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PubMed2006

Genetic engineering neural stem cell modified by lentivirus for repair of spinal cord injury in rats.

OBJECTIVE: To explore the feasibility for therapy of spinal cord injury (SCI) by genetic engineering neural stem cell (NSC) modified by lentiviral vector. METHODS: Following the construction of the genetic engineering NSC modified by lentivirus to secrete both neurotrophic factor-3 (NT-3) and green fluorescence protein (GFP), hemisection of spinal cord at the level of T10 was performed in 56 adult Wistar rats that were randomly divided into 4 groups (n = 14), namely 3 therapeutic groups and 1 control group. The therapeutic groups were dealed with NSC, genetic engineering NSC, and concentrated lentiviral supernatant which carries both GFP and NT-3, respectively. Then used fluorescence microscope to detect the transgenic expression in vitro and in vivo, migration of the grafted cells in vivo, and used the Basso, Beattie, and Bresnahan (BBB) open-field locomotor test to assess the recovery of function. RESULTS: The transplanted cells could survive for long time in vivo and migrate for long distance. The stable transgenic expression could be detected in vivo. The hindlimb function of the injured rats in 3 therapeutic groups, especially those dealed with genetic engineering NSC, improved obviously. CONCLUSION: It is feasible to combine NSC with lentivirus for the repair of SCI. NSC modified by lentivirus to deliver NT-3, acting as a source of neurotrophic factors and function cell in vivo, has the potential to participate in spinal cord repair.

Animals↗
PubMed2006

A novel approach to periodontal tissue regeneration with mesenchymal stem cells and platelet-rich plasma using tissue engineering technology: A clinical case report.

Tissue engineering represents one of the most exciting advances in regenerative medicine. However, little has been reported on the application of tissue engineering for regeneration of periodontal tissues. Therefore, the aim of this study was to show how a technique based on tissue engineering principles can be applied to periodontology. Mesenchymal stem cells (MSCs) were isolated from a patient's iliac crest marrow aspirates. Platelet-rich plasma (PRP) was isolated from peripheral blood. Full-thickness periodontal flaps were elevated and the root surfaces were scaled and planed. A MSCs-PRP gel was prepared and applied to the root surface and adjacent defect space. The primary outcome measures were changes in pocket depth, clinical attachment level, bleeding on probing, and defect bone fill. Re-examination demonstrated that the treatment, including the application of MSCs-PRP gel at periodontal sites with angular defects, resulted in a 4-mm reduction in probing depths and a 4-mm clinical attachment gain, while bleeding and tooth mobility disappeared. Radiographic assessments showed that the bone defect had been reduced in depth. Interdental papillae supported by this tissue engineering technology regenerated. The use of MSCs in PRP gel might be helpful for periodontal tissue regeneration, treatment of esthetically sensitive sites, and reduction of patient morbidity.

Alveolar Bone Loss↗
PubMed1991

[Hematologic engineering in modern transfusiology].

Three groups of hematological engineering methods have been considered: (1) blood gravitation surgery, (2) sorption methods, (3) blood irradiation methods. They were comparatively characterized with respect to their effectiveness. Combined employment of various methods of hematological engineering permits one to avoid shortcomings and intensify the effectiveness of each group of methods. It is shown that new internal environment of the body is developed in the process of hematological engineering operations. It is stressed that hematological engineering combines methods of blood reconstruction.

Biomedical Engineering↗
PubMedDate not supplied

[Pharmaceutical engineering in drug formulation].

The industrial pharmacist, a "pharmaceutical engineer"? The prospect is tempting if only beneficial to drug quality. The Pharmaceutical Engineering comes from Chemical Engineering and Engineer sciences and allows the pharmacist to achieve his aim. We define here the basis of this recent concept, its intervention and interest in the pharmaceutical sciences, more particularly in formulation.

Drug Compounding↗
PubMedDate not supplied

[Prospects and achievements of genetic engineering in development of antiviral vaccines].

