Sample records for growth factor manipulation

  1. Neonatal manipulation of oxytocin prevents lipopolysaccharide-induced decrease in gene expression of growth factors in two developmental stages of the female rat.

    PubMed

    Bakos, Jan; Lestanova, Zuzana; Strbak, Vladimir; Havranek, Tomas; Bacova, Zuzana

    2014-10-01

    Oxytocin production and secretion is important for early development of the brain. Long-term consequences of manipulation of oxytocin system might include changes in markers of brain plasticity - cytoskeletal proteins and neurotrophins. The aim of the present study was (1) to determine whether neonatal oxytocin administration affects gene expression of nestin, microtubule-associated protein-2 (MAP-2), brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brain of two developmental stages of rat and (2) to evaluate whether neonatal oxytocin administration protects against lipopolysaccharide (LPS) induced inflammation. Neonatal oxytocin did not prevent a decrease of body weight in the LPS treated animals. Oxytocin significantly increased gene expression of BDNF in the right hippocampus in 21-day and 2-month old rats of both sexes. Gene expression of NGF and MAP-2 significantly increased in males treated with oxytocin. Both, growth factors and intermediate filament-nestin mRNA levels, were reduced in females exposed to LPS. Oxytocin treatment prevented a decrease in the gene expression of only growth factors. In conclusion, neonatal manipulation of oxytocin has developmental and sex-dependent effect on markers of brain plasticity. These results also indicate, that oxytocin may be protective against inflammation particularly in females. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Growth factors, muscle function, and doping.

    PubMed

    Goldspink, Geoffrey; Wessner, Barbara; Tschan, Harald; Bachl, Norbert

    2010-03-01

    This article discusses the inevitable use of growth factors for enhancing muscle strength and athletic performance. Much effort has been expended on developing a treatment of muscle wasting associated with a range of diseases and aging. Frailty in the aging population is a major socioeconomic and medical problem. Emerging molecular techniques have made it possible to gain a better understanding of the growth factor genes and how they are activated by physical activity. The ways that misuse of growth factors may be detected and verified in athletes and future challenges for detecting manipulation of signaling pathways are discussed. Copyright 2010. Published by Elsevier Inc.

  3. Growth responses of mature loblolly pine to dead wood.manipulations.

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ulyshen, Michael D.; Horn, Scott; Hanula, James L.

    Large-scale manipulations of dead wood in mature Pinus taeda L. stands in the southeastern United States included a major one-time input of logs (fivefold increase in log volume) created by felling trees onsite, annual removals of all dead wood above >10 cm in diameter and >60 cm in length, and a reference in which no manipulations took place. We returned over a decade later to determine how these treatments affected tree growth using increment cores. There were no significant differences in tree density, basal area or tree diameters among treatments at the time of sampling. Although tree growth was consistentlymore » higher in the log-input plots and lower in the removal plots, this was true even during the 5 year period before the experiment began. When growth data from this initial period were included in the model as a covariate, no differences in post-treatment tree growth were detected. It is possible that treatment effects will become apparent after more time has passed, however.« less

  4. Positive density-dependent growth supports costs sharing hypothesis and population density sensing in a manipulative parasite.

    PubMed

    Gopko, Mikhail; Mikheev, Victor N; Taskinen, Jouni

    2017-09-01

    Parasites manipulate their hosts' phenotype to increase their own fitness. Like any evolutionary adaptation, parasitic manipulations should be costly. Though it is difficult to measure costs of the manipulation directly, they can be evaluated using an indirect approach. For instance, theory suggests that as the parasite infrapopulation grows, the investment of individual parasites in host manipulation decreases, because of cost sharing. Another assumption is that in environments where manipulation does not pay off for the parasite, it can decrease its investment in the manipulation to save resources. We experimentally infected rainbow trout Oncorhynchus mykiss with the immature larvae of the trematode Diplostomum pseudospathaceum, to test these assumptions. Immature D. pseudospathaceum metacercariae are known for their ability to manipulate the behaviour of their host enhancing its anti-predator defenses to avoid concomitant predation. We found that the growth rate of individual parasites in rainbow trout increased with the infrapopulation size (positive density-dependence) suggesting cost sharing. Moreover, parasites adjusted their growth to the intensity of infection within the eye lens where they were localized suggesting population density sensing. Results of this study support the hypothesis that macroparasites can adjust their growth rate and manipulation investment according to cost sharing level and infrapopulation size.

  5. Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor.

    PubMed

    Gilmore, Andrew P; Valentijn, Anthony J; Wang, Pengbo; Ranger, Ann M; Bundred, Nigel; O'Hare, Michael J; Wakeling, Alan; Korsmeyer, Stanley J; Streuli, Charles H

    2002-08-02

    Novel cancer chemotherapeutics are required to induce apoptosis by activating pro-apoptotic proteins. Both epidermal growth factor (EGF) and insulin-like growth factor (IGF) provide potent survival stimuli in many epithelia, and activation of their receptors is commonly observed in solid human tumors. Here we demonstrate that blockade of the EGF receptor by a new drug in phase III clinical trails for cancer, ZD1839, potently induces apoptosis in mammary epithelial cell lines and primary cultures, as well as in a primary pleural effusion from a breast cancer patient. We identified the mechanism of apoptosis induction by ZD1839. We showed that it prevents cell survival by activating the pro-apoptotic protein BAD. Moreover, we demonstrate that IGF transactivates the EGF receptor and that ZD1839 blocks IGF-mediated phosphorylation of MAPK and BAD. Many cancer therapies kill tumor cells by inducing apoptosis as a consequence of targeting DNA; however, the threshold at which apoptosis can be triggered through DNA damage is often different from that in normal cells. Our results indicate that by targeting a growth factor-mediated survival signaling pathway, BAD phosphorylation can be manipulated therapeutically to induce apoptosis.

  6. Contribution of manipulable and non-manipulable environmental factors to trapping efficiency of invasive sea lamprey

    USGS Publications Warehouse

    Dawson, Heather A.; Bravener, Gale; Beaulaurier, Joshua; Johnson, Nicholas S.; Twohey, Michael; McLaughlin, Robert L.; Brenden, Travis O.

    2017-01-01

    We identified aspects of the trapping process that afforded opportunities for improving trap efficiency of invasive sea lamprey (Petromyzon marinus) in a Great Lake's tributary. Capturing a sea lamprey requires it to encounter the trap, enter, and be retained until removed. Probabilities of these events depend on the interplay between sea lamprey behavior, environmental conditions, and trap design. We first tested how strongly seasonal patterns in daily trap catches (a measure of trapping success) were related to nightly rates of trap encounter, entry, and retention (outcomes of sea lamprey behavior). We then tested the degree to which variation in rates of trap encounter, entry, and retention were related to environmental features that control agents can manipulate (attractant pheromone addition, discharge) and features agents cannot manipulate (water temperature, season), but could be used as indicators for when to increase trapping effort. Daily trap catch was most strongly associated with rate of encounter. Relative and absolute measures of predictive strength for environmental factors that managers could potentially manipulate were low, suggesting that opportunities to improve trapping success by manipulating factors that affect rates of encounter, entry, and retention are limited. According to results at this trap, more sea lamprey would be captured by increasing trapping effort early in the season when sea lamprey encounter rates with traps are high. The approach used in this study could be applied to trapping of other invasive or valued species.

  7. Targeted manipulation of leaf form via local growth repression.

    PubMed

    Malinowski, Robert; Kasprzewska, Ania; Fleming, Andrew J

    2011-06-01

    A classical view is that leaf shape is the result of local promotion of growth linked to cell proliferation. However, an alternative hypothesis is that leaf form is the result of local repression of growth in an otherwise growing system. Here we show that leaf form can indeed be manipulated in a directed fashion by local repression of growth. We show that targeting expression of an inhibitor of a cyclin-dependent kinase (KRP1) to the sinus area of developing leaves of Arabidopsis leads to local growth repression and the formation of organs with extreme lobing, including generation of leaflet-like organs. Directing KRP1 expression to other regions of the leaf using an miRNA target sequence tagging approach also leads to predictable novel leaf forms, and repression of growth in the leaf margin blocks the outgrowth of lobes, leading to a smoother perimeter. In addition, we show that decreased growth around the perimeter and across the leaf abaxial surface leads to a change in 3D form, as predicted by mechanical models of leaf growth. Our analysis provides experimental evidence that local repression of growth influences leaf shape, suggesting that it could be part of the mechanism of morphogenesis in plants in the context of an otherwise growing system. © 2011 The Authors. The Plant Journal © 2011 Blackwell Publishing Ltd.

  8. In situ cell manipulation through enzymatic hydrogel photopatterning

    NASA Astrophysics Data System (ADS)

    Mosiewicz, Katarzyna A.; Kolb, Laura; van der Vlies, André J.; Martino, Mikaël M.; Lienemann, Philipp S.; Hubbell, Jeffrey A.; Ehrbar, Martin; Lutolf, Matthias P.

    2013-11-01

    The physicochemical properties of hydrogels can be manipulated in both space and time through the controlled application of a light beam. However, methods for hydrogel photopatterning either fail to maintain the bioactivity of fragile proteins and are thus limited to short peptides, or have been used in hydrogels that often do not support three-dimensional (3D) cell growth. Here, we show that the 3D invasion of primary human mesenchymal stem cells can be spatiotemporally controlled by micropatterning the hydrogel with desired extracellular matrix (ECM) proteins and growth factors. A peptide substrate of activated transglutaminase factor XIII (FXIIIa)—a key ECM crosslinking enzyme—is rendered photosensitive by masking its active site with a photolabile cage group. Covalent incorporation of the caged FXIIIa substrate into poly(ethylene glycol) hydrogels and subsequent laser-scanning lithography affords highly localized biomolecule tethering. This approach for the 3D manipulation of cells within gels should open up avenues for the study and manipulation of cell signalling.

  9. Transforming growth factor alpha, Shope fibroma growth factor, and vaccinia growth factor can replace myxoma growth factor in the induction of myxomatosis in rabbits.

    PubMed

    Opgenorth, A; Nation, N; Graham, K; McFadden, G

    1993-02-01

    The epidermal growth factor (EGF) homologues encoded by vaccinia virus, myxoma virus, and malignant rabbit fibroma virus have been shown to contribute to the pathogenicity of virus infection upon inoculation of susceptible hosts. However, since the primary structures of these growth factors and the disease profiles induced by different poxvirus genera vary substantially, the degree to which the various EGF homologues perform similar roles in viral pathogenesis remains unclear. In order to determine whether different EGF-like growth factors can perform qualitatively similar functions in the induction of myxomatosis in rabbits, we created recombinant myxoma virus variants in which the native growth factor, myxoma growth factor (MGF), was disrupted and replaced with either vaccinia virus growth factor, Shope fibroma growth factor, or rat transforming growth factor alpha. Unlike the control virus containing an inactivated MGF gene, which caused marked attenuation of the disease syndrome and substantially less proliferation of the epithelial cell layers in the conjunctiva and respiratory tract, the recombinant myxoma virus strains expressing heterologous growth factors produced infections which were both clinically and histopathologically indistinguishable from wild-type myxomatosis. We conclude that these poxviral and cellular EGF-like growth factors, which are diverse with respect to primary structure and origin, have similar biological functions in the context of myxoma virus pathogenesis and are mitogenic for the same target cells.

  10. Dietary Manipulations That Induce Ketosis Activate the HPA Axis in Male Rats and Mice: A Potential Role for Fibroblast Growth Factor-21.

    PubMed

    Ryan, Karen K; Packard, Amy E B; Larson, Karlton R; Stout, Jayna; Fourman, Sarah M; Thompson, Abigail M K; Ludwick, Kristen; Habegger, Kirk M; Stemmer, Kerstin; Itoh, Nobuyuki; Perez-Tilve, Diego; Tschöp, Matthias H; Seeley, Randy J; Ulrich-Lai, Yvonne M

    2018-01-01

    In response to an acute threat to homeostasis or well-being, the hypothalamic-pituitary-adrenocortical (HPA) axis is engaged. A major outcome of this HPA axis activation is the mobilization of stored energy, to fuel an appropriate behavioral and/or physiological response to the perceived threat. Importantly, the extent of HPA axis activity is thought to be modulated by an individual's nutritional environment. In this study, we report that nutritional manipulations signaling a relative depletion of dietary carbohydrates, thereby inducing nutritional ketosis, acutely and chronically activate the HPA axis. Male rats and mice maintained on a low-carbohydrate high-fat ketogenic diet (KD) exhibited canonical markers of chronic stress, including increased basal and stress-evoked plasma corticosterone, increased adrenal sensitivity to adrenocorticotropin hormone, increased stress-evoked c-Fos immunolabeling in the paraventricular nucleus of the hypothalamus, and thymic atrophy, an indicator of chronic glucocorticoid exposure. Moreover, acutely feeding medium-chain triglycerides (MCTs) to rapidly induce ketosis among chow-fed male rats and mice also acutely increased HPA axis activity. Lastly, and consistent with a growing literature that characterizes the hepatokine fibroblast growth factor-21 (FGF21) as both a marker of the ketotic state and as a key metabolic stress hormone, the HPA response to both KD and MCTs was significantly blunted among mice lacking FGF21. We conclude that dietary manipulations that induce ketosis lead to increased HPA axis tone, and that the hepatokine FGF21 may play an important role to facilitate this effect. Copyright © 2018 Endocrine Society.

  11. Media composition: growth factors.

    PubMed

    Hegde, Aparna; Behr, Barry

    2012-01-01

    Despite the fact that the fundamental principle underlying the most common method of culture media constitution is that of mimicking the natural environment of the preimplantation embryo, one major difference that remains between current embryo culture media and in vivo conditions is the absence of growth factors in vitro. Numerous growth factors are known to be present in the in vivo environment of human and nonhuman preimplantation embryos, often with peak concentrations corresponding to when fertilization and preimplantation embryo growth would occur. Although these growth factors are found in very small concentrations, they have a profound effect on tissue growth and differentiation through attachment to factor-specific receptors on cell surfaces. Receptors for many different growth factors have also been detected in human preimplantation embryos. Preimplantation embryos themselves express many growth factors. The growth factors and receptors are metabolically costly to produce, and thus their presence in the environment of the preimplantation embryo and in the embryo respectively strongly implies that embryos are designed to encounter and respond to the corresponding factors. Studies of embryo coculture also indirectly suggest that growth factors can improve in vitro development. Several animal and human studies attest to a probable beneficial effect of addition of growth factors to culture media. However, there is still ambiguity regarding the exact role of growth factors in embryonic development, the optimal dose of growth factors to be added to culture media, the combinatorial effect and endocrine of growth factors in embryonic development.

  12. Enhancement of Arabidopsis growth characteristics using genome interrogation with artificial transcription factors

    PubMed Central

    Pinas, Johan E.; Henkel, Christiaan V.; Augustijn, Dieuwertje; Hooykaas, Paul J. J.; van der Zaal, Bert J.

    2017-01-01

    The rapidly growing world population has a greatly increasing demand for plant biomass, thus creating a great interest in the development of methods to enhance the growth and biomass accumulation of crop species. In this study, we used zinc finger artificial transcription factor (ZF-ATF)-mediated genome interrogation to manipulate the growth characteristics and biomass of Arabidopsis plants. We describe the construction of two collections of Arabidopsis lines expressing fusions of three zinc fingers (3F) to the transcriptional repressor motif EAR (3F-EAR) or the transcriptional activator VP16 (3F-VP16), and the characterization of their growth characteristics. In total, six different 3F-ATF lines with a consistent increase in rosette surface area (RSA) of up to 55% were isolated. For two lines we demonstrated that 3F-ATF constructs function as dominant in trans acting causative agents for an increase in RSA and biomass, and for five larger plant lines we have investigated 3F-ATF induced transcriptomic changes. Our results indicate that genome interrogation can be used as a powerful tool for the manipulation of plant growth and biomass and that it might supply novel cues for the discovery of genes and pathways involved in these properties. PMID:28358915

  13. Enhancement of Arabidopsis growth characteristics using genome interrogation with artificial transcription factors.

    PubMed

    Tol, Niels van; Rolloos, Martijn; Pinas, Johan E; Henkel, Christiaan V; Augustijn, Dieuwertje; Hooykaas, Paul J J; van der Zaal, Bert J

    2017-01-01

    The rapidly growing world population has a greatly increasing demand for plant biomass, thus creating a great interest in the development of methods to enhance the growth and biomass accumulation of crop species. In this study, we used zinc finger artificial transcription factor (ZF-ATF)-mediated genome interrogation to manipulate the growth characteristics and biomass of Arabidopsis plants. We describe the construction of two collections of Arabidopsis lines expressing fusions of three zinc fingers (3F) to the transcriptional repressor motif EAR (3F-EAR) or the transcriptional activator VP16 (3F-VP16), and the characterization of their growth characteristics. In total, six different 3F-ATF lines with a consistent increase in rosette surface area (RSA) of up to 55% were isolated. For two lines we demonstrated that 3F-ATF constructs function as dominant in trans acting causative agents for an increase in RSA and biomass, and for five larger plant lines we have investigated 3F-ATF induced transcriptomic changes. Our results indicate that genome interrogation can be used as a powerful tool for the manipulation of plant growth and biomass and that it might supply novel cues for the discovery of genes and pathways involved in these properties.

  14. Immobilization and Application of Electrospun Nanofiber Scaffold-based Growth Factor in Bone Tissue Engineering.

    PubMed

    Chen, Guobao; Lv, Yonggang

    2015-01-01

    Electrospun nanofibers have been extensively used in growth factor delivery and regenerative medicine due to many advantages including large surface area to volume ratio, high porosity, excellent loading capacity, ease of access and cost effectiveness. Their relatively large surface area is helpful for cell adhesion and growth factor loading, while storage and release of growth factor are essential to guide cellular behaviors and tissue formation and organization. In bone tissue engineering, growth factors are expected to transmit signals that stimulate cellular proliferation, migration, differentiation, metabolism, apoptosis and extracellular matrix (ECM) deposition. Bolus administration is not always an effective method for the delivery of growth factors because of their rapid diffusion from the target site and quick deactivation. Therefore, the integration of controlled release strategy within electrospun nanofibers can provide protection for growth factors against in vivo degradation, and can manipulate desired signal at an effective level with extended duration in local microenvironment to support tissue regeneration and repair which normally takes a much longer time. In this review, we provide an overview of growth factor delivery using biomimetic electrospun nanofiber scaffolds in bone tissue engineering. It begins with a brief introduction of different kinds of polymers that were used in electrospinning and their applications in bone tissue engineering. The review further focuses on the nanofiber-based growth factor delivery and summarizes the strategies of growth factors loading on the nanofiber scaffolds for bone tissue engineering applications. The perspectives on future challenges in this area are also pointed out.

  15. Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation.

    PubMed

    Gaviglio, Angela L; Knelson, Erik H; Blobe, Gerard C

    2017-05-01

    High-risk neuroblastoma is characterized by undifferentiated neuroblasts and low schwannian stroma content. The tumor stroma contributes to the suppression of tumor growth by releasing soluble factors that promote neuroblast differentiation. Here we identify heparin-binding epidermal growth factor-like growth factor (HBEGF) as a potent prodifferentiating factor in neuroblastoma. HBEGF mRNA expression is decreased in human neuroblastoma tumors compared with benign tumors, with loss correlating with decreased survival. HBEGF protein is expressed only in stromal compartments of human neuroblastoma specimens, with tissue from high-stage disease containing very little stroma or HBEGF expression. In 3 human neuroblastoma cell lines (SK-N-AS, SK-N-BE2, and SH-SY5Y), soluble HBEGF is sufficient to promote neuroblast differentiation and decrease proliferation. Heparan sulfate proteoglycans and heparin derivatives further enhance HBEGF-induced differentiation by forming a complex with the epidermal growth factor receptor, leading to activation of the ERK1/2 and STAT3 pathways and up-regulation of the inhibitor of DNA binding transcription factor. These data support a role for loss of HBEGF in the neuroblastoma tumor microenvironment in neuroblastoma pathogenesis.-Gaviglio, A. L., Knelson, E. H., Blobe, G. C. Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation. © FASEB.

  16. Spatial operator factorization and inversion of the manipulator mass matrix

    NASA Technical Reports Server (NTRS)

    Rodriguez, Guillermo; Kreutz-Delgado, Kenneth

    1992-01-01

    This paper advances two linear operator factorizations of the manipulator mass matrix. Embedded in the factorizations are many of the techniques that are regarded as very efficient computational solutions to inverse and forward dynamics problems. The operator factorizations provide a high-level architectural understanding of the mass matrix and its inverse, which is not visible in the detailed algorithms. They also lead to a new approach to the development of computer programs or organize complexity in robot dynamics.

  17. Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation

    PubMed Central

    Gaviglio, Angela L.; Knelson, Erik H.; Blobe, Gerard C.

    2017-01-01

    High-risk neuroblastoma is characterized by undifferentiated neuroblasts and low schwannian stroma content. The tumor stroma contributes to the suppression of tumor growth by releasing soluble factors that promote neuroblast differentiation. Here we identify heparin-binding epidermal growth factor–like growth factor (HBEGF) as a potent prodifferentiating factor in neuroblastoma. HBEGF mRNA expression is decreased in human neuroblastoma tumors compared with benign tumors, with loss correlating with decreased survival. HBEGF protein is expressed only in stromal compartments of human neuroblastoma specimens, with tissue from high-stage disease containing very little stroma or HBEGF expression. In 3 human neuroblastoma cell lines (SK-N-AS, SK-N-BE2, and SH-SY5Y), soluble HBEGF is sufficient to promote neuroblast differentiation and decrease proliferation. Heparan sulfate proteoglycans and heparin derivatives further enhance HBEGF-induced differentiation by forming a complex with the epidermal growth factor receptor, leading to activation of the ERK1/2 and STAT3 pathways and up-regulation of the inhibitor of DNA binding transcription factor. These data support a role for loss of HBEGF in the neuroblastoma tumor microenvironment in neuroblastoma pathogenesis.—Gaviglio, A. L., Knelson, E. H., Blobe, G. C. Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation. PMID:28174207

  18. Tree-ring growth and wood chemistry response to manipulated precipitation variation for two temperate Quercus species

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wagner, Rebekah J.; Kaye, Margot W.; Abrams, Marc D.

    2012-01-01

    We examined the relationship among ambient and manipulated precipitation, wood chemistry, and their relationship with radial growth for two oak species in eastern Tennessee. The study took place on the Walker Branch Throughfall Displacement Experiment (TDE) site, located at the Oak Ridge National Laboratory in Oak Ridge, TN. Two dominant species, white oak (Quercus alba) and chestnut oak (Quercus prinus), were selected for study from a 13-year experiment of whole-stand precipitation manipulation (wet, ambient and dry). The relationships between tree-ring width and climate were compared for both species to determine the impact of precipitation manipulations on ring width index. Thismore » study used experimental spectroscopy techniques to measure the sensitivity of tree-ring responses to directional changes in precipitation over 13 years, and the results suggest that oaks at this study site are resilient to imposed changes, but sensitive to inter-annual variations in climate. Laser-induced breakdown spectroscopy (LIBS) allowed us to measure nutrient intensities (similar to element concentrations) at 0.5-1.0 mm spacing along the radial growth axis of trees growing in the wet, ambient, and dry treatment sites. A difference in stemwood nutrient levels was observed between the two oak species and among the three treatments. Significant variation in element intensity was observed across treatments for some elements (Ca, K, Mg, Na, N and P) suggesting the potential for long-term impacts on growth under a changing climate regimes for southeastern oaks.« less

  19. Insulin-like growth factor and fibroblast growth factor expression profiles in growth-restricted fetal sheep pancreas.

    PubMed

    Chen, Xiaochuan; Rozance, Paul J; Hay, William W; Limesand, Sean W

    2012-05-01

    Placental insufficiency results in intrauterine growth restriction (IUGR), impaired fetal insulin secretion and less fetal pancreatic β-cell mass, partly due to lower β-cell proliferation rates. Insulin-like growth factors (IGFs) and fibroblast growth factors (FGFs) regulate fetal β-cell proliferation and pancreas development, along with transcription factors, such as pancreatic and duodenal homeobox 1 (PDX-1). We determined expression levels for these growth factors, their receptors and IGF binding proteins in ovine fetal pancreas and isolated islets. In the IUGR pancreas, relative mRNA expression levels of IGF-I, PDX-1, FGF7 and FGFR2IIIb were 64% (P < 0.01), 76% (P < 0.05), 76% (P < 0.05) and 52% (P < 0.01) lower, respectively, compared with control fetuses. Conversely, insulin-like growth factor binding protein 2 (IGFBP-2) mRNA and protein concentrations were 2.25- and 1.2-fold greater (P < 0.05) in the IUGR pancreas compared with controls. In isolated islets from IUGR fetuses, IGF-II and IGFBP-2 mRNA concentrations were 1.5- and 3.7-fold greater (P < 0.05), and insulin mRNA was 56% less (P < 0.05) than control islets. The growth factor expression profiles for IGF and FGF signaling pathways indicate that declines in β-cell mass are due to decreased growth factor signals for both pancreatic progenitor epithelial cell and mature β-cell replication.

  20. MARCKS Regulates Growth, Radiation Sensitivity and is a Novel Prognostic Factor for Glioma

    PubMed Central

    Jarboe, John S.; Anderson, Joshua C.; Duarte, Christine W.; Mehta, Tapan; Nowsheen, Somaira; Hicks, Patricia H.; Whitley, Alexander C.; Rohrbach, Timothy D.; McCubrey, Raymond O.; Chiu, Sherard; Burleson, Tamara M.; Bonner, James A.; Gillespie, G. Yancey; Yang, Eddy S.; Willey, Christopher D.

    2013-01-01

    Purpose This study assessed whether Myristoylated Alanine Rich C-Kinase Substrate (MARCKS) can regulate glioblastoma (GBM) growth, radiation sensitivity and clinical outcome. Experimental Design MARCKS protein levels were analyzed in five GBM explant cell lines and eight patient-derived xenograft tumors by immunoblot, and these levels were correlated to proliferation rates and intracranial growth rates, respectively. Manipulation of MARCKS protein levels was assessed by lentiviral-mediated shRNA knockdown in the U251 cell line and MARCKS over-expression in the U87 cell line. The effect of manipulation of MARCKS on proliferation, radiation sensitivity and senescence was assessed. MARCKS gene expression was correlated with survival outcomes in the Repository of Molecular Brain Neoplasia Data (REMBRANDT) Database and The Cancer Genome Atlas (TCGA). Results MARCKS protein expression was inversely correlated with GBM proliferation and intracranial xenograft growth rates. Genetic silencing of MARCKS promoted GBM proliferation and radiation resistance, while MARCKS overexpression greatly reduced GBM growth potential and induced senescence. We found MARCKS gene expression to be directly correlated with survival in both the REMBRANDT and TCGA databases. Specifically, patients with high MARCKS expressing tumors of the Proneural molecular subtype had significantly increased survival rates. This effect was most pronounced in tumors with unmethylated O6-methylguanine DNA methyltransferase (MGMT) promoters, a traditionally poor prognostic factor. Conclusions MARCKS levels impact GBM growth and radiation sensitivity. High MARCKS expressing GBM tumors are associated with improved survival, particularly with unmethylated MGMT promoters. These findings suggest the use of MARCKS as a novel target and biomarker for prognosis in the Proneural subtype of GBM. PMID:22619307

  1. Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer.

    PubMed

    Anan, K; Morisaki, T; Katano, M; Ikubo, A; Kitsuki, H; Uchiyama, A; Kuroki, S; Tanaka, M; Torisu, M

    1996-03-01

    Angiogenesis is a prerequisite for tumor growth and metastasis. Tumor angiogenesis may be mediated by several angiogenic factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-alpha, and basic fibroblast growth factor. Differential mRNA expressions of VEGF, PDGF (A chain), transforming growth factor-alpha and basic fibroblast growth factor in 32 primary invasive breast tumors were examined by reverse transcriptase-polymerase chain reaction. We analyzed relationships between mRNA expressions of these angiogenic factors and the degree of angiogenesis, tumor size, and metastasis. Quantification of angiogenesis was achieved by the immunohistochemical staining of endothelial cells with antibody to CD31. VEGF and PDGF-A mRNAs were expressed more frequently in breast tumors than in nontumor breast tissues, whereas no difference was found in expression frequency of either transforming growth factor-alpha or basic fibroblast growth factor mRNA. Vascular counts in tumors correlated with each expression frequency of VEGF and PDGF-A mRNA. PDGF-A mRNA was expressed more frequently in tumors with lymph node metastasis than in those without metastasis. Expression of VEGF and PDGF mRNAs detected by reverse transcriptase-polymerase chain reaction in breast tumors correlates with tumor-related characteristics of angiogenesis and metastatic potential. Analysis of these mRNAs by reverse transcriptase-polymerase chain reaction may be useful for assessing the biologic behavior of a breast tumor before surgical treatment.

  2. Epidermal growth factor- and hepatocyte growth factor-receptor activity in serum-free cultures of human hepatocytes.

    PubMed

    Runge, D M; Runge, D; Dorko, K; Pisarov, L A; Leckel, K; Kostrubsky, V E; Thomas, D; Strom, S C; Michalopoulos, G K

    1999-02-01

    Serum-free primary cultures of hepatocytes are a useful tool to study factors triggering hepatocyte proliferation and regeneration. We have developed a chemically defined serum-free system that allows human hepatocyte proliferation in the presence of epidermal growth factor and hepatocyte growth factor. DNA synthesis and accumulation were determined by [3H]thymidine incorporation and fluorometry, respectively. Western blot analyses and co-immunoprecipitations were used to investigate the association of proteins involved in epidermal growth factor and hepatocyte growth factor activation and signaling: epidermal growth factor receptor, hepatocyte growth factor receptor (MET), urokinase-type plasminogen activator and its receptor, and a member of the signal transducer and activator of transcription family, STAT-3. Primary human hepatocytes proliferated under serum-free conditions in a chemically defined medium for up to 12 days. Epidermal growth factor-receptor and MET were present and functional, decreasing over time. MET, urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor co-precipitated to varying degrees during the culture period. STAT-3 co-precipitated with epidermal growth factor-receptor and MET to varying degrees. Proliferation of human hepatocytes can improve by modification of a chemically defined medium originally used for rat hepatocyte cultures. In these long-term cultures of human hepatocytes, hepatocyte growth factor and epidermal growth factor can stimulate growth and differentiation by interacting with their receptors and initiating downstream signaling. This involves complex formation of the receptors with other plasma membrane components for MET (urokinase-type plasminogen activator in context of its receptor) and activation of STAT-3 for both receptors.

  3. Growth factor involvement in tension-induced skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman H.

    1993-01-01

    Long-term manned space travel will require a better understanding of skeletal muscle atrophy which results from microgravity. Astronaut strength and dexterity must be maintained for normal mission operations and for emergency situations. Although exercise in space slows the rate of muscle loss, it does not prevent it. A biochemical understanding of how gravity/tension/exercise help to maintain muscle size by altering protein synthesis and/or degradation rate should ultimately allow pharmacological intervention to prevent muscle atrophy in microgravity. The overall objective is to examine some of the basic biochemical processes involved in tension-induced muscle growth. With an experimental in vitro system, the role of exogenous and endogenous muscle growth factors in mechanically stimulated muscle growth are examined. Differentiated avian skeletal myofibers can be 'exercised' in tissue culture using a newly developed dynamic mechanical cell stimulator device which simulates different muscle activity patterns. Patterns of mechanical activity which significantly affect muscle growth and metabolic characteristics were found. Both exogenous and endogenous growth factors are essential for tension-induced muscle growth. Exogenous growth factors found in serum, such as insulin, insulin-like growth factors, and steroids, are important regulators of muscle protein turnover rates and mechanically-induced muscle growth. Endogenous growth factors are synthesized and released into the culture medium when muscle cells are mechanically stimulated. At least one family of mechanically induced endogenous factors, the prostaglandins, help to regulate the rates of protein turnover in muscle cells. Endogenously synthesized IGF-1 is another. The interaction of muscle mechanical activity and these growth factors in the regulation of muscle protein turnover rates with our in vitro model system is studied.

  4. Manipulating cyanobacteria: Spirulina for potential CELSS diet

    NASA Technical Reports Server (NTRS)

    Tadros, Mahasin G.; Smith, Woodrow; Mbuthia, Peter; Joseph, Beverly

    1989-01-01

    Spirulina sp. as a bioregenerative photosynthetic and an edible alga for spacecraft crew in a CELSS, was characterized for the biomass yield in batch cultures, under various environmental conditions. The partitioning of the assimalitory products (proteins, carbohydrates, lipids) were manipulated by varying the environmental growth conditions. Experiments with Spirulina have shown that under stress conditions (i.e., high light 160 uE/sq m/s, temperature 38 C, nitrogen or phosphate limitation; 0.1 M sodium chloride) carbohydrates increased at the expense of proteins. In other experiments, where the growth media were sufficient in nutrients and incubated under optimum growth conditions, the total of the algal could be manipulated by growth conditions. These results support the feasibility of considering Spirulina as a subsystem in CELSS because of the ease with which its nutrient content can be manipulated.

  5. Neurotrophins, growth-factor-regulated genes and the control of energy balance.

    PubMed

    Salton, Stephen R J

    2003-03-01

    Neurotrophic growth factors are proteins that control neuronal differentiation and survival, and consequently play important roles in the developing and adult stages of the nervous system. Study of the genes that are regulated by these growth factors has provided insight into the proteins that are critical to the maturation of the nervous system, suggesting that select neurotrophins may play a role in the control of body homeostasis by the brain and peripheral nervous system. Our understanding of the mechanisms of action of neurotrophic growth factors has increased through experimental manipulation of cultured neurons and neuronal cell lines. In particular, the PC12 pheochromocytoma cell line, which displays many properties of adrenal chromaffin cells and undergoes differentiation into sympathetic neuron-like cells when treated with nerve growth factor, has been extensively investigated to identify components of neurotrophin signaling pathways as well as the genes that they regulate. VGF was one of the first neurotrophin-regulated clones identified in NGF-treated PC12 cells. Subsequent studies indicate that the vgf gene is regulated in vivo in the nervous system by neurotrophins, by electrical activity, in response to injury or seizure, and by feeding and the circadian clock. The vgf gene encodes a polypeptide rich in paired basic amino acids; this polypeptide is differentially processed in neuronal and neuroendocrine cells and is released via the regulated secretory pathway. Generation and analysis of knockout mice that fail to synthesize VGF indicate that this protein plays a critical, non-redundant role in the regulation of energy homeostasis, providing a possible link between neurotrophin function in the nervous system and the peripheral control of feeding and metabolic activity. Future experiments should clarify the sites and mechanisms of action of this neurotrophin-regulated neuronal and neuroendocrine protein.

  6. Neonatal hyperthyroidism impairs epinephrine-provoked secretion of nerve growth factor and epidermal growth factor in mouse saliva.

    PubMed

    Lakshmanan, J; Landel, C P

    1986-07-01

    We examined long-term effects of neonatal hyperthyroidism on salivary secretions of nerve growth factor and epidermal growth factor in male and female mice at the age of 31 days. Hyperthyroidism was induced by thyroxine (T4) injections (0.4 microgram/g body weight/day) during days 0-6. Littermate control mice were treated with vehicle. T4 treatment did not alter the amounts of protein secreted into saliva but hormone administration induced alteration in the types of protein secreted. T4 treatment decreased the contents of both nerve growth factor and epidermal growth factor secreted into the saliva. A Sephadex G-200 column chromatographic profile revealed the presence of two distinct nerve growth factor immunoreactive peaks, while epidermal growth factor immunoreactivity predominantly eluted as a single low molecular weight form. T4 treatment did not alter the molecular nature of their secretion, but the treatment decreased their contents. These results indicate an impairment in salivary secretion of nerve growth factor and epidermal growth factor long after T4 treatment has been discontinued.

  7. Fibroblast growth factor receptors in breast cancer.

    PubMed

    Wang, Shuwei; Ding, Zhongyang

    2017-05-01

    Fibroblast growth factor receptors are growth factor receptor tyrosine kinases, exerting their roles in embryogenesis, tissue homeostasis, and development of breast cancer. Recent genetic studies have identified some subtypes of fibroblast growth factor receptors as strong genetic loci associated with breast cancer. In this article, we review the recent epidemiological findings and experiment results of fibroblast growth factor receptors in breast cancer. First, we summarized the structure and physiological function of fibroblast growth factor receptors in humans. Then, we discussed the common genetic variations in fibroblast growth factor receptors that affect breast cancer risk. In addition, we also introduced the potential roles of each fibroblast growth factor receptors isoform in breast cancer. Finally, we explored the potential therapeutics targeting fibroblast growth factor receptors for breast cancer. Based on the biological mechanisms of fibroblast growth factor receptors leading to the pathogenesis in breast cancer, targeting fibroblast growth factor receptors may provide new opportunities for breast cancer therapeutic strategies.

  8. Liposomal gene transfer of keratinocyte growth factor improves wound healing by altering growth factor and collagen expression.

    PubMed

    Pereira, Clifford T; Herndon, David N; Rocker, Roland; Jeschke, Marc G

    2007-05-15

    Growth factors affect the complex cascade of wound healing; however, interaction between different growth factors during dermal and epidermal regeneration are still not entirely defined. In the present study, we thought to determine the interaction between keratinocyte growth factor (KGF) administered as liposomal cDNA with other dermal and epidermal growth factors and collagen synthesis in an acute wound. Rats received an acute wound and were divided into two groups to receive weekly subcutaneous injections of liposomes plus the Lac-Z gene (0.22 microg, vehicle), or liposomes plus the KGF cDNA (2.2 microg) and Lac-Z gene (0.22 microg). Histological and immunohistochemical techniques were used to determine growth factor, collagen expression, and dermal and epidermal structure. KGF cDNA increased insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3), and fibroblast growth factor (FGF), decreased transforming growth factor-beta (TGF-beta), while it had no effect on platelet-derived growth factor (PDGF) levels in the wound. KGF cDNA significantly increased collagen Type IV at both the wound edge as well as the wound bed, while it had no effect on collagen Type I and III. KGF cDNA increased re-epithelialization, improved dermal regeneration, and increased neovascularization. Exogenous administered KGF cDNA causes increases in IGF-I, IGF-BP3, FGF, and collagen IV and decreases TGF-beta concentration. KGF gene transfer accelerates wound healing without causing an increase in collagen I or III.

