelium in vivo.

Animals↗
PubMed1976

Introduction of missing enzymes into the cytoplasm of cultured mammalian cells by means of fusion-prone liposomes.

It is therefore possible to introduce enzyme-laden liposomes into two sites within the cytoplasm of cells previously lacking such enzymes. The first site is gained after enzyme-laden liposomes are phagocytosed into the lysosomal apparatus. Liposomes coated with immunoglobulins engender their own uptake by inducing the Fc receptor of phagocytic cells to launch ingestion of the vector as if it were an opsonized bacteria or virus against which the host had mounted an immune response. As for the second site, described here, involving enzyme deficiencies of the free cytosol, these may be corrected when liposomes have lysolecithin incorporated as a fusogen. The fusogen induces merger of the liposomal membrane with that of the plasma membrane presumably by virtue of the capacity of lysolecithin to engender mixed, fusion-prone micelles. Introjection of enzymes or other sequestered molecules is accomplished without access of these to external solutes, such as calcium. Consequently, uptake of enzyme cannot be due to trivial factors such as pinocytosis induced by lysolecithin or to phagocytosis per se. These two new techniques of cellular engineering now render it possible to introduce either into phagocytic or into non-phagocytic cells, enzymes or macromolecules in which these cells are genetically deficient.

Cell Fusion↗
PubMed1976

Long survival and immunologic reconstitution following transplantation with syngeneic or allogeneic fetal liver and neonatal spleen cells.

(1)Spleen cells from newborn syngeneic and allogeneic mice that lack fully differentiated T lymphocytes can be used as a hematopoietic source to reconstitute both hematopoietic and lymphoid systems of lethally irradiated mice without producing a GVHR. (2) Fetal liver cells from syngeneic and allogeneic mice that lack postthymic T lymphocytes can also be used for hematopoietic and immunologic reconstitution of lethally irradiated mice without producing GVHR. (3) Immunologic deficiency is observed in some experiments in mice given supralethal irradiation (1000 R) and fetal liver as reconstituting hematopoietic tissue. (4) The findings suggest that Tcells, at an early stage of differentiation, are more susceptible to tolerance induction than are T lymphocytes at later stages of differentiation and do not, in general, produce GVHR. (5) It is postulated that hematopoietic cells, free of postthymic lymphoid cells, can be used for hematopoietic or immunologic reconstituting and cellular engineering without producing GVHD.

Animals↗
PubMed1992

[Biotechnology for rheumatology researches].

Recent developments in biotechnology include cellular engineering and molecular engineering. In order to further investigate several aspects of rheumatic diseases, it is necessary to know and apply these new techniques. They are, for example, monoclonal antibody productions, T cell lines, T cell hybridomas, gene cloning, Southern blot, Northern blot, recombinant protein productions and PCR. Out lines of these techniques are described.

Antibodies, Monoclonal↗
PubMed2005

[Cryopreserved allo-grafts in aortic valve surgery].

Bakulev Scientific Center for Cardiovascular Surgery resumed research into cryopreservation and creation of valve bank in 1990. This technology allowed preparation of valve allo-grafts with preserved cell reproductive capacity for clinical use. A new technology, allowing reduction of calcinosis in the graft's aortic wall, was developed and experimentally tested in 2003. 61 aortic valve replacements with cryopreserved allo-grafts were performed between 1992 and 2003. The three techniques of implantation included: subcoronary (38), intraaortic cylinder (8) and "free-standing root" (15). 44 patients developed active infective or prosthetic endocarditis. Hospital mortality rate was 11.5%, 12-year survival rate--90%. Dysfunctions and reoperations were significantly rarer in cases of inclusion cylinder and free standing root. The authors conclude that cryopreserved allo-grafts allow good quality of life without use of anticoagulants and low rate of reinfection. The use of subcoronary technique for implantation must be limited and method of choice should be free-standing root, especially in cases of destructive infective or prosthetic endocarditis. Cellular engineering probably will elongate the stability of long-term results.

Adolescent↗
PubMed1987

Future perspectives in the development of new animal models.

It is essential to develop animal models for human diseases with disease onset mechanisms the same as those of humans to study the causes, and therapeutic and preventive methods for human disease, as well as to develop new drugs. In the past, many beneficial experiments were performed by selecting animals with symptoms similar to those of humans from nature or breeding colonies. Experimental systems using induced disease models have been developed and provided useful results. The current basis of biology has reached the molecular level, and various phenomena of life have come to be understood through clarification of the expression of genes (DNA). Human diseases are one of these life phenomena, and the study of the relation between life phenomena and genes (DNA) has already started in the field of genetics. The next step appears to be the manipulation of genes to produce animal models for various human diseases. Progress has already been made in genetic and cellular engineering and embryonic manipulation on the basis of their respective methodologies and principles. One of the topics for future studies will be the development of models for human diseases through the integrated application of these fields. It is clear from documents on medical history that experiments using animals have been performed from the earliest period of ancient medical research. Therefore, pioneers in each period continued such studies and by the time of Claude Bernard, animal experiments had become an essential part of medical research. He stated in 1865 in his "Introduction to the Study of Experimental Medicine" that "I not only conclude that experiments made on animals from the physiological, pathological and therapeutic points of view have results that are applicable to theoretic medicine, but I think that without such comparative study of animals, practical medicine can never acquire a scientific character." Following this, animal experiments were widely performed in all fields of medical research, but the animals used in such experiments were only improved to the level they have reached today through the modernization movement which started in Europe, the United States and Japan from the end of the 1940's through the beginning of the 1950's. From the 1960's, the term "biomedical research" came into use in the United States to describe experiments using animals in the fields of medical research.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Plasmid delivery in vivo from porous tissue-engineering scaffolds: transgene expression and cellular transfection.

