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  • hematopoiesis  (6)
  • Female  (3)
  • Male  (3)
  • linear optimization  (3)
  • 1
    Electronic Resource
    Electronic Resource
    Different measures of human hematopoietic cell culture performance are optimized under vastly different conditions (1996)
    New York, NY [u.a.] : Wiley-Blackwell
    Biotechnology and Bioengineering 50 (1996), S. 505-513 
    Details
    ISSN: 0006-3592
    Keywords: bone marrow ; hematopoiesis ; perfusion ; culture optimization ; stroma ; stem cells ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Hematopoiesis, the formation of mature blood cells from stem (LTC-IC) and progenitor (CFU-GM) cells in the bone marrow, is a complex tissue-forming process that leads to many important physiological functionalities. Consequently, a functioning ex vivo hematopoietic system has a variety of basic scientific and clinical uses. The design and operation of such a system presents the tissue engineer with challenges and choices. In this study, three culture variables were used to control ex vivo human hematopoiesis. Systematic variation of inoculum density (ID), medium exchange interval (MEI), and the use of preformed stroma (PFS) showed that (1) all three variables significantly influenced culture performance, (2) the three variables interacted strongly, and (3) the variables could be manipulated to achieve the optimization of different performance criteria. Donor-to-donor variability in culture performance was great at low ID but was minimized at higher ID. PFS had a large positive effect on cell and CFU-GM output at low ID, but had minimal effect at higher ID. In fact, PFS caused a decrease in LTC-IC output at high ID. The effects of PFS indicated that stromal cell elements became more limiting than proliferative cell elements as ID was reduced.In cultures without PFS, maximum cell output was obtained with high ID using a short MEI, whereas the greatest cell expansion ratio was obtained at low ID with an intermediate MEI. Maximum CFU-GM output was obtained from cultures with high ID using a short to intermediate MEI, whereas the greatest CFU-GM expansion ratio was obtained at intermediate ID with an intermediate MEI. The addition of PFS altered the locations of these maxima. In general, PFS moved the maxima to lower ID, and culture output became more sensitive to MEI. Therefore, the optimization of one performance criterion always resulted in a decline of the others. This study demonstrates that ex vivo tissue function is sensitive to many culture variables in an interactive fashion and that systematic multivariable studies are required to characterize tissue function. Once the effects of individual variables and their interactions are known, this knowledge can be used to optimize tissue performance with respect to desired criteria. © 1996 John Wiley & Sons, Inc.
    Additional Material: 6 Ill.
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  • 2
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    A common variant on chromosome 9p21 affects the risk of myocardial infarction (2007)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2007-05-05
    Description: The global endemic of cardiovascular diseases calls for improved risk assessment and treatment. Here, we describe an association between myocardial infarction (MI) and a common sequence variant on chromosome 9p21. This study included a total of 4587 cases and 12,767 controls. The identified variant, adjacent to the tumor suppressor genes CDKN2A and CDKN2B, was associated with the disease with high significance. Approximately 21% of individuals in the population are homozygous for this variant, and their estimated risk of suffering myocardial infarction is 1.64 times as great as that of noncarriers. The corresponding risk is 2.02 times as great for early-onset cases. The population attributable risk is 21% for MI in general and 31% for early-onset cases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Helgadottir, Anna -- Thorleifsson, Gudmar -- Manolescu, Andrei -- Gretarsdottir, Solveig -- Blondal, Thorarinn -- Jonasdottir, Aslaug -- Jonasdottir, Adalbjorg -- Sigurdsson, Asgeir -- Baker, Adam -- Palsson, Arnar -- Masson, Gisli -- Gudbjartsson, Daniel F -- Magnusson, Kristinn P -- Andersen, Karl -- Levey, Allan I -- Backman, Valgerdur M -- Matthiasdottir, Sigurborg -- Jonsdottir, Thorbjorg -- Palsson, Stefan -- Einarsdottir, Helga -- Gunnarsdottir, Steinunn -- Gylfason, Arnaldur -- Vaccarino, Viola -- Hooper, W Craig -- Reilly, Muredach P -- Granger, Christopher B -- Austin, Harland -- Rader, Daniel J -- Shah, Svati H -- Quyyumi, Arshed A -- Gulcher, Jeffrey R -- Thorgeirsson, Gudmundur -- Thorsteinsdottir, Unnur -- Kong, Augustine -- Stefansson, Kari -- New York, N.Y. -- Science. 2007 Jun 8;316(5830):1491-3. Epub 2007 May 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17478679" target="_blank"〉PubMed〈/a〉
    Keywords: Age of Onset ; Aged ; Case-Control Studies ; Chromosome Mapping ; Chromosomes, Human, Pair 9/*genetics ; Coronary Artery Disease/genetics ; Female ; Genes, p16 ; *Genetic Predisposition to Disease ; *Genetic Variation ; Genotype ; Haplotypes ; Heterozygote ; Homozygote ; Humans ; Linkage Disequilibrium ; Male ; Middle Aged ; Myocardial Infarction/*genetics ; *Polymorphism, Single Nucleotide ; Risk Factors
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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    PAPER CURRENT
  • 3
    Electronic Resource
    Electronic Resource
    The influence of extra-cellular matrix and stroma remodeling on the productivity of long-term human bone marrow cultures (1992)
    Springer
    Cytotechnology 10 (1992), S. 217-224 
    Details
    ISSN: 1573-0778