  9. Insulin-Like Growth Factor Receptor Signaling is Necessary for Epidermal Growth Factor Mediated Proliferation of SVZ Neural Precursors in vitro Following Neonatal Hypoxia–Ischemia

    PubMed Central

    Alagappan, Dhivyaa; Ziegler, Amber N.; Chidambaram, Shravanthi; Min, Jungsoo; Wood, Teresa L.; Levison, Steven W.

    2014-01-01

    In this study, we assessed the importance of insulin-like growth factor (IGF) and epidermal growth factor (EGF) receptor co-signaling for rat neural precursor (NP) cell proliferation and self-renewal in the context of a developmental brain injury that is associated with cerebral palsy. Consistent with previous studies, we found that there is an increase in the in vitro growth of subventricular zone NPs isolated acutely after cerebral hypoxia–ischemia; however, when cultured in medium that is insufficient to stimulate the IGF type 1 receptor, neurosphere formation and the proliferative capacity of those NPs was severely curtailed. This reduced growth capacity could not be attributed simply to failure to survive. The growth and self-renewal of the NPs could be restored by addition of both IGF-I and IGF-II. Since the size of the neurosphere is predominantly due to cell proliferation we hypothesized that the IGFs were regulating progression through the cell cycle. Analyses of cell cycle progression revealed that IGF-1R activation together with EGFR co-signaling decreased the percentage of cells in G1 and enhanced cell progression into S and G2. This was accompanied by increases in expression of cyclin D1, phosphorylated histone 3, and phosphorylated Rb. Based on these data, we conclude that coordinate signaling between the EGF receptor and the IGF type 1 receptor is necessary for the normal proliferation of NPs as well as for their reactive expansion after injury. These data indicate that manipulations that maintain or amplify IGF signaling in the brain during recovery from developmental brain injuries will enhance the production of new brain cells to improve neurological function in children who are at risk for developing cerebral palsy. PMID:24904523

  10. The top-ten in journal impact factor manipulation.

    PubMed

    Falagas, Matthew E; Alexiou, Vangelis G

    2008-01-01

    A considerable part of the scientific community is, at least to some degree, involved in the "impact factor game". Editors strive to increase their journals' impact factor (IF) in order to gain influence in the fields of basic and applied research and scientists seek to profit from the "added value" of publishing in top IF journals. In this article we point out the most common "tricks" of engineering and manipulating the IF undertaken by a portion of professionals of the scientific publishing industry. They attempt to increase the nominator or decrease the denominator of the IF equation by taking advantage of certain design flaws and disadvantages of the IF that permit a degree of artificial and arbitrary inflation. Some of these practices, if not scientifically unethical, are at least questionable and should be abandoned. Editors and publishers should strive for quality through fair and thoughtful selection of papers forwarded for peer review and editorial comments that enhance the quality and scientific accuracy of a manuscript.

  11. New microbial growth factor

    NASA Technical Reports Server (NTRS)

    Bok, S. H.; Casida, L. E., Jr.

    1977-01-01

    A screening procedure was used to isolate from soil a Penicillium sp., two bacterial isolates, and a Streptomyces sp. that produced a previously unknown microbial growth factor. This factor was an absolute growth requirement for three soil bacteria. The Penicillium sp. and one of the bacteria requiring the factor, an Arthrobacter sp., were selected for more extensive study concerning the production and characteristics of the growth factor. It did not seem to be related to the siderochromes. It was not present in soil extract, rumen fluid, or any other medium component tested. It appears to be a glycoprotein of high molecular weight and has high specific activity. When added to the diets for a meadow-vole mammalian test system, it caused an increased consumption of diet without a concurrent increase in rate of weight gain.

  12. Factors That Influence Language Growth.

    ERIC Educational Resources Information Center

    McCarthy, Dorothea, Ed.; And Others

    This booklet contains four articles that discuss factors influencing language growth. The first, "The Child's Equipment for Language Growth" by Charlotte Wells, examines what the child needs for language learning, how the child uses his equipment for language growth, and what school factors facilitate the child's use of his equipment for language…

  13. Exploring the Influencing Factors in Students' Acquisition of Manipulative Skills during Transition from Primary to Secondary School

    ERIC Educational Resources Information Center

    Fadzil, Hidayah Mohd; Saat, Rohaida Mohd

    2014-01-01

    This paper discusses the contributing factors that influence students' acquisition of manipulative skills. Incompetence in manipulative skills in science at a primary level may impede science learning at secondary school. Thus, to confront these issues, an in-depth study was conducted. The research involved 10 primary school students who were…

  14. Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factors.

    PubMed

    Bortvedt, Sarah F; Lund, P Kay

    2012-03-01

    To summarize the recent evidence that insulin-like growth factor 1 (IGF1) mediates growth effects of multiple trophic factors and discuss clinical relevance. Recent reviews and original reports indicate benefits of growth hormone (GH) and long-acting glucagon-like peptide 2 (GLP2) analogs in short bowel syndrome and Crohn's disease. This review highlights the evidence that biomarkers of sustained small intestinal growth or mucosal healing and evaluation of intestinal epithelial stem cell biomarkers may improve clinical measures of intestinal growth or response to trophic hormones. Compelling evidence that IGF1 mediates growth effects of GH and GLP2 on intestine or linear growth in preclinical models of resection or Crohn's disease is presented, along with a concept that these hormones or IGF1 may enhance sustained growth if given early after bowel resection. Evidence that suppressor of cytokine signaling protein induction by GH or GLP2 in normal or inflamed intestine may limit IGF1-induced growth, but protect against risk of dysplasia or fibrosis, is reviewed. Whether IGF1 receptor mediates IGF1 action and potential roles of insulin receptors are addressed. IGF1 has a central role in mediating trophic hormone action in small intestine. Better understanding of benefits and risks of IGF1, receptors that mediate IGF1 action, and factors that limit undesirable growth are needed.

  15. FGF growth factor analogs

    DOEpatents

    Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY; Takahashi, Kazuyuki [Germantown, MD

    2012-07-24

    The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

  16. Growth factors in porcine full and partial thickness burn repair. Differing targets and effects of keratinocyte growth factor, platelet-derived growth factor-BB, epidermal growth factor, and neu differentiation factor.

    PubMed Central

    Danilenko, D. M.; Ring, B. D.; Tarpley, J. E.; Morris, B.; Van, G. Y.; Morawiecki, A.; Callahan, W.; Goldenberg, M.; Hershenson, S.; Pierce, G. F.

    1995-01-01

    The topical application of recombinant growth factors such as epidermal growth factor, platelet-derived growth factor-BB homodimer (rPDGF-BB), keratinocyte growth factor (rKGF), and neu differentiation factor has resulted in significant acceleration of healing in several animal models of wound repair. In this study, we established highly reproducible and quantifiable full and deep partial thickness porcine burn models in which burns were escharectomized 4 or 5 days postburn and covered with an occlusive dressing to replicate the standard treatment in human burn patients. We then applied these growth factors to assess their efficacy on several parameters of wound repair: extracellular matrix and granulation tissue production, percent reepithelialization, and new epithelial area. In full thickness burns, only rPDGF-BB and the combination of rPDGF-BB and rKGF induced significant changes in burn repair. rPDGF-BB induced marked extracellular matrix and granulation tissue production (P = 0.013) such that the burn defect was filled within several days of escharectomy, but had no effect on new epithelial area or reepithelialization. The combination of rPDGF-BB and rKGF in full thickness burns resulted in a highly significant increase in extracellular matrix and granulation tissue area (P = 0.0009) and a significant increase in new epithelial area (P = 0.007), but had no effect on reepithelialization. In deep partial thickness burns, rKGF induced the most consistent changes. Daily application of rKGF induced a highly significant increase in new epithelial area (P < 0.0001) but induced only a modest increase in reepithelialization (83.7% rKGF-treated versus 70.2% control; P = 0.016) 12 days postburn. rKGF also doubled the number of fully reepithelialized burns (P = 0.02) at 13 days postburn, at least partially because of marked stimulation of both epidermal and follicular proliferation as assessed by proliferating cell nuclear antigen expression. In situ hybridization for

  17. Regulation of Transforming Growth Factor β1, Platelet-Derived Growth Factor, and Basic Fibroblast Growth Factor by Silicone Gel Sheeting in Early-Stage Scarring.

    PubMed

    Choi, Jaehoon; Lee, Eun Hee; Park, Sang Woo; Chang, Hak

    2015-01-01

    Hypertrophic scars and keloids are associated with abnormal levels of growth factors. Silicone gel sheets are effective in treating and preventing hypertrophic scars and keloids. There has been no report on the change in growth factors in the scar tissue following the use of silicone gel sheeting for scar prevention. A prospective controlled trial was performed to evaluate whether growth factors are altered by the application of a silicone gel sheet on a fresh surgical scar. Four of seven enrolled patients completed the study. Transforming growth factor (TGF)-β1, platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) were investigated immunohistochemically in biopsies taken from five scars at 4 months following surgery. In both the epidermis and the dermis, the expression of TGF-β1 (P=0.042 and P=0.042) and PDGF (P=0.043 and P=0.042) was significantly lower in the case of silicone gel sheet-treated scars than in the case of untreated scars. The expression of bFGF in the dermis was significantly higher in the case of silicone gel sheet-treated scars than in the case of untreated scars (P=0.042), but in the epidermis, the expression of bFGF showed no significant difference between the groups (P=0.655). The levels of TGF-β1, PDGF, and bFGF are altered by the silicone gel sheet treatment, which might be one of the mechanisms of action in scar prevention.

  18. Growth factors, nutrient signaling, and cardiovascular aging.

    PubMed

    Fontana, Luigi; Vinciguerra, Manlio; Longo, Valter D

    2012-04-13

    Growth factors regulated by specific macronutrients have been shown to promote aging and accelerate mortality in the majority of the organisms studied. In particular, the enzymes activated by growth hormone, insulin, and insulin-like growth factor-1 in mammals and their orthologs in simple model organisms represent perhaps the best-understood proteins involved in the aging process. Dietary restriction, which reduces the level of insulin-like growth factor-1 and of other growth factors, has been associated with protection from diabetes, cancer, and cardiovascular diseases, and deficiencies in growth hormone signaling and insulin-like growth factor-1 are strongly associated with protection from cancer and diabetes in both mice and humans; however, their role in cardiac function and cardiovascular diseases is controversial. Here, we review the link between growth factors, cardiac function, and heart disease with focus on the cardioprotective and sensitizing effect of growth factors in both model organisms and humans.

  19. Exploring Task- and Student-Related Factors in the Method of Propositional Manipulation (MPM)

    ERIC Educational Resources Information Center

    Leppink, Jimmie; Broers, Nick J.; Imbos, Tjaart; van der Vleuten, Cees P. M.; Berger, Martijn P. F.

    2011-01-01

    The method of propositional manipulation (MPM) aims to help students develop conceptual understanding of statistics by guiding them into self-explaining propositions. To explore task- and student-related factors influencing students' ability to learn from MPM, twenty undergraduate students performed six learning tasks while thinking aloud. The…

  20. Growth/differentiation factor-11: an evolutionary conserved growth factor in vertebrates.

    PubMed

    Funkenstein, Bruria; Olekh, Elena

    2010-11-01

    Growth and differentiation factor-11 (GDF-11) is a member of the transforming growth factor-β superfamily and is thought to be derived together with myostatin (known also as GDF-8) from an ancestral gene. In the present study, we report the isolation and characterization of GDF-11 homolog from a marine teleost, the gilthead sea bream Sparus aurata, and show that this growth factor is highly conserved throughout vertebrates. Using bioinformatics, we identified GDF-11 in Tetraodon, Takifugu, medaka, and stickleback and found that they are highly conserved at the amino acid sequence as well as gene organization. Moreover, we found conservation of syntenic relationships among vertebrates in the GDF-11 locus. Transcripts for GDF-11 can be found in eggs and early embryos, albeit at low levels, while in post-hatching larvae expression levels are high and decreases as development progresses, suggesting that GDF-11 might have a role during early development of fish as found in tetrapods and zebrafish. Finally, GDF-11 is expressed in various tissues in the adult fish including muscle, brain, and eye.

  1. Release kinetics of platelet-derived and plasma-derived growth factors from autologous plasma rich in growth factors.

    PubMed

    Anitua, Eduardo; Zalduendo, Mari Mar; Alkhraisat, Mohammad Hamdan; Orive, Gorka

    2013-10-01

    Many studies have evaluated the biological effects of platelet rich plasma reporting the final outcomes on cell and tissues. However, few studies have dealt with the kinetics of growth factor delivery by plasma rich in growth factors. Venous blood was obtained from three healthy volunteers and processed with PRGF-Endoret technology to prepare autologous plasma rich in growth factors. The gel-like fibrin scaffolds were then incubated in triplicate, in a cell culture medium to monitor the release of PDGF-AB, VEGF, HGF and IGF-I during 8 days of incubation. A leukocyte-platelet rich plasma was prepared employing the same technology and the concentrations of growth factors and interleukin-1β were determined after 24h of incubation. After each period, the medium was collected, fibrin clot was destroyed and the supernatants were stored at -80°C until analysis. The growth factor delivery is diffusion controlled with a rapid initial release by 30% of the bioactive content after 1h of incubation and a steady state release when almost 70% of the growth factor content has been delivered. Autologous fibrin matrix retained almost 30% of the amount of the growth factors after 8 days of incubation. The addition of leukocytes to the formula of platelet rich plasma did not increase the concentration of the growth factors, while it drastically increased the presence of pro-inflammatory IL-1β. Further studies employing an in vitro inflammatory model would be interesting to study the difference in growth factors and pro-inflammatory cytokines between leukocyte-free and leukocyte-rich platelet rich plasma. Copyright © 2013 Elsevier GmbH. All rights reserved.

  2. Insulin-Like Growth Factor and Epidermal Growth Factor Signaling in Breast Cancer Cell Growth: Focus on Endocrine Resistant Disease

    PubMed Central

    Berdiaki, Aikaterini; Tzardi, Maria

    2015-01-01

    Breast cancer is the most common type of cancer for women worldwide with a lifetime risk amounting to a staggering total of 10%. It is well established that the endogenous synthesis of insulin-like growth factor (IGF) and epidermal growth factor (EGF) polypeptide growth factors are closely correlated to malignant transformation and all the steps of the breast cancer metastatic cascade. Numerous studies have demonstrated that both estrogens and growth factors stimulate the proliferation of steroid-dependent tumor cells, and that the interaction between these signaling pathways occurs at several levels. Importantly, the majority of breast cancer cases are estrogen receptor- (ER-) positive which have a more favorable prognosis and pattern of recurrence with endocrine therapy being the backbone of treatment. Unfortunately, the majority of patients progress to endocrine therapy resistant disease (acquired resistance) whereas a proportion of patients may fail to respond to initial therapy (de novo resistance). The IGF-I and EGF downstream signaling pathways are closely involved in the process of progression to therapy resistant disease. Modifications in the bioavailability of these growth factors contribute critically to disease progression. In the present review therefore, we will discuss in depth how IGF and EGF signaling participate in breast cancer pathogenesis and progression to endocrine resistant disease. PMID:26258011

  3. Insulin-like growth factor I (IGF-1) Ec/Mechano Growth factor--a splice variant of IGF-1 within the growth plate.

    PubMed

    Schlegel, Werner; Raimann, Adalbert; Halbauer, Daniel; Scharmer, Daniela; Sagmeister, Susanne; Wessner, Barbara; Helmreich, Magdalena; Haeusler, Gabriele; Egerbacher, Monika

    2013-01-01

    Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation.

  4. Growth factors for nanobacteria

    NASA Astrophysics Data System (ADS)

    Ciftcioglu, Neva; Kajander, E. Olavi

    1999-12-01

    Nanobacteria are novel microorganisms recently isolated from fetal bovine serum and blood of cows and humans. These coccoid, gram negative bacteria in alpha-2 subgroup of Proteobacteria grow slowly under mammalian cell culture conditions but not in common media for microbes. Now we have found two different kinds of culture supplement preparations that improve their growth and make them culturable in the classical sense. These are supernatant fractions of conditioned media obtained from 1 - 3 months old nanobacteria cultures and from about a 2 weeks old Bacillus species culture. Both improved multiplication and particle yields and the latter increased their resistance to gentamicin. Nanobacteria cultured with any of the methods shared similar immunological property, structure and protein pattern. The growth supporting factors were heat-stabile and nondialyzable, and dialysis improved the growth promoting action. Nanobacteria formed stony colonies in a bacteriological medium supplemented with the growth factors. This is an implication that nanobacterial growth is influenced by pre-existing bacterial flora.

  5. Research on growth factors in periodontology.

    PubMed

    Smith, Patricio C; Martínez, Constanza; Cáceres, Mónica; Martínez, Jorge

    2015-02-01

    Growth factors play critical roles in periodontal repair through the regulation of cell behavior. Many of the cell responses regulated by these proteins include cell adhesion, migration, proliferation and differentiation. Periodontal regeneration involves an organized response of different cells, tissues and growth factors implicated in the coordination of these events. However, periodontal tissue reconstruction is an extremely difficult task. Multiple studies have been performed to understand the specific role of growth factors in periodontal wound healing. In the present review we analyze the evidence that supports the roles of growth factors in periodontal wound healing and regeneration. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Synthetic heparin-binding growth factor analogs

    DOEpatents

    Pena, Louis A.; Zamora, Paul; Lin, Xinhua; Glass, John D.

    2007-01-23

    The invention provides synthetic heparin-binding growth factor analogs having at least one peptide chain that binds a heparin-binding growth factor receptor, covalently bound to a hydrophobic linker, which is in turn covalently bound to a non-signaling peptide that includes a heparin-binding domain. The synthetic heparin-binding growth factor analogs are useful as soluble biologics or as surface coatings for medical devices.

  7. Fibroblast growth factor regulates insulin-like growth factor-binding protein production by vascular smooth muscle cells.

    PubMed

    Ververis, J; Ku, L; Delafontaine, P

    1994-02-01

    Insulin-like growth factor I is an important mitogen for vascular smooth muscle cells, and its effects are regulated by several binding proteins. Western ligand blotting of conditioned medium from rat aortic smooth muscle cells detected a 24 kDa binding protein and a 28 kDa glycosylated variant of this protein, consistent with insulin-like growth factor binding protein-4 by size. Low amounts of a glycosylated 38 to 42 kDa doublet (consistent with binding protein-3) and a 31 kDa non-glycosylated protein also were present. Basic fibroblast growth factor markedly increased secretion of the 24 kDa binding protein and its 28 kDa glycosylated variant. This effect was dose- and time-dependent and was inhibited by co-incubation with cycloheximide. Crosslinking of [125I]-insulin-like growth factor I to cell monolayers revealed no surface-associated binding proteins, either basally or after agonist treatment. Induction of binding protein production by fibroblast growth factor at sites of vascular injury may be important in vascular proliferative responses in vivo.

  8. The Influence of Platelet-Derived Growth Factor and Fibroblast Growth Factor 2 on Oligodendrocyte Development and Remyelination

    DTIC Science & Technology

    2004-01-01

    OLIGODENDROCYTE DEVELOPMENT AND REMYELINATION 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e...Z39-18 ABSTRACT Title: THE INFLUENCE OF PLATELET-DERIVED GROWTH FACTOR AND FIBROBLAST GROWTH FACTOR 2 ON OLIGODENDROCYTE DEVELOPMENT AND...GROWTH FACTOR 2 ON OLIGODENDROCYTE DEVELOPMENT AND REMYELINATION by Joshua C. Murtie Thesis/dissertation submitted to the

  9. A light- and calcium-gated transcription factor for imaging and manipulating activated neurons

    PubMed Central

    Wang, W.; Wildes, C. P.; Pattarabanjird, T.; Sanchez, M. I.; Glober, G.F.; Matthews, G. A.; Tye, K. M.; Ting, A. Y

    2017-01-01

    Activity remodels neurons, altering their molecular, structural, and electrical characteristics. To enable the selective characterization and manipulation of these neurons, we present FLARE, an engineered transcription factor that drives expression of fluorescent proteins, opsins, and other genetically-encoded tools only in the subset of neurons that experienced activity during a user-defined time window. FLARE senses the coincidence of elevated cytosolic calcium and externally-applied blue light, which together produce translocation of a membrane-anchored transcription factor to the nucleus to drive expression of any transgene. In cultured rat neurons, FLARE gives a light-to-dark signal ratio of 120 and a high-to-low calcium signal ratio of 10 after 10 minutes of stimulation. Channelrhodopsin expression permitted functional manipulation of FLARE-marked neurons. In adult mice, FLARE also gave light- and motor activity-dependent transcription in the cortex. Due to its modular design, minute-scale temporal resolution, and minimal dark-state leak, FLARE should be useful for the study of activity-dependent processes in neurons and other cells that signal with calcium. PMID:28650461

  10. A light- and calcium-gated transcription factor for imaging and manipulating activated neurons.

    PubMed

    Wang, Wenjing; Wildes, Craig P; Pattarabanjird, Tanyaporn; Sanchez, Mateo I; Glober, Gordon F; Matthews, Gillian A; Tye, Kay M; Ting, Alice Y

    2017-09-01

    Activity remodels neurons, altering their molecular, structural, and electrical characteristics. To enable the selective characterization and manipulation of these neurons, we present FLARE, an engineered transcription factor that drives expression of fluorescent proteins, opsins, and other genetically encoded tools only in the subset of neurons that experienced activity during a user-defined time window. FLARE senses the coincidence of elevated cytosolic calcium and externally applied blue light, which together produce translocation of a membrane-anchored transcription factor to the nucleus to drive expression of any transgene. In cultured rat neurons, FLARE gives a light-to-dark signal ratio of 120 and a high- to low-calcium signal ratio of 10 after 10 min of stimulation. Opsin expression permitted functional manipulation of FLARE-marked neurons. In adult mice, FLARE also gave light- and motor-activity-dependent transcription in the cortex. Due to its modular design, minute-scale temporal resolution, and minimal dark-state leak, FLARE should be useful for the study of activity-dependent processes in neurons and other cells that signal with calcium.

  11. Insulin-Like Growth Factor I (IGF-1) Ec/Mechano Growth Factor – A Splice Variant of IGF-1 within the Growth Plate

    PubMed Central

    Schlegel, Werner; Raimann, Adalbert; Halbauer, Daniel; Scharmer, Daniela; Sagmeister, Susanne; Wessner, Barbara; Helmreich, Magdalena; Haeusler, Gabriele; Egerbacher, Monika

    2013-01-01

    Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation. PMID:24146828

  12. Growth factor transgenes interactively regulate articular chondrocytes.

    PubMed

    Shi, Shuiliang; Mercer, Scott; Eckert, George J; Trippel, Stephen B

    2013-04-01

    Adult articular chondrocytes lack an effective repair response to correct damage from injury or osteoarthritis. Polypeptide growth factors that stimulate articular chondrocyte proliferation and cartilage matrix synthesis may augment this response. Gene transfer is a promising approach to delivering such factors. Multiple growth factor genes regulate these cell functions, but multiple growth factor gene transfer remains unexplored. We tested the hypothesis that multiple growth factor gene transfer selectively modulates articular chondrocyte proliferation and matrix synthesis. We tested the hypothesis by delivering combinations of the transgenes encoding insulin-like growth factor I (IGF-I), fibroblast growth factor-2 (FGF-2), transforming growth factor beta1 (TGF-β1), bone morphogenetic protein-2 (BMP-2), and bone morphogenetic protien-7 (BMP-7) to articular chondrocytes and measured changes in the production of DNA, glycosaminoglycan, and collagen. The transgenes differentially regulated all these chondrocyte activities. In concert, the transgenes interacted to generate widely divergent responses from the cells. These interactions ranged from inhibitory to synergistic. The transgene pair encoding IGF-I and FGF-2 maximized cell proliferation. The three-transgene group encoding IGF-I, BMP-2, and BMP-7 maximized matrix production and also optimized the balance between cell proliferation and matrix production. These data demonstrate an approach to articular chondrocyte regulation that may be tailored to stimulate specific cell functions, and suggest that certain growth factor gene combinations have potential value for cell-based articular cartilage repair. Copyright © 2012 Wiley Periodicals, Inc.

  13. Reduced growth factor requirement of keloid-derived fibroblasts may account for tumor growth

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Russell, S.B.; Trupin, K.M.; Rodriguez-Eaton, S.

    Keloids are benign dermal tumors that form during an abnormal wound-healing process is genetically susceptible individuals. Although growth of normal and keloid cells did not differ in medium containing 10% (vol/vol) fetal bovine serum, keloid culture grew to significantly higher densities than normal cells in medium containing 5% (vol/vol) fetal bovine serum, keloid cultures grew to significantly higher densities than normal cells in medium containing 5% (vol/vol) plasma or 1% fetal bovine serum. Conditioned medium from keloid cultures did not stimulate growth of normal cells in plasma nor did it contain detectable platelet-derived growth factor or epidermal growth factor. Keloidmore » fibroblasts responded differently than normal adult fibroblasts to transforming growth factor ..beta... Whereas transforming growth factor ..beta.. reduced growth stimulation by epidermal growth factor in cells from normal adult skin or scars, it enhanced the activity of epidermal growth factor in cells from normal adult skin or scars, it enhanced the activity of epidermal growth factor in cells from keloids. Normal and keloid fibroblasts also responded differently to hydrocortisone: growth was stimulated in normal adult cells and unaffected or inhibited in keloid cells. Fetal fibroblasts resembled keloid cells in their ability to grow in plasma and in their response to hydrocortisone. The ability of keloid fibroblasts to grow to higher cell densities in low-serum medium than cells from normal adult skin or from normal early or mature scars suggests that a reduced dependence on serum growth factors may account for their prolonged growth in vivo. Similarities between keloid and fetal cells suggest that keloids may result from the untimely expression of growth-control mechanism that is developmentally regulated.« less

  14. Growth factors, nutrient signaling, and cardiovascular aging

    PubMed Central

    Fontana, Luigi; Vinciguerra, Manlio; Longo, Valter D.

    2012-01-01

    Growth factors regulated by specific macronutrients have been shown to promote aging and accelerate mortality in the great majority of the organisms studied. In particular, the enzymes activated by growth hormone (GH), insulin and insulin-like growth factor 1 (IGF-I) in mammals and their orthologs in simple model organisms represent perhaps the best-understood proteins involved in the aging process. Dietary restriction (DR), which reduces the level of IGF-I and of other growth factors, has been associated with protection from diabetes, cancer, and cardiovascular diseases and deficiencies in GH signaling and IGF-I are strongly associated with protection from cancer and diabetes in both mice and humans, but their role in cardiac function and cardiovascular diseases is controversial. Here we review the link between growth factors, cardiac function and heart disease with focus on the cardioprotective and sensitizing effect of growth factors in both model organisms and humans. PMID:22499903

  15. Role of epidermal growth factor and transforming growth factor α in the developing stomach

    PubMed Central

    Kelly, E; Newell, S; Brownlee, K; Farmery, S; Cullinane, C; Reid, W; Jackson, P; Gray, S; Primrose, J; Lagopoulos, M

    1997-01-01

    AIMS—To determine whether epidermal growth factor (EGF) or the related transforming growth factor α (TGFα) may have a role in the developing human stomach; to substantiate the presence of EGF in human liquor in the non-stressed infant and whether EGF in amniotic fluid is maternally or fetally derived.
METHODS—The temporal expression and localisation of EGF, TGFα, and their receptors during fetal and neonatal life were examined in 20 fetal and five infant stomachs. Simultaneously, samples of amniotic fluid and fetal urine from 10 newborn infants were collected and assayed for EGF by radioimmunoassay.
RESULTS—EGF immunoreactivity was not noted in any of the specimens examined. In contrast, TGFα immunoreactivity was shown in mucous cells from 18 weeks of gestation onwards. EGF receptor immunoreactivity was seen on superficial mucous cells in gastric mucosa from 18 weeks of gestation onwards. The median concentration of EGF was 30 and 8.5 pg/ml in amniotic fluid and fetal urine, respectively, suggesting that EGF is not produced by the fetus.
CONCLUSIONS—This study adds weight to the hypothesis that swallowed EGF, probably produced by the amniotic membranes, and locally produced TGFα, may have a role in the growth and maturation of the human stomach.

 Keywords: epidermal growth factor; transforming growth factor α; EGF receptors; stomach PMID:9175944

  16. Laser nano-surgery for neuronal manipulation (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Sarker, Hori Pada; Chudal, Lalit; Mahapatra, Vasu; Kim, Young-tae; Mohanty, Samarendra K.

    2016-03-01

    Optical manipulation has enabled study of bio-chemical and bio-mechanical properties of the cells. Laser nanosurgery by ultrafast laser beam with appropriate laser parameters provides spatially-targeted manipulation of neurons in a minimal invasiveness manner with high efficiency. We utilized femto-second laser nano-surgery for both axotomy and sub-axotomy of rat cortical neurons. Degeneration and regeneration after axotomy was studied with and without external growth-factor(s) and biochemical(s). Further, axonal injury was studied as a function of pulse energy, exposure and site of injury. The ability to study the response of neurons to localized injury opens up opportunities for screening potential molecules for repair and regeneration after nerve injury. Sub-axotomy enabled transient opening of axonal membrane for optical delivery of impermeable molecules to the axoplasm. Fast resealing of the axonal membrane after sub-axotomy without significant long-term damage to axon (monitored by its growth) was observed. We will present these experimental results along with theoretical simulation of injury due to laser nano-surgery and delivery via the transient pore. Targeted delivery of proteins such as antibodies, genes encoding reporter proteins, ion-channels and voltage indicators will allow visualization, activation and detection of the neuronal structure and function.

  17. Nonlinear structural crack growth monitoring

    DOEpatents

    Welch, Donald E.; Hively, Lee M.; Holdaway, Ray F.

    2002-01-01

    A method and apparatus are provided for the detection, through nonlinear manipulation of data, of an indicator of imminent failure due to crack growth in structural elements. The method is a process of determining energy consumption due to crack growth and correlating the energy consumption with physical phenomena indicative of a failure event. The apparatus includes sensors for sensing physical data factors, processors or the like for computing a relationship between the physical data factors and phenomena indicative of the failure event, and apparatus for providing notification of the characteristics and extent of such phenomena.

  18. Microstructural and Mechanical-Property Manipulation through Rapid Dendrite Growth and Undercooling in an Fe-based Multinary Alloy

    PubMed Central

    Ruan, Ying; Mohajerani, Amirhossein; Dao, Ming

    2016-01-01

    Rapid dendrite growth in single- or dual-phase multicomponent alloys can be manipulated to improve the mechanical properties of such metallic materials. Rapid growth of (αFe) dendrites was realized in an undercooled Fe-5Ni-5Mo-5Ge-5Co (wt.%) multinary alloy using the glass fluxing method. The relationship between rapid dendrite growth and the micro-/nano-mechanical properties of the alloy was investigated by analyzing the grain refinement and microstructural evolution resulting from the rapid dendrite growth. It was found that (αFe) dendrites grow sluggishly within a low but wide undercooling range. Once the undercooling exceeds 250 K, the dendritic growth velocity increases steeply until reaching a plateau of 31.8 ms−1. The increase in the alloy Vickers microhardness with increasing dendritic growth velocity results from the hardening effects of increased grain/phase boundaries due to the grain refinement, the more homogeneous distribution of the second phase along the boundaries, and the more uniform distribution of solutes with increased contents inside the grain, as verified also by nanohardness maps. Once the dendritic growth velocity exceeds ~8 ms−1, the rate of Vickers microhardness increase slows down significantly with a further increase in dendritic growth velocity, owing to the microstructural transition of the (αFe) phase from a trunk-dendrite to an equiaxed-grain microstructure. PMID:27539749

  19. Epidermal growth factor-like growth factors prevent apoptosis of alcohol-exposed human placental cytotrophoblast cells.

    PubMed

    Wolff, Garen S; Chiang, Po Jen; Smith, Susan M; Romero, Roberto; Armant, D Randall

    2007-07-01

    Maternal alcohol abuse during pregnancy can produce an array of birth defects comprising fetal alcohol syndrome. A hallmark of fetal alcohol syndrome is intrauterine growth retardation, which is associated with elevated apoptosis of placental cytotrophoblast cells. Using a human first trimester cytotrophoblast cell line, we examined the relationship between exposure to ethanol and cytotrophoblast survival, as well as the ameliorating effects of epidermal growth factor (EGF)-like growth factors produced by human cytotrophoblast cells. After exposure to 0-100 mM ethanol, cell death was quantified by the TUNEL method, and expression of the nuclear proliferation marker, Ki67, was measured by immunohistochemistry. The mode of cell death was determined by assessing annexin V binding, caspase 3 activation, pyknotic nuclear morphology, reduction of TUNEL by caspase inhibition, and cellular release of lactate dehydrogenase. Ethanol significantly reduced proliferation and increased cell death approximately 2.5-fold through the apoptotic pathway within 1-2 h of exposure to 50 mM alcohol. Exposure to 25-50 mM ethanol significantly increased transforming growth factor alpha (TGFA) and heparin-binding EGF-like growth factor (HBEGF), but not EGF or amphiregulin (AREG). When cytotrophoblasts were exposed concurrently to 100 mM ethanol and 1 nM HBEGF or TGFA, the increase in apoptosis was prevented, while EGF ameliorated at 10 nM and AREG was weakly effective. HBEGF survival-promoting activity required ligation of either of its cognate receptors, HER1 or HER4. These findings reveal the potential for ethanol to rapidly induce cytotrophoblast apoptosis. However, survival factor induction could provide cytotrophoblasts with an endogenous cytoprotective mechanism.

  20. Manipulation of follicle development to ensure optimal oocyte quality and conception rates in cattle.

    PubMed

    Baruselli, P S; Sá Filho, M F; Ferreira, R M; Sales, J N S; Gimenes, L U; Vieira, L M; Mendanha, M F; Bó, G A

    2012-08-01

    Over the last several decades, a number of therapies have been developed that manipulate ovarian follicle growth to improve oocyte quality and conception rates in cattle. Various strategies have been proposed to improve the responses to reproductive biotechnologies following timed artificial insemination (TAI), superovulation (SOV) or ovum pickup (OPU) programmes. During TAI protocols, final follicular growth and size of the ovulatory follicle are key factors that may significantly influence oocyte quality, ovulation, the uterine environment and consequently pregnancy outcomes. Progesterone concentrations during SOV protocols influence follicular growth, oocyte quality and embryo quality; therefore, several adjustments to SOV protocols have been proposed depending on the animal category and breed. In addition, the success of in vitro embryo production is directly related to the number and quality of cumulus oocyte complexes harvested by OPU. Control of follicle development has a significant impact on the OPU outcome. This article discusses a number of key points related to the manipulation of ovarian follicular growth to maximize oocyte quality and improve conception rates following TAI and embryo transfer of in vivo- and in vitro-derived embryos in cattle. © 2012 Blackwell Verlag GmbH.

  1. Controlling the Growth of Au on Icosahedral Seeds of Pd by Manipulating the Reduction Kinetics

    DOE PAGES

    Lv, Tian; Yang, Xuan; Zheng, Yiqun; ...

    2016-03-29

    This article reports a systematic study of how Au atoms nucleate and grow on Pd icosahedral seeds with a multiply twinned structure. By manipulating the reduction kinetics, we obtained Pd–Au bimetallic nanocrystals with two distinct shapes and structures. Specifically, Pd@Au core–shell icosahedra were formed when a relatively fast reduction rate was used for the HAuCl 4 precursor. At a slow reduction rate, in contrast, the nucleation and growth of Au atoms were mainly confined to one of the vertices of a Pd icosahedral seed, resulting in the formation of a Au icosahedron by sharing five adjacent faces with the Pdmore » seed. The same growth pattern was observed for Pd icosahedral seeds with both sizes of 32 and 20 nm. Also, we have also investigated the effects of other kinetic parameters, including the concentration of reducing agent and reaction temperature, on the growth pathway undertaken by the Au atoms. In conclusion, we believe that the mechanistic insights obtained from this study can be extended to other systems, including the involvement of different metals and/or seeds with different morphologies.« less

  2. Growth factor and pro-inflammatory cytokine contents in platelet-rich plasma (PRP), plasma rich in growth factors (PRGF), advanced platelet-rich fibrin (A-PRF), and concentrated growth factors (CGF).

    PubMed

    Masuki, Hideo; Okudera, Toshimitsu; Watanebe, Taisuke; Suzuki, Masashi; Nishiyama, Kazuhiko; Okudera, Hajime; Nakata, Koh; Uematsu, Kohya; Su, Chen-Yao; Kawase, Tomoyuki

    2016-12-01

    The development of platelet-rich fibrin (PRF) drastically simplified the preparation procedure of platelet-concentrated biomaterials, such as platelet-rich plasma (PRP), and facilitated their clinical application. PRF's clinical effectiveness has often been demonstrated in pre-clinical and clinical studies; however, it is still controversial whether growth factors are significantly concentrated in PRF preparations to facilitate wound healing and tissue regeneration. To address this matter, we performed a comparative study of growth factor contents in PRP and its derivatives, such as advanced PRF (A-PRF) and concentrated growth factors (CGF). PRP and its derivatives were prepared from the same peripheral blood samples collected from healthy donors. A-PRF and CGF preparations were homogenized and centrifuged to produce extracts. Platelet and white blood cell counts in A-PRF and CGF preparations were determined by subtracting those counts in red blood cell fractions, supernatant acellular serum fractions, and A-PRF/CGF exudate fractions from those counts of whole blood samples. Concentrations of growth factors (TGF-β1, PDGF-BB, VEGF) and pro-inflammatory cytokines (IL-1β, IL-6) were determined using ELISA kits. Compared to PRP preparations, both A-PRF and CGF extracts contained compatible or higher levels of platelets and platelet-derived growth factors. In a cell proliferation assay, both A-PRF and CGF extracts significantly stimulated the proliferation of human periosteal cells without significant reduction at higher doses. These data clearly demonstrate that both A-PRF and CGF preparations contain significant amounts of growth factors capable of stimulating periosteal cell proliferation, suggesting that A-PRF and CGF preparations function not only as a scaffolding material but also as a reservoir to deliver certain growth factors at the site of application.