Proceeding from the known data various theoretical and experimental approaches to the construction of gene-engineering vaccines are considered. Gene-engineering subunit vaccines of the first generation are based on isolation of the genes coding for the synthesis of full length capsid proteins with the main antigenic determinants and their subsequent expression in suitable recipient cells. Initial idea of the microbiological synthesis as the main way for production of any antiviral vaccines was not confirmed by the later development. Now for this type of vaccines eucaryotic systems are widely employed using the animal virus vectors and the animal cell cultures. Gene-engineering subunit vaccine of the second generation appears to be a chimeric protein with built-in antigenic determinants of different viruses and maximal immunogenicity in monomeric form. The last point reopens the perspective to use a microbiological synthesis for the production of antiviral vaccines. Besides that the chemically synthesized polypeptide antiviral vaccine will be used widely. In gene-engineering subunit vaccines of the third generation it is possible to use not the natural antigenic determinants which often are characterized by high level of the primary structure changes but artificial (non-natural) antigens, that are the capsid protein conservative regions which under natural conditions of infection or immunization do not induce the protective antiviral antibodies. The recombinant DNA technology in addition to subunit type vaccine allows to construct living vaccines which represent a DNA-containing attenuated virus with build-in natural or synthetic gene of the capsid or chimeric protein with antigenic determinants of another viral species.

Animals↗
PubMed1995

Peptide engineering allows cytotoxic T-cell vaccination against human papilloma virus tumour antigen, E6.

Major histocompatibility complex (MHC) class I allele-specific binding motifs have proved useful in predicting cytotoxic T-cell epitopes from immunogenic proteins. In a search of the E6 protein from human papilloma virus type 16 utilizing the Kb binding motif, we discovered four potential binding peptides. One peptide, E6.1 (sequence 50-57, YDFAFRDL), was poor in its ability to stabilize empty Kb on RMA-S cells, with a t1/2 = 33 min versus 30 min for empty Kb. This peptide subsequently proved to be non-immunogenic upon mouse in vivo vaccination. It was hypothesized that an isoleucine for aspartate substitution at position 2 would improve Kb stabilization kinetics and therefore immunogenic potential. The engineered peptide E6.1 I2 increased the Kb t1/2 to 100 min and was immunogenic upon in vivo vaccination. Cytolytic T lymphocytes (CTL) raised with the E6.1 I2 peptide responded to cells pulsed with either the wild-type peptide or the engineered peptide, implying a blindness to the substitution. More striking, these CTL also lysed a syngeneic cell line transfected with the E6 gene, implying that the E6.1 peptide was processed and presented. These data demonstrate that subimmunogenic peptides can be engineered to improve binding kinetics, which in turn improves immunogenicity. Provided that poor binding peptides are processed, the induction threshold for CTL activation can be achieved with engineered peptides, thus allowing for the kill of wild-type target cells. This approach may prove relevant to the design of subunit vaccines to virally induced tumours.

Animals↗
PubMedDate not supplied

The nurse engineer: a way to better nursing information systems.

Currently, there are few significant nursing information systems that can meet the basic needs of nursing (Zielstorff, McHugh, & Clinton, 1988). Some factors that may relate to this problem include the amount of nurse input, the effectiveness of communications between nurses and engineers, and the state of nursing practice. One method that may address this problem is to involve nurse engineers, nurses with technical degrees, in the development process. As a key member of the development team, the nurse engineer can encourage intensive use of nurse input, function as a translator and clarifier, thereby reducing communication problems, and assist the development team to analyze the diversity in nursing practice. Using nurse engineers in the development process may result in better nursing information systems.

Career Choice↗
PubMed1996

Tissue-engineered heart valves. Autologous valve leaflet replacement study in a lamb model.