    Keywords: hematopoiesis ; extra-cellular matrix ; stromal cells ; conditioned medium ; rapid perfusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract The stromal cell layer is believed to play an important role in long-term human bone marrow cultures (LTHBMCs). At present, neither the role that the stromal cell extra-cellular matrix (ECM) plays in influencing stroma behavior is well understood nor are the effects of stroma aging. Rapid medium exchanged LTHBMCs were established on surfaces precoated with human natural fibronectin and type 1 rat tail collagen. Although initial adhesion of hematopoietic cells was improved by the presence of both ECMs, the overall progenitor and nonadherent cell productivity was not improved nor did the stroma grow to confluency faster. Thus, the ECMs used did not significantly influence the cell productivity of LTHBMCs. To examine the influence of stromal cell layer aging, conditioned medium was obtained from the first two weeks of LTHBMCs that was subsequently concentrated and used as a medium supplement in a second set of slowly exchanged LTHBMCs. The presence of the concentrated conditioned medium (conCM) enhanced the production of nonadherent cells three-fold compared with control over an eight week culture period. Control cultures that were exposed to conCM after 4 weeks in culture significantly improved their cell productivity during the latter 4 weeks of culture compared with control. The productivity of cultures exposed to conCM for 4 weeks dropped significantly when unsupplemented medium was used for the latter 4 weeks of culture. Interestingly, phytohemagglutin-stimulated leukocyte-conditioned medium stimulated LTHMBCs in a similar fashion, as did conditioned medium from early LTHBMCs. Taken together, these results strongly suggest that the stromal cell layer does produce important factors for active hematopoiesis during its growth to confluence.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00146672
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  • 4
    Electronic Resource
    Electronic Resource
    Biochemical production capabilities of escherichia coli (1993)
    New York, NY [u.a.] : Wiley-Blackwell
    Biotechnology and Bioengineering 42 (1993), S. 59-73 
    Details
    ISSN: 0006-3592
    Keywords: Escherichia coli ; amino acids ; nucleotides ; biosynthesis ; linear optimization ; metabolic fluxes ; metabolic engineering ; stoichiometry ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Microbial metabolism provides at mechanism for the conversion of substrates into useful biochemicals. Utilization of microbes in industrial processes requires a modification of their natural metabolism in order to increase the efficiency of the desired conversion. Redirection of metabolic fluxes forms the basis of the newly defined field of metabolic engineering. In this study we use a flux balance based approach to study the biosynthesis of the 20 amino acids and 4 nucleotides as biochemical products. These amino acids and nucleotides are primary products of biosynthesis as well as important industrial products and precursors for the production of other biochemicals. The biosynthetic reactions of the bacterium Escherichia coli have been formulated into a metabolic network, and growth has been defined as a balanced drain on the metabolite pools corresponding to the cellular composition. Theoretical limits on the conversion of glucose, glycerol, and acetate substrates to biomass as well as the biochemical products have been computed. The substrate that results in the maximal carbon conversion to a particular product is identified. Criteria have been developed to identify metabolic constraints in the optimal solutions. The constraints of stoichiometry, energy, and redox have been determined in the conversions of glucose, glycerol, and acetate substrates into the biochemicals. Flux distributions corresponding to the maximal production of the biochemicals are presented. The goals of metabolic engineering are the optimal redirection of fluxes from generating biomass toward producing the desired biochemical. Optimal biomass generation is shown to decrease in a piecewise linear manner with increasing product formation. In some cases, synergy is observed between biochemical production and growth, leading to an increased overall carbon conversion. Balanced growth and product formation are important in a bioprocess, particularly for nonsecreted products. © 1993 John Wiley & Sons, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/bit.260420109
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  • 5
    Electronic Resource
    Electronic Resource
    Predictions for oxygen supply control to enhance population stability of engineered production strains (1994)
    New York, NY [u.a.] : Wiley-Blackwell
    Biotechnology and Bioengineering 43 (1994), S. 275-285 
    Details
    ISSN: 0006-3592
    Keywords: Escherichia coli ; amino acids ; linear optimization ; metabolic fluxes ; metabolic engineering ; culture stability ; oxygen ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: The simultaneous growth and product formation in a microbial culture is an important feature of several laboratory, industrial, and environmental bioprocesses. Metabolic burden associated with product formation in these bioprocesses may lead to growth advantage of a nonproducing mutant leading to a loss of the producing population over time. A simple population dynamics model demonstrates the extreme sensitivity of population stability to the engineered productivity of a strain. Here we use flux balance analysis to estimate the effects of the metabolic burden associated with product secretion on optimal growth rates. Comparing the optimal growth rates of the producing and nonproducing strains under a given processing condition allows us to predict the population stability. In order to increase stability of an engineered strain, we determine processing conditions that simultaneously maximize the growth rate of the producing population while minimizing the growth rate of a nonproducing population. Using valine, tryptophan, and lysine production as specific examples, we demonstrate that although an appropriate choice of oxygenation may increase culture longevity more than twofold, total production as governed by economic criterion can be increased by several orders of magnitude. Choice of optimal nutrient and oxygen supply rates to enhance stability is important both for strain screening as well as for culture of engineered strains. Appropriate design of the culture environment can thus be used to enhance the productivity of bioprocesses that use engineered production strains. © 1994 John Wiley & Sons, Inc.