  3. Growth factors and chronic wound healing: past, present, and future.

    PubMed

    Goldman, Robert

    2004-01-01

    Growth substances (cytokines and growth factors) are soluble signaling proteins affecting the process of normal wound healing. Cytokines govern the inflammatory phase that clears cellular and extracellular matrix debris. Wound repair is controlled by growth factors (platelet-derived growth factor [PDGF], keratinocyte growth factor, and transforming growth factor beta). Endogenous growth factors communicate across the dermal-epidermal interface. PDGF is important for most phases of wound healing. Becaplermin (PDGF-BB), the only growth factor approved by the Food and Drug Administration, requires daily application for neuropathic wound healing. Gene therapy is under development for more efficient growth factor delivery; a single application will induce constitutive growth factor expression for weeks. Based on dramatic preclinical animal studies, a phase 1 clinical trial planned on a PDGF genetic construct appears promising.

  4. Human memory manipulated: dissociating factors contributing to MTL activity, an fMRI study.

    PubMed

    Pustina, Dorian; Gizewski, Elke; Forsting, Michael; Daum, Irene; Suchan, Boris

    2012-04-01

    Memory processes are mainly studied with subjective rating procedures. We used a morphing procedure to objectively manipulate the similarity of target stimuli. While undergoing functional magnetic resonance imaging, nineteen subjects performed a encoding and recognition task on face and scene stimuli, varying the degree of manipulation of previously studied targets at 0%, 20%, 40% or 60%. Analyses were performed with parametric modulations for objective stimulus status (morphing level), subjective memory (confidence rating), and reaction times (RTs). Results showed that medial temporal lobe (MTL) activity can be best explained by a combination of subjective and objective factors. Memory success is associated with activity modulation in the hippocampus both for faces and for scenes. Memory failures correlated with lower hippocampal activity for scenes, but not for faces. Activity changed during retrieval on similar areas activated during encoding. There was a considerable impact of RTs on memory-related areas. Objective perceptual identity correlated with activity in the left MTL, while subjective memory experience correlated with activity in the right MTL for both types of material. Overall, the results indicate that MTL activity is heterogeneous, showing both linear and non-linear activity, depending on the factor analyzed. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. Image manipulation as research misconduct.

    PubMed

    Parrish, Debra; Noonan, Bridget

    2009-06-01

    A growing number of research misconduct cases handled by the Office of Research Integrity involve image manipulations. Manipulations may include simple image enhancements, misrepresenting an image as something different from what it is, and altering specific features of an image. Through a study of specific cases, the misconduct findings associated with image manipulation, detection methods and those likely to identify such manipulations, are discussed. This article explores sanctions imposed against guilty researchers and the factors that resulted in no misconduct finding although relevant images clearly were flawed. Although new detection tools are available for universities and journals to detect questionable images, this article explores why these tools have not been embraced.

  6. Predictive factors for intrauterine growth restriction

    PubMed Central

    Albu, AR; Anca, AF; Horhoianu, VV; Horhoianu, IA

    2014-01-01

    Abstract Reduced fetal growth is seen in about 10% of the pregnancies but only a minority has a pathological background and is known as intrauterine growth restriction or fetal growth restriction (IUGR / FGR). Increased fetal and neonatal mortality and morbidity as well as adult pathologic conditions are often associated to IUGR. Risk factors for IUGR are easy to assess but have poor predictive value. For the diagnostic purpose, biochemical serum markers, ultrasound and Doppler study of uterine and spiral arteries, placental volume and vascularization, first trimester growth pattern are object of assessment today. Modern evaluations propose combined algorithms using these strategies, all with the goal of a better prediction of risk pregnancies. Abbreviations: SGA = small for gestational age; IUGR = intrauterine growth restriction; FGR = fetal growth restriction; IUFD = intrauterine fetal demise; HIV = human immunodeficiency virus; PAPP-A = pregnancy associated plasmatic protein A; β-hCG = beta human chorionic gonadotropin; MoM = multiple of median; ADAM-12 = A-disintegrin and metalloprotease 12; PP-13 = placental protein 13; VEGF = vascular endothelial growth factor; PlGF = placental growth factor; sFlt-1 = soluble fms-like tyrosine kinase-1; UAD = uterine arteries Doppler ultrasound; RI = resistence index; PI = pulsatility index; VOCAL = Virtual Organ Computer–Aided Analysis software; VI = vascularization index; FI = flow index; VFI = vascularization flow index; PQ = placental quotient PMID:25408721

  7. Growth factors and growth factor receptors in the hippocampus. Role in plasticity and response to injury.

    PubMed

    Nieto-Sampedro, M; Bovolenta, P

    1990-01-01

    Various growth factors are present in the hippocampal formation and appear responsible for the prominent plasticity of this brain area. Although hormone-like growth-promoting polypeptides are the best known, recent studies emphasize the importance in the growth response of molecules such as laminin proteoglycans, neurotransmitters and growth inhibitors. The progress and problems in the study of these substances are reviewed.

  8. Engineering growth factors for regenerative medicine applications.

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mitchell, Aaron C.; Briquez, Priscilla S.; Hubbell, Jeffrey A.

    Growth factors are important morphogenetic proteins that instruct cell behavior and guide tissue repair and renewal. Although their therapeutic potential holds great promise in regenerative medicine applications, translation of growth factors into clinical treatments has been hindered by limitations including poor protein stability, low recombinant expression yield, and suboptimal efficacy. This review highlights current tools, technologies, and approaches to design integrated and effective growth factor-based therapies for regenerative medicine applications. The first section describes rational and combinatorial protein engineering approaches that have been utilized to improve growth factor stability, expression yield, biodistribution, and serum half-life, or alter their cell traffickingmore » behavior or receptor binding affinity. The second section highlights elegant biomaterial-based systems, inspired by the natural extracellular matrix milieu, that have been developed for effective spatial and temporal delivery of growth factors to cell surface receptors. Although appearing distinct, these two approaches are highly complementary and involve principles of molecular design and engineering to be considered in parallel when developing optimal materials for clinical applications.« less

  9. Effects of heparin-binding epidermal growth factor-like growth factor on cell repopulation and signal transduction in periodontal ligament cells after scratch wounding in vitro.

    PubMed

    Lee, J S; Kim, J M; Hong, E K; Kim, S-O; Yoo, Y-J; Cha, J-H

    2009-02-01

    A growing amount of attention has been placed on periodontal regeneration and wound healing for periodontal therapy. This study was conducted in an effort to determine the effects of heparin-binding epidermal growth factor-like growth factor on cell repopulation and signal transduction in periodontal ligament cells after scratch wounding in vitro. Human periodontal ligament cells were acquired from explant tissue of human healthy periodontal ligament. After the wounding of periodontal ligament cells, the change in expression of heparin-binding epidermal growth factor-like growth factor and epidermal growth factor receptors 1-4 mRNA was assessed. The effects of heparin-binding epidermal growth factor-like growth factor on periodontal ligament cell proliferation and repopulation were assessed in vitro via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and by photographing the injuries, respectively. Extracellular signal-regulated kinase (Erk)1/2, p38 and Akt phosphorylation was characterized via western blotting. Scratch wounding resulted in a significant up-regulation of heparin-binding epidermal growth factor-like growth factor mRNA expression, whereas wounding had no effect on the expression levels of epidermal growth factor receptors 1-4. Interestingly, no expression of epidermal growth factor receptors 2 and 4 was detectable prior to or after wounding. Heparin-binding epidermal growth factor-like growth factor treatment promoted the proliferation and repopulation of periodontal ligament cells. The scratch wounding also stimulated the phosphorylation of Erk1/2 and p38, but not of Akt, in periodontal ligament cells, and heparin-binding epidermal growth factor-like growth factor treatment applied after wounding amplified and extended the activations of Erk1/2 and p38, but not of Akt. Furthermore, Erk1/2 inhibition blocked the process of cell repopulation induced by heparin-binding epidermal growth factor-like growth factor, whereas the

  10. Growth factor involvement in tension-induced skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, H. H.

    1987-01-01

    Muscle tissue culture techniques were developed to grow skeletal myofibers which differentiate into more adult-like myofibers. Mechanical simulation studies of these muscle cells in a newly developed mechanical cell simulator can now be performed to study growth processes in skeletal muscle. Conditions in the mechanical cell simulator were defined where mechanical activity can either prevent muscle wasting or stimulate muscle growth. The role of endogenous and exogenous growth factors in tension-induced muscle growth is being investigated under the defined conditions of tissue culture.

  11. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo

    NASA Astrophysics Data System (ADS)

    Kim, K. Jin; Li, Bing; Winer, Jane; Armanini, Mark; Gillett, Nancy; Phillips, Heidi S.; Ferrara, Napoleone

    1993-04-01

    THE development of new blood vessels (angiogenesis) is required for many physiological processes including embryogenesis, wound healing and corpus luteum formation1,2. Blood vessel neoformation is also important in the pathogenesis of many disorders1-5, particularly rapid growth and metastasis of solid tumours3-5. There are several potential mediators of tumour angiogenesis, including basic and acidic fibroblast growth factors, tumour necrosis factor-α and transforming factors-α and -β 1,2. But it is unclear whether any of these agents actually mediates angiogenesis and tumour growth in vivo. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and an angiogenesis inducer released by a variety of tumour cells and expressed in human tumours in situ. To test whether VEGF may be a tumour angiogenesis factor in vivo, we injected human rhabdomyosar-coma, glioblastoma multiforme or leiomyosarcoma cell lines into nude mice. We report here that treatment with a monoclonal antibody specific for VEGF inhibited the growth of the tumours, but had no effect on the growth rate of the tumour cells In vitro. The density of vessels was decreased in the antibody-treated tumours. These findings demonstrate that inhibition of the action of an angiogenic factor spontaneously produced by tumour cells may suppress tumour growth in vivo.

  12. Fibroblast growth factor receptor inhibitors.

    PubMed

    Kumar, Suneel B V S; Narasu, Lakshmi; Gundla, Rambabu; Dayam, Raveendra; J A R P, Sarma

    2013-01-01

    Fibroblast growth factor receptors (FGFRs) play an important role in embryonic development, angiogenesis, wound healing, cell proliferation and differentiation. The fibroblast growth factor receptor (FGFR) isoforms have been under intense scrutiny for effective anticancer drug candidates. The fibroblast growth factor (FGF) and its receptor (FGFR) provide another pathway that seems critical to monitoring angiogenesis. Recent findings suggest that FGFR mediates signaling, regulates the PKM2 activity, and plays a crucial role in cancer metabolism. The current review also covers the recent findings on the role of FGFR1 in cancer metabolism. This paper reviews the progress, mechanism, and binding modes of recently known kinase inhibitors such as PD173074, SU series and other inhibitors still under clinical development. Some of the structural classes that will be highlighted in this review include Pyrido[2,3-d]pyrimidines, Indolin- 2-one, Pyrrolo[2,1-f][1,2,4]triazine, Pyrido[2,3-d]pyrimidin-7(8H)-one, and 1,6- Naphthyridin-2(1H)-ones.

  13. The growth receptors and their role in wound healing.

    PubMed

    Rolfe, Kerstin J; Grobbelaar, Adriaan O

    2010-11-01

    Abnormal wound healing is a major problem in healthcare today, with both scarring and chronic wounds affecting large numbers of individuals worldwide. Wound healing is a complex process involving several variables, including growth factors and their receptors. Chronic wounds fail to complete the wound healing process, while scarring is considered to be an overzealous wound healing process. Growth factor receptors and their ligands are being investigated to assess their potential in the development of therapeutic strategies to improve wound healing. This review discusses potential therapeutics for manipulating growth factors and their corresponding receptors for the treatment of abnormal wound healing.

  14. Expression of a transmembrane phosphotyrosine phosphatase inhibits cellular response to platelet-derived growth factor and insulin-like growth factor-1.

    PubMed

    Mooney, R A; Freund, G G; Way, B A; Bordwell, K L

    1992-11-25

    Tyrosine phosphorylation is a mechanism of signal transduction shared by many growth factor receptors and oncogene products. Phosphotyrosine phosphatases (PTPases) potentially modulate or counter-regulate these signaling pathways. To test this hypothesis, the transmembrane PTPase CD45 (leukocyte common antigen) was expressed in the murine cell line C127. Hormone-dependent autophosphorylation of the platelet-derived growth factor (PDGF) and insulin-like growth factor-1 (IGF-1) receptors was markedly reduced in cells expressing the transmembrane PTPase. Tyrosine phosphorylation of other PDGF-dependent phosphoproteins (160, 140, and 55 kDa) and IGF-1-dependent phosphoproteins (145 kDa) was similarly decreased. Interestingly, the pattern of growth factor-independent tyrosine phosphorylations was comparable in cells expressing the PTPase and control cells. This suggests a selectivity or accessibility of the PTPase limited to a subset of cellular phosphotyrosyl proteins. The maximum mitogenic response to PDGF and IGF-1 in cells expressing the PTPase was decreased by 67 and 71%, respectively. These results demonstrate that a transmembrane PTPase can both affect the tyrosine phosphorylation state of growth factor receptors and modulate proximal and distal cellular responses to the growth factors.

  15. Cross-talk between GPER and growth factor signaling.

    PubMed

    Lappano, Rosamaria; De Marco, Paola; De Francesco, Ernestina Marianna; Chimento, Adele; Pezzi, Vincenzo; Maggiolini, Marcello

    2013-09-01

    G protein-coupled receptors (GPCRs) and growth factor receptors mediate multiple physio-pathological responses to a diverse array of extracellular stimuli. In this regard, it has been largely demonstrated that GPCRs and growth factor receptors generate a multifaceted signaling network, which triggers relevant biological effects in normal and cancer cells. For instance, some GPCRs transactivate the epidermal growth factor receptor (EGFR), which stimulates diverse transduction pathways leading to gene expression changes, cell migration, survival and proliferation. Moreover, it has been reported that a functional interaction between growth factor receptors and steroid hormones like estrogens is involved in the growth of many types of tumors as well as in the resistance to endocrine therapy. This review highlights recent findings on the cross-talk between a member of the GPCR family, the G protein-coupled estrogen receptor 1 (GPER, formerly known as GPR30) and two main growth factor receptors like EGFR and insulin-like growth factor-I receptor (IGF-IR). The biological implications of the functional interaction between these important mediators of cell responses particularly in cancer are discussed. This article is part of a Special Issue entitled 'CSR 2013'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. The effects of thermal manipulations during embryogenesis of broiler chicks on growth of embryo and skeletal traits

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Aygün, Ali, E-mail: aaygun@selcuk.edu.tr; Narinç, Doğan, E-mail: narincd@gmail.com

    Incubation temperature is one of the important environmental factors that can induce epigenetic thermal adaptation of different physiological control systems. Thus, post hatch thermo tolerance ability of birds may be gained using these manipulations during different incubation periods. The current study was carried out to reveal the effects of temperature manipulations during early and late embryogenesis on weight of embryo and size of skeletal bilateral traits (face, wings, metatarsus, tibia, and femur) in broiler chicken embryos. One thousand commercial broiler eggs from 46 week old breeder flock were used in study. Treatments consisted of eggs incubated at 37.8°C and 55%more » relative humidity throughout (control; DG1), heated to 36.9°C and supplied 60% relative humidity for 6 hours daily from day 0 to 8 (DG2), heated to 36.9°C and supplied 60% relative humidity for 6 hours daily from day 10 to 18 (DG3), heated to 41°C and supplied 65% relative humidity for 3 hours daily from day 8 to 10 (DG4), and heated to 41°C and supplied 65% relative humidity for 3 hours daily from day 16 to 18 (DG5). Measurements of embryo weight and bilateral traits were obtained at 20 day of incubation and at hatch (at day 21). It was determined that the live weights of embryo and chick were affected significantly by treatment; DG3 group has shown higher mean values than the other treatment groups (P<0.05). There were differences in lengths of femur, tibia and metatarsus among treatment groups at hatch. Particularly, the high incubator temperatures at the second half of incubation accelerated growth of body and bone in embryos. These consequences of the treatments performed at different temperatures and times indicate that the different metabolic shifts realized by the embryos.« less

  17. The effects of thermal manipulations during embryogenesis of broiler chicks on growth of embryo and skeletal traits

    NASA Astrophysics Data System (ADS)

    Aygün, Ali; Narinç, Doǧan

    2016-04-01

    Incubation temperature is one of the important environmental factors that can induce epigenetic thermal adaptation of different physiological control systems. Thus, post hatch thermo tolerance ability of birds may be gained using these manipulations during different incubation periods. The current study was carried out to reveal the effects of temperature manipulations during early and late embryogenesis on weight of embryo and size of skeletal bilateral traits (face, wings, metatarsus, tibia, and femur) in broiler chicken embryos. One thousand commercial broiler eggs from 46 week old breeder flock were used in study. Treatments consisted of eggs incubated at 37.8°C and 55% relative humidity throughout (control; DG1), heated to 36.9°C and supplied 60% relative humidity for 6 hours daily from day 0 to 8 (DG2), heated to 36.9°C and supplied 60% relative humidity for 6 hours daily from day 10 to 18 (DG3), heated to 41°C and supplied 65% relative humidity for 3 hours daily from day 8 to 10 (DG4), and heated to 41°C and supplied 65% relative humidity for 3 hours daily from day 16 to 18 (DG5). Measurements of embryo weight and bilateral traits were obtained at 20 day of incubation and at hatch (at day 21). It was determined that the live weights of embryo and chick were affected significantly by treatment; DG3 group has shown higher mean values than the other treatment groups (P<0.05). There were differences in lengths of femur, tibia and metatarsus among treatment groups at hatch. Particularly, the high incubator temperatures at the second half of incubation accelerated growth of body and bone in embryos. These consequences of the treatments performed at different temperatures and times indicate that the different metabolic shifts realized by the embryos.

  18. Time dependent impact of perinatal hypoxia on growth hormone, insulin-like growth factor 1 and insulin-like growth factor binding protein-3.

    PubMed

    Kartal, Ömer; Aydınöz, Seçil; Kartal, Ayşe Tuğba; Kelestemur, Taha; Caglayan, Ahmet Burak; Beker, Mustafa Caglar; Karademir, Ferhan; Süleymanoğlu, Selami; Kul, Mustafa; Yulug, Burak; Kilic, Ertugrul

    2016-08-01

    Hypoxic-ischemia (HI) is a widely used animal model to mimic the preterm or perinatal sublethal hypoxia, including hypoxic-ischemic encephalopathy. It causes diffuse neurodegeneration in the brain and results in mental retardation, hyperactivity, cerebral palsy, epilepsy and neuroendocrine disturbances. Herein, we examined acute and subacute correlations between neuronal degeneration and serum growth factor changes, including growth hormone (GH), insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after hypoxic-ischemia (HI) in neonatal rats. In the acute phase of hypoxia, brain volume was increased significantly as compared with control animals, which was associated with reduced GH and IGF-1 secretions. Reduced neuronal survival and increased DNA fragmentation were also noticed in these animals. However, in the subacute phase of hypoxia, neuronal survival and brain volume were significantly decreased, accompanied by increased apoptotic cell death in the hippocampus and cortex. Serum GH, IGF-1, and IGFBP-3 levels were significantly reduced in the subacute phase of HI. Significant retardation in the brain and body development were noted in the subacute phase of hypoxia. Here, we provide evidence that serum levels of growth-hormone and factors were decreased in the acute and subacute phase of hypoxia, which was associated with increased DNA fragmentation and decreased neuronal survival.

  19. The effects of functional magnetic nanotubes with incorporated nerve growth factor in neuronal differentiation of PC12 cells

    NASA Astrophysics Data System (ADS)

    Xie, Jining; Chen, Linfeng; Varadan, Vijay K.; Yancey, Justin; Srivatsan, Malathi

    2008-03-01

    In this in vitro study the efficiency of magnetic nanotubes to bind with nerve growth factor (NGF) and the ability of NGF-incorporated magnetic nanotubes to release the bound NGF are investigated using rat pheochromocytoma cells (PC12 cells). It is found that functional magnetic nanotubes with NGF incorporation enabled the differentiation of PC12 cells into neurons exhibiting growth cones and neurite outgrowth. Microscope observations show that filopodia extending from neuron growth cones were in close proximity to the NGF-incorporated magnetic nanotubes, at times appearing to extend towards or into them. These results show that magnetic nanotubes can be used as a delivery vehicle for NGF and thus may be exploited in attempts to treat neurodegenerative disorders such as Parkinson's disease with neurotrophins. Further neurite outgrowth can be controlled by manipulating magnetic nanotubes with external magnetic fields, thus helping in directed regeneration.

  20. An evolutionary resolution of manipulation conflict.

    PubMed

    González-Forero, Mauricio

    2014-07-01

    Individuals can manipulate the behavior of social partners. However, manipulation may conflict with the fitness interests of the manipulated individuals. Manipulated individuals can then be favored to resist manipulation, possibly reducing or eliminating the manipulated behavior in the long run. I use a mathematical model to show that conflicts where manipulation and resistance coevolve can disappear as a result of the coevolutionary process. I find that while manipulated individuals are selected to resist, they can simultaneously be favored to express the manipulated behavior at higher efficiency (i.e., providing increasing fitness effects to recipients of the manipulated behavior). Efficiency can increase to a point at which selection for resistance disappears. This process yields an efficient social behavior that is induced by social partners, and over which the inducing and induced individuals are no longer in conflict. A necessary factor is costly inefficiency. I develop the model to address the evolution of advanced eusociality via maternal manipulation (AEMM). The model predicts AEMM to be particularly likely in taxa with ancestrally imperfect resistance to maternal manipulation. Costly inefficiency occurs if the cost of delayed dispersal is larger than the benefit of exploiting the maternal patch. I discuss broader implications of the process. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

  1. Targeted delivery of growth factors in ischemic stroke animal models.

    PubMed

    Rhim, Taiyoun; Lee, Minhyung

    2016-01-01

    Ischemic stroke is caused by reduced blood supply and leads to loss of brain function. The reduced oxygen and nutrient supply stimulates various physiological responses, including induction of growth factors. Growth factors prevent neuronal cell death, promote neovascularization, and induce cell growth. However, the concentration of growth factors is not sufficient to recover brain function after the ischemic damage, suggesting that delivery of growth factors into the ischemic brain may be a useful treatment for ischemic stroke. In this review, various approaches for the delivery of growth factors to ischemic brain tissue are discussed, including local and targeting delivery systems. To develop growth factor therapy for ischemic stroke, important considerations should be taken into account. First, growth factors may have possible side effects. Thus, concentration of growth factors should be restricted to the ischemic tissues by local administration or targeted delivery. Second, the duration of growth factor therapy should be optimized. Growth factor proteins may be degraded too fast to have a high enough therapeutic effect. Therefore, delivery systems for controlled release or gene delivery may be useful. Third, the delivery systems to the brain should be optimized according to the delivery route.

  2. Priming Dental Pulp Stem Cells With Fibroblast Growth Factor-2 Increases Angiogenesis of Implanted Tissue-Engineered Constructs Through Hepatocyte Growth Factor and Vascular Endothelial Growth Factor Secretion

    PubMed Central

    Gorin, Caroline; Rochefort, Gael Y.; Bascetin, Rumeyza; Ying, Hanru; Lesieur, Julie; Sadoine, Jérémy; Beckouche, Nathan; Berndt, Sarah; Novais, Anita; Lesage, Matthieu; Hosten, Benoit; Vercellino, Laetitia; Merlet, Pascal; Le-Denmat, Dominique; Marchiol, Carmen; Letourneur, Didier; Nicoletti, Antonino; Vital, Sibylle Opsahl; Poliard, Anne; Salmon, Benjamin; Germain, Stéphane

    2016-01-01

    Tissue engineering strategies based on implanting cellularized biomaterials are promising therapeutic approaches for the reconstruction of large tissue defects. A major hurdle for the reliable establishment of such therapeutic approaches is the lack of rapid blood perfusion of the tissue construct to provide oxygen and nutrients. Numerous sources of mesenchymal stem cells (MSCs) displaying angiogenic potential have been characterized in the past years, including the adult dental pulp. Establishment of efficient strategies for improving angiogenesis in tissue constructs is nevertheless still an important challenge. Hypoxia was proposed as a priming treatment owing to its capacity to enhance the angiogenic potential of stem cells through vascular endothelial growth factor (VEGF) release. The present study aimed to characterize additional key factors regulating the angiogenic capacity of such MSCs, namely, dental pulp stem cells derived from deciduous teeth (SHED). We identified fibroblast growth factor-2 (FGF-2) as a potent inducer of the release of VEGF and hepatocyte growth factor (HGF) by SHED. We found that FGF-2 limited hypoxia-induced downregulation of HGF release. Using three-dimensional culture models of angiogenesis, we demonstrated that VEGF and HGF were both responsible for the high angiogenic potential of SHED through direct targeting of endothelial cells. In addition, FGF-2 treatment increased the fraction of Stro-1+/CD146+ progenitor cells. We then applied in vitro FGF-2 priming to SHED before encapsulation in hydrogels and in vivo subcutaneous implantation. Our results showed that FGF-2 priming is more efficient than hypoxia at increasing SHED-induced vascularization compared with nonprimed controls. Altogether, these data demonstrate that FGF-2 priming enhances the angiogenic potential of SHED through the secretion of both HGF and VEGF. Significance The results from the present study show that fibroblast growth factor-2 (FGF-2) priming is more

  3. Role of growth hormone, insulin-like growth factor-I, and insulin-like growth factor binding proteins in the catabolic response to injury and infection.

    PubMed

    Lang, Charles H; Frost, Robert A

    2002-05-01

    The erosion of lean body mass resulting from protracted critical illness remains a significant risk factor for increased morbidity and mortality in this patient population. Previous studies have documented the well known impairment in nitrogen balance results from both an increase in muscle protein degradation as well as a decreased rate of both myofibrillar and sacroplasmic protein synthesis. This protein imbalance may be caused by an increased presence or activity of various catabolic agents, such as tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 or glucocorticoids, or may be mediated via a decreased concentration or responsiveness to various anabolic hormones, such as growth hormone or insulin-like growth factor-I. This review focuses on recent developments pertaining to the importance of alterations in the growth hormone-insulin-like growth factor-I axis as a mechanism for the observed defects in muscle protein balance.

  4. Constructing a blood vessel on the porous scaffold modified with vascular endothelial growth factor and basic fibroblast growth factor

    NASA Astrophysics Data System (ADS)

    Sevostyanova, V. V.; Matveeva, V. G.; Antonova, L. V.; Velikanova, E. A.; Shabaev, A. R.; Senokosova, E. A.; Krivkina, E. O.; Vasyukov, G. Yu.; Glushkova, T. V.; Kudryavtseva, Yu. A.; Barbarash, O. L.; Barbarash, L. S.

    2016-11-01

    Incorporation of the growth factors into biodegradable polymers is a promising approach for the fabrication of tissue-engineered vascular grafts. Here we blended poly(ɛ-caprolactone) (PCL) with poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) following incorporation of either vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) and then fabricated electrospun 2 mm diameter vascular grafts. Grafts without the growth factors were used as a control group. Structure of the grafts was assessed utilizing scanning electron microscopy. We further implanted our grafts into rat abdominal aorta for 1 and 3 months with the aim to test endothelialization, cell infiltration, and patency in vivo. Histological and immunofluorescence examination demonstrated enhanced endothelialization and cell infiltration of the grafts with either VEGF or bFGF compared to those without the growth factors. Grafts with VEGF showed higher patency compared to those with bFGF; however, bFGF promoted migration of smooth muscle cells and fibroblasts into the graft. Therefore, we conclude that incorporation of VEGF and bFGF into the inner and medial/outer layer, respectively, can be a promising option for the fabrication of tissue-engineered vascular grafts.

  5. Impact of Chiropractic Manipulation on Bone and Skeletal Muscle of Ovariectomized Rats.

    PubMed

    López-Herradón, A; Fujikawa, R; Gómez-Marín, M; Stedile-Lovatel, J P; Mulero, F; Ardura, J A; Ruiz, P; Muñoz, I; Esbrit, P; Mahíllo-Fernández, I; Ortega-de Mues, A

    2017-11-01

    Evidence suggests that chiropractic manipulation might exert positive effects in osteoporotic patients. The aim of this study was to evaluate the effects of chiropractic manipulation on bone structure and skeletal muscle in rats with bone loss caused by ovariectomy (OVX). The 6-month old Sprague-Dawley rats at 10 weeks following OVX or sham operation (Sh) did not suffer chiropractic manipulation (NM group) or were submitted to true chiropractic manipulation using the chiropractic adjusting instrument Activator V ® three times/week for 6 weeks as follows: Force 1 setting was applied onto the tibial tubercle of the rat right hind limb (TM group), whereas the corresponding left hind limb received a false manipulation (FM group) consisting of ActivatorV ® firing in the air and slightly touching the tibial tubercle. Bone mineral density (BMD) and bone mineral content (BMC) were determined in long bones and L3-L4 vertebrae in all rats. Femora and tibia were analyzed by μCT. Mechano growth factor (MGF) was detected in long bones and soleus, quadriceps and tibial muscles by immunohistochemistry and Western blot. The decrease of BMD and BMC as well as trabecular bone impairment in the long bones of OVX rats vs Sh controls was partially reversed in the TM group versus FM or NM rats. This bone improvement by chiropractic manipulation was associated with an increased MGF expression in the quadriceps and the anterior tibial muscle in OVX rats. These findings support the notion that chiropractic manipulation can ameliorate osteoporotic bone at least partly by targeting skeletal muscle.

  6. TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF)

    EPA Science Inventory

    TITLE:
    TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF). AUTHORS (ALL): Abbott, Barbara D.1; Best, Deborah S.1; Narotsky, Michael G.1. SPONSOR NAME: None INSTITUTIONS (ALL): 1. Repro Tox ...

  7. Delivery of growth factors for tissue regeneration and wound healing.

    PubMed

    Koria, Piyush

    2012-06-01

    Growth factors are soluble secreted proteins capable of affecting a variety of cellular processes important for tissue regeneration. Consequently, the self-healing capacity of patients can be augmented by artificially enhancing one or more processes important for healing through the application of growth factors. However, their application in clinics remains limited due to lack of robust delivery systems and biomaterial carriers. Interestingly, all clinically approved therapies involving growth factors utilize some sort of a biomaterial carrier for growth factor delivery. This suggests that biomaterial delivery systems are extremely important for successful usage of growth factors in regenerative medicine. This review outlines the role of growth factors in tissue regeneration, and their application in both pre-clinical animal models of regeneration and clinical trials is discussed. Additionally, current status of biomaterial substrates and sophisticated delivery systems such as nanoparticles for delivery of exogenous growth factors and peptides in humans are reviewed. Finally, issues and possible future research directions for growth factor therapy in regenerative medicine are discussed.

  8. Effect of Temperature and Nutrient Manipulations on eelgrass ...

    EPA Pesticide Factsheets

    Global climate change will have a large impact on the three predominate drivers of estuarine seagrass productivity, temperature, light and nutrients. I experimentally evaluate the response of Pacific Northwest Z. marina to interactive effects of temperature and nutrient conditions. Experimental manipulations were conducted hydroponically in acrylic chambers and spanned a range of temperatures and nutrient concentrations. Preliminary single factor experiments were conducted to evaluate physiological tolerances to temperature and nitrogen concentrations. Eelgrass exhibited a linear increase in specific growth with increasing NH4 concentration (range from 10 to 1000 µM); in contrast, there was no significant relationship between specific growth rate and increasing NO3 concentration over the same concentration range. Leaf growth metrics all exhibited strong linear relationships with increasing water temperature (temperature range 4-25 ºC). In the factorial experiment, plants were exposed to 3 temperatures (10, 18 and 25 ºC) and 3 nitrate concentrations (10, 30 and 100 µM) with 3 replicate chambers per treatment combination. Most metrics (leaf elongation, growth, specific growth, wasting index) exhibited a significant temperature effect indicating the importance of temperature on metabolic rates. Tissue stable isotope ratios and C:N values exhibited a significant nutrient effect and in some cases a significant temperature effect. Whole plant non structur

  9. Nanoconjugation prolongs endosomal signaling of the epidermal growth factor receptor and enhances apoptosis

    NASA Astrophysics Data System (ADS)

    Wu, L.; Xu, F.; Reinhard, B. M.

    2016-07-01

    It is becoming increasingly clear that intracellular signaling can be subject to strict spatial control. As the covalent attachment of a signaling ligand to a nanoparticle (NP) impacts ligand-receptor binding, uptake, and trafficking, nanoconjugation provides new opportunities for manipulating intracellular signaling in a controlled fashion. To establish the effect of nanoconjugation on epidermal growth factor (EGF) mediated signaling, we investigate here the intracellular fate of nanoconjugated EGF (NP-EGF) and its bound receptor (EGFR) by quantitative correlated darkfield/fluorescence microscopy and density-based endosomal fractionation. We demonstrate that nanoconjugation prolongs the dwell time of phosphorylated receptors in the early endosomes and that the retention of activated EGFR in the early endosomes is accompanied by an EGF mediated apoptosis at effective concentrations that do not induce apoptosis in the case of free EGF. Overall, these findings indicate nanoconjugation as a rational strategy for modifying signaling that acts by modulating the temporo-spatial distribution of the activated EGF-EGFR ligand-receptor complex.It is becoming increasingly clear that intracellular signaling can be subject to strict spatial control. As the covalent attachment of a signaling ligand to a nanoparticle (NP) impacts ligand-receptor binding, uptake, and trafficking, nanoconjugation provides new opportunities for manipulating intracellular signaling in a controlled fashion. To establish the effect of nanoconjugation on epidermal growth factor (EGF) mediated signaling, we investigate here the intracellular fate of nanoconjugated EGF (NP-EGF) and its bound receptor (EGFR) by quantitative correlated darkfield/fluorescence microscopy and density-based endosomal fractionation. We demonstrate that nanoconjugation prolongs the dwell time of phosphorylated receptors in the early endosomes and that the retention of activated EGFR in the early endosomes is accompanied by an EGF

  10. Beliefs and Practice Patterns in Spinal Manipulation and Spinal Motion Palpation Reported by Canadian Manipulative Physiotherapists

    PubMed Central

    Macdermid, Joy C.; Santaguida, P. Lina; Thabane, Lehana; Giulekas, Kevin; Larocque, Leo; Millard, James; Williams, Caitlin; Miller, Jack; Chesworth, Bert M.

    2013-01-01

    ABSTRACT Purpose: This practice survey describes how Fellows of the Canadian Academy of Manipulative Physiotherapy (FCAMPT) use spinal manipulation and mobilization and how they perceive their competence in performing spinal assessment; it also quantifies relationships between clinical experience and use of spinal manipulation. Methods: A cross-sectional survey was designed based on input from experts and the literature was administered to a random sample of the FCAMPT mailing list. Descriptive (including frequencies) and inferential statistical analyses (including linear regression) were performed. Results: The response rate was 82% (278/338 eligible FCAMPTs). Most (99%) used spinal manipulation. Two-thirds (62%) used clinical presentation as a factor when deciding to mobilize or manipulate. The least frequently manipulated spinal region was the cervical spine (2% of patients); 60% felt that cervical manipulation generated more adverse events. Increased experience was associated with increased use of upper cervical manipulation among male respondents (14% more often for every 10 years after certification; β, 95% CI=1.37, 0.89–1.85, p<0.001) but not among female respondents. Confidence in palpation accuracy decreased in lower regions of the spine. Conclusion: The use of spinal manipulation/mobilization is prevalent among FCAMPTs, but is less commonly used in the neck because of a perceived association with adverse events. PMID:24403681

  11. Fibroblast Growth Factor 2: An Epithelial Ductal Cell Growth Inhibitor That Drops Out in Breast Cancer

    DTIC Science & Technology

    2009-10-01

    AD_________________ Award Number: W81XWH-08-1-0708 TITLE: Fibroblast Growth Factor 2: an...September 2008 – 14 September 2009 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Fibroblast Growth Factor 2: an Epithelial Ductal Cell Growth Inhibitor...9 Fibroblast Growth Factor -2: an Epithelial Ductal Cell Growth Inhibitor that Drops Out in Breast Cancer

  12. Manipulations to regenerate aspen ecosystems

    Treesearch

    Wayne D. Shepperd

    2001-01-01

    Vegetative regeneration of aspen can be initiated through manipulations that provide hormonal stimulation, proper growth environment, and sucker protection - the three elements of the aspen regeneration triangle. The correct course of action depends upon a careful evaluation of the size, vigor, age, and successional status of the existing clone. Soils and site...

  13. Endogenous versus Exogenous Growth Factor Regulation of Articular Chondrocytes

    PubMed Central

    Shi, Shuiliang; Chan, Albert G.; Mercer, Scott; Eckert, George J.; Trippel, Stephen B.