BACKGROUND: We have previously reported the successful creation of tissue-engineered valve leaflets and the implantation of these autologous tissue leaflets in the pulmonary valve position. This study was designed to trace cultured cells that were seeded onto a biodegradable polymer with the use of a 1,1'-dioctadecyl-3,3,3' 3'-tetramethylindo-carbocyanine perchlorate (Di-1) cell-labeling method. We also examined the time-related biochemical, biomechanical, and histological characteristics and evolution of these tissue constructs. METHODS AND RESULTS: Mixed cell populations of endothelial cells and fibroblasts were isolated from explanted ovine arteries. Endothelial cells were selectively labeled with an acetylated low density lipoprotein marker and separated from fibroblasts with the use of a fluorescence-activated cell sorter. A synthetic biodegradable scaffold consisting of polyglycolic acid fibers was seeded first with fibroblasts, then coated with endothelial cells. Using these methods, we implanted autologous cell/polymer constructs in six animals. In two additional control animals, a leaflet of polymer was implanted without prior cell seeding. In each animal, cardiopulmonary bypass was used to completely resect the right posterior leaflet of the pulmonary valve and replace it with an engineered valve leaflet with (n = 6) or without (n = 2) prior cultured cell seeding. The animals were killed either after 6 hours or after 1, 6, 7, 9, or 11 weeks, and the implanted valve leaflets were examined histologically, biochemically, and biomechanically. 4-Hydroxyproline assays were performed to determine collagen content. Leaflet strength was evaluated in vitro with a mechanical tester Factor VIII and elastin stains were done to verify histologically that endothelial cells and elastin, respectively, were present. Animals receiving leaflets made from polymers without cell seeding were killed and examined in a similar fashion after 8 weeks. In the control animals, the acellular polymer leaflets were completely degraded, with no residual leaflet tissue at 8 weeks. The tissue-engineered valve leaflet persisted in each animal in the experimental group. 4-Hydroxyproline analysis of the constructs showed a progressive increase in collagen content. Immunohistochemical staining demonstrated elastin fibers in the matrix and factor VIII on the surface of the leaflet. The cell-labeling experiments demonstrated that the cells on the leaflets had persisted from the in vitro seeding of the leaflets. CONCLUSIONS: In the tissue-engineered heart valve leaflet, transplanted autologous cells generated a proper matrix on the polymer scaffold in a physiological environment at a period of 8 weeks after implantation.

Animals↗
PubMed1997

Practical development of genetically engineered animals as human disease models.

Since transgenic (Tg) mice were first produced in 1980, the technology to produce genetically engineered animals, such as Tg and knock-out mice, has advanced exponentially. These animals have contributed greatly to basic research at the molecular level and have proven to be powerful tools for elucidating complex biological processes. The effort that is required to develop and establish genetically engineered animals as models for human diseases or toxicologic studies is not always appreciated by researchers and laboratory animal scientists. Genetically engineered animals remain only candidates of defined animal models until they are developed for practical use, in accordance with their objectives, through cooperation between the researchers performing the experiments and laboratory animal scientists. The practical development of these animals consists of three steps: establishment as standardized laboratory animals through the setting of quality standards and the establishment of a production and supply system; establishment as defined animal models through confirmation of the usefulness and limitations of the animal in the purpose of use; and establishment of an in vivo experimentation system (an animal experimentation system), using the defined animal models. This report serves as an introduction to those that follow and describes our concept of how best to establish genetically engineered animals as valid animal models. The development of Tg mice carrying the poliovirus receptor gene (PVR) will be used as an example. The TgPVR mice were produced by the introduction of the human poliovirus receptor gene into the mouse genome, mainly to study the molecular mechanisms of pathogenesis of the virus. The value of these mice is that they mimic human and nonhuman primate susceptibility to poliovirus infection and thus serve as a model for the study of the disease and for the assessment of poliovirus vaccines. They are being touted as a replacement for nonhuman primates in the neurovirulence testing of oral poliovirus vaccine.

Animals↗
PubMed1997

A case-control study of lung cancer at a foundry and two engine plants.