    Additional Material: 11 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/bit.260430403
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  • 6
    Electronic Resource
    Electronic Resource
    Parametric sensitivity of stoichiometric flux balance models applied to wild-type Escherichia coli metabolism (1995)
    New York, NY [u.a.] : Wiley-Blackwell
    Biotechnology and Bioengineering 45 (1995), S. 69-79 
    Details
    ISSN: 0006-3592
    Keywords: E. coli ; linear optimization ; metabolic fluxes ; stoichiometry ; sensitivity analysis ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Stoichiometrically based flux balance models provide a method to quantify the metabolic pathway fluxes within a living cell. Predictions of flux balance models are expected to have applications in pathway engineering as well as in bioprocess design and control. These models utilize optimality principles applied to metabolic pathway stoichiometry along with the metabolic requirements for growth to determine the flux distribution in a metabolic network. A flux balance model has been developed for Escherichia coli W3110 using five experimentally determined strain-specific parameters. In this report, we determine the sensitivity of the predictions of the flux balance model to these five strain-specific parameters. Model predictions are shown to be sensitive to the two parameters describing metabolic capacity, while they are relatively insensitive to the three parameters that describe the metabolic requirements for growth. Thus, when stoichiometrically based models are formulated for additional strains one needs to measure the metabolic capacity (maximum rates of nutrient and oxygen utilization) accurately. Determination of metabolic capacity from batch experiments is relatively easy to perform. On the other hand, the harder to determine maintenance parameters need not be as accurately determined. © 1995 John Wiley & Sons, Inc.
    Additional Material: 8 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/bit.260450110
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  • 7
    Electronic Resource
    Electronic Resource
    Frequent harvesting from perfused bone marrow cultures results in increased overall cell and progenitor expansion (1994)
    New York, NY [u.a.] : Wiley-Blackwell
    Biotechnology and Bioengineering 44 (1994), S. 609-616 
    Details
    ISSN: 0006-3592
    Keywords: stem cells ; bone marrow ; ex vivo expansion ; perfusion culture ; hematopoiesis ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: The establishment of prolific long-term human bone marrow cultures has led to the development of hematopoietic bioreactor systems. A single batch expansion of bone marrow mononuclear cell populations leads to a 10- to 30-fold increase in total cell number and in the number of colony forming units-granulocyte/macrophage (CFU-GMs), and a four- to tenfold increase in the number of long-term culture initiating cells (LTC-ICs). In principle, unlimited expansion of cells should be attainable from a pool of stem cells if all the necessary requirements leading to stem cell maintenance and division are met. In this article, we take the first step toward the identification of factors that limit single batch expansion of ex vivo bone marrow cells in perfusion-based bioreactor systems. One possible constraint is the size of the growth surface area required. This constraint can be overcome by harvesting half the cell population periodically. We found that harvesting cells every 3 to 4 days, beginning on day 11 of culture, led to an extended growth period. Overall calculated cell expansion exceeded 100-fold and the CFU-GM expansion exceeded 30-fold over a 27-day period. These calculated values are based on growth that could be obtained from the harvested cell population. Growth of the adherent cell layer was stable, whereas the nonadherent cell population diminished with increasing number of passages. These results show that the bioreactor protocols published to date are suboptimal for long-term cultivation, and that further definition and refinement is likely to lead to even greater expansion of hematopoietic cell populations obtained from bone marrow. More importantly, these results show that the LTC-IC measured during the single pass expansion do have further expansion potential that can be realized by frequent harvesting. Finally, the present culture conditions provide a basis for an assay system for the identifications provide a basis for an assay system for the identification of the factors that determine the long-term maintenance and replication of human stem cells ex vivo. © 1994 John Wiley & Sons, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/bit.260440507
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  • 8
    Electronic Resource
    Electronic Resource
    Review: Tissue engineering: Reconstitution of human hematopoiesis ex vivo (1993)
    New York, NY [u.a.] : Wiley-Blackwell
    Biotechnology and Bioengineering 42 (1993), S. 909-930 
    Details
    ISSN: 0006-3592