    2014-01-01

    Anabolic growth factors that regulate the function of articular chondrocytes are candidates for articular cartilage repair. Such factors may be delivered by pharmacotherapy in the form of exogenous proteins, or by gene therapy as endogenous proteins. It is unknown whether delivery method influences growth factor effectiveness in regulating articular chondrocyte reparative functions. We treated adult bovine articular chondrocytes with exogenous recombinant insulin-like growth factor-I (IGF-I) and transforming growth factor-beta1 (TGF-β1), or with the genes encoding these growth factors for endogenous production. Treatment effects were measured as change in chondrocyte DNA content, glycosaminoglycan production, and aggrecan gene expression. We found that IGF-I stimulated chondrocyte biosynthesis similarly when delivered by either exogenous or endogenous means. In contrast, exogenous TGF-ß1 stimulated these reparative functions, while endogenous TGF-ß1 had little effect. Endogenous TGF-ß1 became more bioactive following activation of the transgene protein product. These data indicate that effective mechanisms of growth factor delivery for articular cartilage repair may differ for different growth factors. In the case of IGF-I, gene therapy or protein therapy appear to be viable options. In contrast, TGF-ß1 gene therapy may be constrained by a limited ability of chondrocytes to convert latent complexes to an active form. PMID:24105960

  14. Growth responses of Scots pine to climatic factors on reclaimed oil shale mined land.

    PubMed

    Metslaid, Sandra; Stanturf, John A; Hordo, Maris; Korjus, Henn; Laarmann, Diana; Kiviste, Andres

    2016-07-01

    Afforestation on reclaimed mining areas has high ecological and economic importance. However, ecosystems established on post-mining substrate can become vulnerable due to climate variability. We used tree-ring data and dendrochronological techniques to study the relationship between climate variables and annual growth of Scots pine (Pinus sylvestris L.) growing on reclaimed open cast oil shale mining areas in Northeast Estonia. Chronologies for trees of different age classes (50, 40, 30) were developed. Pearson's correlation analysis between radial growth indices and monthly climate variables revealed that precipitation in June-July and higher mean temperatures in spring season enhanced radial growth of pine plantations, while higher than average temperatures in summer months inhibited wood production. Sensitivity of radial increment to climatic factors on post-mining soils was not homogenous among the studied populations. Older trees growing on more developed soils were more sensitive to precipitation deficit in summer, while growth indices of two other stand groups (young and middle-aged) were highly correlated to temperature. High mean temperatures in August were negatively related to annual wood production in all trees, while trees in the youngest stands benefited from warmer temperatures in January. As a response to thinning, mean annual basal area increment increased up to 50 %. By managing tree competition in the closed-canopy stands, through the thinning activities, tree sensitivity and response to climate could be manipulated.

  15. Fibroblast Growth Factors and Vascular Endothelial Growth Factor Promote Cardiac Reprogramming under Defined Conditions

    PubMed Central

    Yamakawa, Hiroyuki; Muraoka, Naoto; Miyamoto, Kazutaka; Sadahiro, Taketaro; Isomi, Mari; Haginiwa, Sho; Kojima, Hidenori; Umei, Tomohiko; Akiyama, Mizuha; Kuishi, Yuki; Kurokawa, Junko; Furukawa, Tetsushi; Fukuda, Keiichi; Ieda, Masaki

    2015-01-01

    Summary Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors, including Gata4, Mef2c, and Tbx5; however, this process is inefficient under serum-based culture conditions, in which conversion of partially reprogrammed cells into fully reprogrammed functional iCMs has been a major hurdle. Here, we report that a combination of fibroblast growth factor (FGF) 2, FGF10, and vascular endothelial growth factor (VEGF), termed FFV, promoted cardiac reprogramming under defined serum-free conditions, increasing spontaneously beating iCMs by 100-fold compared with those under conventional serum-based conditions. Mechanistically, FFV activated multiple cardiac transcriptional regulators and converted partially reprogrammed cells into functional iCMs through the p38 mitogen-activated protein kinase and phosphoinositol 3-kinase/AKT pathways. Moreover, FFV enabled cardiac reprogramming with only Mef2c and Tbx5 through the induction of cardiac reprogramming factors, including Gata4. Thus, defined culture conditions promoted the quality of cardiac reprogramming, and this finding provides new insight into the mechanism of cardiac reprogramming. PMID:26626177

  16. Endorsement of Growth Factors in Experiential Training Groups

    ERIC Educational Resources Information Center

    Kiweewa, John; Gilbride, Dennis; Luke, Melissa; Seward, Derek

    2013-01-01

    The purpose of this study was to identify student growth factors during a semester long Master's level group counseling class. Results indicated that 12 growth factors accounted for 86% of the total number of critical incidents that participants reported as influencing their personal growth and awareness during the group experience. Two other…

  17. Placenta Growth Factor in Diabetic Wound Healing

    PubMed Central

    Cianfarani, Francesca; Zambruno, Giovanna; Brogelli, Laura; Sera, Francesco; Lacal, Pedro Miguel; Pesce, Maurizio; Capogrossi, Maurizio C.; Failla, Cristina Maria; Napolitano, Monica; Odorisio, Teresa

    2006-01-01

    Reduced microcirculation and diminished expression of growth factors contribute to wound healing impairment in diabetes. Placenta growth factor (PlGF), an angiogenic mediator promoting pathophysiological neovascularization, is expressed during cutaneous wound healing and improves wound closure by enhancing angiogenesis. By using streptozotocin-induced diabetic mice, we here demonstrate that PlGF induction is strongly reduced in diabetic wounds. Diabetic transgenic mice overexpressing PlGF in the skin displayed accelerated wound closure compared with diabetic wild-type littermates. Moreover, diabetic wound treatment with an adenovirus vector expressing the human PlGF gene (AdCMV.PlGF) significantly accelerated the healing process compared with wounds treated with a control vector. The analysis of treated wounds showed that PlGF gene transfer improved granulation tissue formation, maturation, and vascularization, as well as monocytes/macrophages local recruitment. Platelet-derived growth factor, fibroblast growth factor-2, and vascular endothelial growth factor mRNA levels were increased in AdCMV.PlGF-treated wounds, possibly enhancing PlGF-mediated effects. Finally, PlGF treatment stimulated cultured dermal fibroblast migration, pointing to a direct role of PlGF in accelerating granulation tissue maturation. In conclusion, our data indicate that reduced PlGF expression contributes to impaired wound healing in diabetes and that PlGF gene transfer to diabetic wounds exerts therapeutic activity by promoting different aspects of the repair process. PMID:17003476

  18. Fibroblast Growth Factor 2: An Epithelial Ductal Cell Growth Inhibitor That Drops Out in Breast Cancer

    DTIC Science & Technology

    2011-10-01

    fibroblast   growth   factor   receptors  and  their  prognostic...AD_________________ Award Number: W81XWH-08-1-0708 TITLE: Fibroblast Growth Factor 2: an...September 2008 – 14 September 2011 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Fibroblast Growth Factor 2: an Epithelial Ductal Cell Growth

  19. Therapeutic angiogenesis: angiogenic growth factors for ischemic heart disease.

    PubMed

    Henning, Robert J

    2016-09-01

    Stem cells encode vascular endothelial growth factors (VEGFs), fibroblastic growth factors (FGFs), stem cell factor, stromal cell-derived factor, platelet growth factor and angiopoietin that can contribute to myocardial vascularization. VEGFs and FGFs are the most investigated growth factors. VEGFs regulate angiogenesis and vasculogenesis. FGFs stimulate vessel cell proliferation and differentiation and are regulators of endothelial cell migration, proliferation and survival. Clinical trials of VEGF or FGF for myocardial angiogenesis have produced disparate results. The efficacy of therapeutic angiogenesis can be improved by: (1) identifying the most optimal patients; (2) increased knowledge of angiogenic factor pharmacokinetics and proper dose; (3) prolonging contact of angiogenic factors with the myocardium; (4) increasing the efficiency of VEGF or FGF gene transduction; and (5) utilizing PET or MRI to measure myocardial perfusion and perfusion reserve.

  20. Clinical Application of Growth Factors and Cytokines in Wound Healing

    PubMed Central

    Barrientos, Stephan; Brem, Harold; Stojadinovic, Olivera; Tomic-Canic, Marjana

    2016-01-01

    Wound healing is a complex and dynamic biological process that involves the coordinated efforts of multiple cell types and is executed and regulated by numerous growth factors and cytokines. There has been a drive in the past two decades to study the therapeutic effects of various growth factors in the clinical management of non-healing wounds (e.g. pressure ulcers, chronic venous ulcers, diabetic foot ulcers). For this review, we conducted a nonline search of Medline and Pub Medical and critically analyzed the literature regarding the role of growth factors and cytokines in the management of these wounds. We focused on currently approved therapies, emerging therapies and future research possibilities. In this review we discuss four growth factors and cytokines currently being used on and off label for the healing of wounds. These include: granulocyte-macrophage colony stimulating factor (GM-CSF), platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF). While the clinical results of using growth factors and cytokines are encouraging, many studies involved a small sample size and are disparate in measured endpoints. Therefore, further research is required to provide definitive evidence of efficacy. PMID:24942811

  1. Broodstock management and hormonal manipulations of fish reproduction.

    PubMed

    Mylonas, Constantinos C; Fostier, Alexis; Zanuy, Silvia

    2010-02-01

    Control of reproductive function in captivity is essential for the sustainability of commercial aquaculture production, and in many fishes it can be achieved by manipulating photoperiod, water temperature or spawning substrate. The fish reproductive cycle is separated in the growth (gametogenesis) and maturation phase (oocyte maturation and spermiation), both controlled by the reproductive hormones of the brain, pituitary and gonad. Although the growth phase of reproductive development is concluded in captivity in most fishes-the major exemption being the freshwater eel (Anguilla spp.), oocyte maturation (OM) and ovulation in females, and spermiation in males may require exogenous hormonal therapies. In some fishes, these hormonal manipulations are used only as a management tool to enhance the efficiency of egg production and facilitate hatchery operations, but in others exogenous hormones are the only way to produce fertilized eggs reliably. Hormonal manipulations of reproductive function in cultured fishes have focused on the use of either exogenous luteinizing hormone (LH) preparations that act directly at the level of the gonad, or synthetic agonists of gonadotropin-releasing hormone (GnRHa) that act at the level of the pituitary to induce release of the endogenous LH stores, which, in turn act at the level of the gonad to induce steroidogenesis and the process of OM and spermiation. After hormonal induction of maturation, broodstock should spawn spontaneously in their rearing enclosures, however, the natural breeding behavior followed by spontaneous spawning may be lost in aquaculture conditions. Therefore, for many species it is also necessary to employ artificial gamete collection and fertilization. Finally, a common question in regards to hormonal therapies is their effect on gamete quality, compared to naturally maturing or spawning broodfish. The main factors that may have significant consequences on gamete quality-mainly on eggs-and should be considered

  2. Advances in pubertal growth and factors influencing it: Can we increase pubertal growth?

    PubMed Central

    Soliman, Ashraf; De Sanctis, Vincenzo; Elalaily, Rania; Bedair, Said

    2014-01-01

    Puberty is a period of development characterized by partially concurrent changes which includes growth acceleration, alteration in body composition and appearance of secondary sex characteristics. Puberty is characterized by an acceleration and then deceleration in skeletal growth. The initiation, duration and amount of growth vary considerably during the growth spurt. Pubertal growth and biological maturation are dynamic processes regulated by a variety of genetic and environmental factors. Changes in skeletal maturation and bone mineral accretion concomitant with the stage of pubertal development constitute essential components in the evaluation of growth during this pubertal period. Genetic, endocrine and nutritional factors and ethnicity contribute variably to the amount of growth gained during this important period of rapid changes. Many studies investigated the possibility of increasing pubertal growth to gain taller final adult height in adolescents with idiopathic short stature (ISS). The pattern of pubertal growth, its relation to sex maturity rating and factors affecting them has been addressed in this review. The results of different trials to increase final adult height of adolescents using different hormones have been summarized. These data enables Endocrinologists to give in-depth explanations to patients and families about the efficacy and clinical significance as well as the safety of using these therapies in the treatment of adolescents with ISS. PMID:25538878

  3. Intracellular processing of epidermal growth factor. I. Acidification of 125I-epidermal growth factor in intracellular organelles.

    PubMed

    Matrisian, L M; Planck, S R; Magun, B E

    1984-03-10

    We previously reported that 125I-labeled epidermal growth factor is processed intracellularly to acidic macromolecules in Rat-1 fibroblasts. The present study defines the precursor-product relationship and localization of the processing steps to subcellular organelles by the use of a single isoelectric species of 125I-epidermal growth factor and Percoll gradient fractionation. The native pI 4.55 125I-epidermal growth factor was rapidly processed to a pI 4.2 species on or near the cell surface and in organelles corresponding to clathrin-coated vesicles, Golgi, and endoplasmic reticulum. This species was then processed to a pI 4.35 species in similar organelles. The pI 4.2 and 4.35 species were converted to a pI 4.0 species in dense, lysosome-like organelles. This species was ultimately degraded and exocytosed from the cell as low molecular weight products.

  4. Insulin-like growth factor-I and growth differentiation factor-5 promote the formation of tissue-engineered human nasal septal cartilage.

    PubMed

    Alexander, Thomas H; Sage, August B; Chen, Albert C; Schumacher, Barbara L; Shelton, Elliot; Masuda, Koichi; Sah, Robert L; Watson, Deborah

    2010-10-01

    Tissue engineering of human nasal septal chondrocytes offers the potential to create large quantities of autologous material for use in reconstructive surgery of the head and neck. Culture with recombinant human growth factors may improve the biochemical and biomechanical properties of engineered tissue. The objectives of this study were to (1) perform a high-throughput screen to assess multiple combinations of growth factors and (2) perform more detailed testing of candidates identified in part I. In part I, human nasal septal chondrocytes from three donors were expanded in monolayer with pooled human serum (HS). Cells were then embedded in alginate beads for 2 weeks of culture in medium supplemented with 2% or 10% HS and 1 of 90 different growth factor combinations. Combinations of insulin-like growth factor-I (IGF-1), bone morphogenetic protein (BMP)-2, BMP-7, BMP-13, growth differentiation factor-5 (GDF-5), transforming growth factor β (TGFβ)-2, insulin, and dexamethasone were evaluated. Glycosaminoglycan (GAG) accumulation was measured. A combination of IGF-1 and GDF-5 was selected for further testing based on the results of part I. Chondrocytes from four donors underwent expansion followed by three-dimensional alginate culture for 2 weeks in medium supplemented with 2% or 10% HS with or without IGF-1 and GDF-5. Chondrocytes and their associated matrix were then recovered and cultured for 4 weeks in 12 mm transwells in medium supplemented with 2% or 10% HS with or without IGF-1 and GDF-5 (the same medium used for alginate culture). Biochemical and biomechanical properties of the neocartilage were measured. In part I, GAG accumulation was highest for growth factor combinations including both IGF-1 and GDF-5. In part II, the addition of IGF-1 and GDF-5 to 2% HS resulted in a 12-fold increase in construct thickness compared with 2% HS alone (p < 0.0001). GAG and type II collagen accumulation was significantly higher with IGF-1 and GDF-5. Confined compression

  5. Growth factor effects on costal chondrocytes for tissue engineering fibrocartilage

    PubMed Central

    Johns, D.E.; Athanasiou, K.A.

    2010-01-01

    Tissue engineered fibrocartilage could become a feasible option for replacing tissues like the knee meniscus or temporomandibular joint disc. This study employed five growth factors insulin-like growth factor-I, transforming growth factor-β1, epidermal growth factor, platelet-derived growth factor-BB, and basic fibroblast growth factor in a scaffoldless approach with costal chondrocytes, attempting to improve biochemical and mechanical properties of engineered constructs. Samples were quantitatively assessed for total collagen, glycosaminoglycans, collagen type I, collagen type II, cells, compressive properties, and tensile properties at two time points. Most treated constructs were worse than the no growth factor control, suggesting a detrimental effect, but the IGF treatment tended to improve the constructs. Additionally, the 6wk time point was consistently better than 3wks, with total collagen, glycosaminoglycans, and aggregate modulus doubling during this time. Further optimization of the time in culture and exogenous stimuli will be important in making a more functional replacement tissue. PMID:18597118

  6. The future of recombinant growth factors in wound healing.

    PubMed

    Robson, M C; Mustoe, T A; Hunt, T K

    1998-08-01

    For more than a decade, clinical trials have been conducted of the application of topical exogenous recombinant growth factors in attempts to accelerate the healing of chronic wounds. Although the results of some of these trials have been encouraging, overall the results have been somewhat discouraging. Much of the difficulty lies in the paucity of carefully controlled clinical trials of wound healing. Since wound healing is a complex process that can be influenced, both positively and negatively, by many factors, designing these trials has proved difficult. To date, only a single recombinant growth factor-recombinant human platelet-derived growth factor-BB (rhPDGF-BB)- has been approved by the US Food and Drug Administration; and that only for use in diabetic foot ulcers. It is unlikely, however, that a single growth factor will be able to resolve all issues of repair or strengthen all vulnerabilities of chronic wounds. Our expectation, therefore, is that growth factors, cytokines, and other biologic agents will be used more specifically in the future, for example, by targeting growth factor therapy at those specific components or processes that a given wound uses to heal.

  7. Fibroblast Growth Factors and Vascular Endothelial Growth Factor Promote Cardiac Reprogramming under Defined Conditions.

    PubMed

    Yamakawa, Hiroyuki; Muraoka, Naoto; Miyamoto, Kazutaka; Sadahiro, Taketaro; Isomi, Mari; Haginiwa, Sho; Kojima, Hidenori; Umei, Tomohiko; Akiyama, Mizuha; Kuishi, Yuki; Kurokawa, Junko; Furukawa, Tetsushi; Fukuda, Keiichi; Ieda, Masaki

    2015-12-08

    Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors, including Gata4, Mef2c, and Tbx5; however, this process is inefficient under serum-based culture conditions, in which conversion of partially reprogrammed cells into fully reprogrammed functional iCMs has been a major hurdle. Here, we report that a combination of fibroblast growth factor (FGF) 2, FGF10, and vascular endothelial growth factor (VEGF), termed FFV, promoted cardiac reprogramming under defined serum-free conditions, increasing spontaneously beating iCMs by 100-fold compared with those under conventional serum-based conditions. Mechanistically, FFV activated multiple cardiac transcriptional regulators and converted partially reprogrammed cells into functional iCMs through the p38 mitogen-activated protein kinase and phosphoinositol 3-kinase/AKT pathways. Moreover, FFV enabled cardiac reprogramming with only Mef2c and Tbx5 through the induction of cardiac reprogramming factors, including Gata4. Thus, defined culture conditions promoted the quality of cardiac reprogramming, and this finding provides new insight into the mechanism of cardiac reprogramming. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Localisation of stem cell factor, stanniocalcin-1, connective tissue growth factor and heparin-binding epidermal growth factor in the bovine uterus at the time of blastocyst formation.

    PubMed

    Muñoz, M; Martin, D; Carrocera, S; Alonso-Guervos, M; Mora, M I; Corrales, F J; Peynot, N; Giraud-Delville, C; Duranthon, V; Sandra, O; Gómez, E

    2017-10-01

    Early embryonic losses before implantation account for the highest rates of reproductive failure in mammals, in particular when in vitro-produced embryos are transferred. In the present study, we used molecular biology techniques (real-time quantitative polymerase chain reaction), classical immunohistochemical staining coupled with confocal microscopy and proteomic analysis (multiple reaction monitoring and western blot analysis) to investigate the role of four growth factors in embryo-uterine interactions during blastocyst development. Supported by a validated embryo transfer model, the study investigated: (1) the expression of stem cell factor (SCF), stanniocalcin-1 (STC1), connective tissue growth factor (CTGF) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) in bovine uterine fluid; (2) the presence of SCF, STC1, CTGF and HB-EGF mRNA and protein in the bovine endometrium and embryos; and (3) the existence of reciprocal regulation between endometrial and embryonic expression of SCF, STC1, CTGF and HB-EGF. The results suggest that these growth factors most likely play an important role during preimplantation embryo development in cattle. The information obtained from the present study can contribute to improving the performance of in vitro culture technology in cattle and other species.

  9. Teachers' Beliefs and Teaching Mathematics with Manipulatives

    ERIC Educational Resources Information Center

    Golafshani, Nahid

    2013-01-01

    To promote the implementation of manipulatives into mathematics instruction, this research project examined how the instructional practices of four Grade 9 applied mathematics teachers related to their beliefs about the use of manipulatives in teaching mathematics, its effects on students' learning, and enabling and disabling factors. Teacher…

  10. Temporal expression of growth factors triggered by epiregulin regulates inflammation development.

    PubMed

    Harada, Masaya; Kamimura, Daisuke; Arima, Yasunobu; Kohsaka, Hitoshi; Nakatsuji, Yuji; Nishida, Makoto; Atsumi, Toru; Meng, Jie; Bando, Hidenori; Singh, Rajeev; Sabharwal, Lavannya; Jiang, Jing-Jing; Kumai, Noriko; Miyasaka, Nobuyuki; Sakoda, Saburo; Yamauchi-Takihara, Keiko; Ogura, Hideki; Hirano, Toshio; Murakami, Masaaki

    2015-02-01

    In this study, we investigated the relationship between several growth factors and inflammation development. Serum concentrations of epiregulin, amphiregulin, betacellulin, TGF-α, fibroblast growth factor 2, placental growth factor (PLGF), and tenascin C were increased in rheumatoid arthritis patients. Furthermore, local blockades of these growth factors suppressed the development of cytokine-induced arthritis in mice by inhibiting chemokine and IL-6 expressions. We found that epiregulin expression was early and followed by the induction of other growth factors at different sites of the joints. The same growth factors then regulated the expression of epiregulin at later time points of the arthritis. These growth factors were increased in patients suffering from multiple sclerosis (MS) and also played a role in the development of an MS model, experimental autoimmune encephalomyelitis. The results suggest that the temporal expression of growth factors is involved in the inflammation development seen in several diseases, including rheumatoid arthritis and MS. Therefore, various growth factor pathways might be good therapeutic targets for various inflammatory diseases. Copyright © 2015 by The American Association of Immunologists, Inc.

  11. A role of placental growth factor in hair growth.

    PubMed

    Yoon, Sun-Young; Yoon, Ji-Seon; Jo, Seong Jin; Shin, Chang Yup; Shin, Jong-Yeon; Kim, Jong-Il; Kwon, Ohsang; Kim, Kyu Han

    2014-05-01

    The dermal papilla (DP) comprises specialized mesenchymal cells at the bottom of the hair follicle and plays a pivotal role in hair formation, anagen induction and the hair cycle. In this study, DPs were isolated from human hair follicles and serially subcultured. From each subculture at passages 1, 3, and 5 (n=4), we compared gene expression profiles using mRNA sequencing. Among the growth factors that were down-regulated in later passages of human DP cells (hDPCs), placental growth factor (PlGF) was selected. To elucidate the effect of PlGF on hair growth. We evaluated the effect of PlGF on hDPCs and on ex vivo hair organ culture. We investigated the effect of PlGF on an in vivo model of depilation-induced hair regeneration. We confirmed that the mRNA and protein expression levels of PlGF significantly decreased following subculture of the cells. It was shown that PlGF enhanced hair shaft elongation in ex vivo hair organ culture. Furthermore, PlGF significantly accelerated hair follicle growth and markedly prolonged anagen hair growth in an in vivo model of depilation-induced hair regeneration. PlGF prevented cell death by increasing the levels of phosphorylated extracellular signal-regulated kinase (ERK) and cyclin D1 and promoted survival by up-regulation of phosphorylated Akt and Bcl2, as determined by Western blotting. Our results suggest that PlGF plays a role in the promotion of hair growth and therefore may serve as an additional therapeutic target for the treatment of alopecia. Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  12. Growth Factors and Tension-Induced Skeletal Muscle Growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman H.

    1994-01-01

    The project investigated biochemical mechanisms to enhance skeletal muscle growth, and developed a computer based mechanical cell stimulator system. The biochemicals investigated in this study were insulin/(Insulin like Growth Factor) IGF-1 and Steroids. In order to analyze which growth factors are essential for stretch-induced muscle growth in vitro, we developed a defined, serum-free medium in which the differentiated, cultured avian muscle fibers could be maintained for extended periods of time. The defined medium (muscle maintenance medium, MM medium) maintains the nitrogen balance of the myofibers for 3 to 7 days, based on myofiber diameter measurements and myosin heavy chain content. Insulin and IGF-1, but not IGF-2, induced pronounced myofiber hypertrophy when added to this medium. In 5 to 7 days, muscle fiber diameters increase by 71 % to 98% compared to untreated controls. Mechanical stimulation of the avian muscle fibers in MM medium increased the sensitivity of the cells to insulin and IGF-1, based on a leftward shift of the insulin dose/response curve for protein synthesis rates. (54). We developed a ligand binding assay for IGF-1 binding proteins and found that the avian skeletal muscle cultures produced three major species of 31, 36 and 43 kD molecular weight (54) Stretch of the myofibers was found to have no significant effect on the efflux of IGF-1 binding proteins, but addition of exogenous collagen stimulated IGF-1 binding protein production 1.5 to 5 fold. Steroid hormones have a profound effect on muscle protein turnover rates in vivo, with the stress-related glucocorticoids inducing rapid skeletal muscle atrophy while androgenic steroids induce skeletal muscle growth. Exercise in humans and animals reduces the catabolic effects of glucocorticoids and may enhance the anabolic effects of androgenic steroids on skeletal muscle. In our continuing work on the involvement of exogenrus growth factors in stretch-induced avian skeletal muscle growth, we

  13. The missing link in parasite manipulation of host behaviour.

    PubMed

    Herbison, Ryan; Lagrue, Clement; Poulin, Robert

    2018-04-03

    The observation that certain species of parasite my adaptively manipulate its host behaviour is a fascinating phenomenon. As a result, the recently established field of 'host manipulation' has seen rapid expansion over the past few decades with public and scientific interest steadily increasing. However, progress appears to falter when researchers ask how parasites manipulate behaviour, rather than why. A vast majority of the published literature investigating the mechanistic basis underlying behavioural manipulation fails to connect the establishment of the parasite with the reported physiological changes in its host. This has left researchers unable to empirically distinguish/identify adaptive physiological changes enforced by the parasites from pathological side effects of infection, resulting in scientists relying on narratives to explain results, rather than empirical evidence. By contrasting correlative mechanistic evidence for host manipulation against rare cases of causative evidence and drawing from the advanced understanding of physiological systems from other disciplines it is clear we are often skipping over a crucial step in host-manipulation: the production, potential storage, and release of molecules (manipulation factors) that must create the observed physiological changes in hosts if they are adaptive. Identifying these manipulation factors, via associating gene expression shifts in the parasite with behavioural changes in the host and following their effects will provide researchers with a bottom-up approach to unraveling the mechanisms of behavioural manipulation and by extension behaviour itself.

  14. Dual chain synthetic heparin-binding growth factor analogs

    DOEpatents

    Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY

    2012-04-24

    The invention provides synthetic heparin-binding growth factor analogs having two peptide chains each branched from a branch moiety, such as trifunctional amino acid residues, the branch moieties separated by a first linker of from 3 to about 20 backbone atoms, which peptide chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a second linker, which may be a hydrophobic second linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

  15. Dual chain synthetic heparin-binding growth factor analogs

    DOEpatents

    Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY

    2009-10-06

    The invention provides synthetic heparin-binding growth factor analogs having two peptide chains each branched from a branch moiety, such as trifunctional amino acid residues, the branch moieties separated by a first linker of from 3 to about 20 backbone atoms, which peptide chains bind a heparin-binding growth factor receptor and are covalently bound to a non-signaling peptide that includes a heparin-binding domain, preferably by a second linker, which may be a hydrophobic second linker. The synthetic heparin-binding growth factor analogs are useful as pharmaceutical agents, soluble biologics or as surface coatings for medical devices.

  16. Growth factors in urologic tissues: detection, characterization, and clinical applications.

    PubMed

    Mydlo, J H; Macchia, R J

    1992-12-01

    During the last two decades, enormous strides have been made in understanding cellular and molecular biology. The direction of treatment of many neoplasms and other diseases are starting at the microscopic level. Growth factors are polypeptides that play a part in the development and maintenance of living tissues. We, as well as others, have investigated the role that growth factors play particularly in urologic tissues, both benign and malignant. We review several well-known growth factors and their function in prostate, kidney, and bladder tissues, as well as their functions in other regulating processes of the human body, and also the use of growth factors as tumor markers, and antibodies to growth factors as possible treatment of disease.

  17. Manipulation of the apoplastic pH of intact plants mimics stomatal and growth responses to water availability and microclimatic variation.

    PubMed

    Wilkinson, Sally; Davies, William J

    2008-01-01

    The apoplastic pH of intact Forsythiaxintermedia (cv. Lynwood) and tomato (Solanum lycopersicum) plants has been manipulated using buffered foliar sprays, and thereby stomatal conductance (g(s)), leaf growth rate, and plant water loss have been controlled. The more alkaline the pH of the foliar spray, the lower the g(s) and/or leaf growth rate subsequently measured. The most alkaline pH that was applied corresponds to that measured in sap extracted from shoots of tomato and Forsythia plants experiencing, respectively, soil drying or a relatively high photon flux density (PFD), vapour pressure deficit (VPD), and temperature in the leaf microclimate. The negative correlation between PFD/VPD/temperature and g(s) determined in well-watered Forsythia plants exposed to a naturally varying summer microclimate was eliminated by spraying the plants with relatively alkaline but not acidic buffers, providing evidence for a novel pH-based signalling mechanism linking the aerial microclimate with stomatal aperture. Increasing the pH of the foliar spray only reduced g(s) in plants of the abscisic acid (ABA)-deficient flacca mutant of tomato when ABA was simultaneously sprayed onto leaves or injected into stems. In well-watered Forsythia plants exposed to a naturally varying summer microclimate (variable PFD, VPD, and temperature), xylem pH and leaf ABA concentration fluctuated but were positively correlated. Manipulation of foliar apoplastic pH also affected the response of g(s) and leaf growth to ABA injected into stems of intact Forsythia plants. The techniques used here to control physiology and water use in intact growing plants could easily be applied in a horticultural context.

  18. Minoxidil Promotes Hair Growth through Stimulation of Growth Factor Release from Adipose-Derived Stem Cells

    PubMed Central

    Choi, Nahyun; Shin, Soyoung; Song, Sun U.; Sung, Jong-Hyuk

    2018-01-01

    Minoxidil directly promotes hair growth via the stimulation of dermal papilla (DP) and epithelial cells. Alternatively, there is little evidence for indirect promotion of hair growth via stimulation of adipose-derived stem cells (ASCs). We investigated whether minoxidil stimulates ASCs and if increased growth factor secretion by ASCs facilitates minoxidil-induced hair growth. Telogen-to-anagen induction was examined in mice. Cultured DP cells and vibrissae hair follicle organ cultures were used to further examine the underlying mechanisms. Subcutaneous injection of minoxidil-treated ASCs accelerated telogen-to-anagen transition in mice, and increased hair weight at day 14 post-injection. Minoxidil did not alter ASC proliferation, but increased migration and tube formation. Minoxidil also increased the secretion of growth factors from ASCs, including chemokine (C-X-C motif) ligand 1 (CXCL1), platelet-derived endothelial cell growth factor (PD-ECGF), and platelet-derived growth factor-C (PDGF-C). Minoxidil increased extracellular signal–regulated kinases 1/2 (ERK1/2) phosphorylation, and concomitant upregulation of PD-ECGF and PDGF-C mRNA levels were attenuated by an ERK inhibitor. Subcutaneous injection of CXCL1, PD-ECGF, or PDGF-C enhanced anagen induction in mice, and both CXCL1 and PDGF-C increased hair length in ex vivo organ culture. Treatment with CXCL1, PD-ECGF, or PDGF-C also increased the proliferation index in DP cells. Finally, topical application of CXCL1, PD-ECGF, or PDGF-C with 2% minoxidil enhanced anagen induction when compared to minoxidil alone. Minoxidil stimulates ASC motility and increases paracrine growth factor signaling. Minoxidil-stimulated secretion of growth factors by ASCs may enhance hair growth by promoting DP proliferation. Therefore, minoxidil can be used as an ASC preconditioning agent for hair regeneration. PMID:29495622

  19. Minoxidil Promotes Hair Growth through Stimulation of Growth Factor Release from Adipose-Derived Stem Cells.

    PubMed

    Choi, Nahyun; Shin, Soyoung; Song, Sun U; Sung, Jong-Hyuk

    2018-02-28

    Minoxidil directly promotes hair growth via the stimulation of dermal papilla (DP) and epithelial cells. Alternatively, there is little evidence for indirect promotion of hair growth via stimulation of adipose-derived stem cells (ASCs). We investigated whether minoxidil stimulates ASCs and if increased growth factor secretion by ASCs facilitates minoxidil-induced hair growth. Telogen-to-anagen induction was examined in mice. Cultured DP cells and vibrissae hair follicle organ cultures were used to further examine the underlying mechanisms. Subcutaneous injection of minoxidil-treated ASCs accelerated telogen-to-anagen transition in mice, and increased hair weight at day 14 post-injection. Minoxidil did not alter ASC proliferation, but increased migration and tube formation. Minoxidil also increased the secretion of growth factors from ASCs, including chemokine (C-X-C motif) ligand 1 (CXCL1), platelet-derived endothelial cell growth factor (PD-ECGF), and platelet-derived growth factor-C (PDGF-C). Minoxidil increased extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation, and concomitant upregulation of PD-ECGF and PDGF-C mRNA levels were attenuated by an ERK inhibitor. Subcutaneous injection of CXCL1, PD-ECGF, or PDGF-C enhanced anagen induction in mice, and both CXCL1 and PDGF-C increased hair length in ex vivo organ culture. Treatment with CXCL1, PD-ECGF, or PDGF-C also increased the proliferation index in DP cells. Finally, topical application of CXCL1, PD-ECGF, or PDGF-C with 2% minoxidil enhanced anagen induction when compared to minoxidil alone. Minoxidil stimulates ASC motility and increases paracrine growth factor signaling. Minoxidil-stimulated secretion of growth factors by ASCs may enhance hair growth by promoting DP proliferation. Therefore, minoxidil can be used as an ASC preconditioning agent for hair regeneration.

  20. Genetic factors in fetal growth restriction and miscarriage.

    PubMed

    Yamada, Hideto; Sata, Fumihiro; Saijo, Yasuaki; Kishi, Reiko; Minakami, Hisanori

    2005-06-01

    Recently, several investigations concerning disadvantageous genetic factors in human reproduction have progressed. Inherited thrombophilia, such as factor V Leiden, prothrombin, and methylenetetrahydrofolate reductase mutations; gene polymorphisms of detoxification enzyme (CYP1A1); growth factors (insulin-like growth factor-I); and hormones such as angiotensinogen and CYP17 are involved in the pathogenesis of fetal growth restriction. The inherited thrombophilia, gene polymorphisms of coagulation and anticoagulation factor such as thrombomodulin, endothelial protein C receptor, plasminogen activator inhibitor 1, and factor XIII; human lymphocyte antigen (HLA-G); detoxification enzymes (glutathione- S-transferase M1); cytokines such as interleukin (IL) -1 and IL-6; hormones (CYP17); vasodilators (nitric oxide synthase 3); and vitamins (transcobalamin) are involved in the pathogenesis of sporadic and recurrent miscarriage. It is likely that a gene polymorphism or mutation susceptible to reproductive failure has a beneficial effect on the process of human reproduction with or without the environmental interaction. The factor V Leiden mutation has genetic advantages that are believed to be an improved implantation rate in in vitro fertilization and a reduction of maternal intrapartum blood loss. It has also been demonstrated that the CYP17 A2 allele has bidirectional effects on human reproduction, including increases in susceptibility to recurrent miscarriage and fetal growth enhancement.

  1. Controlled growth factor release from synthetic extracellular matrices

    NASA Astrophysics Data System (ADS)

    Lee, Kuen Yong; Peters, Martin C.; Anderson, Kenneth W.; Mooney, David J.

    2000-12-01

    Polymeric matrices can be used to grow new tissues and organs, and the delivery of growth factors from these matrices is one method to regenerate tissues. A problem with engineering tissues that exist in a mechanically dynamic environment, such as bone, muscle and blood vessels, is that most drug delivery systems have been designed to operate under static conditions. We thought that polymeric matrices, which release growth factors in response to mechanical signals, might provide a new approach to guide tissue formation in mechanically stressed environments. Critical design features for this type of system include the ability to undergo repeated deformation, and a reversible binding of the protein growth factors to polymeric matrices to allow for responses to repeated stimuli. Here we report a model delivery system that can respond to mechanical signalling and upregulate the release of a growth factor to promote blood vessel formation. This approach may find a number of applications, including regeneration and engineering of new tissues and more general drug-delivery applications.

  2. Transforming growth factor-alpha short-circuits downregulation of the epidermal growth factor receptor.

    PubMed

    Ouyang, X; Gulliford, T; Huang, G; Epstein, R J

    1999-04-01

    Transforming growth factor-alpha (TGFalpha) is an epidermal growth factor receptor (EGFR) ligand which is distinguished from EGF by its acid-labile structure and potent transforming function. We recently reported that TGFalpha induces less efficient EGFR heterodimerization and downregulation than does EGF (Gulliford et al., 1997, Oncogene, 15:2219-2223). Here we use isoform-specific EGFR and ErbB2 antibodies to show that the duration of EGFR signalling induced by a single TGFalpha exposure is less than that induced by equimolar EGF. The protein trafficking inhibitor brefeldin A (BFA) reduces the duration of EGF signalling to an extent similar to that seen with TGFalpha alone; the effects of TGFalpha and BFA on EGFR degradation are opposite, however, with TGFalpha sparing EGFR from downregulation but BFA accelerating EGF-dependent receptor loss. This suggests that BFA blocks EGFR recycling and thus shortens EGF-dependent receptor signalling, whereas TGFalpha shortens receptor signalling and thus blocks EGFR downregulation. Consistent with this, repeated application of TGFalpha is accompanied by prolonged EGFR expression and signalling, whereas similar application of EGF causes receptor downregulation and signal termination. These findings indicate that constitutive secretion of pH-labile TGFalpha may perpetuate EGFR signalling by permitting early oligomer dissociation and dephosphorylation within acidic endosomes, thereby extinguishing a phosphotyrosine-based downregulation signal and creating an irreversible autocrine growth loop.