Tissue engineering scaffolds capable of sustained plasmid release can promote gene transfer locally and stimulate new tissue formation. We have investigated the scaffold design parameters that influence the extent and duration of transgene expression and have characterized the distribution of transfected cells. Porous scaffolds with encapsulated plasmid were fabricated from poly(lactide-co-glycolide) with a gas foaming procedure, with wet granulation employed to mix the components homogeneously prior to foaming. Wet granulation enhanced plasmid incorporation relative to standard procedures and also enhanced in vivo transgene expression, possibly through the increased loading and maintenance of the scaffold pore structure. The plasmid loading regulated the quantity and duration of transgene expression, with expression for 105 days achieved at the highest dosage. Expression was localized to the implantation site, though the distribution of transfected cells varied with time. Transfected cells were initially observed at the scaffold periphery (day 3), then within the pores and adjacent to the polymer (day 17), and finally throughout the scaffold interior (day 126). Delivery of a plasmid encoding VEGF increased the blood vessel density relative to control. Correlating scaffold design with gene transfer efficiency and tissue formation will facilitate application of plasmid-releasing scaffolds to multiple tissues.

Animals↗
PubMed1997

In vivo engineering of a cellular immune response by coadministration of IL-12 expression vector with a DNA immunogen.

Recent studies support the importance of investigating a DNA vaccination approach for the immunologic control of HIV-1. In this regard, it may be important to specifically engineer immune responses in order to improve on first generation vaccine attempts. Especially for HIV, induction of cell-mediated immunity may be an important feature for any candidate vaccine. In an attempt to engineer in vivo the enhancement of cellular immune response and to direct Ag-dependent immune response from Th2 to Th1 type, we investigated the role of codelivery of genes for IL-12 and granulocyte-macrophage-CSF along with DNA vaccine formulations for HIV-1 Ag. We found that codelivery of IL-12 expression cassettes with DNA vaccines for HIV-1 in mice resulted in splenomegaly as well as a shift in the specific immune responses induced. The codelivery of IL-12 genes resulted in the reduction of specific Ab response, while the coinjection of granulocyte-macrophage-CSF genes resulted in the enhancement of specific Ab response. In addition, we observed a significant Ag-specific stimulation of T cells with codelivery of both cytokines. Most importantly, we observed a dramatic increase in specific CTL response from the group coimmunized with the HIV-1 DNA vaccine and IL-12 genes. This work demonstrates the power of DNA delivery in vivo for both the production of a new generation of more effective and targeted vaccines or immunotherapies as well as an analytic tool for the molecular dissection of the mechanisms of immune function.

Animals↗
PubMed2002

[Experimental methods for mechanically stimulating the cells in vitro].

Cellular mechanics is a branch of tissue engineering and cellular engineering. As one of the important method, loading different mechanical stimuli to culturing cells in vitro so as to study the influence that the stress has on the cells is one of the important fields of cellular mechanics. This paper reviews the experimental methods for mechanically stimulating the cells in vitro, according to the different loading modalities, the methods can be categorized into micropipette aspiration, compression loading, substrate distention, fluid shear, etc. And it also points out their advantages and disadvantages.

Cell Culture Techniques↗
PubMed2006

Botulinum neurotoxin structure, engineering, and novel cellular trafficking and targeting.

Botulinum neurotoxins are multifaceted molecules, which are truly unique not only in their mode of action, but also their utility as a drug carrier either across the gut wall or to the nerve terminals. The molecule is divided in clear functional domains that can operate independently. This feature can be used to employ them as cargo carrier by linking other drugs or vaccines with the binding and translocation domains of BoNT. While the domain structures are largely independent of each other, the dynamic structure of these domains, especially that of the enzymatic domain (L chain), is quite different from the reported crystal structures for several BoNT serotypes and their enzymatic domain. This review discusses the comparative structures of BoNT in crystal and solution for their relevance to the molecular mechanism of BoNT action, especially in view of our recent discovery that the enzymatically active structure of the BoNT exists as a molten-globule and that of the endopeptidase domain as a novel PRIME conformation. Finally, a non-exhaustive discussion has been included to explain the long-lasting biological effects of certain serotypes of BoNT, based on the current knowledge of the structure-function of different serotypes of botulinum neurotoxins.