A nested case-control study of lung cancer was conducted among workers at an iron foundry and two engine manufacturing plants whose lung cancer mortality rates were slightly higher than expected. The study included 231 lung cancer cases and 408 controls for whom complete work histories were obtained. There was no association between usual plant of employment and lung cancer mortality. The odds ratio for persons employed for 20 or more years in the foundry compared with persons employed in the engine plants was 0.90 (95% confidence interval: 0.55, 1.5). Long-term employment as an engine plant worker was associated with odds ratios slightly, but not statistically significantly, below unity. In the foundry, only usual employment in the material handling departmental group and any employment in the quality control departmental group were statistically significantly directly related to lung cancer risk. However, the number of subjects so employed was small and there was no dose-response relation between length of employment in these departmental groups and lung cancer risk. Cases were less frequently employed than were controls in engine plant machining and assembly jobs and departments. It is concluded that employment in this facility was either unrelated, or only weakly related, to lung cancer risk.

Carcinogens↗
PubMed1998

Engineering protein-based machines to emulate key steps of metabolism (biological energy conversion)

Metabolism is the conversion of available energy sources to those energy forms required for sustaining and propagating living organisms; this is simply biological energy conversion. Proteins are the machines of metabolism; they are the engines of motility and the other machines that interconvert energy forms not involving motion. Accordingly, metabolic engineering becomes the use of natural protein-based machines for the good of society. In addition, metabolic engineering can utilize the principles, whereby proteins function, to design new protein-based machines to fulfill roles for society that proteins have never been called upon throughout evolution to fulfill. This article presents arguments for a universal mechanism whereby proteins perform their diverse energy conversions; it begins with background information, and then asserts a set of five axioms for protein folding, assembly, and function and for protein engineering. The key process is the hydrophobic folding and assembly transition exhibited by properly balanced amphiphilic protein sequences. The fundamental molecular process is the competition for hydration between hydrophobic and polar, e.g., charged, residues. This competition determines Tt, the onset temperature for the hydrophobic folding and assembly transition, Nhh, the numbers of waters of hydrophobic hydration, and the pKa of ionizable functions. Reported acid-base titrations and pH dependence of microwave dielectric relaxation data simultaneously demonstrate the interdependence of Tt, Nhh and the pKa using a series of microbially prepared protein-based poly(30mers) with one glutamic acid residue per 30mer and with an increasing number of more hydrophobic phenylalanine residues replacing valine residues. Also, reduction of nicotinamides and flavins is shown to lower Tt, i.e., to increase hydrophobicity. Furthermore, the argument is presented, and related to an extended Henderson-Hasselbalch equation, wherein reduction of nicotinamides represents an increase in hydrophobicity and resulting hydrophobic-induced pKa shifts become the basis for understanding a primary energy conversion (proton transport) process of mitochondria. Copyright 1998 John Wiley & Sons, Inc.

Journal Article↗
PubMed1998

Metabolic engineering of bacteria for ethanol production

Technologies are available which will allow the conversion of lignocellulose into fuel ethanol using genetically engineered bacteria. Assembling these into a cost-effective process remains a challenge. Our work has focused primarily on the genetic engineering of enteric bacteria using a portable ethanol production pathway. Genes encoding Zymomonas mobilis pyruvate decarboxylase and alcohol dehydrogenase have been integrated into the chromosome of Escherichia coli B to produce strain KO11 for the fermentation of hemicellulose-derived syrups. This organism can efficiently ferment all hexose and pentose sugars present in the polymers of hemicellulose. Klebsiella oxytoca M5A1 has been genetically engineered in a similar manner to produce strain P2 for ethanol production from cellulose. This organism has the native ability to ferment cellobiose and cellotriose, eliminating the need for one class of cellulase enzymes. The optimal pH for cellulose fermentation with this organism (pH 5.0-5.5) is near that of fungal cellulases. The general approach for the genetic engineering of new biocatalysts has been most successful with enteric bacteria thus far. However, this approach may also prove useful with Gram-positive bacteria which have other important traits for lignocellulose conversion. Many opportunities remain for further improvements in the biomass to ethanol processes. These include the development of enzyme-based systems which eliminate the need for dilute acid hydrolysis or other pretreatments, improvements in existing pretreatments for enzymatic hydrolysis, process improvements to increase the effective use of cellulase and hemicellulase enzymes, improvements in rates of ethanol production, decreased nutrient costs, increases in ethanol concentrations achieved in biomass beers, increased resistance of the biocatalysts to lignocellulosic-derived toxins, etc. To be useful, each of these improvements must result in a decrease in the cost for ethanol production. Copyright 1998 John Wiley & Sons, Inc.