  3. A new method to manipulate broiler chicken growth and metabolism: Response to mixed LED light system

    PubMed Central

    Yang, Yefeng; Yu, Yonghua; Pan, Jinming; Ying, Yibin; Zhou, Hong

    2016-01-01

    Present study introduced a new method to manipulate broiler chicken growth and metabolism by mixing the growth-advantage LED. We found that the green/blue LED mixed light system (G-B and G × B) have the similar stimulatory effect on chick body weight with single green light and single blue light (G and B), compared with normal artificial light (P = 0.028). Moreover, the percentage of carcass was significantly greater in the mixed light (G × B) when compared with the single light (P = 0.003). Synchronized with body weight, the mixed light (G-B and G × B) had a significant improved influence on the feed conversion of birds compared with normal light (P = 0.002). A significant improvement in feed conversion were found in mixed light (G × B) compared with single LED light (P = 0.037). G group resulted in a greater high-density lipoprotein cholesterol level than B group (P = 0.002), whereas B group resulted in a greater low-density lipoprotein cholesterol level than G group (P = 0.017). The mixed light significantly increased the birds’ glucose level in comparison with the single light (P = 0.003). This study might establish an effective strategy for maximizing growth of chickens by mixed LED technology. PMID:27170597

  4. A new method to manipulate broiler chicken growth and metabolism: Response to mixed LED light system.

    PubMed

    Yang, Yefeng; Yu, Yonghua; Pan, Jinming; Ying, Yibin; Zhou, Hong

    2016-05-12

    Present study introduced a new method to manipulate broiler chicken growth and metabolism by mixing the growth-advantage LED. We found that the green/blue LED mixed light system (G-B and G × B) have the similar stimulatory effect on chick body weight with single green light and single blue light (G and B), compared with normal artificial light (P = 0.028). Moreover, the percentage of carcass was significantly greater in the mixed light (G × B) when compared with the single light (P = 0.003). Synchronized with body weight, the mixed light (G-B and G × B) had a significant improved influence on the feed conversion of birds compared with normal light (P = 0.002). A significant improvement in feed conversion were found in mixed light (G × B) compared with single LED light (P = 0.037). G group resulted in a greater high-density lipoprotein cholesterol level than B group (P = 0.002), whereas B group resulted in a greater low-density lipoprotein cholesterol level than G group (P = 0.017). The mixed light significantly increased the birds' glucose level in comparison with the single light (P = 0.003). This study might establish an effective strategy for maximizing growth of chickens by mixed LED technology.

  5. A new method to manipulate broiler chicken growth and metabolism: Response to mixed LED light system

    NASA Astrophysics Data System (ADS)

    Yang, Yefeng; Yu, Yonghua; Pan, Jinming; Ying, Yibin; Zhou, Hong

    2016-05-01

    Present study introduced a new method to manipulate broiler chicken growth and metabolism by mixing the growth-advantage LED. We found that the green/blue LED mixed light system (G-B and G × B) have the similar stimulatory effect on chick body weight with single green light and single blue light (G and B), compared with normal artificial light (P = 0.028). Moreover, the percentage of carcass was significantly greater in the mixed light (G × B) when compared with the single light (P = 0.003). Synchronized with body weight, the mixed light (G-B and G × B) had a significant improved influence on the feed conversion of birds compared with normal light (P = 0.002). A significant improvement in feed conversion were found in mixed light (G × B) compared with single LED light (P = 0.037). G group resulted in a greater high-density lipoprotein cholesterol level than B group (P = 0.002), whereas B group resulted in a greater low-density lipoprotein cholesterol level than G group (P = 0.017). The mixed light significantly increased the birds’ glucose level in comparison with the single light (P = 0.003). This study might establish an effective strategy for maximizing growth of chickens by mixed LED technology.

  6. Extracellular matrix and growth factors in branching morphogenesis

    NASA Technical Reports Server (NTRS)

    Hardman, P.; Spooner, B. S.

    1993-01-01

    The unifying hypothesis of the NSCORT in gravitational biology postulates that the ECM and growth factors are key interrelated components of a macromolecular regulatory system. The ECM is known to be important in growth and branching morphogenesis of embryonic organs. Growth factors have been detected in the developing embryo, and often the pattern of localization is associated with areas undergoing epithelial-mesenchymal interactions. Causal relationships between these components may be of fundamental importance in control of branching morphogenesis.

  7. Haploinsufficiency of the insulin-like growth factor-1 receptor enhances endothelial repair and favorably modifies angiogenic progenitor cell phenotype.

    PubMed

    Yuldasheva, Nadira Y; Rashid, Sheikh Tawqeer; Haywood, Natalie J; Cordell, Paul; Mughal, Romana; Viswambharan, Hema; Imrie, Helen; Sukumar, Piruthivi; Cubbon, Richard M; Aziz, Amir; Gage, Matthew; Mbonye, Kamatamu Amanda; Smith, Jessica; Galloway, Stacey; Skromna, Anna; Scott, D Julian A; Kearney, Mark T; Wheatcroft, Stephen B

    2014-09-01

    Defective endothelial regeneration predisposes to adverse arterial remodeling and is thought to contribute to cardiovascular disease in type 2 diabetes mellitus. We recently demonstrated that the type 1 insulin-like growth factor receptor (IGF1R) is a negative regulator of insulin sensitivity and nitric oxide bioavailability. In this report, we examined partial deletion of the IGF1R as a potential strategy to enhance endothelial repair. We assessed endothelial regeneration after wire injury in mice and abundance and function of angiogenic progenitor cells in mice with haploinsufficiency of the IGF1R (IGF1R(+/-)). Endothelial regeneration after arterial injury was accelerated in IGF1R(+/-) mice. Although the yield of angiogenic progenitor cells was lower in IGF1R(+/-) mice, these angiogenic progenitor cells displayed enhanced adhesion, increased secretion of insulin-like growth factor-1, and enhanced angiogenic capacity. To examine the relevance of IGF1R manipulation to cell-based therapy, we transfused IGF1R(+/-) bone marrow-derived CD117(+) cells into wild-type mice. IGF1R(+/-) cells accelerated endothelial regeneration after arterial injury compared with wild-type cells and did not alter atherosclerotic lesion formation. Haploinsufficiency of the IGF1R is associated with accelerated endothelial regeneration in vivo and enhanced tube forming and adhesive potential of angiogenic progenitor cells in vitro. Partial deletion of IGF1R in transfused bone marrow-derived CD117(+) cells enhanced their capacity to promote endothelial regeneration without altering atherosclerosis. Our data suggest that manipulation of the IGF1R could be exploited as novel therapeutic approach to enhance repair of the arterial wall after injury. © 2014 American Heart Association, Inc.

  8. Growth and Growth hormone - Insulin Like Growth Factor -I (GH-IGF-I) Axis in Chronic Anemias.

    PubMed

    Soliman, Ashraf T; De Sanctis, Vincenzo; Yassin, Mohamed; Adel, Ashraf

    2017-04-28

    Anaemia is a global public health problem affecting both developing and developed countries with major consequences for human health as well as social and economic development. It occurs at all stages of the life cycle, but is more prevalent in pregnant women and young children. Iron deficiency anaemia (IDA) was considered to be among the most important contributing factors to the global burden of disease. Prolonged and/or chronic anemia has a negative effect on linear growth especially during the rapid phases (infancy and puberty). Additionally infants with chronic IDA have delayed cognitive, motor, and affective development that may be long-lasting. In view of the significant impact of chronic anemias on growth, pediatricians endocrinologists and hematologists should advocate primary prevention and screening for growth disturbance in these forms of anemias. The extent of the negative effect of different forms of chronic anemias on linear growth and its possible reversibilty is addressed in this review. The possible mechanisms that may impair growth in the different forms of anemias are addressed with special attention to their effect on the growth hormone (GH) - insulin like growth factor -I (IGF-I).

  9. Fibroblast Growth Factors Stimulate Hair Growth through β-Catenin and Shh Expression in C57BL/6 Mice

    PubMed Central

    Lin, Wei-hong; Xiang, Li-Jun; Shi, Hong-Xue; Zhang, Jian; Jiang, Li-ping; Cai, Ping-tao; Lin, Zhen-Lang; Lin, Bei-Bei; Huang, Yan; Zhang, Hai-Lin; Fu, Xiao-Bing; Guo, Ding-Jiong; Li, Xiao-Kun; Wang, Xiao-Jie; Xiao, Jian

    2015-01-01

    Growth factors are involved in the regulation of hair morphogenesis and cycle hair growth. The present study sought to investigate the hair growth promoting activities of three approved growth factor drugs, fibroblast growth factor 10 (FGF-10), acidic fibroblast growth factor (FGF-1), and basic fibroblast growth factor (FGF-2), and the mechanism of action. We observed that FGFs promoted hair growth by inducing the anagen phase in telogenic C57BL/6 mice. Specifically, the histomorphometric analysis data indicates that topical application of FGFs induced an earlier anagen phase and prolonged the mature anagen phase, in contrast to the control group. Moreover, the immunohistochemical analysis reveals earlier induction of β-catenin and Sonic hedgehog (Shh) in hair follicles of the FGFs-treated group. These results suggest that FGFs promote hair growth by inducing the anagen phase in resting hair follicles and might be a potential hair growth-promoting agent. PMID:25685806

  10. Effect of growth factors on hyaluronan production by canine vocal fold fibroblasts.

    PubMed

    Hirano, Shigeru; Bless, Diane M; Heisey, Dennis; Ford, Charles N

    2003-07-01

    Hyaluronan (HYA) is considered to be a crucial factor in scarless wound healing and in maintaining tissue viscosity of the vocal fold lamina propria. In this study focusing on the effects of growth factors, we examined how HYA is produced and controlled in canine cultured vocal fold fibroblasts. Fibroblasts were taken from the lamina propria of the vocal folds of 8 dogs and cultured with and without growth factors. The production of HYA in the supernatant culture was quantitatively examined by enzyme-linked immunosorbent assay. Hepatocyte growth factor, epidermal growth factor, basic fibroblast growth factor, and transforming growth factor beta1 all stimulated HYA synthesis from vocal fold fibroblasts. These effects differed with the concentration of growth factors and the incubation period. We also examined how frequently the growth factors had to be administered in order to maintain appropriate levels of HYA. A single administration was sufficient to maintain appropriate HYA levels for at least 7 days. The present studies have demonstrated positive effects of growth factors in stimulating HYA production. Further in vivo study is needed to clarify the usefulness of these growth factors in the management of vocal fold scarring.

  11. Friends Turned Foes: Angiogenic Growth Factors beyond Angiogenesis.

    PubMed

    Matkar, Pratiek N; Ariyagunarajah, Ramya; Leong-Poi, Howard; Singh, Krishna K

    2017-10-02

    Angiogenesis, the formation of new blood vessels from pre-existing ones is a biological process that ensures an adequate blood flow is maintained to provide the cells with a sufficient supply of nutrients and oxygen within the body. Numerous soluble growth factors and inhibitors, cytokines, proteases as well as extracellular matrix proteins and adhesion molecules stringently regulate the multi-factorial process of angiogenesis. The properties and interactions of key angiogenic molecules such as vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs) and angiopoietins have been investigated in great detail with respect to their molecular impact on angiogenesis. Since the discovery of angiogenic growth factors, much research has been focused on their biological actions and their potential use as therapeutic targets for angiogenic or anti-angiogenic strategies in a context-dependent manner depending on the pathologies. It is generally accepted that these factors play an indispensable role in angiogenesis. However, it is becoming increasingly evident that this is not their only role and it is likely that the angiogenic factors have important functions in a wider range of biological and pathological processes. The additional roles played by these molecules in numerous pathologies and biological processes beyond angiogenesis are discussed in this review.

  12. Friends Turned Foes: Angiogenic Growth Factors beyond Angiogenesis

    PubMed Central

    Matkar, Pratiek N.; Ariyagunarajah, Ramya; Leong-Poi, Howard; Singh, Krishna K.

    2017-01-01

    Angiogenesis, the formation of new blood vessels from pre-existing ones is a biological process that ensures an adequate blood flow is maintained to provide the cells with a sufficient supply of nutrients and oxygen within the body. Numerous soluble growth factors and inhibitors, cytokines, proteases as well as extracellular matrix proteins and adhesion molecules stringently regulate the multi-factorial process of angiogenesis. The properties and interactions of key angiogenic molecules such as vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs) and angiopoietins have been investigated in great detail with respect to their molecular impact on angiogenesis. Since the discovery of angiogenic growth factors, much research has been focused on their biological actions and their potential use as therapeutic targets for angiogenic or anti-angiogenic strategies in a context-dependent manner depending on the pathologies. It is generally accepted that these factors play an indispensable role in angiogenesis. However, it is becoming increasingly evident that this is not their only role and it is likely that the angiogenic factors have important functions in a wider range of biological and pathological processes. The additional roles played by these molecules in numerous pathologies and biological processes beyond angiogenesis are discussed in this review. PMID:28974056

  13. Alterations of Growth Factors in Autism and Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Galvez-Contreras, Alma Y.; Campos-Ordonez, Tania; Gonzalez-Castaneda, Rocio E.; Gonzalez-Perez, Oscar

    2017-01-01

    Growth factors (GFs) are cytokines that regulate the neural development. Recent evidence indicates that alterations in the expression level of GFs during embryogenesis are linked to the pathophysiology and clinical manifestations of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). In this concise review, we summarize the current evidence that supports the role of brain-derived neurotrophic factor, insulin-like growth factor 2, hepatocyte growth factor (HGF), glial-derived neurotrophic factor, nerve growth factor, neurotrophins 3 and 4, and epidermal growth factor in the pathogenesis of ADHD and ASD. We also highlight the potential use of these GFs as clinical markers for diagnosis and prognosis of these neurodevelopmental disorders. PMID:28751869

  14. Epidermal growth factor in alkali-burned corneal epithelial wound healing.

    PubMed

    Singh, G; Foster, C S

    1987-06-15

    We conducted a double-masked study to evaluate the effect of epidermal growth factor on epithelial wound healing and recurrent erosions in alkali-burned rabbit corneas. Epithelial wounds 10 mm in diameter healed completely under the influence of topical epidermal growth factor, whereas the control corneas did not resurface in the center. On reversal of treatment, the previously nonhealing epithelial defects healed when treated with topical epidermal growth factor eyedrops. Conversely, the epidermal growth factor-treated and resurfaced corneas developed epithelial defects when treatment was discontinued. Histopathologic examination disclosed hyperplastic epithelium growing over the damaged stroma laden with polymorphonuclear leukocytes when treated with epidermal growth factor eyedrops, but it did not adhere to the underlying tissue. Hydropic changes were seen intracellularly as well as between the epithelial cells and the stroma.

  15. Human corpus luteum: presence of epidermal growth factor receptors and binding characteristics

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ayyagari, R.R.; Khan-Dawood, F.S.

    Epidermal growth factor receptors are present in many reproductive tissues but have not been demonstrated in the human corpus luteum. To determine the presence of epidermal growth factor receptors and its binding characteristics, we carried out studies on the plasma cell membrane fraction of seven human corpora lutea (days 16 to 25) of the menstrual cycle. Specific epidermal growth factor receptors were present in human corpus luteum. Insulin, nerve growth factor, and human chorionic gonadotropin did not competitively displace epidermal growth factor binding. The optimal conditions for corpus luteum-epidermal growth factor receptor binding were found to be incubation for 2more » hours at 4 degrees C with 500 micrograms plasma membrane protein and 140 femtomol /sup 125/I-epidermal growth factor per incubate. The number (mean +/- SEM) of epidermal growth factor binding sites was 12.34 +/- 2.99 X 10(-19) mol/micrograms protein; the dissociation constant was 2.26 +/- 0.56 X 10(-9) mol/L; the association constant was 0.59 +/- 0.12 X 10(9) L/mol. In two regressing corpora lutea obtained on days 2 and 3 of the menstrual cycle, there was no detectable specific epidermal growth factor receptor binding activity. Similarly no epidermal growth factor receptor binding activity could be detected in ovarian stromal tissue. Our findings demonstrate that specific receptors for epidermal growth factor are present in the human corpus luteum. The physiologic significance of epidermal growth factor receptors in human corpus luteum is unknown, but epidermal growth factor may be involved in intragonadal regulation of luteal function.« less

  16. Predictive factors for intrauterine growth restriction.

    PubMed

    Albu, A R; Anca, A F; Horhoianu, V V; Horhoianu, I A

    2014-06-15

    Reduced fetal growth is seen in about 10% of the pregnancies but only a minority has a pathological background and is known as intrauterine growth restriction or fetal growth restriction (IUGR / FGR). Increased fetal and neonatal mortality and morbidity as well as adult pathologic conditions are often associated to IUGR. Risk factors for IUGR are easy to assess but have poor predictive value. For the diagnostic purpose, biochemical serum markers, ultrasound and Doppler study of uterine and spiral arteries, placental volume and vascularization, first trimester growth pattern are object of assessment today. Modern evaluations propose combined algorithms using these strategies, all with the goal of a better prediction of risk pregnancies.

  17. Ocular Angiogenesis: Vascular Endothelial Growth Factor and Other Factors.

    PubMed

    Rubio, Roman G; Adamis, Anthony P

    2016-01-01

    Systematic study of the mechanisms underlying pathological ocular neovascularization has yielded a wealth of knowledge about pro- and anti-angiogenic factors that modulate diseases such as neovascular age-related macular degeneration. The evidence implicating vascular endothelial growth factor (VEGF) in particular has led to the development of a number of approved anti-VEGF therapies. Additional proangiogenic targets that have emerged as potential mediators of ocular neovascularization include hypoxia-inducible factor-1, angiopoietin-2, platelet-derived growth factor-B and components of the alternative complement pathway. As for VEGF, knowledge of these factors has led to a product pipeline of many more novel agents that are in various stages of clinical development in the setting of ocular neovascularization. These agents are represented by a range of drug classes and, in addition to novel small- and large-molecule VEGF inhibitors, include gene therapies, small interfering RNA agents and tyrosine kinase inhibitors. In addition, combination therapy is beginning to emerge as a strategy to improve the efficacy of individual therapies. Thus, a variety of agents, whether administered alone or as adjunctive therapy with agents targeting VEGF, offer the promise of expanding the range of treatments for ocular neovascular diseases. © 2016 S. Karger AG, Basel.

  18. Bone-Derived Growth Factors

    PubMed Central

    Capanna, R.; Campanacci, D.A.; De Biase, P.; Cuomo, P.; Lorenzoni, A.

    2010-01-01

    Bone regeneration is based on the synergy between osteconduction, osteoinduction and osteogenesis. In recent years, we have witnessed the birth and development of numerous osteoconductive substrates, created with the intention of replacing bone grafts, both autologous and homologous. Recently, attention has shifted to osteogenesis, in other words, to the study of mesenchymal cells and their differentiation into osteoblastic cell lines that can be cultured in vitro (as already seen with chondroblasts). Osteoinduction, too, has been shown to be equally important, ever since Urist’s 1967 study which drew attention to the demineralised bone matrix and its properties. The following twenty years led to the definition of bone morphogenetic protein (BMP) and finally to the marketing of the first ostegenic protein (OP-1) obtained by means of the gene recombination technique. The BMPs produced using this technique that, so far, have been shown to be most active are BMP-2 (Infuse) and BMP-7 (Osigraft). The BMPs are not the only molecules with osteoinductive capacity. Other molecules capable of influencing bone regeneration are: platelet-derived growth factors (PDGFs), the transforming growth factor-beta (TGF-β) family, insulin-like growth factor (IGF-I) and the acidic and basic fibroblast growth factors (FGFs). All these growth factors act in synergy with the BMPs, modulating their action and exerting an inductive and proliferative action on the cell lines responsible for regenerating the bone matrix. The literature has been literally invaded by studies, both experimental and preclinical, on these proteins (Termaat, 2005), and they have provided ample demonstration that the BMPs are effective in improving healing of fractures, pseudoarthrosis and spinal fusions. Important advantages of BMPs are the complete absence of risk of transmissible disease, given that they are produced using recombination technology; their purity, and thus absence of an immune response (although

  19. A Histologically Distinctive Interstitial Pneumonia Induced by Overexpression of the Interleukin 6, Transforming Growth Factor β1, or Platelet-Derived Growth Factor B Gene

    NASA Astrophysics Data System (ADS)

    Yoshida, Mitsuhiro; Sakuma, Junko; Hayashi, Seiji; Abe, Kin'ya; Saito, Izumu; Harada, Shizuko; Sakatani, Mitsunoir; Yamamoto, Satoru; Matsumoto, Norinao; Kaneda, Yasufumi; Kishmoto, Tadamitsu

    1995-10-01

    Interstitial pneumonia is characterized by alveolitis with resulting fibrosis of the interstitium. To determine the relevance of humoral factors in the pathogenesis of interstitial pneumonia, we introduced expression vectors into Wistar rats via the trachea to locally overexpress humoral factors in the lungs. Human interleukin (IL) 6 and IL-6 receptor genes induced lymphocytic alveolitis without marked fibroblast proliferation. In contrast, overexpression of human transforming growth factor β1 or human platelet-derived growth factor B gene induced only mild or apparent cellular infiltration in the alveoli, respectively. However, both factors induced significant proliferation of fibroblasts and deposition of collagen fibrils. These histopathologic changes induced by the transforming growth factor β1 and platelet-derived growth factor B gene are partly akin to those changes seen in lung tissues from patients with pulmonary fibrosis and markedly contrast with the changes induced by overexpression of the IL-6 and IL-6 receptor genes that mimics lymphocytic interstitial pneumonia.

  20. Potential role of fibroblast growth factor in enhancement of fracture healing.

    PubMed

    Radomsky, M L; Thompson, A Y; Spiro, R C; Poser, J W

    1998-10-01

    Fibroblast growth factors are present in significant amounts in bone and several studies have suggested that they may be involved in normal fracture healing. It is well established that fibroblast growth factors have mitogenic and angiogenic activity on mesoderm and neuroectoderm derived cells. Of particular interest as a member of the fibroblast growth factor family, basic fibroblast growth factor stimulates mitogenesis, chemotaxis, differentiation, and angiogenesis. It also plays an important role in the development of vascular, nervous, and skeletal systems, promotes the maintenance and survival of certain tissues, and stimulates wound healing and tissue repair. Animal studies have shown that the direct injection of fibroblast growth factor into fresh fractures stimulates callus formation, which provides mechanical stability to the fracture, accelerates healing, and restores competence. The matrix used to present the fibroblast growth factor at the fracture site plays a critical role in the effectiveness of the treatment. The evaluation of injectable basic fibroblast growth factor in a sodium hyaluronate gel for its effectiveness in stimulating fracture healing is described. When applied directly into a freshly created fracture in the rabbit fibula, a single injection of the basic fibroblast growth factor and hyaluronan results in the stimulation of callus formation, increased bone formation, and earlier restoration of mechanical strength at the fracture site. The hyaluronan gel serves as a reservoir that sequesters the basic fibroblast growth factor at the injection site for the length of time necessary to create an environment conducive to fracture healing. It is concluded that basic fibroblast growth factor and sodium hyaluronate act synergistically to accelerate fracture healing and that the combination is suitable for clinical evaluation as a therapy in fracture treatment.

  1. Neural Stem Cell Differentiation Using Microfluidic Device-Generated Growth Factor Gradient.

    PubMed

    Kim, Ji Hyeon; Sim, Jiyeon; Kim, Hyun-Jung

    2018-04-11

    Neural stem cells (NSCs) have the ability to self-renew and differentiate into multiple nervous system cell types. During embryonic development, the concentrations of soluble biological molecules have a critical role in controlling cell proliferation, migration, differentiation and apoptosis. In an effort to find optimal culture conditions for the generation of desired cell types in vitro , we used a microfluidic chip-generated growth factor gradient system. In the current study, NSCs in the microfluidic device remained healthy during the entire period of cell culture, and proliferated and differentiated in response to the concentration gradient of growth factors (epithermal growth factor and basic fibroblast growth factor). We also showed that overexpression of ASCL1 in NSCs increased neuronal differentiation depending on the concentration gradient of growth factors generated in the microfluidic gradient chip. The microfluidic system allowed us to study concentration-dependent effects of growth factors within a single device, while a traditional system requires multiple independent cultures using fixed growth factor concentrations. Our study suggests that the microfluidic gradient-generating chip is a powerful tool for determining the optimal culture conditions.

  2. Nutritional catch-up growth.

    PubMed

    Gat-Yablonski, Galia; Pando, Rakefet; Phillip, Moshe

    2013-01-01

    Malnutrition, marked by variant nutrient deficiencies, is considered a leading cause of stunted growth worldwide. In developing countries, malnutrition is caused mainly by food shortage and infectious diseases. Malnutrition may also be found in the developed world, where it is due mostly to prematurity, chronic diseases, and anorexia nervosa. In most cases, when food consumption is corrected, spontaneous catch-up (CU) growth occurs. However, CU growth is not always complete, leading to growth deficits. Therefore, it is important to understand the mechanisms that govern this process. Using a rat model of food restriction followed by refeeding, we established a nutrition-induced CU growth model. Levels of leptin and insulin-like growth factor-1 were found to significantly decrease when food was restricted and to increase already 1 day after refeeding. Gene expression analysis of the growth plate revealed that food restriction specifically affects transcription factors such as the hypoxia inducible factor-1 and its downstream targets on the one hand, and global gene expression, indicating epigenetic regulation, on the other. Food restriction also reduced the level of several microRNAs, including the chondrocyte-specific miR-140, which led to an increase in its target, SIRT1, a class III histone deacetylase. These findings may explain the global changes in gene expression observed under nutritional manipulation. We suggest that multiple levels of regulation, including transcription factors, epigenetic mechanisms, and microRNAs respond to nutritional cues and offer a possible explanation for some of the effects of food restriction on epiphyseal growth plate growth. The means whereby these components sense changes in nutritional status are still unknown. Deciphering the role of epigenetic regulation in growth may pave the way for the development of new treatments for children with growth disorders. Copyright © 2013 S. Karger AG, Basel.

  3. Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications

    PubMed Central

    Ciarmela, Pasquapina; Islam, Md. Soriful; Reis, Fernando M.; Gray, Peter C.; Bloise, Enrrico; Petraglia, Felice; Vale, Wylie; Castellucci, Mario

    2011-01-01

    BACKGROUND Growth factors are proteins secreted by a number of cell types that are capable of modulating cellular growth, proliferation and cellular differentiation. It is well accepted that uterine cellular events such as proliferation and differentiation are regulated by sex steroids and their actions in target tissues are mediated by local production of growth factors acting through paracrine and/or autocrine mechanisms. Myometrial mass is ultimately modified in pregnancy as well as in tumour conditions such as leiomyoma and leiomyosarcoma. Leiomyomas, also known as fibroids, are benign tumours of the uterus, considered to be one of the most frequent causes of infertility in reproductive years in women. METHODS For this review, we searched the database MEDLINE and Google Scholar for articles with content related to growth factors acting on myometrium; the findings are hereby reviewed and discussed. RESULTS Different growth factors such as epidermal growth factor (EGF), transforming growth factor-α (TGF-α), heparin-binding EGF (HB-EGF), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF) and TGF-β perform actions in myometrium and in leiomyomas. In addition to these growth factors, activin and myostatin have been recently identified in myometrium and leiomyoma. CONCLUSIONS Growth factors play an important role in the mechanisms involved in myometrial patho-physiology. PMID:21788281

  4. Effects of basic fibroblast growth factor and insulin-like growth factor on cultured cartilage cells from skate Raja porasa

    NASA Astrophysics Data System (ADS)

    Fan, Tingjun; Jin, Lingyun; Wang, Xiaofeng

    2003-12-01

    Effects of basic fibroblast growth factor (bFGF) and insulin-like growth factor II (IGF-II) on cartilage cells from proboscis of skate, Raja porasa Günther, were investigated in this study. The cartilage cells were cultured in 20% FBS-supplemented MEM medium at 24°C. Twelve hours after culture initiation, the cartilage cells were treated with bFGF and IGF-II at different concentration combinations. It was found that 20 ng/ml of bFGF or 80 ng/ml of IGF-II was enough to have obvious stimulating effect on the growth and division of skate cartilage cells. Test of bFGF and IGF-II together, revealed that 20 ng/ml of bFGF and 80 ng/ml of IGF-II together had the best stimulating effect on the growth and division of skate cartilage cells. The cartilage cells cultured could form a monolayer at day 7.

  5. Chitosan conduits combined with nerve growth factor microspheres repair facial nerve defects

    PubMed Central

    Liu, Huawei; Wen, Weisheng; Hu, Min; Bi, Wenting; Chen, Lijie; Liu, Sanxia; Chen, Peng; Tan, Xinying

    2013-01-01

    Microspheres containing nerve growth factor for sustained release were prepared by a compound method, and implanted into chitosan conduits to repair 10-mm defects on the right buccal branches of the facial nerve in rabbits. In addition, chitosan conduits combined with nerve growth factor or normal saline, as well as autologous nerve, were used as controls. At 90 days post-surgery, the muscular atrophy on the right upper lip was more evident in the nerve growth factor and normal sa-line groups than in the nerve growth factor-microspheres and autologous nerve groups. physiological analysis revealed that the nerve conduction velocity and amplitude were significantly higher in the nerve growth factor-microspheres and autologous nerve groups than in the nerve growth factor and normal saline groups. Moreover, histological observation illustrated that the di-ameter, number, alignment and myelin sheath thickness of myelinated nerves derived from rabbits were higher in the nerve growth factor-microspheres and autologous nerve groups than in the nerve growth factor and normal saline groups. These findings indicate that chitosan nerve conduits bined with microspheres for sustained release of nerve growth factor can significantly improve facial nerve defect repair in rabbits. PMID:25206635

  6. Fibroblast Growth Factor 2: An Epithelial Ductal Cell Growth Inhibitor That Drops Out in Breast Cancer

    DTIC Science & Technology

    2010-10-01

    AD_________________ Award Number: W81XWH-08-1-0708 TITLE: Fibroblast Growth Factor 2: an...September 2009 – 14 September 2010 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Fibroblast Growth Factor 2: an Epithelial Ductal Cell Growth ...8 Appendices…………………………………………………………………………… 8 Supporting Data……………………………………………………………………... 8 Fibroblast Growth Factor -2: an

  7. Manipulating crystallization with molecular additives.

    PubMed

    Shtukenberg, Alexander G; Lee, Stephanie S; Kahr, Bart; Ward, Michael D

    2014-01-01

    Given the importance of organic crystals in a wide range of industrial applications, the chemistry, biology, materials science, and chemical engineering communities have focused considerable attention on developing methods to control crystal structure, size, shape, and orientation. Tailored additives have been used to control crystallization to great effect, presumably by selectively binding to particular crystallographic surfaces and sites. However, substantial knowledge gaps still exist in the fundamental mechanisms that govern the formation and growth of organic crystals in both the absence and presence of additives. In this review, we highlight research discoveries that reveal the role of additives, either introduced by design or present adventitiously, on various stages of formation and growth of organic crystals, including nucleation, dislocation spiral growth mechanisms, growth inhibition, and nonclassical crystal morphologies. The insights from these investigations and others of their kind are likely to guide the development of innovative methods to manipulate crystallization for a wide range of materials and applications.

  8. Growth responses of mature loblolly pine to dead wood manipulations

    Treesearch

    Michael D. Ulyshen; Scott Horn; James L. Hanula

    2012-01-01

    Large-scale manipulations of dead wood in mature Pinus taeda L. stands in the southeastern United States included a major one-time input of logs (fivefold increase in log volume) created by felling trees onsite, annual removals of all dead wood above ≥10 cm in diameter and ≥60 cm in length, and a reference in which no...

  9. Platelet-derived growth factor inhibits platelet activation in heparinized whole blood.

    PubMed

    Selheim, F; Holmsen, H; Vassbotn, F S

    1999-08-15

    We previously have demonstrated that human platelets have functionally active platelet-derived growth factor alpha-receptors. Studies with gel-filtered platelets showed that an autocrine inhibition pathway is transduced through this tyrosine kinase receptor during platelet activation. The physiological significance of this inhibitory effect of platelet-derived growth factor on gel-filtered platelets activation is, however, not known. In the present study, we investigated whether platelet-derived growth factor inhibits platelet activation under more physiological conditions in heparinized whole blood, which represents a more physiological condition than gel-filtered platelets. Using flow cytometric assays, we demonstrate here that platelet-derived growth factor inhibits thrombin-, thrombin receptor agonist peptide SFLLRN-, and collagen-induced platelet aggregation and shedding of platelet-derived microparticles from the platelet plasma membrane during platelet aggregation in stirred heparinized whole blood. The inhibitory effect of platelet-derived growth factor was dose dependent. However, under nonaggregating conditions (no stirring), we could not demonstrate any significant effect of platelet-derived growth factor on thrombin- and thrombin receptor agonist peptide-induced platelet surface expression of P-selectin. Our results demonstrate that platelet-derived growth factor appears to be a true antithrombotic agent only under aggregating conditions in heparinized whole blood.

  10. Gelatin Methacrylate Microspheres for Growth Factor Controlled Release

    PubMed Central

    Nguyen, Anh H.; McKinney, Jay; Miller, Tobias; Bongiorno, Tom; McDevitt, Todd C.

    2014-01-01

    Gelatin has been commonly used as a delivery vehicle for various biomolecules for tissue engineering and regenerative medicine applications due to its simple fabrication methods, inherent electrostatic binding properties, and proteolytic degradability. Compared to traditional chemical cross-linking methods, such as the use of glutaraldehyde (GA), methacrylate modification of gelatin offers an alternative method to better control the extent of hydrogel cross-linking. Here we examined the physical properties and growth factor delivery of gelatin methacrylate (GMA) microparticles formulated with a wide range of different cross-linking densities (15–90%). Less methacrylated MPs had decreased elastic moduli and larger mesh sizes compared to GA MPs, with increasing methacrylation correlating to greater moduli and smaller mesh sizes. As expected, an inverse correlation between microparticle cross-linking density and degradation was observed, with the lowest cross-linked GMA MPs degrading at the fastest rate, comparable to GA MPs. Interestingly, GMA MPs at lower cross-linking densities could be loaded with up to a 10-fold higher relative amount of growth factor over conventional GA cross-linked MPs, despite an order of magnitude greater gelatin content of GA MPs. Moreover, a reduced GMA cross-linking density resulted in more complete release of bone morphogenic protein 4 (BMP4) and basic fibroblast growth factor (bFGF) and accelerated release rate with collagenase treatment. These studies demonstrate that GMA MPs provide a more flexible platform for growth factor delivery by enhancing the relative binding capacity and permitting proteolytic degradation tunability, thereby offering a more potent controlled release system for growth factor delivery. PMID:25463489

  11. Quinones are growth factors for the human gut microbiota.

    PubMed

    Fenn, Kathrin; Strandwitz, Philip; Stewart, Eric J; Dimise, Eric; Rubin, Sarah; Gurubacharya, Shreya; Clardy, Jon; Lewis, Kim

    2017-12-20

    The human gut microbiome has been linked to numerous components of health and disease. However, approximately 25% of the bacterial species in the gut remain uncultured, which limits our ability to properly understand, and exploit, the human microbiome. Previously, we found that growing environmental bacteria in situ in a diffusion chamber enables growth of uncultured species, suggesting the existence of growth factors in the natural environment not found in traditional cultivation media. One source of growth factors proved to be neighboring bacteria, and by using co-culture, we isolated previously uncultured organisms from the marine environment and identified siderophores as a major class of bacterial growth factors. Here, we employ similar co-culture techniques to grow bacteria from the human gut microbiome and identify novel growth factors. By testing dependence of slow-growing colonies on faster-growing neighboring bacteria in a co-culture assay, eight taxonomically diverse pairs of bacteria were identified, in which an "induced" isolate formed a gradient of growth around a cultivatable "helper." This set included two novel species Faecalibacterium sp. KLE1255-belonging to the anti-inflammatory Faecalibacterium genus-and Sutterella sp. KLE1607. While multiple helper strains were identified, Escherichia coli was also capable of promoting growth of all induced isolates. Screening a knockout library of E. coli showed that a menaquinone biosynthesis pathway was required for growth induction of Faecalibacterium sp. KLE1255 and other induced isolates. Purified menaquinones induced growth of 7/8 of the isolated strains, quinone specificity profiles for individual bacteria were identified, and genome analysis suggests an incomplete menaquinone biosynthetic capability yet the presence of anaerobic terminal reductases in the induced strains, indicating an ability to respire anaerobically. Our data show that menaquinones are a major class of growth factors for bacteria

  12. Regulation of corneal repair by particle-mediated gene transfer of opioid growth factor receptor complementary DNA.

    PubMed

    Zagon, Ian S; Sassani, Joseph W; Malefyt, Kristin J; McLaughlin, Patricia J

    2006-11-01

    To determine whether molecular manipulation of the opioid growth factor receptor (OGFr) alters corneal reepithelialization following central corneal abrasion in rats. The plasmid pcDNA3.1 + OGFr, carrying the rat OGFr complementary DNA in both the sense and antisense orientations, and empty vector (EV), were delivered by gene gun to the rat cornea. After 24 hours, corneas were abraded and reepithelialization was documented by fluorescein photography. Twenty-four hours after wounding, DNA synthesis (with bromodeoxyuridine) was examined. Eyes transfected with sense constructs of OGFr had corneal defects that were 24%, 52%, and 50% larger than the EV group at 16, 24, and 28 hours, respectively. Conversely, corneas transfected with antisense constructs of OGFr had corneal defects that were 56% and 48% smaller than the EV group at 16 and 24 hours, respectively. Bromodeoxyuridine labeling in the basal and suprabasal layers of the antisense group were increased 3.3- and 3.7-fold, respectively, in DNA synthesis from corresponding EV layers; DNA synthesis was comparable in the sense and EV groups. Excess OGFr delays reepithelialization, whereas attenuation of OGFr accelerates repair of the corneal surface. Clinical Relevance Inhibition of opioid growth factor action using gene therapy could be important in the treatment of corneal diseases such as nonhealing and recurrent erosions, diabetic keratopathy, and neurotrophic keratitis.