Amino Acid Sequence↗
PubMed2002

Engineering of molecular and cellular biocatalysts: selected contributions by James E. Bailey.

James (Jay) E. Bailey was a pioneer in biotechnology and biochemical engineering. During his 30 years in academia he made seminal contributions to many fields of chemical engineering science, including catalysis and reaction engineering, bioprocess engineering, mathematical modeling of cellular processes, recombinant DNA technology, enzyme engineering, and metabolic engineering. This article celebrates some of his contributions to the engineering of molecular and cellular biocatalysts, and identifies the influence he had on current and future research in biotechnology.

Biochemistry↗
PubMed2001

Designer gene networks: Towards fundamental cellular control.

The engineered control of cellular function through the design of synthetic genetic networks is becoming plausible. Here we show how a naturally occurring network can be used as a parts list for artificial network design, and how model formulation leads to computational and analytical approaches relevant to nonlinear dynamics and statistical physics. We first review the relevant work on synthetic gene networks, highlighting the important experimental findings with regard to genetic switches and oscillators. We then present the derivation of a deterministic model describing the temporal evolution of the concentration of protein in a single-gene network. Bistability in the steady-state protein concentration arises naturally as a consequence of autoregulatory feedback, and we focus on the hysteretic properties of the protein concentration as a function of the degradation rate. We then formulate the effect of an external noise source which interacts with the protein degradation rate. We demonstrate the utility of such a formulation by constructing a protein switch, whereby external noise pulses are used to switch the protein concentration between two values. Following the lead of earlier work, we show how the addition of a second network component can be used to construct a relaxation oscillator, whereby the system is driven around the hysteresis loop. We highlight the frequency dependence on the tunable parameter values, and discuss design plausibility. We emphasize how the model equations can be used to develop design criteria for robust oscillations, and illustrate this point with parameter plots illuminating the oscillatory regions for given parameter values. We then turn to the utilization of an intrinsic cellular process as a means of controlling the oscillations. We consider a network design which exhibits self-sustained oscillations, and discuss the driving of the oscillator in the context of synchronization. Then, as a second design, we consider a synthetic network with parameter values near, but outside, the oscillatory boundary. In this case, we show how resonance can lead to the induction of oscillations and amplification of a cellular signal. Finally, we construct a toggle switch from positive regulatory elements, and compare the switching properties for this network with those of a network constructed using negative regulation. Our results demonstrate the utility of model analysis in the construction of synthetic gene regulatory networks. (c) 2001 American Institute of Physics.

Journal Article↗
PubMed2006

Antitumor antibodies in the treatment of cancer: Fc receptors link opsonic antibody with cellular immunity.

Engineered antibody therapeutics have provided new treatment options in cancer. Genetic evidence in man and in the mouse suggests that Fc receptor (FcR) engagement contributes mechanistically to the therapeutic activity of naked antibodies. Preferential activation of activating FcRs and limited engagement of inhibitory FcRs enhance tumor responses in mouse models. Thus, engineered Fc domains with favorable affinities for specific FcR types may prove to be clinically superior.

Animals↗
PubMedDate not supplied

[Metabolic engineering in design of cellular elements of biosensors].

An extended definition of the term "metabolic engineering" is given and main spheres of its using in fundamental studies and modern biotechnology are discussed in this article. Emphasis is made on specific using the approaches of metabolic engineering in construction of the cell elements of sensors based on the use of mutant and chemically modified cells of methylotrophic yeasts. This investigation is designed in the laboratory of Biochemical Genetics of the Division of Cell Regulatory Systems, A. V. Palladin Institute of Biochemistry. Genetic and chemical modifications have allowed to provide some directed changes in cell sensoring output toward methanol, ethanol and formaldehyde that result in enhanced selectivity and shortened time-output of the corresponding potentiometric and amperometric sensors.

Biomedical Engineering↗
PubMed2003

Monitoring cellular responses of engine-emitted particles by using a direct air-cell interface deposition technique.

The impacts of ultrafine airborne particles generated by diesel or gasoline engines on human lung cells have been investigated using a new in vitro cellular exposure technique. This technique enables direct deposition of the gasoline engine exhaust particles (GEP) and diesel engine exhaust particles (DEP) on human lung cells located at the air-cell interface on a transwell membrane in an exposure apparatus. The cellular responses to particle exposure were measured by the levels of IL-8 chemokines produced as a function of exposure time. The findings suggest that GEP and high-sulfur DEP induced the production of similar levels of IL-8 by unprimed A549 cells. The level of IL-8 produced by unprimed A549 cells in response to low-sulfur DEP was found lower than that produced in response to high-sulfur DEP and GEP. When cells were primed, simulating predisposed conditions, significant levels of IL-8 were produced. GEP triggered a much higher level of IL-8 production than DEP did. Furthermore, the time profile of IL-8 production induced by GEP was markedly different from that induced by DEP. The findings indicate that GEP could induce the production of higher levels of chemokines (i.e., IL-8) than DEP did, implying that exposure to GEP could be a greater health risk than exposure to DEP.

Atmosphere Exposure Chambers↗