    Keywords: tissue engineering ; hematopoiesis ; review ; bioreactors ; transplantation ; scaleup ; cell culture ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: The reconstruction of functioning human tissues ex vivo is becoming an important part of biotechnology. There are compelling scientific, clinical, and biotechnological reasons for fully or partially reconstituting human tissues such as skin, bone marrow, and liver ex vivo. In particular, bone marrow is a tissue of much importance, and there are significant societal and health benefits derived from a successfully constructed ex vivo hematopoietic system. In this article, we review the current status of this effort. The topics covered include the current understanding of the biology of human hematopoiesis, the motivation for reconstructing it ex vivo, the current state of ex vivo human hematopoietic cultures, the development of important metrics to judge culture performance, and an approach based on in vivo mimetics to accomplish this goal. We discuss some applications of functional ex vivo hematopoietic cultures and the biological and engineering challenges that face research in this area. © 1993 John Wiley & Sons, Inc.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/bit.260420802
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  • 9
    Electronic Resource
    Electronic Resource
    The construction of high efficiency human bone marrow tissue ex vivo (1991)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 45 (1991), S. 268-272 
    Details
    ISSN: 0730-2312
    Keywords: hematopoiesis ; stem cell ; perfusion ; hematopoietic growth factor ; genetic engineering ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: The successful ex vivo reconstruction of human bone marrow is an extraordinarily important basic scientific and clinical goal. Fundamentally, the system is the paradigm of a complex interactive tissue, in which the proliferation and regulated differentiation of one parenchymal cell type (the hematopoietic stem cell) is governed by the surrounding stromal cells. Understanding and reproducing the molecular interactions between bone marrow stromal cells and stem cells in tissue culture models is therefore the critical step in successful bone marrow tissue culture. Clinically, successful reconstruction of human bone marrow would permit the controlled production of mature blood cells for transfusion therapy, and immature bone marrow stem cells for bone marrow transplantation. In approaching the bone marrow culture system, we recognize the critical role that hematopoietic growth factors (HGFs) play in hematopoiesis. Since stromal cells in traditional human bone marrow cultures produce little HGFs, we have begun by asking whether local supplementation of hematopoietic growth factors via genetically engineered stromal cells might augment hematopoiesis in liquid cultures. The results indicate that locally produced GM-CSF and IL-3 do augment hematopoiesis for several weeks in culture. In combination with geometric and dynamic approaches to reconstructing physiological bone marrow microenvironments, we believe that this approach has promise for reconstructing human bone marrow ex vivo, thereby permitting its application to a variety of basic and clinical problems.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240450308
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  • 10
    Electronic Resource
    Electronic Resource
    Unilineage model of hematopoiesis predicts self-renewal of stem and progenitor cells based on ex vivo growth data (1996)
    New York, NY [u.a.] : Wiley-Blackwell
    Biotechnology and Bioengineering 52 (1996), S. 24-33 
    Details
    ISSN: 0006-3592
    Keywords: unilineage model ; tissue function ex vivo ; hematopoiesis ; stem cell expansion ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Stem cell models are used to describe the function of several tissues. We present unilineage kinetic description of stem cell models and their application to the analysis of ex vivo hematopoietic cell expansion data. This model has the capability to simulate the total cell number and the number of cells at each stage of differentiation over time as a function of the stem cell self-renewal probability, the growth rate of each subpopulation, and the mature cell death rate. The model predicts experimental observations in perfusion-based hematopoietic bioreactor systems. To obtain net cell expansion ex vivo, the model simulations show that the stem cell self-renewal probability must exceed one-half, thus resulting in net expansion of the stem cell population. Experimental data on long-term culture-initiating cells (LTC-IC) confirm this prediction and the probability of self-renewal is estimated to be 0.62 to 0.73. This self-renewal probability, along with the death rate, define a relationship in which the apparent overall growth rate is less than the compartmental growth rate. Finally, the model predicts that cells beyond the stem cell stage of differentiation must self-renew to achieve the level of expansion within the time frame observed in experimental systems. © 1996 John Wiley & Sons, Inc.
    Additional Material: 7 Ill.
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