  13. Growth factor-functionalized silk membranes support wound healing in vitro.

    PubMed

    Bienert, M; Hoss, M; Bartneck, M; Weinandy, S; Böbel, M; Jockenhövel, S; Knüchel, R; Pottbacker, K; Wöltje, M; Jahnen-Dechent, W; Neuss, S

    2017-08-16

    Chronic wounds represent a serious problem in daily medical routine requiring improved wound care. Silk of the domesticated silkworm (Bombyx mori) has been used to form a variety of biomaterials for medical applications. We genetically engineered B. mori to produce silk functionalized with growth factors to promote wound healing in vitro. In this study FGF-, EGF-, KGF-, PDGF- or VEGF-functionalized silk membranes were compared to native B. mori silk membranes without growth factors for their ability to support wound healing in vitro. All silk membranes were cytocompatible and supported macrophage secretion of neutrophil recruiting factor CXCL1 and monocyte chemoattractant protein 1 (MCP-1). VEGF-functionalized silk significantly outperformed other growth factor-functionalized silk membranes, but not native silk in angiogenesis assays. In addition, EGF- and VEGF-functionalized silk membranes slightly enhanced macrophage adhesion compared to silk without growth factors. In wound healing assays in vitro (reduction of wound lesion), dermal equivalents showed a higher wound healing capacity when covered with EGF-, FGF- or VEGF-functionalized silk membranes compared to native, KGF- or PDGF-functionalized silk membranes. Keratinocyte migration and growth is overstimulated by KGF- and VEGF-functionalized silk membranes. In conclusion, growth factor-functionalized silk membranes prepared from genetically engineered silk worm glands are promising wound dressings for future wound healing therapies.

  14. Observation of Metal Nanoparticles for Acoustic Manipulation

    PubMed Central

    Chen, Mian; Cai, Feiyan; Wang, Chen; Wang, Zhiyong; Meng, Long; Li, Fei; Zhang, Pengfei; Liu, Xin

    2017-01-01

    Use of acoustic trapping for the manipulation of objects is invaluable to many applications from cellular subdivision to biological assays. Despite remarkable progress in a wide size range, the precise acoustic manipulation of 0D nanoparticles where all the structural dimensions are much smaller than the acoustic wavelength is still present challenges. This study reports on the observation of metal nanoparticles with different nanostructures for acoustic manipulation. Results for the first time exhibit that the hollow nanostructures play more important factor than size in the nanoscale acoustic manipulation. The acoustic levitation and swarm aggregations of the metal nanoparticles can be easily realized at low energy and clinically acceptable acoustic frequency by hollowing their nanostructures. In addition, the behaviors of swarm aggregations can be flexibly regulated by the applied voltage and frequency. This study anticipates that the strategy based on the unique properties of the metal hollow nanostructures and the manipulation method will be highly desirable for many applications. PMID:28546912

  15. Observation of Metal Nanoparticles for Acoustic Manipulation.

    PubMed

    Chen, Mian; Cai, Feiyan; Wang, Chen; Wang, Zhiyong; Meng, Long; Li, Fei; Zhang, Pengfei; Liu, Xin; Zheng, Hairong

    2017-05-01

    Use of acoustic trapping for the manipulation of objects is invaluable to many applications from cellular subdivision to biological assays. Despite remarkable progress in a wide size range, the precise acoustic manipulation of 0D nanoparticles where all the structural dimensions are much smaller than the acoustic wavelength is still present challenges. This study reports on the observation of metal nanoparticles with different nanostructures for acoustic manipulation. Results for the first time exhibit that the hollow nanostructures play more important factor than size in the nanoscale acoustic manipulation. The acoustic levitation and swarm aggregations of the metal nanoparticles can be easily realized at low energy and clinically acceptable acoustic frequency by hollowing their nanostructures. In addition, the behaviors of swarm aggregations can be flexibly regulated by the applied voltage and frequency. This study anticipates that the strategy based on the unique properties of the metal hollow nanostructures and the manipulation method will be highly desirable for many applications.

  16. Therapeutic modulation of growth factors and cytokines in regenerative medicine.

    PubMed

    Ioannidou, Effie

    2006-01-01

    Regeneration that takes place in the human body is limited throughout life. Therefore, when organs are irreparably damaged, they are usually replaced with an artificial device or donor organ. The term "regenerative medicine" covers the restoration or replacement of cells, tissues, and organs. Stem cells play a major role in regenerative medicine by providing the way to repopulate organs damaged by disease. Stem cells have the ability to self renew and to regenerate cells of diverse lineages within the tissue in which they reside. Stem cells could originate from embryos or adult tissues. Growth factors are proteins that may act locally or systemically to affect the growth of cells in several ways. Various cell activities, including division, are influenced by growth factors. Cytokines are a family of low-molecular-weight proteins that are produced by numerous cell types and are responsible for regulating the immune response, inflammation, tissue remodeling and cellular differentiation. Target cells of growth factors and cytokines are mesenchymal, epithelial and endothelial cells. These molecules frequently have overlapping activities and can act in an autocrine or paracrine fashion. A complex network of growth factors and cytokines guides cellular differentiation and regeneration in all organs and tissues. The aim of this paper is to review the role of growth factors and cytokines in different organs or systems and explore their therapeutic application in regenerative medicine. The role of stem cells combined with growth factors and cytokines in the regeneration of vascular and hematopoietic, neural, skeletal, pancreatic, periodontal, and mucosal tissue is reviewed. There is evidence that supports the use of growth factors and cytokines in the treatment of neurological diseases, diabetes, cardiovascular disease, periodontal disease, cancer and its complication, oral mucositis. After solving the ethical issues and establishing clear and reasonable regulations

  17. [Effect of cryotherapy over the expression of vascular endothelial growth factor and pigment epithelium-derived factor].

    PubMed

    Toscano-Garibay, Julia Dolores; Quiroz-Mercado, Hugo; Espitia-Pinzón, Clara; Gil-Carrasco, Félix; Flores-Estrada, José Javier

    2014-01-01

    Cryotherapy is a no invasive technique that uses intense cold to freeze and destroy cancer tissues. There are no descriptions of its effects over the expression of vascular endothelial growth factor and pigment epithelium-derived factor. Experimental study in cryogenic spot were applied in the right sclera of twelve pigs for ten minutes. Other 3 pigs were used as normal controls. Animals were sacrificed at 7, 14 and 21 and the tissues of choriodes and retina were dissected in areas of approximately 1 cm2 surrounding cryogenic spots. Expression levels of vascular endothelial growth factor and pigment epithelium-derived factor were determined analyzed using polymerase chain reaction coupled to reverse-transcription. Vascular endothelial growth factor was significantly downregulated (24%, p< 0.05) seven days post-treatment meanwhile pigment epithelium-derived factor levels increased 44.8% (p< 0.05) as compared to normal controls (untreated). Both vascular endothelial growth factor and pigment epithelium-derived factor levels remain the same until day 14 but returned to basal expression at day 21. This work expose the relation of cryotherapy with the expression of two factors related to angiogenesis. RESULTS showed significant changes on the expression of vascular endothelial growth factor and pigment epithelium-derived factor illustrating that both proteins are regulated in response to cryogenic treatment in relatively short periods (21 days).

  18. Experimental manipulation of psychosocial exposure and questionnaire sensitivity in a simulated manufacturing setting.

    PubMed

    Ikuma, Laura H; Babski-Reeves, Kari; Nussbaum, Maury A

    2009-05-01

    The objectives of this study were to determine the efficacy of experimental manipulations of psychosocial exposures and to evaluate the sensitivity of a psychosocial questionnaire by determining the factors perceived. A 50-item questionnaire was developed from the job content questionnaire (JCQ) and the quality of worklife survey (QWL). The experiment involved simulated work at different physical and psychosocial levels. Forty-eight participants were exposed to two levels of one psychosocial manipulation (job control, job demands, social support, or time pressure). Significantly different questionnaire responses supported the effectiveness of psychosocial manipulations. Exploratory factor analysis revealed five factors: skill discretion and decision authority, stress level and supervisor support, physical demands, quality of coworker support, and decision-making support. These results suggest that psychosocial factors can be manipulated experimentally, and that questionnaires can distinguish perceptions of these factors. These questionnaires may be used to assess perceptions of psychosocial factors in experimental settings.

  19. EGFR ligands drive multipotential stromal cells to produce multiple growth factors and cytokines via early growth response-1.

    PubMed

    Kerpedjieva, Svetoslava S; Kim, Duk Soo; Barbeau, Dominique J; Tamama, Kenichi

    2012-09-01

    Cell therapy with adult bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) presents a promising approach to promote wound healing and tissue regeneration. The strong paracrine capability of various growth factors and cytokines is a key mechanism of MSC-mediated wound healing and tissue regeneration, and the goal of this study is to understand the underlying mechanism that supports the strong paracrine machineries in MSCs. Microarray database analyses revealed that early growth response-1 (EGR1) is highly expressed in MSCs. Our previous studies showed that epidermal growth factor (EGF) treatment induces growth factor production in MSCs in vitro. Since EGF strongly upregulates EGR1, we hypothesized that EGF receptor (EGFR)-EGR1 signaling plays a pivotal role in MSC paracrine activity. EGF treatment upregulated the gene expression of growth factors and cytokines, including EGFR ligands in a protein kinase C (PKC)- and/or mitogen-activated protein kinase-extracellular-signal-regulated kinase-dependent manner, and it was reversed by shRNA against EGR1. PKC activator phorbol 12-myristate 13-acetate enhanced EGFR tyrosyl phosphorylation and upregulated the gene expression of growth factors and cytokines in a heparin-binding EGF-like growth factor (HBEGF) inhibitor CRM197 sensitive manner, indicating an involvement of autocrined HBEGF in the downstream of PKC signaling. Moreover, stimulation with growth factors and cytokines induced the expression of EGFR ligands, presumably via EGR1 upregulation. These data indicate EGR1 as a convergence point of multiple signaling pathways, which in turn augments the production of multiple growth factors and cytokines by enhancing the autocrine signaling with EGFR ligands.

  20. Keratinocyte growth factor is a growth factor for mammary epithelium in vivo. The mammary epithelium of lactating rats is resistant to the proliferative action of keratinocyte growth factor.

    PubMed Central

    Ulich, T. R.; Yi, E. S.; Cardiff, R.; Yin, S.; Bikhazi, N.; Biltz, R.; Morris, C. F.; Pierce, G. F.

    1994-01-01

    Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family. KGF is secreted by stromal cells and affects epithelial but not mesenchymal cell proliferation. KGF injected intravenously was found to cause dramatic proliferation of mammary epithelium in the mammary glands of rats. KGF causes ductal neogenesis and intraductal epithelial hyperplasia but not lobular differentiation in nulliparous female rats. KGF causes ductal and lobular epithelial hyperplasia in male rats. KGF causes proliferation of ductal and acinar cells in the mammary glands of pregnant rats. On the other hand, the ductal epithelium of lactating postpartum rats is resistant to the proliferative action of KGF. The mammary glands of lactating rats did not express less KGF receptor mRNA than the glands of pregnant rats, suggesting that the resistance of the ductal epithelium to KGF during lactation is not related to KGF receptor mRNA down-regulation. The mammary glands of both pregnant and postpartum lactating rats express KGF mRNA with more KGF present in the glands of lactating rats. In conclusion, the KGF and KGF receptor genes are expressed in rat mammary glands and recombinant KGF is a potent growth factor for mammary epithelium. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8178937

  1. The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia.

    PubMed

    Moises, Hans W; Zoega, Tomas; Gottesman, Irving I

    2002-07-03

    A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors. Based on a co-localization of loci approach and a large amount of circumstantial evidence, we here propose that a functional deficiency of glial growth factors and of growth factors produced by glial cells are among the distal causes in the genotype-to-phenotype chain leading to the development of schizophrenia. These factors include neuregulin, insulin-like growth factor I, insulin, epidermal growth factor, neurotrophic growth factors, erbB receptors, phosphatidylinositol-3 kinase, growth arrest specific genes, neuritin, tumor necrosis factor alpha, glutamate, NMDA and cholinergic receptors. A genetically and epigenetically determined low baseline of glial growth factor signaling and synaptic strength is expected to increase the vulnerability for additional reductions (e.g., by viruses such as HHV-6 and JC virus infecting glial cells). This should lead to a weakening of the positive feedback loop between the presynaptic neuron and its targets, and below a certain threshold to synaptic destabilization and schizophrenia. Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations. The hypothesis suggests glial cells as the locus of the genes-environment interactions in schizophrenia, with glial asthenia as an important factor for the genetic liability to the disorder, and an increase of prolactin and/or insulin as possible working mechanisms of traditional and atypical neuroleptic treatments.

  2. Cloning of a cancer cell-producing hepatocyte growth factor, vascular endothelial growth factor, and interleukin-8 from gastric cancer cells.

    PubMed

    Iwai, Mineko; Matsuda, Masahiko; Iwai, Yoshiaki

    2003-01-01

    A cell colony (IM95m) that produces hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) was cloned from gastric cancer cells (IM95 cell line). In culture medium, the highest levels of HGF, VEGF, and IL-8 were about 1.1, 0.9, and 0.17 ng/ml culture medium at 3 d from 10(5) cells. IM95m may be useful in elucidating the role of tumor cells in angiogenesis.

  3. Impaired growth in Rabson-Mendenhall syndrome: lack of effect of growth hormone and insulin-like growth factor-I.

    PubMed

    Longo, N; Singh, R; Griffin, L D; Langley, S D; Parks, J S; Elsas, L J

    1994-09-01

    Mutations in the insulin receptor gene cause the severe insulin-resistant syndromes leprechaunism and Rabson-Mendenhall syndrome. There is no accepted therapy for these inherited conditions. Here we report the results of recombinant human GH (rhGH) and recombinant human insulin-like growth factor-I (rhIGF-I) treatment of a male patient, Atl-2, with Rabson-Mendenhall syndrome. The patient was small for gestational age, had premature dentition, absence of sc fat, acanthosis nigricans, fasting hypoglycemia and postprandial hyperglycemia, and extremely high concentrations of circulating insulin (up to 8500 microU/mL). Fibroblasts and lymphoblasts established from this patient had reduced insulin binding, which was 20-30% of the control value. Binding of epidermal growth factor, IGF-I, and GH to the patient's fibroblasts was normal. The growth of fibroblasts cultured from patient Atl-2 in vitro was intermediate between that of fibroblasts from patients with leprechaunism and control values. The patient's growth curve in vivo was far below the fifth percentile despite adequate nutrition. To stimulate growth, therapy with rhGH was initiated, the rationale being to stimulate hepatic IGF-I production and IGF-I receptor signaling, and bypass the inherited block in insulin receptor signaling. Therapy with rhGH (up to 0.5 mg/kg.week) did not improve growth and failed to increase the levels of circulating IGF-I and IGF-binding protein-3 over a 14-month period. As rhGH could not stimulate growth, rhIGF-I (up to 100 micrograms/kg.day) was given by daily sc injection. No increase in growth velocity was observed over a 14-month period. These results indicate that both GH and IGF-I fail to correct growth in a patient with severe inherited insulin resistance. The lack of efficacy of IGF-I treatment may be related to multiple factors, such as the poor metabolic state of the patient, the deficiency of serum carrier protein for IGF-I, an increased clearance of the growth factor, IGF

  4. Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway.

    PubMed

    Zhang, Mingdi; Cai, Shizhong; Zuo, Bin; Gong, Wei; Tang, Zhaohui; Zhou, Di; Weng, Mingzhe; Qin, Yiyu; Wang, Shouhua; Liu, Jun; Ma, Fei; Quan, Zhiwei

    2017-05-01

    Gallbladder cancer has poor prognosis and limited therapeutic options. Arctigenin, a representative dibenzylbutyrolactone lignan, occurs in a variety of plants. However, the molecular mechanisms involved in the antitumor effect of arctigenin on gallbladder cancer have not been fully elucidated. The expression levels of epidermal growth factor receptor were examined in 100 matched pairs of gallbladder cancer tissues. A positive correlation between high epidermal growth factor receptor expression levels and poor prognosis was observed in gallbladder cancer tissues. Pharmacological inhibition or inhibition via RNA interference of epidermal growth factor receptor induced cellular senescence in gallbladder cancer cells. The antitumor effect of arctigenin on gallbladder cancer cells was primarily achieved by inducing cellular senescence. In gallbladder cancer cells treated with arctigenin, the expression level of epidermal growth factor receptor significantly decreased. The analysis of the activity of the kinases downstream of epidermal growth factor receptor revealed that the RAF-MEK-ERK signaling pathway was significantly inhibited. Furthermore, the cellular senescence induced by arctigenin could be reverted by pcDNA-epidermal growth factor receptor. Arctigenin also potently inhibited the growth of tumor xenografts, which was accompanied by the downregulation of epidermal growth factor receptor and induction of senescence. This study demonstrates arctigenin could induce cellular senescence in gallbladder cancer through the modulation of epidermal growth factor receptor pathway. These data identify epidermal growth factor receptor as a key regulator in arctigenin-induced gallbladder cancer senescence.

  5. Redox-regulated growth factor survival signaling.

    PubMed

    Woolley, John F; Corcoran, Aoife; Groeger, Gillian; Landry, William D; Cotter, Thomas G

    2013-11-20

    Once the thought of as unwanted byproducts of cellular respiration in eukaryotes, reactive oxygen species (ROS) have been shown to facilitate essential physiological roles. It is now understood that ROS are critical mediators of intracellular signaling. Control of signal transduction downstream of growth factor receptors by ROS is a complex process whose details are only recently coming to light. Indeed, recent evidence points to control of signal propagation by ROS at multiple levels in the typical cascade. Growth factor stimulation activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Noxs) at the membrane, producing superoxide in the extracellular matrix, which is catalyzed to the membrane-permeable hydrogen peroxide (H2O2) that mediates intracellular signaling events. The potential for H2O2, however, to disrupt cellular functions by damaging proteins and nucleic acids demands that its levels are kept in check by receptor-associated peroxiredoxins. This interplay of Nox and peroxiredoxin activity moderates levels of H2O2 sufficiently to modify signaling partners locally. Among the best studied of these partners are redox-controlled phosphatases that are inactivated by H2O2. Phosphatases regulate signal propagation downstream of receptors, and thus their inactivation allows a further level of control. Transmission of information further downstream to targets such as transcription factors, themselves regulated by ROS, completes this pathway. Thus, signal propagation or attenuation can be dictated by ROS at multiple points. Given the complex nature of these processes, we envisage the emerging trends in the field of redox signaling in the context of growth factor stimulation.

  6. Endosomal receptor kinetics determine the stability of intracellular growth factor signalling complexes

    PubMed Central

    Tzafriri, A. Rami; Edelman, Elazer R.

    2006-01-01

    There is an emerging paradigm that growth factor signalling continues in the endosome and that cell response to a growth factor is defined by the integration of cell surface and endosomal events. As activated receptors in the endosome are exposed to a different set of binding partners, they probably elicit differential signals compared with when they are at the cell surface. As such, complete appreciation of growth factor signalling requires understanding of growth factor–receptor binding and trafficking kinetics both at the cell surface and in endosomes. Growth factor binding to surface receptors is well characterized, and endosomal binding is assumed to follow surface kinetics if one accounts for changes in pH. Yet, specific binding kinetics within the endosome has not been examined in detail. To parse the factors governing the binding state of endosomal receptors we analysed a whole-cell mathematical model of epidermal growth factor receptor trafficking and binding. We discovered that the stability of growth factor–receptor complexes within endosomes is governed by three primary independent factors: the endosomal dissociation constant, total endosomal volume and the number of endosomal receptors. These factors were combined into a single dimensionless parameter that determines the endosomal binding state of the growth factor–receptor complex and can distinguish different growth factors from each other and different cell states. Our findings indicate that growth factor binding within endosomal compartments cannot be appreciated solely on the basis of the pH-dependence of the dissociation constant and that the concentration of receptors in the endosomal compartment must also be considered. PMID:17117924

  7. EGFR Ligands Drive Multipotential Stromal Cells to Produce Multiple Growth Factors and Cytokines via Early Growth Response-1

    PubMed Central

    Kerpedjieva, Svetoslava S.; Kim, Duk Soo; Barbeau, Dominique J.

    2012-01-01

    Cell therapy with adult bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) presents a promising approach to promote wound healing and tissue regeneration. The strong paracrine capability of various growth factors and cytokines is a key mechanism of MSC-mediated wound healing and tissue regeneration, and the goal of this study is to understand the underlying mechanism that supports the strong paracrine machineries in MSCs. Microarray database analyses revealed that early growth response-1 (EGR1) is highly expressed in MSCs. Our previous studies showed that epidermal growth factor (EGF) treatment induces growth factor production in MSCs in vitro. Since EGF strongly upregulates EGR1, we hypothesized that EGF receptor (EGFR)–EGR1 signaling plays a pivotal role in MSC paracrine activity. EGF treatment upregulated the gene expression of growth factors and cytokines, including EGFR ligands in a protein kinase C (PKC)- and/or mitogen-activated protein kinase–extracellular-signal-regulated kinase-dependent manner, and it was reversed by shRNA against EGR1. PKC activator phorbol 12-myristate 13-acetate enhanced EGFR tyrosyl phosphorylation and upregulated the gene expression of growth factors and cytokines in a heparin-binding EGF-like growth factor (HBEGF) inhibitor CRM197 sensitive manner, indicating an involvement of autocrined HBEGF in the downstream of PKC signaling. Moreover, stimulation with growth factors and cytokines induced the expression of EGFR ligands, presumably via EGR1 upregulation. These data indicate EGR1 as a convergence point of multiple signaling pathways, which in turn augments the production of multiple growth factors and cytokines by enhancing the autocrine signaling with EGFR ligands. PMID:22316125

  8. Isolation of a cDNA for a Growth Factor of Vascular Endothelial Cells from Human Lung Cancer Cells: Its Identity with Insulin‐like Growth Factor II

    PubMed Central

    Hagiwara, Koichi; Kobayashi, Tatsuo; Tobita, Masato; Kikyo, Nobuaki; Yazaki, Yoshio

    1995-01-01

    We have found growth‐promoting activity for vascular endothelial cells in the conditioned medium of a human lung cancer cell line, T3M‐11. Purification and characterization of the growth‐promoting activity have been carried out using ammonium sulfate precipitation and gel‐exclusion chromatography. The activity migrated as a single peak just after ribonuclease. It did not bind to a heparin affinity column. These results suggest that the activity is not a heparin‐binding growth factor (including fibroblast growth factors) or a vascular endothelial growth factor. To identify the molecule exhibiting the growth‐promoting activity, a cDNA encoding the growth factor was isolated through functional expression cloning in COS‐1 cells from a cDNA library prepared from T3M‐11 cells. The nucleotide sequence encoded by the cDNA proved to be identical with that of insulin‐like growth factor II. PMID:7730145

  9. Insulin-like growth factor-I receptor activity is essential for Kaposi's sarcoma growth and survival.

    PubMed

    Catrina, S-B; Lewitt, M; Massambu, C; Dricu, A; Grünler, J; Axelson, M; Biberfeld, P; Brismar, K

    2005-04-25

    Kaposi's sarcoma (KS) is a highly vascular tumour and is the most common neoplasm associated with human immunodeficiency virus (HIV-1) infection. Growth factors, in particular vascular endothelial growth factor (VEGF), have been shown to play an important role in its development. The role of insulin-like growth factors (IGFs) in the pathophysiology of different tumours led us to evaluate the role of IGF system in KS. The IGF-I receptors (IGF-IR) were identified by immunohistochemistry in biopsies taken from patients with different AIDS/HIV-related KS stages and on KSIMM cells (an established KS-derived cell line). Insulin-like growth factor-I is a growth factor for KSIMM cells with a maximum increase of 3H-thymidine incorporation of 130 +/- 27.6% (P < 0.05) similar to that induced by VEGF and with which it is additive (281 +/- 13%) (P < 0.05). Moreover, specific blockade of the receptor (either by alpha IR3 antibody or by picropodophyllin, a recently described selective IGF-IR tyrosine phosphorylation inhibitor) induced KSIMM apoptosis, suggesting that IGF-IR agonists (IGF-I and -II) mediate antiapoptotic signals for these cells. We were able to identify an autocrine loop essential for KSIMM cell survival in which IGF-II is the IGF-IR agonist secreted by the cells. In conclusion, IGF-I pathway inhibition is a promising therapeutical approach for KS tumours.

  10. The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia

    PubMed Central

    Moises, Hans W; Zoega, Tomas; Gottesman, Irving I

    2002-01-01

    Background A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors. Presentation of the hypothesis Based on a co-localization of loci approach and a large amount of circumstantial evidence, we here propose that a functional deficiency of glial growth factors and of growth factors produced by glial cells are among the distal causes in the genotype-to-phenotype chain leading to the development of schizophrenia. These factors include neuregulin, insulin-like growth factor I, insulin, epidermal growth factor, neurotrophic growth factors, erbB receptors, phosphatidylinositol-3 kinase, growth arrest specific genes, neuritin, tumor necrosis factor alpha, glutamate, NMDA and cholinergic receptors. A genetically and epigenetically determined low baseline of glial growth factor signaling and synaptic strength is expected to increase the vulnerability for additional reductions (e.g., by viruses such as HHV-6 and JC virus infecting glial cells). This should lead to a weakening of the positive feedback loop between the presynaptic neuron and its targets, and below a certain threshold to synaptic destabilization and schizophrenia. Testing the hypothesis Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations. Implications of the hypothesis The hypothesis suggests glial cells as the locus of the genes-environment interactions in schizophrenia, with glial asthenia as an important factor for the genetic liability to the disorder, and an increase of prolactin and/or insulin as possible working mechanisms of traditional and atypical neuroleptic treatments. PMID:12095426

  11. The Effects of Hematopoietic Growth Factors on Neurite Outgrowth

    PubMed Central

    Su, Ye; Cui, Lili; Piao, Chunshu; Li, Bin; Zhao, Li-Ru

    2013-01-01

    Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) are initially discovered as the essential hematopoietic growth factors regulating bone marrow stem cell proliferation and differentiation, and SCF in combination with G-CSF (SCF+G-CSF) has synergistic effects on bone marrow stem cell mobilization. In this study we have determined the effect of SCF and G-CSF on neurite outgrowth in rat cortical neurons. Using molecular and cellular biology and live cell imaging approaches, we have revealed that receptors for SCF and G-CSF are expressed on the growth core of cortical neurons, and that SCF+G-CSF synergistically enhances neurite extension through PI3K/AKT and NFκB signaling pathways. Moreover, SCF+G-CSF induces much greater NFκB activation, NFκB transcriptional binding and brain-derived neurotrophic factor (BDNF) production than SCF or G-CSF alone. In addition, we have also observed that BDNF, the target gene of NFκB, is required for SCF+G-CSF-induced neurite outgrowth. These data suggest that SCF+G-CSF has synergistic effects to promote neurite growth. This study provides new insights into the contribution of hematopoietic growth factors in neuronal plasticity. PMID:24116056

  12. Normal growth and development in the absence of hepatic insulin-like growth factor I

    PubMed Central

    Yakar, Shoshana; Liu, Jun-Li; Stannard, Bethel; Butler, Andrew; Accili, Domenici; Sauer, Brian; LeRoith, Derek

    1999-01-01

    The somatomedin hypothesis proposed that insulin-like growth factor I (IGF-I) was a hepatically derived circulating mediator of growth hormone and is a crucial factor for postnatal growth and development. To reassess this hypothesis, we have used the Cre/loxP recombination system to delete the igf1 gene exclusively in the liver. igf1 gene deletion in the liver abrogated expression of igf1 mRNA and caused a dramatic reduction in circulating IGF-I levels. However, growth as determined by body weight, body length, and femoral length did not differ from wild-type littermates. Although our model proves that hepatic IGF-I is indeed the major contributor to circulating IGF-I levels in mice it challenges the concept that circulating IGF-I is crucial for normal postnatal growth. Rather, our model provides direct evidence for the importance of the autocrine/paracrine role of IGF-I. PMID:10377413

  13. Insulin-like growth factor 1 (IGF-1): a growth hormone

    PubMed Central

    Laron, Z

    2001-01-01

    Aim—To contribute to the debate about whether growth hormone (GH) and insulin-like growth factor 1 (IGF-1) act independently on the growth process. Methods—To describe growth in human and animal models of isolated IGF-1 deficiency (IGHD), such as in Laron syndrome (LS; primary IGF-1 deficiency and GH resistance) and IGF-1 gene or GH receptor gene knockout (KO) mice. Results—Since the description of LS in 1966, 51 patients were followed, many since infancy. Newborns with LS are shorter (42–47 cm) than healthy babies (49–52 cm), suggesting that IGF-1 has some influence on intrauterine growth. Newborn mice with IGF-1 gene KO are 30% smaller. The postnatal growth rate of patients with LS is very slow, the distance from the lowest normal centile increasing progressively. If untreated, the final height is 100–136 cm for female and 109–138 cm for male patients. They have acromicia, organomicria including the brain, heart, gonads, genitalia, and retardation of skeletal maturation. The availability of biosynthetic IGF-1 since 1988 has enabled it to be administered to children with LS. It accelerated linear growth rates to 8–9 cm in the first year of treatment, compared with 10–12 cm/year during GH treatment of IGHD. The growth rate in following years was 5–6.5 cm/year. Conclusion—IGF-1 is an important growth hormone, mediating the protein anabolic and linear growth promoting effect of pituitary GH. It has a GH independent growth stimulating effect, which with respect to cartilage cells is possibly optimised by the synergistic action with GH. PMID:11577173

  14. Increased Melanoma Growth and Metastasis Spreading in Mice Overexpressing Placenta Growth Factor

    PubMed Central

    Marcellini, Marcella; De Luca, Naomi; Riccioni, Teresa; Ciucci, Alessandro; Orecchia, Angela; Lacal, Pedro Miguel; Ruffini, Federica; Pesce, Maurizio; Cianfarani, Francesca; Zambruno, Giovanna; Orlandi, Augusto; Failla, Cristina Maria

    2006-01-01

    Placenta growth factor (PlGF), a member of the vascular endothelial growth factor family, plays an important role in adult pathological angiogenesis. To further investigate PlGF functions in tumor growth and metastasis formation, we used transgenic mice overexpressing PlGF in the skin under the control of the keratin 14 promoter. These animals showed a hypervascularized phenotype of the skin and increased levels of circulating PlGF with respect to their wild-type littermates. Transgenic mice and controls were inoculated intradermally with B16-BL6 melanoma cells. The tumor growth rate was fivefold increased in transgenic animals compared to wild-type mice, in the presence of a similar percentage of tumor necrotic tissue. Tumor vessel area was increased in transgenic mice as compared to controls. Augmented mobilization of endothelial and hematopoietic stem cells from the bone marrow was observed in transgenic animals, possibly contributing to tumor vascularization. The number and size of pulmonary metastases were significantly higher in transgenic mice compared to wild-type littermates. Finally, PlGF promoted tumor cell invasion of the extracellular matrix and increased the activity of selected matrix metalloproteinases. These findings indicate that PlGF, in addition to enhancing tumor angiogenesis and favoring tumor growth, may directly influence melanoma dissemination. PMID:16877362

  15. Regulation of cell growth by redox-mediated extracellular proteolysis of platelet-derived growth factor receptor beta.

    PubMed

    Okuyama, H; Shimahara, Y; Kawada, N; Seki, S; Kristensen, D B; Yoshizato, K; Uyama, N; Yamaoka, Y

    2001-07-27

    Redox-regulated processes are important elements in various cellular functions. Reducing agents, such as N-acetyl-l-cysteine (NAC), are known to regulate signal transduction and cell growth through their radical scavenging action. However, recent studies have shown that reactive oxygen species are not always involved in ligand-stimulated intracellular signaling. Here, we report a novel mechanism by which NAC blocks platelet-derived growth factor (PDGF)-induced signaling pathways in hepatic stellate cells, a fibrogenic player in the liver. Unlike in vascular smooth muscle cells, we found that reducing agents, including NAC, triggered extracellular proteolysis of PDGF receptor-beta, leading to desensitization of hepatic stellate cells toward PDGF-BB. This effect was mediated by secreted mature cathepsin B. In addition, type II transforming growth factor-beta receptor was also down-regulated. Furthermore, these events seemed to cause a dramatic improvement of rat liver fibrosis. These results indicated that redox processes impact the cell's response to growth factors by regulating the turnover of growth factor receptors and that "redox therapy" is promising for fibrosis-related disease.

  16. Autocrine expression of the epidermal growth factor receptor ligand heparin-binding EGF-like growth factor in cervical cancer.

    PubMed

    Schrevel, Marlies; Osse, E Michelle; Prins, Frans A; Trimbos, J Baptist M Z; Fleuren, Gert Jan; Gorter, Arko; Jordanova, Ekaterina S

    2017-06-01

    In cervical cancer, the epidermal growth factor receptor (EGFR) is overexpressed in 70-90% of the cases and has been associated with poor prognosis. EGFR-based therapy is currently being explored in cervical cancer. We investigated which EGFR ligand is primarily expressed in cervical cancer and which cell type functions as the major source of this ligand. We hypothesized that macrophages are the main source of EGFR ligands and that a paracrine loop between tumor cells and macrophages is responsible for ligand expression. mRNA expression analysis was performed on 32 cervical cancer cases to determine the expression of the EGFR ligands amphiregulin, β-cellulin, epidermal growth factor (EGF), epiregulin, heparin-binding EGF-like growth factor (HB‑EGF) and transforming growth factor α (TGFα). Subsequently, protein expression was determined immunohistochemically on 36 additional cases. To assess whether macrophages are the major source of EGFR ligands, immunohistochemical double staining was performed on four representative tissue slides. Expression of the chemokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and C-C motif ligand 2 (CCL2) was determined by mRNA in situ hybridization. Of the known EGFR ligands, HB‑EGF had the highest mRNA expression and HB‑EGF and EGFR protein expression were highly correlated. Tumor specimens with high EGFR expression showed higher numbers of macrophages, and higher expression of GM-CSF and CCL2, but only a small subset (9%) of macrophages was found to be HB‑EGF-positive. Strikingly, 78% of cervical cancer specimens were found to express HB‑EGF. Standardized assessment of staining intensity, using spectral imaging analysis, showed that HB‑EGF expression was higher in the tumor compartment than in the stromal compartment. These results suggest that HB‑EGF is an important EGFR ligand in cervical cancer and that cervical cancer cells are the predominant source of HB‑EGF. Therefore, we propose an autocrine

  17. Mitochondrial respiratory control is lost during growth factor deprivation.

    PubMed

    Gottlieb, Eyal; Armour, Sean M; Thompson, Craig B

    2002-10-01

    The ability of cells to maintain a bioenergetically favorable ATP/ADP ratio confers a tight balance between cellular events that consume ATP and the rate of ATP production. However, after growth factor withdrawal, the cellular ATP/ADP ratio declines. To investigate these changes, mitochondria from growth factor-deprived cells isolated before the onset of apoptosis were characterized in vitro. Mitochondria from growth factor-deprived cells have lost their ability to undergo matrix condensation in response to ADP, which is accompanied by a failure to perform ADP-coupled respiration. At the time of analysis, mitochondria from growth factor-deprived cells were not depleted of cytochrome c and cytochrome c-dependent respiration was unaffected, demonstrating that the inhibition of the respiratory rate is not due to loss of cytochrome c. Agents that disrupt the mitochondrial outer membrane, such as digitonin, or maintain outer membrane exchange of adenine nucleotide, such as Bcl-x(L), restored ADP-dependent control of mitochondrial respiration. Together, these data suggest that the regulation of mitochondrial outer membrane permeability contributes to respiratory control.

  18. Mitochondrial respiratory control is lost during growth factor deprivation

    PubMed Central

    Gottlieb, Eyal; Armour, Sean M.; Thompson, Craig B.

    2002-01-01

    The ability of cells to maintain a bioenergetically favorable ATP/ADP ratio confers a tight balance between cellular events that consume ATP and the rate of ATP production. However, after growth factor withdrawal, the cellular ATP/ADP ratio declines. To investigate these changes, mitochondria from growth factor-deprived cells isolated before the onset of apoptosis were characterized in vitro. Mitochondria from growth factor-deprived cells have lost their ability to undergo matrix condensation in response to ADP, which is accompanied by a failure to perform ADP-coupled respiration. At the time of analysis, mitochondria from growth factor-deprived cells were not depleted of cytochrome c and cytochrome c-dependent respiration was unaffected, demonstrating that the inhibition of the respiratory rate is not due to loss of cytochrome c. Agents that disrupt the mitochondrial outer membrane, such as digitonin, or maintain outer membrane exchange of adenine nucleotide, such as Bcl-xL, restored ADP-dependent control of mitochondrial respiration. Together, these data suggest that the regulation of mitochondrial outer membrane permeability contributes to respiratory control. PMID:12228733

  19. Intestinal hormones and growth factors: Effects on the small intestine

    PubMed Central

    Drozdowski, Laurie; Thomson, Alan BR

    2009-01-01

    There are various hormones and growth factors which may modify the intestinal absorption of nutrients, and which might thereby be useful in a therapeutic setting, such as in persons with short bowel syndrome. In partI, we focus first on insulin-like growth factors, epidermal and transferring growth factors, thyroid hormones and glucocorticosteroids. Part II will detail the effects of glucagon-like peptide (GLP)-2 on intestinal absorption and adaptation, and the potential for an additive effect of GLP2 plus steroids. PMID:19152442

  20. E2F1 transcription factor and its impact on growth factor and cytokine signaling.

    PubMed

    Ertosun, Mustafa Gokhan; Hapil, Fatma Zehra; Osman Nidai, Ozes

    2016-10-01

    E2F1 is a transcription factor involved in cell cycle regulation and apoptosis. The transactivation capacity of E2F1 is regulated by pRb. In its hypophosphorylated form, pRb binds and inactivates DNA binding and transactivating functions of E2F1. The growth factor stimulation of cells leads to activation of CDKs (cyclin dependent kinases), which in turn phosphorylate Rb and hyperphosphorylated Rb is released from E2F1 or E2F1/DP complex, and free E2F1 can induce transcription of several genes involved in cell cycle entry, induction or inhibition of apoptosis. Thus, growth factors and cytokines generally utilize E2F1 to direct cells to either fate. Furthermore, E2F1 regulates expressions of various cytokines and growth factor receptors, establishing positive or negative feedback mechanisms. This review focuses on the relationship between E2F1 transcription factor and cytokines (IL-1, IL-2, IL-3, IL-6, TGF-beta, G-CSF, LIF), growth factors (EGF, KGF, VEGF, IGF, FGF, PDGF, HGF, NGF), and interferons (IFN-α, IFN-β and IFN-γ). Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Natural Killer Cells Control Tumor Growth by Sensing a Growth Factor.