Journal Article↗
PubMedDate not supplied

Engineered human mesenchymal stem cells: a novel platform for skeletal cell mediated gene therapy.

BACKGROUND: Human mesenchymal stem cells (hMSCs) are pluripotent cells that can differentiate to various mesenchymal cell types. Recently, a method to isolate hMSCs from bone marrow and expand them in culture was described. Here we report on the use of hMSCs as a platform for gene therapy aimed at bone lesions. METHODS: Bone marrow derived hMSCs were expanded in culture and infected with recombinant adenoviral vector encoding the osteogenic factor, human BMP-2. The osteogenic potential of genetically engineered hMSCs was assessed in vitro and in vivo. RESULTS: Genetically engineered hMSCs displayed enhanced proliferation and osteogenic differentiation in culture. In vivo, transplanted genetically engineered hMSCs were able to engraft and form bone and cartilage in ectopic sites, and regenerate bone defects (non-union fractures) in mice radius bone. Importantly, the same results were obtained with hMSCs isolated from a patient suffering from osteoporosis. CONCLUSIONS: hMSCs represent a novel platform for skeletal gene therapy and the present results suggest that they can be genetically engineered to express desired therapeutic proteins inducing specific differentiation pathways. Moreover, hMSCs obtained from osteoporotic patients can restore their osteogenic activity following human BMP-2 gene transduction, an important finding in the future planning of gene therapy treatment for osteoporosis.

Adenoviridae↗
PubMed2004

Risk of esophageal, ovarian, testicular, kidney and bladder cancers and leukemia among finnish workers exposed to diesel or gasoline engine exhaust.

Occupational exposure to diesel exhaust has been classified as probably carcinogenic and that to gasoline engine exhaust as possibly carcinogenic to humans. Earlier results concerning cancers other than lung cancer are scarce and inconsistent, and exposure-response relations have seldom been reported. We followed up a cohort of all economically active Finns born between 1906 and 1945 for 30 million person-years during 1971-1995. Incident cases of esophageal cancer (n = 2,198), ovarian cancer (5,082), testicular cancer (387), kidney cancer (7,366), bladder cancer (8,110) and leukemia (4,562) were identified through a record linkage with the Finnish Cancer Registry. Occupations from the population census in 1970 were converted to exposures to diesel and gasoline engine exhausts with a job-exposure matrix (FINJEM). Cumulative exposure (CE) was calculated as product of prevalence, level and estimated duration of exposure. The relative risk (RR) of cancer for exposure categories in relation to the unexposed group was calculated using the Poisson regression model and adjusted for confounders. An increasing RR for ovarian cancer was observed with the increasing CE of diesel exhaust (p for trend = 0.006). The RR in the highest CE category was 3.69 (95% CI = 1.38-9.86). For gasoline engine exhaust, the RR was significantly increased only in the middle CE category (1.70; 95% CI = 1.11-2.62). Slight elevations of RR for bladder and kidney cancers were found at the lowest exposure level of engine exhausts, largely attributable to drivers. No effect of the exposures was observed for the other cancers. This study suggests an exposure-response relation between diesel exhaust and ovarian cancer.

Aged↗
PubMed1993

Mitotic stability and nuclear inheritance of integrated viral cDNA in engineered hypovirulent strains of the chestnut blight fungus.