    PubMed

    Barrow, Alexander D; Edeling, Melissa A; Trifonov, Vladimir; Luo, Jingqin; Goyal, Piyush; Bohl, Benjamin; Bando, Jennifer K; Kim, Albert H; Walker, John; Andahazy, Mary; Bugatti, Mattia; Melocchi, Laura; Vermi, William; Fremont, Daved H; Cox, Sarah; Cella, Marina; Schmedt, Christian; Colonna, Marco

    2018-01-25

    Many tumors produce platelet-derived growth factor (PDGF)-DD, which promotes cellular proliferation, epithelial-mesenchymal transition, stromal reaction, and angiogenesis through autocrine and paracrine PDGFRβ signaling. By screening a secretome library, we found that the human immunoreceptor NKp44, encoded by NCR2 and expressed on natural killer (NK) cells and innate lymphoid cells, recognizes PDGF-DD. PDGF-DD engagement of NKp44 triggered NK cell secretion of interferon gamma (IFN)-γ and tumor necrosis factor alpha (TNF-α) that induced tumor cell growth arrest. A distinctive transcriptional signature of PDGF-DD-induced cytokines and the downregulation of tumor cell-cycle genes correlated with NCR2 expression and greater survival in glioblastoma. NKp44 expression in mouse NK cells controlled the dissemination of tumors expressing PDGF-DD more effectively than control mice, an effect enhanced by blockade of the inhibitory receptor CD96 or CpG-oligonucleotide treatment. Thus, while cancer cell production of PDGF-DD supports tumor growth and stromal reaction, it concomitantly activates innate immune responses to tumor expansion. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Skeletal Effects of Growth Hormone and Insulin-like Growth Factor-I Therapy

    PubMed Central

    Lindsey, Richard C.; Mohan, Subburaman

    2015-01-01

    The growth hormone/insulin-like growth factor (GH/IGF) axis is critically important for the regulation of bone formation, and deficiencies in this system have been shown to contribute to the development of osteoporosis and other diseases of low bone mass. The GH/IGF axis is regulated by a complex set of hormonal and local factors which can act to regulate this system at the level of the ligands, receptors, IGF binding proteins (IGFBPs), or IGFBP proteases. A combination of in vitro studies, transgenic animal models, and clinical human investigations has provided ample evidence of the importance of the endocrine and local actions of both GH and IGF-I, the two major components of the GH/IGF axis, in skeletal growth and maintenance. GH- and IGF-based therapies provide a useful avenue of approach for the prevention and treatment of diseases such as osteoporosis. PMID:26408965

  3. Stimulation of body weight increase and epiphyseal cartilage growth by insulin like growth factor

    NASA Technical Reports Server (NTRS)

    Ellis, S.

    1981-01-01

    The ability of insulin-like growth factor (IGF) to induce growth in hypophysectomized immature rats was tested by continuous infusion of the partially purified factor at daily doses of 6, 21, and 46 mU for an 8-day period. A dose-dependent growth of the proximal epiphyseal cartilage of the tibia and an associated stimulation of the primary spongiosa were produced by these amounts of IGF. The two highest doses of IGF also resulted in dose-dependent increases of body weight. Gel permeation of the sera at neutrality showed that the large-molecular-weight IGF binding protein was not induced by the infusion of IGF, whereas it ws generated in the sera of hypophysectomized rats that were infused with daily doses of 86 mU of human growth hormone.

  4. LATE EVALUATION OF PATIENTS UNDERGOING MANIPULATION OF THE KNEE AFTER TOTAL ARTHROPLASTY.

    PubMed

    DE Sousa, Pedro Guilme Teixeira; Chisté, Yuri Lubiana; Albuquerque, Rodrigo Sattamini Pires E; Cobra, Hugo Alexandre DE Araújo Barros; Barretto, João Maurício; Cavanellas, Naasson Trindade

    2017-01-01

    We compared gains in range of motion in patients who underwent manipulation within 12 weeks of total knee arthroplasty (TKA) and after this period. We also evaluated maintenance of the arc obtained from knee manipulation in late follow-up, along with factors associated with poorer outcomes. The study was divided into two groups according to the time after TKA; the surgeries took place between January 2008 and December 2014. When comparing the range of motion between early and late manipulations, the group that underwent manipulation within 12 weeks of the TKA exhibited better outcomes, but these were not statistically significant. We observed that 14.3% of cases retained the same range attained at the time of manipulation. In late evaluation after manipulation, 47.7% of the sample had a range of less than 90 degrees. The significant risk factors for recurrence of knee stiffness in the long term are poor range of motion before TKA and before manipulation, female sex, and secondary arthritis. Women previously diagnosed with secondary osteoarthritis and poor range of motion before TKA or manipulation are at higher risk for late stiffness. Level of Evidence III, Retrospective Comparative Study.

  5. Insulin-like growth factors in embryonic and fetal growth and skeletal development (Review).

    PubMed

    Agrogiannis, Georgios D; Sifakis, Stavros; Patsouris, Efstratios S; Konstantinidou, Anastasia E

    2014-08-01

    The insulin-like growth factors (IGF)-I and -II have a predominant role in fetal growth and development. IGFs are involved in the proliferation, differentiation and apoptosis of fetal cells in vitro and the IGF serum concentration has been shown to be closely correlated with fetal growth and length. IGF transcripts and peptides have been detected in almost every fetal tissue from as early in development as pre‑implantation to the final maturation stage. Furthermore, IGFs have been demonstrated to be involved in limb morphogenesis. However, although ablation of Igf genes in mice resulted in growth retardation and delay in skeletal maturation, no impact on outgrowth and patterning of embryonic limbs was observed. Additionally, various molecular defects in the Igf1 and Igf1r genes in humans have been associated with severe intrauterine growth retardation and impaired skeletal maturation, but not with truncated limbs or severe skeletal dysplasia. The conflicting data between in vitro and in vivo observations with regard to bone morphogenesis suggests that IGFs may not be the sole trophic factors involved in fetal skeletal growth and that redundant mechanisms may exist in chondro- and osteogenesis. Further investigation is required in order to elucidate the functions of IGFs in skeletal development.

  6. Fish genome manipulation and directional breeding.

    PubMed

    Ye, Ding; Zhu, ZuoYan; Sun, YongHua

    2015-02-01

    Aquaculture is one of the fastest developing agricultural industries worldwide. One of the most important factors for sustainable aquaculture is the development of high performing culture strains. Genome manipulation offers a powerful method to achieve rapid and directional breeding in fish. We review the history of fish breeding methods based on classical genome manipulation, including polyploidy breeding and nuclear transfer. Then, we discuss the advances and applications of fish directional breeding based on transgenic technology and recently developed genome editing technologies. These methods offer increased efficiency, precision and predictability in genetic improvement over traditional methods.

  7. Why do spinal manipulation techniques take the form they do? Towards a general model of spinal manipulation.

    PubMed

    Evans, David W

    2010-06-01

    For centuries, techniques used to manipulate joints in the spine have been passed down from one generation of manipulators to the next. Today, spinal manipulation is in the curious position that positive clinical effects have now been demonstrated, yet the theoretical base underpinning every aspect of its use is still underdeveloped. An important question is posed in this masterclass: why do spinal manipulation techniques take the form they do? From the available literature, two factors appear to provide an answer: 1. Action of a force upon vertebrae. Any 'direct' spinal manipulation technique requires that the patient be orientated in such a way that force is applied perpendicular to the overlying skin surface so as to act upon the vertebrae beneath. If the vertebral motion produced by 'directly' applied force is insufficient to produce the desired effect (e.g. cavitation), then force must be applied 'indirectly', often through remote body segments such as the head, thorax, abdomen, pelvis, and extremities. 2. Spinal segment morphology. A new hypothesis is presented. Spinal manipulation techniques exploit the morphology of vertebrae by inducing rotation at a spinal segment, about an axis that is always parallel to the articular surfaces of the constituent zygapophysial joints. In doing so, the articular surfaces of one zygapophysial joint appose to the point of contact, resulting in migration of the axis of rotation towards these contacting surfaces, and in turn this facilitates gapping of the other (target) zygapophysial joint. Other variations in the form of spinal manipulation techniques are likely to depend upon the personal style and individual choices of the practitioner.

  8. Growth factor delivery: How surface interactions modulate release in vitro and in vivo

    PubMed Central

    King, William J.; Krebsbach, Paul H.

    2013-01-01

    Biomaterial scaffolds have been extensively used to deliver growth factors to induce new bone formation. The pharmacokinetics of growth factor delivery has been a critical regulator of their clinical success. This review will focus on the surface interactions that control the non-covalent incorporation of growth factors into scaffolds and the mechanisms that control growth factor release from clinically relevant biomaterials. We will focus on the delivery of recombinant human bone morphogenetic protein-2 from materials currently used in the clinical practice, but also suggest how general mechanisms that control growth factor incorporation and release delineated with this growth factor could extend to other systems. A better understanding of the changing mechanisms that control growth factor release during the different stages of preclinical development could instruct the development of future scaffolds for currently untreatable injuries and diseases. PMID:22433783

  9. Selective Manipulation of Neural Circuits.

    PubMed

    Park, Hong Geun; Carmel, Jason B

    2016-04-01

    Unraveling the complex network of neural circuits that form the nervous system demands tools that can manipulate specific circuits. The recent evolution of genetic tools to target neural circuits allows an unprecedented precision in elucidating their function. Here we describe two general approaches for achieving circuit specificity. The first uses the genetic identity of a cell, such as a transcription factor unique to a circuit, to drive expression of a molecule that can manipulate cell function. The second uses the spatial connectivity of a circuit to achieve specificity: one genetic element is introduced at the origin of a circuit and the other at its termination. When the two genetic elements combine within a neuron, they can alter its function. These two general approaches can be combined to allow manipulation of neurons with a specific genetic identity by introducing a regulatory gene into the origin or termination of the circuit. We consider the advantages and disadvantages of both these general approaches with regard to specificity and efficacy of the manipulations. We also review the genetic techniques that allow gain- and loss-of-function within specific neural circuits. These approaches introduce light-sensitive channels (optogenetic) or drug sensitive channels (chemogenetic) into neurons that form specific circuits. We compare these tools with others developed for circuit-specific manipulation and describe the advantages of each. Finally, we discuss how these tools might be applied for identification of the neural circuits that mediate behavior and for repair of neural connections.

  10. Cytokines and growth factors which regulate bone cell function

    NASA Astrophysics Data System (ADS)

    Seino, Yoshiki

    Everybody knows that growth factors are most important in making bone. Hormones enhance bone formation from a long distance. Growth factors promote bone formation as an autocrine or paracrine factor in nearby bone. BMP-2 through BMP-8 are in the TGF-β family. BMP makes bone by enchondral ossification. In bone, IGF-II is most abundant, second, TGF-β, and third IGF-I. TGF-β enhances bone formation mainly by intramembranous ossification in vivo. TGF-β affects both cell proliferation and differentiation, however, TGF-β mainly enhances bone formation by intramembranous ossification. Interestingly, TGF-β is increased by estrogen(E 2), androgen, vitamin D, TGF-β and FGF. IGF-I and IGF-II also enhance bone formation. At present it remains unclear why IGF-I is more active in bone formation than IGF-II, although IGF-II is more abundant in bone compared to IGF-I. However, if only type I receptor signal transduction promotes bone formation, the strong activity of IGF-I in bone formation is understandable. GH, PTH and E 2 promotes IGF-I production. Recent data suggest that hormones containing vitamin D or E 2 enhance bone formation through growth factors. Therefore, growth factors are the key to clarifying the mechanism of bone formation.

  11. Regulation of insulin-like growth factor I receptors on vascular smooth muscle cells by growth factors and phorbol esters.

    PubMed

    Ververis, J J; Ku, L; Delafontaine, P

    1993-06-01

    Insulin-like growth factor I (IGF I) is an important mitogen for vascular smooth muscle cells. To characterize regulation of vascular IGF I receptors, we performed radioligand displacement experiments using rat aortic smooth muscle cells (RASMs). Serum deprivation for 48 hours caused a 40% decrease in IGF I receptor number. Exposure of quiescent RASMs to platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), or angiotensin II (Ang II) caused a 1.5-2.0-fold increase in IGF I receptors per cell. After FGF exposure, there was a marked increase in the mitogenic response to IGF I. IGF I downregulated its receptors in the presence of platelet-poor plasma. Stimulation of protein kinase C (PKC) by exposure of quiescent RASMs to phorbol 12-myristate 13-acetate caused a biphasic response in IGF I binding; there was a 42% decrease in receptor number at 45 minutes and a 238% increase at 24 hours. To determine the role of PKC in growth factor-induced regulation of IGF I receptors, we downregulated PKC by exposing RASMs to phorbol 12,13-dibutyrate (PDBu) for 48 hours. PDGF- and FGF- but not Ang II-mediated upregulation of IGF I receptors was completely inhibited in PDBu-treated cells. Thus, acute PKC activation by phorbol esters inhibits IGF I binding, whereas chronic PKC activation increases IGF I binding. PDGF and FGF but not Ang II regulate vascular IGF I receptors through a PKC-dependent pathway. These data provide new insights into the regulation of vascular smooth muscle cell IGF I receptors in vitro and are of potential importance in characterizing vascular proliferative responses in vivo.

  12. Growth Hormone and Insulin-Like Growth Factor-1.

    PubMed

    Nicholls, Adam R; Holt, Richard I G

    2016-01-01

    Human growth hormone (GH) was first isolated from the human pituitary gland in 1945 and found to promote the growth of children with hypopituitarism. Since the formation of the World Anti-Doping Association, human GH has appeared on the list of forbidden substances. There is a significant amount of anecdotal evidence that human GH is misused by athletes to enhance performance, and there have been a number of high-profile cases of GH use in professional sport. GH secretagogues (GH-Ss), which increase GH secretion, and insulin-like growth factor (IGF-1), which mediates many of the effects of GH, are also misused, although there is less evidence for this. The effectiveness of GH, IGF-1, and GH-Ss as performance-enhancing drugs remains unclear. Evidence from studies of GH use in people with hypopituitarism show several desirable outcomes, including increased lean body mass, increased strength, and increased exercise capacity. These anabolic and metabolic properties, coupled with the difficulty in detecting them, make them attractive as agents of misuse. Studies in healthy young adults have also demonstrated a performance benefit with GH and IGF-1. © 2016 S. Karger AG, Basel.

  13. Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension.

    PubMed

    Spradley, Frank T; Tan, Adelene Y; Joo, Woo S; Daniels, Garrett; Kussie, Paul; Karumanchi, S Ananth; Granger, Joey P

    2016-04-01

    Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia because placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and vascular endothelial growth factor are both natural ligands for sFlt-1, vascular endothelial growth factor also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to 4 groups: normal pregnant or RUPP±infusion of recombinant human PlGF (180 μg/kg per day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than normal pregnant rats. Infusion of recombinant human PlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that recombinant human PlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. © 2016 American Heart Association, Inc.

  14. Temporally controlled release of multiple growth factors from a self-assembling peptide hydrogel

    NASA Astrophysics Data System (ADS)

    Bruggeman, Kiara F.; Rodriguez, Alexandra L.; Parish, Clare L.; Williams, Richard J.; Nisbet, David R.

    2016-09-01

    Protein growth factors have demonstrated great potential for tissue repair, but their inherent instability and large size prevents meaningful presentation to biologically protected nervous tissue. Here, we create a nanofibrous network from a self-assembling peptide (SAP) hydrogel to carry and stabilize the growth factors. We significantly reduced growth factor degradation to increase their lifespan by over 40 times. To control the temporal release profile we covalently attached polysaccharide chitosan molecules to the growth factor to increase its interactions with the hydrogel nanofibers and achieved a 4 h delay, demonstrating the potential of this method to provide temporally controlled growth factor delivery. We also describe release rate based analysis to examine the growth factor delivery in more detail than standard cumulative release profiles allow and show that the chitosan attachment method provided a more consistent release profile with a 60% reduction in fluctuations. To prove the potential of this system as a complex growth factor delivery platform we demonstrate for the first time temporally distinct release of multiple growth factors from a single tissue specific SAP hydrogel: a significant goal in regenerative medicine.

  15. Priming Dental Pulp Stem Cells With Fibroblast Growth Factor-2 Increases Angiogenesis of Implanted Tissue-Engineered Constructs Through Hepatocyte Growth Factor and Vascular Endothelial Growth Factor Secretion.

    PubMed

    Gorin, Caroline; Rochefort, Gael Y; Bascetin, Rumeyza; Ying, Hanru; Lesieur, Julie; Sadoine, Jérémy; Beckouche, Nathan; Berndt, Sarah; Novais, Anita; Lesage, Matthieu; Hosten, Benoit; Vercellino, Laetitia; Merlet, Pascal; Le-Denmat, Dominique; Marchiol, Carmen; Letourneur, Didier; Nicoletti, Antonino; Vital, Sibylle Opsahl; Poliard, Anne; Salmon, Benjamin; Muller, Laurent; Chaussain, Catherine; Germain, Stéphane

    2016-03-01

    Tissue engineering strategies based on implanting cellularized biomaterials are promising therapeutic approaches for the reconstruction of large tissue defects. A major hurdle for the reliable establishment of such therapeutic approaches is the lack of rapid blood perfusion of the tissue construct to provide oxygen and nutrients. Numerous sources of mesenchymal stem cells (MSCs) displaying angiogenic potential have been characterized in the past years, including the adult dental pulp. Establishment of efficient strategies for improving angiogenesis in tissue constructs is nevertheless still an important challenge. Hypoxia was proposed as a priming treatment owing to its capacity to enhance the angiogenic potential of stem cells through vascular endothelial growth factor (VEGF) release. The present study aimed to characterize additional key factors regulating the angiogenic capacity of such MSCs, namely, dental pulp stem cells derived from deciduous teeth (SHED). We identified fibroblast growth factor-2 (FGF-2) as a potent inducer of the release of VEGF and hepatocyte growth factor (HGF) by SHED. We found that FGF-2 limited hypoxia-induced downregulation of HGF release. Using three-dimensional culture models of angiogenesis, we demonstrated that VEGF and HGF were both responsible for the high angiogenic potential of SHED through direct targeting of endothelial cells. In addition, FGF-2 treatment increased the fraction of Stro-1+/CD146+ progenitor cells. We then applied in vitro FGF-2 priming to SHED before encapsulation in hydrogels and in vivo subcutaneous implantation. Our results showed that FGF-2 priming is more efficient than hypoxia at increasing SHED-induced vascularization compared with nonprimed controls. Altogether, these data demonstrate that FGF-2 priming enhances the angiogenic potential of SHED through the secretion of both HGF and VEGF. ©AlphaMed Press.

  16. Extracellular growth factors and mitogens cooperate to drive mitochondrial biogenesis

    PubMed Central

    Echave, Pedro; Machado-da-Silva, Gisela; Arkell, Rebecca S.; Duchen, Michael R.; Jacobson, Jake; Mitter, Richard; Lloyd, Alison C.

    2009-01-01

    Summary Cells generate new organelles when stimulated by extracellular factors to grow and divide; however, little is known about how growth and mitogenic signalling pathways regulate organelle biogenesis. Using mitochondria as a model organelle, we have investigated this problem in primary Schwann cells, for which distinct factors act solely as mitogens (neuregulin) or as promoters of cell growth (insulin-like growth factor 1; IGF1). We find that neuregulin and IGF1 act synergistically to increase mitochondrial biogenesis and mitochondrial DNA replication, resulting in increased mitochondrial density in these cells. Moreover, constitutive oncogenic Ras signalling results in a further increase in mitochondrial density. This synergistic effect is seen at the global transcriptional level, requires both the ERK and phosphoinositide 3-kinase (PI3K) signalling pathways and is mediated by the transcription factor ERRα. Interestingly, the effect is independent of Akt-TOR signalling, a major regulator of cell growth in these cells. This separation of the pathways that drive mitochondrial biogenesis and cell growth provides a mechanism for the modulation of mitochondrial density according to the metabolic requirements of the cell. PMID:19920079

  17. Nerve Growth Factor Expression Is Not Associated with Perineural Invasion in Extrahepatic Cholangiocarcinoma.

    PubMed

    Urabe, Kazuhide; Murakami, Yoshiaki; Kondo, Naru; Uemura, Kenichiro; Hashimoto, Yasushi; Nakagawa, Naoya; Sasaki, Hayato; Hiyama, Eiso; Takahashi, Shinya; Sueda, Taijiro

    2016-03-01

    Although the presence of perineural invasion has been recognized as a poor prognostic factor in extrahepatic cholangiocarcinoma, the molecular mechanisms of perineural invasion in extrahepatic cholangiocarcinoma remain unclear. Nerve growth factor has been reported to be a candidate predictive biomarker of perineural invasion in some cancers. To investigate the impact of intratumoral nerve growth factor expression in resected extrahepatic cholangiocarcinoma on survival. Intratumoral nerve growth factor expression was investigated immunohistochemically in 112 patients with resected extrahepatic cholangiocarcinoma. Associations between nerve growth factor expression and clinicopathological factors were statistically evaluated, and risk factors for poor survival were analyzed using univariate and multivariate analyses. High and low nerve growth factor expression was observed in 62 (55%) and 50 (45%) patients, respectively. For all 112 patients, no significant correlation was found between nerve growth factor expression and presence of perineural invasion (P = 0.942). Moreover, nerve growth factor expression was not associated with recurrence-free survival (P = 0.861) and overall survival (P = 0.973). In multivariate analysis, lymph node metastasis (P = 0.004) was identified as an independent risk factor for early recurrence and the presence of perineural invasion (P = 0.002) and lymph node metastasis (P < 0.001) was identified as independent risk factors for poor survival. Intratumoral nerve growth factor expression is not associated with perineural invasion or recurrence-free and overall survival in patients with resected extrahepatic cholangiocarcinoma.

  18. Fatigue Crack Growth Rate and Stress-Intensity Factor Corrections for Out-of-Plane Crack Growth

    NASA Technical Reports Server (NTRS)

    Forth, Scott C.; Herman, Dave J.; James, Mark A.

    2003-01-01

    Fatigue crack growth rate testing is performed by automated data collection systems that assume straight crack growth in the plane of symmetry and use standard polynomial solutions to compute crack length and stress-intensity factors from compliance or potential drop measurements. Visual measurements used to correct the collected data typically include only the horizontal crack length, which for cracks that propagate out-of-plane, under-estimates the crack growth rates and over-estimates the stress-intensity factors. The authors have devised an approach for correcting both the crack growth rates and stress-intensity factors based on two-dimensional mixed mode-I/II finite element analysis (FEA). The approach is used to correct out-of-plane data for 7050-T7451 and 2025-T6 aluminum alloys. Results indicate the correction process works well for high DeltaK levels but fails to capture the mixed-mode effects at DeltaK levels approaching threshold (da/dN approximately 10(exp -10) meter/cycle).

  19. Fibroblast growth factor-2-induced host stroma reaction during initial tumor growth promotes progression of mouse melanoma via vascular endothelial growth factor A-dependent neovascularization.

    PubMed

    Tsunoda, Satoshi; Nakamura, Toshiyuki; Sakurai, Hiroaki; Saiki, Ikuo

    2007-04-01

    Fibroblast growth factor (FGF)-2 has been considered to play a critical role in neovascularization in several tumors; however, its precise role in tumor progression is not fully understood. In the present study, we have characterized the role of FGF-2 in B16-BL6 mouse melanoma cells, focusing on effects during the initial phase of tumor growth. FGF-2 was injected at the tumor inoculation site of dorsal skin during the initial phase. FGF-2 induced marked tumor growth and lymph node metastasis. This was well correlated with an increase in neovascularization in the host stroma. FGF-2 also recruited inflammatory and mesenchymal cells in host stroma. Marked tumor growth, pulmonary metastasis and intensive neovascularization in tumor parenchyma were also observed after a single injection of FGF-2 into the footpad inoculation site. In contrast, repeated injections of FGF-2 at a site remote from the footpad tumor were ineffective in promoting tumor growth and metastasis. These promoting activities of FGF-2 were blocked by local injections of a glucocorticoid hormone, suggesting that host inflammatory responses induced by FGF-2 are associated with FGF-2-induced tumor progression. In addition, although FGF-2 did not promote cellular proliferation and vascular endothelial growth factor A (VEGFA) mRNA expression in B16-BL6 cells in vitro, FGF-2 induced VEGFA expression in host stroma rather than tumor tissue, and local injections of a neutralizing antibody against VEGFA inhibited these activities of FGF-2 in vivo. These results indicate that abundant FGF-2 during the initial phase of tumor growth induces VEGFA-dependent intensive neovascularization in host stroma, and supports marked tumor growth and metastasis.

  20. Sequential growth factor application in bone marrow stromal cell ligament engineering.

    PubMed

    Moreau, Jodie E; Chen, Jingsong; Horan, Rebecca L; Kaplan, David L; Altman, Gregory H

    2005-01-01

    In vitro bone marrow stromal cell (BMSC) growth may be enhanced through culture medium supplementation, mimicking the biochemical environment in which cells optimally proliferate and differentiate. We hypothesize that the sequential administration of growth factors to first proliferate and then differentiate BMSCs cultured on silk fiber matrices will support the enhanced development of ligament tissue in vitro. Confluent second passage (P2) BMSCs obtained from purified bone marrow aspirates were seeded on RGD-modified silk matrices. Seeded matrices were divided into three groups for 5 days of static culture, with medium supplement of basic fibroblast growth factor (B) (1 ng/mL), epidermal growth factor (E; 1 ng/mL), or growth factor-free control (C). After day 5, medium supplementation was changed to transforming growth factor-beta1 (T; 5 ng/mL) or C for an additional 9 days of culture. Real-time RT-PCR, SEM, MTT, histology, and ELISA for collagen type I of all sample groups were performed. Results indicated that BT supported the greatest cell ingrowth after 14 days of culture in addition to the greatest cumulative collagen type I expression measured by ELISA. Sequential growth factor application promoted significant increases in collagen type I transcript expression from day 5 of culture to day 14, for five of six groups tested. All T-supplemented samples surpassed their respective control samples in both cell ingrowth and collagen deposition. All samples supported spindle-shaped, fibroblast cell morphology, aligning with the direction of silk fibers. These findings indicate significant in vitro ligament development after only 14 days of culture when using a sequential growth factor approach.

  1. Do various factors affect the frequency of manipulation under anesthesia after primary total knee arthroplasty?

    PubMed

    Issa, Kimona; Rifai, Aiman; Boylan, Matthew R; Pourtaheri, Sina; McInerney, Vincent K; Mont, Michael A

    2015-01-01

    One of the most important goals of primary total knee arthroplasty (TKA) is to achieve a functional range of motion (ROM). However, up to 20% of patients fail to do so, which can impair activities of daily living. The purpose of this study was to evaluate the effect of various (1) demographic factors; (2) comorbidities; and (3) knee-specific factors on the frequency of manipulation under anesthesia, which was used as an indicator of knee stiffness after a primary TKA. We evaluated the registries of two high-volume centers and reviewed all 3182 TKAs that were performed between 2005 and 2011 to identify all patients who had undergone manipulation under anesthesia (MUA). A total of 156 knees in 133 patients underwent MUA after an index arthroplasty. These patients were compared in a one-to-four ratio with a group of patients with satisfactory ROM drawn from the same database who met prespecified criteria and who had not undergone MUA. Effects of various factors, including age, sex, body mass index, race, comorbidities, and the underlying cause of knee arthritis, were compared between these two cohorts using multivariable logistic regressions. After controlling for various confounding, nonwhite race was associated with an increase (odds ratio [OR], 2.01; p=0.03), and age≥65 years (OR, 0.17; 95% confidence interval [CI], 0.04-0.74; p=0.0179) was associated with a reduction in the incidence of MUA. In comorbidities, diabetes (OR, 1.72; 95% CI, 1.02-2.32; p=0.03), high cholesterol levels (OR, 2.70; p=0.03), and tobacco smoking (OR, 1.59; 95% CI, 1.03-2.47; p=0.03) were associated with an increase in frequency of MUA. In knee-specific factors, preoperative knee ROM of less than 100° (OR, 0.80; p<0.0001) and knee osteonecrosis (p=3.61; 95% CI, 1.29-10.1; p=0.014) were associated with increased frequency of MUA. We identified several demographic, medical, and knee-specific factors that were associated with poor postoperative ROM in our patients undergoing TKA. Patients

  2. Transcription factor EGR-1 suppresses the growth and transformation of human HT-1080 fibrosarcoma cells by induction of transforming growth factor beta 1.

    PubMed Central

    Liu, C; Adamson, E; Mercola, D

    1996-01-01

    The early growth response 1 (EGR-1) gene product is a transcription factor with role in differentiation and growth. We have previously shown that expression of exogenous EGR-1 in various human tumor cells unexpectedly and markedly reduces growth and tumorigenicity and, conversely, that suppression of endogenous Egr-1 expression by antisense RNA eliminates protein expression, enhances growth, and promotes phenotypic transformation. However, the mechanism of these effects remained unknown. The promoter of human transforming growth factor beta 1 (TGF-beta 1) contains two GC-rich EGR-1 binding sites. We show that expression of EGR-1 in human HT-1080 fibrosarcoma cells uses increased secretion of biologically active TGF-beta 1 in direct proportion (rPearson = 0.96) to the amount of EGR-1 expressed and addition of recombinant human TGF-beta 1 is strongly growth-suppressive for these cells. Addition of monoclonal anti-TGF-beta 1 antibodies to EGR-1-expressing HT-1080 cells completely reverses the growth inhibitory effects of EGR-1. Reporter constructs bearing the EGR-1 binding segment of the TGF-beta 1 promoter was activated 4- to 6-fold relative to a control reporter in either HT-1080 cells that stably expressed or parental cells cotransfected with an EGR-1 expression vector. Expression of delta EGR-1, a mutant that cannot interact with the corepressors, nerve growth factor-activated factor binding proteins NAB1 and NAB2, due to deletion of the repressor domain, exhibited enhanced transactivation of 2- to 3.5-fold over that of wild-type EGR-1 showing that the reporter construct reflected the appropriate in vivo regulatory context. The EGR-1-stimulated transactivation was inhibited by expression of the Wilms tumor suppressor, a known specific DNA-binding competitor. These results indicate that EGR-1 suppresses growth of human HT-1080 fibrosarcoma cells by induction of TGF-beta 1. Images Fig. 1 Fig. 5 PMID:8876223

  3. Evaluation of phantom-based education system for acupuncture manipulation.

    PubMed

    Lee, In-Seon; Lee, Ye-Seul; Park, Hi-Joon; Lee, Hyejung; Chae, Younbyoung

    2015-01-01

    Although acupuncture manipulation has been regarded as one of the important factors in clinical outcome, it has been difficult to train novice students to become skillful experts due to a lack of adequate educational program and tools. In the present study, we investigated whether newly developed phantom acupoint tools would be useful to practice-naïve acupuncture students for practicing the three different types of acupuncture manipulation to enhance their skills. We recruited 12 novice students and had them practice acupuncture manipulations on the phantom acupoint (5% agarose gel). We used the Acusensor 2 and compared their acupuncture manipulation techniques, for which the target criteria were depth and time factors, at acupoint LI11 in the human body before and after 10 training sessions. The outcomes were depth of needle insertion, depth error from target criterion, time of rotating, lifting, and thrusting, time error from target criteria and the time ratio. After 10 training sessions, the students showed significantly improved outcomes in depth of needle, depth error (rotation, reducing lifting/thrusting), thumb-forward time error, thumb-backward time error (rotation), and lifting time (reinforcing lifting/thrusting). The phantom acupoint tool could be useful in a phantom-based education program for acupuncture-manipulation training for students. For advanced education programs for acupuncture manipulation, we will need to collect additional information, such as patient responses, acupoint-specific anatomical characteristics, delicate tissue-like modeling, haptic and visual feedback, and data from an acupuncture practice simulator.

  4. Quantification of growth factor signaling and pathway cross talk by live-cell imaging

    PubMed Central

    Gross, Sean M.

    2017-01-01

    Peptide growth factors stimulate cellular responses through activation of their transmembrane receptors. Multiple intracellular signaling cascades are engaged following growth factor–receptor binding, leading to short- and long-term biological effects. Each receptor-activated signaling pathway does not act in isolation but rather interacts at different levels with other pathways to shape signaling networks that are distinctive for each growth factor. To gain insights into the specifics of growth factor-regulated interactions among different signaling cascades, we developed a HeLa cell line stably expressing fluorescent live-cell imaging reporters that are readouts for two major growth factor-stimulated pathways, Ras–Raf–Mek–ERK and phosphatidylinositol (PI) 3-kinase–Akt. Incubation of cells with epidermal growth factor (EGF) resulted in rapid, robust, and sustained ERK signaling but shorter-term activation of Akt. In contrast, hepatocyte growth factor induced sustained Akt signaling but weak and short-lived ERK activity, and insulin-like growth factor-I stimulated strong long-term Akt responses but negligible ERK signaling. To address potential interactions between signaling pathways, we employed specific small-molecule inhibitors. In cells incubated with EGF or platelet-derived growth factor-AA, Raf activation and the subsequent stimulation of ERK reduced Akt signaling, whereas Mek inhibition, which blocked ERK activation, enhanced Akt and turned transient effects into sustained responses. Our results reveal that individual growth factors initiate signaling cascades that vary markedly in strength and duration and demonstrate in living cells the dramatic effects of cross talk from Raf and Mek to PI 3-kinase and Akt. Our data further indicate how specific growth factors can encode distinct cellular behaviors by promoting complex interactions among signaling pathways. PMID:28100485

  5. Effects of Growth Factors on Dental Stem/ProgenitorCells

    PubMed Central

    Kim, Sahng G.; Solomon, Charles; Zheng, Ying; Suzuki, Takahiro; Mo, Chen; Song, Songhee; Jiang, Nan; Cho, Shoko; Zhou, Jian; Mao, Jeremy J.

    2014-01-01

    Synopsis The primary goal of regenerative endodontics is to restore the vitality and functions of the dentin-pulp complex, as opposed to filing of the root canal with bioinert materials. Structural restoration is also important but is likely secondary to vitality and functions. Myriads growth factors regulate multiple cellular functions including migration, proliferation, differentiation and apoptosis of several cell types that are intimately involved in dentin-pulp regeneration: odontoblasts, interstitial fibroblasts, vascular-endothelial cells and sprouting nerve fibers. Recent work showing that growth factor delivery, without cell transplantation, can yield pulp-dentin like tissues in vivo provides one of the tangible pathways for regenerative endodontics. This review synthesizes our knowledge on a multitude of growth factors that are known or anticipated to be efficacious in dental pulp-dentin regeneration. PMID:22835538

  6. Neuronal expression of fibroblast growth factor receptors in zebrafish.

    PubMed

    Rohs, Patricia; Ebert, Alicia M; Zuba, Ania; McFarlane, Sarah

    2013-12-01

    Fibroblast growth factor (FGF) signaling is important for a host of developmental processes such as proliferation, differentiation, tissue patterning, and morphogenesis. In vertebrates, FGFs signal through a family of four fibroblast growth factor receptors (FGFR 1-4), one of which is duplicated in zebrafish (FGFR1). Here we report the mRNA expression of the five known zebrafish fibroblast growth factor receptors at five developmental time points (24, 36, 48, 60, and 72h postfertilization), focusing on expression within the central nervous system. We show that the receptors have distinct and dynamic expression in the developing zebrafish brain, eye, inner ear, lateral line, and pharynx. In many cases, the expression patterns are similar to those of homologous FGFRs in mouse, chicken, amphibians, and other teleosts. Copyright © 2013 Elsevier B.V. All rights reserved.

  7. Quantification of growth factor signaling and pathway cross talk by live-cell imaging.

    PubMed

    Gross, Sean M; Rotwein, Peter

    2017-03-01

    Peptide growth factors stimulate cellular responses through activation of their transmembrane receptors. Multiple intracellular signaling cascades are engaged following growth factor-receptor binding, leading to short- and long-term biological effects. Each receptor-activated signaling pathway does not act in isolation but rather interacts at different levels with other pathways to shape signaling networks that are distinctive for each growth factor. To gain insights into the specifics of growth factor-regulated interactions among different signaling cascades, we developed a HeLa cell line stably expressing fluorescent live-cell imaging reporters that are readouts for two major growth factor-stimulated pathways, Ras-Raf-Mek-ERK and phosphatidylinositol (PI) 3-kinase-Akt. Incubation of cells with epidermal growth factor (EGF) resulted in rapid, robust, and sustained ERK signaling but shorter-term activation of Akt. In contrast, hepatocyte growth factor induced sustained Akt signaling but weak and short-lived ERK activity, and insulin-like growth factor-I stimulated strong long-term Akt responses but negligible ERK signaling. To address potential interactions between signaling pathways, we employed specific small-molecule inhibitors. In cells incubated with EGF or platelet-derived growth factor-AA, Raf activation and the subsequent stimulation of ERK reduced Akt signaling, whereas Mek inhibition, which blocked ERK activation, enhanced Akt and turned transient effects into sustained responses. Our results reveal that individual growth factors initiate signaling cascades that vary markedly in strength and duration and demonstrate in living cells the dramatic effects of cross talk from Raf and Mek to PI 3-kinase and Akt. Our data further indicate how specific growth factors can encode distinct cellular behaviors by promoting complex interactions among signaling pathways. Copyright © 2017 the American Physiological Society.