Transmissible hypovirulence is a novel form of biological control in which virulence of a fungal pathogen is attenuated by an endogenous RNA virus. The feasibility of engineering hypovirulence was recently demonstrated by transformation of the chestnut blight fungus, Cryphonectria parasitica, with a full-length cDNA copy of a hypovirulence-associated viral RNA. Engineered hypovirulent transformants were found to contain both a chromsomally integrated cDNA copy of the viral genome and a resurrected cytoplasmically replicating double-stranded RNA form. We now report stable maintenance of integrated viral cDNA through repeated rounds of asexual sporulation and passages on host plant tissue. We also demonstrate stable nuclear inheritance of the integrated viral cDNA and resurrection of the cytoplasmic viral double-stranded RNA form in progeny resulting from the mating of an engineered hypovirulent C. parasitica strain and a vegetatively incompatible virulent strain. Mitotic stability of the viral cDNA ensures highly efficient transmission of the hypovirulence phenotype through conidia. Meiotic transmission, a mode not observed for natural hypovirulent strains, introduces virus into ascospore progeny representing a spectrum of vegetative compatibility groups, thereby circumventing barriers to anastomosis-mediated transmission imposed by the fungal vegetative incompatibility system. These transmission properties significantly enhance the potential of engineered hypovirulent C. parasitica strains as effective biocontrol agents.

Ascomycota↗
PubMed1997

Engineered porcine pepsinogen exhibits dominant unimolecular activation.

An engineered pepsinogen, which was a fusion protein of thioredoxin and pepsinogen, exhibited dominant self-activation (unimolecular reaction; intramolecular activation) in contrast to recombinant pepsinogen which exhibited both unimolecular and bimolecular reactions (intermolecular activation mediated by pepsin released during activation). At pH values of 1.1, 2.0, and 3.0, activation curves for the engineered pepsinogen were hyperbolic rather than sigmoidal, indicating that self-activation was the dominant activation mechanism in comparison to the slower bimolecular activation. To confirm which activation mechanism was dominant, an equal mole of pepsin was added to accelerate the bimolecular reaction during activation. The addition of exogenous pepsin did not affect the activation rate of the engineered pepsinogen but accelerated pepsinogen activation through the bimolecular reaction. The above results indicated that the engineered pepsinogen exhibited, primarily, a self-activation mechanism and that bimolecular activation was negligible.

Animals↗
PubMed2001

Men, masculinity and food: interviews with Finnish carpenters and engineers.

This study explores how Finnish men from two occupational groups describe food in their everyday life. The concept of masculinity is used in interpreting men's food-related behaviours and beliefs. Data are drawn from semi-structured interviews in the 1990s with twenty carpenters and twenty engineers involved in the building trade. The paper presents analyses of the similarities and differences in how the men talked about meat; vegetables; beer and wine as parts of meals; food as energy, health and pleasure; and cooking. The results show variation both between and within occupational groups. The men did not stress the role of meat, but rather emphasised the role of vegetables. The carpenters tended to favour meat whereas the engineers had a more positive attitude to vegetables. Eating was described as an everyday routine needed to refuel the body and stay healthy. In addition, the engineers talked about the pleasures of eating. The men described cooking as optional or exceptional. The carpenters seemed to more actively embrace hegemonic masculinity and reject what is feminine than the engineers, who have reformulated their definition of masculinity to encompass concerns with health. This study suggests that both masculinity and occupational class play a role in male food-related practices and preferences.

Adult↗
PubMed2000

Conditionally immortalized cell lines, engineered to produce and release GABA, modulate the development of behavioral seizures.

Transplantation of genetically engineered cells can provide sustained focal delivery of naturally occurring molecules, including neurotransmitters and growth factors. We have engineered immortalized mouse cortical neurons and glia to deliver GABA by driving GAD(65) expression. Engineered cell lines showed GAD(65) mRNA expression, enzymatic activity, and GABA release. In vitro, basal flux of GABA was approximately 20% of total cellular GABA. We transplanted these GABA-producing cells bilaterally into either the anterior or the posterior substantia nigra of 43 rats. The rats were subsequently kindled through an electrode placed in the entorhinal cortex. GABA-producing cells, but not beta-galactosidase-producing cells, affected kindling rates. The number of stimulations needed to reach the first stage-5 seizure and to achieve full kindling differed significantly between the anterior and posterior transplantation sites when GAD(65)-producing cells were transplanted but not when beta-galactosidase-producing cells were transplanted. Our data show that transplanted engineered cells can make and release GABA at physiologically meaningful concentrations.

Animals↗