  8. A spatial operator algebra for manipulator modeling and control

    NASA Technical Reports Server (NTRS)

    Rodriguez, G.; Kreutz, K.; Milman, M.

    1988-01-01

    A powerful new spatial operator algebra for modeling, control, and trajectory design of manipulators is discussed along with its implementation in the Ada programming language. Applications of this algebra to robotics include an operator representation of the manipulator Jacobian matrix; the robot dynamical equations formulated in terms of the spatial algebra, showing the complete equivalence between the recursive Newton-Euler formulations to robot dynamics; the operator factorization and inversion of the manipulator mass matrix which immediately results in O(N) recursive forward dynamics algorithms; the joint accelerations of a manipulator due to a tip contact force; the recursive computation of the equivalent mass matrix as seen at the tip of a manipulator; and recursive forward dynamics of a closed chain system. Finally, additional applications and current research involving the use of the spatial operator algebra are discussed in general terms.

  9. Increased Serum Levels of Epidermal Growth Factor in Children with Autism

    ERIC Educational Resources Information Center

    Iseri, Elvan; Guney, Esra; Ceylan, Mehmet F.; Yucel, Aysegul; Aral, Arzu; Bodur, Sahin; Sener, Sahnur

    2011-01-01

    The etiology of autism is unclear, however autism is considered as a multifactorial disorder that is influenced by neurological, environmental, immunological and genetic factors. Growth factors, including epidermal growth factor (EGF), play an important role in the celluler proliferation and the differentiation of the central and peripheral…

  10. Growth factors in the anterior segment: role in tissue maintenance, wound healing and ocular pathology.

    PubMed

    Klenkler, Bettina; Sheardown, Heather

    2004-11-01

    A number of growth factors and their associated receptors, including epidermal growth factor, transforming growth factor-beta, keratinocyte growth factor, hepatocyte growth factor, fibroblast growth factor and platelet-derived growth factor have been detected in the anterior segment of the eye. On binding to cellular receptors, these factors activate signalling cascades, which regulate functions including mitosis, differentiation, motility and apoptosis. Production of growth factors by corneal cells and their presence in the tear fluid and aqueous humour is essential for maintenance and renewal of normal tissue in the anterior eye and the prevention of undesirable immune or angiogenic reactions. Growth factors also play a vital role in corneal wound healing, mediating the proliferation of epithelial and stromal tissue and affecting the remodelling of the extracellular matrix (ECM). These functions depend on a complex interplay between growth factors of different types, the ECM, and regulatory mechanisms of the affected cells. Imbalances may lead to deficient wound healing and various ocular pathologies, including edema, neovascularization and glaucoma. Growth factors may be targeted in therapeutic ophthalmic applications, through exogenous application or selective inhibition, and may be used to elicit specific cellular responses to ophthalmic materials. A thorough understanding of the mechanism and function of growth factors and their actions in the complex environment of the anterior eye is required for these purposes. Growth factors, their function and mechanisms of action as well as the interplay between different growth factors based on recent in vitro and in vivo studies are presented.

  11. Colocalization of insulin-like growth factor-binding protein with insulin-like growth factor I.

    PubMed

    Kobayashi, S; Clemmons, D R; Venkatachalam, M A

    1991-07-01

    We report the localization of insulin-like growth factor I (IGF-I) and a 25-kDa form of insulin-like growth factor-binding protein (IGF-BP-1) in adult rat kidney. The antigens were localized using a rabbit anti-human IGF-I antibody, and a rabbit anti-human IGF-BP-1 antibody raised against human 25-kDa IGF-BP-1 purified from amniotic fluid. Immunohistochemistry by the avidin-biotin peroxidase conjugate technique showed that both peptides are located in the same nephron segments, in the same cell types. The most intense staining was in papillary collecting ducts. There was moderate staining also in cortical collecting ducts and medullary thick ascending limbs of Henle's loop. In collecting ducts the antigens were shown to be present in principal cells but not in intercalated cells. In distal convoluted tubules, cortical thick ascending limbs, and in structures presumptively identified as thin limbs of Henle's loops there was only modest staining. The macula densa, however, lacked immunoreactivity. Colocalization of IGF-I and IGF-BP-1 in the same cells supports the notion, derived from studies on cultured cells, that the actions of IGF-I may be modified by IGF-BPs that are present in the same location.

  12. Vascular endothelial growth factor c/vascular endothelial growth factor receptor 3 signaling regulates chemokine gradients and lymphocyte migration from tissues to lymphatics.

    PubMed

    Iwami, Daiki; Brinkman, C Colin; Bromberg, Jonathan S

    2015-04-01

    Circulation of leukocytes via blood, tissue and lymph is integral to adaptive immunity. Afferent lymphatics form CCL21 gradients to guide dendritic cells and T cells to lymphatics and then to draining lymph nodes (dLN). Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 (VEGFR-3) are the major lymphatic growth factor and receptor. We hypothesized these molecules also regulate chemokine gradients and lymphatic migration. CD4 T cells were injected into the foot pad or ear pinnae, and migration to afferent lymphatics and dLN quantified by flow cytometry or whole mount immunohistochemistry. Vascular endothelial growth factor receptor 3 or its signaling or downstream actions were modified with blocking monoclonal antibodies (mAbs) or other reagents. Anti-VEGFR-3 prevented migration of CD4 T cells into lymphatic lumen and significantly decreased the number that migrated to dLN. Anti-VEGFR-3 abolished CCL21 gradients around lymphatics, although CCL21 production was not inhibited. Heparan sulfate (HS), critical to establish CCL21 gradients, was down-regulated around lymphatics by anti-VEGFR-3 and this was dependent on heparanase-mediated degradation. Moreover, a Phosphoinositide 3-kinase (PI3K)α inhibitor disrupted HS and CCL21 gradients, whereas a PI3K activator prevented the effects of anti-VEGFR-3. During contact hypersensitivity, VEGFR-3, CCL21, and HS expression were all attenuated, and anti-heparanase or PI3K activator reversed these effects. Vascular endothelial growth factor C/VEGFR-3 signaling through PI3Kα regulates the activity of heparanase, which modifies HS and CCL21 gradients around lymphatics. The functional and physical linkages of these molecules regulate lymphatic migration from tissues to dLN. These represent new therapeutic targets to influence immunity and inflammation.

  13. Expression of epidermal growth factor receptor and vascular endothelial growth factor in malignant canine epithelial nasal tumours.

    PubMed

    Shiomitsu, K; Johnson, C L; Malarkey, D E; Pruitt, A F; Thrall, D E

    2009-06-01

    Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) signalling pathways play a role in carcinogenesis. Inhibition of EGF receptor (EGFR) and of VEGF is effective in increasing the radiation responsiveness of neoplastic cells both in vitro and in human trials. In this study, immunohistochemical evaluation was employed to determine and characterize the potential protein expression levels and patterns of EGFR and VEGF in a variety of canine malignant epithelial nasal tumours. Of 24 malignant canine nasal tumours, 13 (54.2%) were positive for EGFR staining and 22 (91.7%) were positive for VEGF staining. The intensity and percentage of immunohistochemically positive neoplastic cells for EGFR varied. These findings indicate that EGFR and VEGF proteins were present in some malignant epithelial nasal tumours in the dogs, and therefore, it may be beneficial to treat canine patients with tumours that overexpress EGFR and VEGF with specific inhibitors in conjunction with radiation.

  14. Fibroblast growth factor receptor signaling crosstalk in skeletogenesis.

    PubMed

    Miraoui, Hichem; Marie, Pierre J

    2010-11-02

    Fibroblast growth factors (FGFs) play important roles in the control of embryonic and postnatal skeletal development by activating signaling through FGF receptors (FGFRs). Germline gain-of-function mutations in FGFR constitutively activate FGFR signaling, causing chondrocyte and osteoblast dysfunctions that result in skeletal dysplasias. Crosstalk between the FGFR pathway and other signaling cascades controls skeletal precursor cell differentiation. Genetic analyses revealed that the interplay of WNT and FGFR1 determines the fate and differentiation of mesenchymal stem cells during mouse craniofacial skeletogenesis. Additionally, interactions between FGFR signaling and other receptor tyrosine kinase networks, such as those mediated by the epidermal growth factor receptor and platelet-derived growth factor receptor α, were associated with excessive osteoblast differentiation and bone formation in the human skeletal dysplasia called craniosynostosis, which is a disorder of skull development. We review the roles of FGFR signaling and its crosstalk with other pathways in controlling skeletal cell fate and discuss how this crosstalk could be pharmacologically targeted to correct the abnormal cell phenotype in skeletal dysplasias caused by aberrant FGFR signaling.

  15. The use of autologous blood-derived growth factors in bone regeneration

    PubMed Central

    Civinini, Roberto; Macera, Armando; Nistri, Lorenzo; Redl, Birgit; Innocenti, Massimo

    2011-01-01

    Platelet-rich plasma (PRP) is defined as a portion of the plasma fraction of autologous blood having platelet concentrations above baseline. When activated the platelets release growth factors that play an essential role in bone healing such as Platelet-derived Growth Factor, Transforming Growth Factor-β, Vascular Endothelial Growth Factor and others. Multiple basic science and in vivo animal studies agree that PRP has a role in the stimulation of the healing cascade in ligament, tendon, muscle cartilage and in bone regeneration in the last years PRP had a widespread diffusion in the treatment of soft tissue and bone healing. The purpose of this review is to describe the biological properties of platelets and its factors, the methods used for producing PRP, to provide a background on the underlying basic science and an overview of evidence based medicine on clinical application of PRP in bone healing. PMID:22461800

  16. Which environmental factors most strongly influence a street's appeal for bicycle transport among adults? A conjoint study using manipulated photographs.

    PubMed

    Mertens, Lieze; Van Dyck, Delfien; Ghekiere, Ariane; De Bourdeaudhuij, Ilse; Deforche, Benedicte; Van de Weghe, Nico; Van Cauwenberg, Jelle

    2016-09-01

    Micro-environmental factors (specific features within a streetscape), instead of macro-environmental factors (urban planning features), are more feasible to modify in existing neighborhoods and thus more practical to target for environmental interventions. Because it is often not possible to change the whole micro-environment at once, the current study aims to determine which micro-environmental factors should get the priority to target in physical environmental interventions increasing bicycle transport. Additionally, interaction effects among micro-environmental factors on the street's appeal for bicycle transport will be determined. In total, 1950 middle-aged adults completed a web-based questionnaire consisting of a set of 12 randomly assigned choice tasks with manipulated photographs. Seven micro-environmental factors (type of cycle path, speed limit, speed bump, vegetation, evenness of the cycle path surface, general upkeep and traffic density) were manipulated in each photograph. Conjoint analysis was used to analyze the data. Providing streets with a cycle path separated from motorized traffic seems to be the best strategy to increase the street's appeal for adults' bicycle transport. If this adjustment is not practically feasible, micro-environmental factors related to safety (i.e. speed limit, traffic density) may be more effective in promoting bicycle transport than micro-environmental factors related to comfort (i.e. evenness of the cycle path surface) or aesthetic (i.e. vegetation, general upkeep). On the other hand, when a more separated cycle path is already provided, micro-environmental factors related to comfort or aesthetic appeared to become more prominent. Findings obtained from this research could provide advice to physical environmental interventions about which environmental factors should get priority to modify in different environmental situations. The study was approved by the Ethics Committee of the Ghent University Hospital. B

  17. CLIMAITE - a three factor climate change ecosystem manipulation experiment.

    NASA Astrophysics Data System (ADS)

    Mikkelsen, T. N.; Beier, C.; Albert, K.; Ro-Poulsen, H.

    2007-12-01

    The Danish multi factorial climate change effects on vegetation experiment (Climaite) have now been conducted for two years on semi-natural grassland. The day time [CO2], night time temperature and precipitation (drought) have been altered, according to a regional climate change model for the year 2075, in a full factorial split plot design. The manipulated area for each treatment is 7 m2 and it is replicated 6 times. The CO2 and temperature treatments have been conducted continuously except for periods with snow cover. The CO2 is enhanced to 510 ppm via a FACE system based on concentrated CO2 released upwind under pressure. The control of the [CO2] varies with wind speed and irradiation, but during 50 percent of the fumigation period the target concentration was kept within +/-5 percent. The temperature treatment is conducted via infrared reflective curtains covering the plots during night time, and the warming of plants and soil depends of the day irradiation, night time wind speed and factors related to seasonality. In general, the air temperature is increased during night time with 1-2 C° and negligible during the day. The soil temperature in 5 cm depth is enhanced to 0.3 - 0.6 C° during night and day. The artificial summer droughts lasted about one month and differences in soil water content were developed over time. By the end of the treatment the èv content in the soil was as low as 0.06 m3 m-3 compared to 0.20 m3 m-3 in the control. Numerous physical and biological parameters in the grassland ecosystem have been measured and several are responding to the changed environment. After 9 months of exposure enhanced [CO2] stimulated the net photosynthesis (based on dry weight) in both of the domination plant species Calluna Vulgaris and Deschampsia flexuosa. When the plants were exposed to short term saturated [CO2] during gasexchange measurements the long term CO2 treated plants also had the highest photosynthesis rate, meaning that the plants were not

  18. Oxygen-sensitive regulation and neuroprotective effects of growth hormone-dependent growth factors during early postnatal development.

    PubMed

    Jung, Susan; Boie, Gudrun; Doerr, Helmuth-Guenther; Trollmann, Regina

    2017-04-01

    Perinatal hypoxia severely disrupts metabolic and somatotrophic development, as well as cerebral maturational programs. Hypoxia-inducible transcription factors (HIFs) represent the most important endogenous adaptive mechanisms to hypoxia, activating a broad spectrum of growth factors that contribute to cell survival and energy homeostasis. To analyze effects of systemic hypoxia and growth hormone (GH) therapy (rhGH) on HIF-dependent growth factors during early postnatal development, we compared protein (using ELISA) and mRNA (using quantitative RT PCR) levels of growth factors in plasma and brain between normoxic and hypoxic mice (8% O 2 , 6 h; postnatal day 7 , P7) at P14. Exposure to hypoxia led to reduced body weight ( P < 0.001) and length ( P < 0.04) compared with controls and was associated with significantly reduced plasma levels of mouse GH ( P < 0.01) and IGF-1 ( P < 0.01). RhGH abrogated these hypoxia-induced changes of the GH/IGF-1 axis associated with normalization of weight and length gain until P14 compared with controls. In addition, rhGH treatment increased cerebral IGF-1, IGF-2, IGFBP-2, and erythropoietin mRNA levels, resulting in significantly reduced apoptotic cell death in the hypoxic, developing mouse brain. These data indicate that rhGH may functionally restore hypoxia-induced systemic dysregulation of the GH/IGF-1 axis and induce upregulation of neuroprotective, HIF-dependent growth factors in the hypoxic developing brain. Copyright © 2017 the American Physiological Society.

  19. Assessment of Growth Factors Secreted by Human Breastmilk Mesenchymal Stem Cells.

    PubMed

    Kaingade, Pankaj Mahipatrao; Somasundaram, Indumathi; Nikam, Amar Babaso; Sarang, Shabari Amit; Patel, Jagdish Shantilal

    2016-01-01

    Human breastmilk is a dynamic, multifaceted biological fluid containing nutrients, bioactive substances, and growth factors. It is effective in supporting growth and development of an infant. As breastmilk has been found to possess mesenchymal stem cells, the importance of the components of breastmilk and their physiological roles is increasing day by day. The present study was intended to identify the secretions of growth factors, mainly vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), from human breastmilk mesenchymal stem cells under basal conditions of in vitro cell culture using synthetic media and human cord serum. The growth factors were analyzed with the enzyme-linked immunosorbent assay technique. The cultured mesenchymal stem cells of breastmilk without serum revealed significant differences in secretions of the VEGF and HGF growth factors (8.55 ± 2.26402 pg/mL and 230.8 ± 45.9861 pg/mL, respectively) compared with mesenchymal stem cells of breastmilk with serum (21.31 ± 4.69 pg/mL and 2,404.42 ± 481.593 pg/mL, respectively). Results obtained from our study demonstrate that both VEGF and HGF are secreted in vitro by human breastmilk mesenchymal stem cells. The roles of VEGF and HGF in surfactant secretion, pulmonary maturation, and neonatal maturity have been well established. Thus, we emphasize that breastmilk-derived MSCs could be a potent therapeutic source in treating neonatal diseases. Besides, due to its immense potency, the study also emphasizes the importance of breastfeeding, which is promoted by organizations like the World Heatlh Organization and UNICEF.

  20. Risk factors for manipulation after total knee arthroplasty: a pooled electronic health record database study.

    PubMed

    Pfefferle, Kiel J; Shemory, Scott T; Dilisio, Matthew F; Fening, Stephen D; Gradisar, Ian M

    2014-10-01

    A commercially available software platform, Explorys (Explorys, Inc., Cleveland, OH), was used to mine a pooled electronic healthcare database consisting of the medical records of more than 27 million patients. A total of 229,420 patients had undergone a total knee arthroplasty; 3470 (1.51%) patients were identified to have undergone manipulation under anesthesia. Individual risk factors of being female, African American race, age less than 60, BMI >30 and nicotine dependence were determined to have relative risk of 1.25, 2.20, 3.46, 1.33 and 1.32 respectively. Depressive disorder, diabetes mellitus, opioid abuse/dependence and rheumatoid arthritis were not significant risk factors. African Americans under the age of 60 at time of TKA had the greatest incidence of MUA (5.17%) and relative risk of 3.73 (CI: 3.36, 4.13). Copyright © 2014 Elsevier Inc. All rights reserved.

  1. The Effects of Autocorrelation on the Curve-of-Factors Growth Model

    ERIC Educational Resources Information Center

    Murphy, Daniel L.; Beretvas, S. Natasha; Pituch, Keenan A.

    2011-01-01

    This simulation study examined the performance of the curve-of-factors model (COFM) when autocorrelation and growth processes were present in the first-level factor structure. In addition to the standard curve-of factors growth model, 2 new models were examined: one COFM that included a first-order autoregressive autocorrelation parameter, and a…

  2. Release of Growth Factors into Root Canal by Irrigations in Regenerative Endodontics.

    PubMed

    Zeng, Qian; Nguyen, Sean; Zhang, Hongming; Chebrolu, Hari Priya; Alzebdeh, Dalia; Badi, Mustafa A; Kim, Jong Ryul; Ling, Junqi; Yang, Maobin

    2016-12-01

    The aim of this study was to investigate the release of growth factors into root canal space after the irrigation procedure of regenerative endodontic procedure. Sixty standardized root segments were prepared from extracted single-root teeth. Nail varnish was applied to all surfaces except the root canal surface. Root segments were irrigated with 1.5% NaOCl + 17% EDTA, 2.5% NaOCl + 17% EDTA, 17% EDTA, or deionized water. The profile of growth factors that were released after irrigation was studied by growth factor array. Enzyme-linked immunosorbent assay was used to validate the release of transforming growth factor (TGF)-β1 and basic fibroblast growth factor (bFGF) at 4 hours, 1 day, and 3 days after irrigation. The final concentrations were calculated on the basis of the root canal volume measured by cone-beam computed tomography. Dental pulp stem cell migration on growth factors released from root segments was measured by using Transwell assay. Total of 11 of 41 growth factors were detected by growth factors array. Enzyme-linked immunosorbent assay showed that TGF-β1 was released in all irrigation groups. Compared with the group with 17% EDTA (6.92 ± 4.49 ng/mL), the groups with 1.5% NaOCl + 17% EDTA and 2.5% NaOCl + 17% EDTA had significantly higher release of TGF-β1 (69.04 ± 30.41 ng/mL and 59.26 ± 3.37 ng/mL, respectively), with a peak release at day 1. The release of bFGF was detected at a low level in all groups (0 ng/mL to 0.43 ± 0.22 ng/mL). Migration assay showed the growth factors released from root segments induced dental pulp stem cell migration. The root segment model in present study simulated clinical scenario and indicated that the current irrigation protocol released a significant amount of TGF-β1 but not bFGF. The growth factors released into root canal space induced dental pulp stem cell migration. Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  3. Evaluation of Phantom-Based Education System for Acupuncture Manipulation

    PubMed Central

    Lee, In-Seon; Lee, Ye-Seul; Park, Hi-Joon; Lee, Hyejung; Chae, Younbyoung

    2015-01-01

    Background Although acupuncture manipulation has been regarded as one of the important factors in clinical outcome, it has been difficult to train novice students to become skillful experts due to a lack of adequate educational program and tools. Objectives In the present study, we investigated whether newly developed phantom acupoint tools would be useful to practice-naïve acupuncture students for practicing the three different types of acupuncture manipulation to enhance their skills. Methods We recruited 12 novice students and had them practice acupuncture manipulations on the phantom acupoint (5% agarose gel). We used the Acusensor 2 and compared their acupuncture manipulation techniques, for which the target criteria were depth and time factors, at acupoint LI11 in the human body before and after 10 training sessions. The outcomes were depth of needle insertion, depth error from target criterion, time of rotating, lifting, and thrusting, time error from target criteria and the time ratio. Results After 10 training sessions, the students showed significantly improved outcomes in depth of needle, depth error (rotation, reducing lifting/thrusting), thumb-forward time error, thumb-backward time error (rotation), and lifting time (reinforcing lifting/thrusting). Conclusions The phantom acupoint tool could be useful in a phantom-based education program for acupuncture-manipulation training for students. For advanced education programs for acupuncture manipulation, we will need to collect additional information, such as patient responses, acupoint-specific anatomical characteristics, delicate tissue-like modeling, haptic and visual feedback, and data from an acupuncture practice simulator. PMID:25689598

  4. Neurotrophic factors switch between two signaling pathways that trigger axonal growth.

    PubMed

    Paveliev, Mikhail; Lume, Maria; Velthut, Agne; Phillips, Matthew; Arumäe, Urmas; Saarma, Mart

    2007-08-01

    Integration of multiple inputs from the extracellular environment, such as extracellular matrix molecules and growth factors, is a crucial process for cell function and information processing in multicellular organisms. Here we demonstrate that co-stimulation of dorsal root ganglion neurons with neurotrophic factors (NTFs) - glial-cell-line-derived neurotrophic factor, neurturin or nerve growth factor - and laminin leads to axonal growth that requires activation of Src family kinases (SFKs). A different, SFK-independent signaling pathway evokes axonal growth on laminin in the absence of the NTFs. By contrast, axonal branching is regulated by SFKs both in the presence and in the absence of NGF. We propose and experimentally verify a Boolean model of the signaling network triggered by NTFs and laminin. Our results demonstrate that NTFs provide an environmental cue that triggers a switch between separate pathways in the cell signaling network.

  5. Interleukin-Driven Insulin-Like Growth Factor Promotes Prostatic Inflammatory Hyperplasia

    PubMed Central

    Hahn, Alana M.; Myers, Jason D.; McFarland, Eliza K.; Lee, Sanghee

    2014-01-01

    Prostatic inflammation is of considerable importance to urologic research because of its association with benign prostatic hyperplasia and prostate cancer. However, the mechanisms by which inflammation leads to proliferation and growth remain obscure. Here, we show that insulin-like growth factors (IGFs), previously known as critical developmental growth factors during prostate organogenesis, are induced by inflammation as part of the proliferative recovery to inflammation. Using genetic models and in vivo IGF receptor blockade, we demonstrate that the hyperplastic response to inflammation depends on interleukin-1–driven IGF signaling. We show that human prostatic hyperplasia is associated with IGF pathway activation specifically localized to foci of inflammation. This demonstrates that mechanisms of inflammation-induced epithelial proliferation and hyperplasia involve the induction of developmental growth factors, further establishing a link between inflammatory and developmental signals and providing a mechanistic basis for the management of proliferative diseases by IGF pathway modulation. PMID:25292180

  6. Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses

    PubMed Central

    Audet, Marie-Claude; Anisman, Hymie

    2013-01-01

    The development of depressive disorders had long been attributed to monoamine variations, and pharmacological treatment strategies likewise focused on methods of altering monoamine availability. However, the limited success achieved by treatments that altered these processes spurred the search for alternative mechanisms and treatments. Here we provide a brief overview concerning a possible role for pro-inflammatory cytokines and growth factors in major depression, as well as the possibility of targeting these factors in treating this disorder. The data suggest that focusing on one or another cytokine or growth factor might be counterproductive, especially as these factors may act sequentially or in parallel in affecting depressive disorders. It is also suggested that cytokines and growth factors might be useful biomarkers for individualized treatments of depressive illnesses. PMID:23675319

  7. Conceptual design of a mobile remote manipulator system

    NASA Technical Reports Server (NTRS)

    Bush, H. G.; Mikulas, M. M., Jr.; Wallsom, R. E.; Jensen, J. K.

    1984-01-01

    A mobile remote manipulator system has been identified as a necessary device for space station. A conceptual design for an MRMS is presented which features (1) tracks on the MRMS and guide pins only on the truss structure, (2) a push/pull drive mechanism which rotates to permit movement in four directions, and (3) spacecrane and mobile foot restraint manipulators (or arms). Operational and design features of the MRMS elements are described and illustrated. Concepts are also presented which permit rotating the operational plane of the MRMS through 90 deg. Such a system has been found to have great utility for initial space station construction, maintenance and repair, and to provide a construction capability for future station growth or large spacecraft assembly and/or servicing.

  8. Automatic Bone Drilling - More Precise, Reliable and Safe Manipulation in the Orthopaedic Surgery

    NASA Astrophysics Data System (ADS)

    Boiadjiev, George; Kastelov, Rumen; Boiadjiev, Tony; Delchev, Kamen; Zagurski, Kazimir

    2016-06-01

    Bone drilling manipulation often occurs in the orthopaedic surgery. By statistics, nowadays, about one million people only in Europe need such an operation every year, where bone implants are inserted. Almost always, the drilling is performed handily, which cannot avoid the subjective factor influence. The question of subjective factor reduction has its answer - automatic bone drilling. The specific features and problems of orthopaedic drilling manipulation are considered in this work. The automatic drilling is presented according the possibilities of robotized system Orthopaedic Drilling Robot (ODRO) for assuring the manipulation accuracy, precision, reliability and safety.

  9. Targeting the fibroblast growth factor receptors for the treatment of cancer.

    PubMed

    Lemieux, Steven M; Hadden, M Kyle

    2013-06-01

    Receptor tyrosine kinases (RTKs) are transmembrane proteins that play a critical role in stimulating signal transduction cascades to influence cell proliferation, growth, and differentiation and they have also been shown to promote angiogenesis when they are up-regulated or mutated. For this reason, their dysfunction has been implicated in the development of human cancer. Over the past decade, much attention has been devoted to developing inhibitors and antibodies against several classes of RTKs, including vascular endothelial growth factor receptors (VEGFRs), epidermal growth factor receptors (EGFRs), and platelet-derived growth factor receptors (PDGFRs). More recently, interest in the fibroblast growth factor receptor (FGFR) class of RTKs as a drug target for the treatment of cancer has emerged. Signaling through FGFRs is critical for normal cellular function and their dysregulation has been linked to various malignancies such as breast and prostate cancer. This review will focus on the current state of both small molecules and antibodies as FGFR inhibitors to provide insight into their development and future potential as anti-cancer agents.

  10. Concentration of platelets and growth factors in platelet-rich plasma from Goettingen minipigs.

    PubMed

    Jungbluth, Pascal; Grassmann, Jan-Peter; Thelen, Simon; Wild, Michael; Sager, Martin; Windolf, Joachim; Hakimi, Mohssen

    2014-01-01

    In minipigs little is known about the concentration of growth factors in plasma, despite their major role in several patho-physiological processes such as healing of fractures. This prompted us to study the concentration of platelets and selected growth factors in plasma and platelet-rich plasma (PRP) preparation of sixteen Goettingen minipigs. Platelet concentrations increased significantly in PRP in comparison to native blood plasma. Generally, significant increase in the concentration of all growth factors tested was observed in the PRP in comparison to the corresponding plasma or serum. Five of the plasma samples examined contained detectable levels of bone morphogenic protein 2 (BMP-2) whereas eleven of the plasma or serum samples contained minimal amounts of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF-bb) respectively. On the other hand variable concentrations of bone morphogenic protein 7 (BMP-7) and transforming growth factor β1 (TGF-β1) were measured in all plasma samples. In contrast, all PRP samples contained significantly increased amounts of growth factors. The level of BMP-2, BMP-7, TGF-β1, VEGF and PDGF-bb increased by 17.6, 1.5, 7.1, 7.2 and 103.3 fold, in comparison to the corresponding non-enriched preparations. Moreover significant positive correlations were found between platelet count and the concentrations of BMP-2 (r=0.62, p<0.001), TGF-β1 (r=0.85, p<0.001), VEGF (r=0.46, p<0.01) and PDGF-bb (r=0.9, p<0.001). Our results demonstrate that selected growth factors are present in the platelet-rich plasma of minipigs which might thus serve as a source of autologous growth factors.

  11. Thyroid hormone increases fibroblast growth factor receptor expression and disrupts cell mechanics in the developing organ of corti

    PubMed Central

    2013-01-01

    Background Thyroid hormones regulate growth and development. However, the molecular mechanisms by which thyroid hormone regulates cell structural development are not fully understood. The mammalian cochlea is an intriguing system to examine these mechanisms, as cellular structure plays a key role in tissue development, and thyroid hormone is required for the maturation of the cochlea in the first postnatal week. Results In hypothyroid conditions, we found disruptions in sensory outer hair cell morphology and fewer microtubules in non-sensory supporting pillar cells. To test the functional consequences of these cytoskeletal defects on cell mechanics, we combined atomic force microscopy with live cell imaging. Hypothyroidism stiffened outer hair cells and supporting pillar cells, but pillar cells ultimately showed reduced cell stiffness, in part from a lack of microtubules. Analyses of changes in transcription and protein phosphorylation suggest that hypothyroidism prolonged expression of fibroblast growth factor receptors, and decreased phosphorylated Cofilin. Conclusions These findings demonstrate that thyroid hormones may be involved in coordinating the processes that regulate cytoskeletal dynamics and suggest that manipulating thyroid hormone sensitivity might provide insight into the relationship between cytoskeletal formation and developing cell mechanical properties. PMID:23394545

  12. [Effects of water table manipulation on leaf photosynthesis, morphology and growth of Phragmites australis and Imperata cylindrica in the reclaimed tidal wetland at Dongtan of Chongming Island, China].

    PubMed

    Zhong, Qi-Cheng; Wang, Jiang-Tao; Zhou, Jian-Hong; Ou, Qiang; Wang, Kai-Yun

    2014-02-01

    During the growing season of 2011, the leaf photosynthesis, morphological and growth traits of Phragmites australis and Imperata cylindrica were investigated along a gradient of water table (low, medium and high) in the reclaimed tidal wetland at the Dongtan of Chongming Island in the Yangtze Estuary of China. A series of soil factors, i. e., soil temperature, moisture, salinity and inorganic nitrogen content, were also measured. During the peak growing season, leaf photosynthetic capacity of P. australis in the wetland with high water table was significantly lower than those in the wetland with low and medium water tables, and no difference was observed in leaf photosynthetic capacity of I. cylindrica at the three water tables. During the entire growing season, at the shoot level, the morphological and growth traits of P. australis got the optimum in the wetland with medium water table, but most of the morphological and growth traits of I. cylindrica had no significant differences at the three water tables. At the population level, the shoot density, leaf area index and aboveground biomass per unit area were the highest in the wetland with high water table for P. australis, but all of the three traits were the highest in the wetland with low water table for I. cylindrica. At the early growing season, the rhizome biomass of P. australis in the 0-20 cm soil layer had no difference at the three water tables, and the rhizome biomass of I. cylindrica in the 0-20 cm soil layer in the wetland with high water table was significantly lower than those in the wetland with low and medium water table. As a native hygrophyte before the reclamation, the variations of performances of P. australis at the three water tables were probably attributed to the differences in the soil factors as well as the intensity of competition from I. cylindrica. To appropriately manipulate water table in the reclaimed tidal wetland may restrict the growth and propagation of the mesophyte I

  13. [Therapeutic use of hematopoietic growth factors. II. GM-CSF and G-CSF].

    PubMed

    Royer, B; Arock, M

    1998-01-01

    The second part of this review on haematopoietic growth factors is focused on the therapeutic use of GM-CSF and G-CSF. Such therapeutic applications have raised very great hopes for clinical haematology. However, it should not be forgotten that these haematopoietic growth factors, which are very costly, are powerful two-edged weapons capable of triggering a cascade of reactions, and have a field of activity that often goes beyond the single highly specific property which it is hoped they possess. The risks and costs of their use are currently being evaluated. Waited developments concerning these molecules focus on three axes: a best use of factors already commercialized, especially concerning adaptation of posologies and new indications, the development of hybrid molecules from already known haematopoietic growth factors, possessing the advantages of respective factors, but not their disadvantages, the discovery of new haematopoietic growth factors with potential therapeutic application.

  14. Autonomous Object Manipulation Using a Soft Planar Grasping Manipulator

    PubMed Central

    Katzschmann, Robert K.; Marchese, Andrew D.

    2015-01-01

    Abstract This article presents the development of an autonomous motion planning algorithm for a soft planar grasping manipulator capable of grasp-and-place operations by encapsulation with uncertainty in the position and shape of the object. The end effector of the soft manipulator is fabricated in one piece without weakening seams using lost-wax casting instead of the commonly used multilayer lamination process. The soft manipulation system can grasp randomly positioned objects within its reachable envelope and move them to a desired location without human intervention. The autonomous planning system leverages the compliance and continuum bending of the soft grasping manipulator to achieve repeatable grasps in the presence of uncertainty. A suite of experiments is presented that demonstrates the system's capabilities. PMID:27625916

  15. Ultrastructure and growth factor content of equine platelet-rich fibrin gels.

    PubMed

    Textor, Jamie A; Murphy, Kaitlin C; Leach, J Kent; Tablin, Fern

    2014-04-01

    To compare fiber diameter, pore area, compressive stiffness, gelation properties, and selected growth factor content of platelet-rich fibrin gels (PRFGs) and conventional fibrin gels (FGs). PRFGs and conventional FGs prepared from the blood of 10 healthy horses. Autologous fibrinogen was used to form conventional FGs. The PRFGs were formed from autologous platelet-rich plasma of various platelet concentrations (100 × 10³ platelets/μL, 250 × 10³ platelets/μL, 500 × 10³ platelets/μL, and 1,000 × 10³ platelets/μL). All gels contained an identical fibrinogen concentration (20 mg/mL). Fiber diameter and pore area were evaluated with scanning electron microscopy. Maximum gelation rate was assessed with spectrophotometry, and gel stiffness was determined by measuring the compressive modulus. Gel weights were measured serially over 14 days as an index of contraction (volume loss). Platelet-derived growth factor-BB and transforming growth factor-β1 concentrations were quantified with ELISAs. Fiber diameters were significantly larger and mean pore areas were significantly smaller in PRFGs than in conventional FGs. Gel weight decreased significantly over time, differed significantly between PRFGs and conventional FGs, and was significantly correlated with platelet concentration. Platelet-derived growth factor-BB and transforming growth factor-β1 concentrations were highest in gels and releasates derived from 1,000 × 10³ platelets/μL. The inclusion of platelets in FGs altered the architecture and increased the growth factor content of the resulting scaffold. Platelets may represent a useful means of modifying these gels for applications in veterinary and human regenerative medicine.

  16. Minimally invasive esthetic ridge preservation with growth-factor enhanced bone matrix.

    PubMed

    Nevins, Marc L; Said, Sherif

    2017-12-28

    Extraction socket preservation procedures are critical to successful esthetic implant therapy. Conventional surgical approaches are technique sensitive and often result in alteration of the soft tissue architecture, which then requires additional corrective surgical procedures. This case series report presents the ability of flapless surgical techniques combined with a growth factor-enhanced bone matrix to provide esthetic ridge preservation at the time of extraction for compromised sockets. When considering esthetic dental implant therapy, preservation, or further enhancement of the available tissue support at the time of tooth extraction may provide an improved esthetic outcome with reduced postoperative sequelae and decreased treatment duration. Advances in minimally invasive surgical techniques combined with recombinant growth factor technology offer an alternative for bone reconstruction while maintaining the gingival architecture for enhanced esthetic outcome. The combination of freeze-dried bone allograft (FDBA) and rhPDGF-BB (platelet-derived growth factor-BB) provides a growth-factor enhanced matrix to induce bone and soft tissue healing. The use of a growth-factor enhanced matrix is an option for minimally invasive ridge preservation procedures for sites with advanced bone loss. Further studies including randomized clinical trials are needed to better understand the extent and limits of these procedures. The use of minimally invasive techniques with growth factors for esthetic ridge preservation reduces patient morbidity associated with more invasive approaches and increases the predictability for enhanced patient outcomes. By reducing the need for autogenous bone grafts the use of this technology is favorable for patient acceptance and ease of treatment process for esthetic dental implant therapy. © 2017 Wiley Periodicals, Inc.

  17. Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer.

    PubMed

    Baker, Cheryl H; Solorzano, Carmen C; Fidler, Isaiah J

    2002-04-01

    We determined whether concurrent blockage of vascular endothelial growth factor (VEGF) receptor and epidermal growth factor (EGF) receptor signaling by two novel tyrosine kinase inhibitors, PTK 787 and PKI 166, respectively, can inhibit angiogenesis and, hence, the growth and metastasis of human pancreatic carcinoma in nude mice. Highly metastatic human pancreatic carcinoma L3.6pl cells were injected into the pancreas of nude mice. Seven days later, groups of mice began receiving oral doses of PTK 787 and PKI 166 three times weekly. Some groups of mice also received i.p. injections of gemcitabine twice a week. The mice were necropsied when the control mice became moribund. Treatment with PTK 787 and PKI 166, with gemcitabine alone, or with the combination of PTK 787, PKI 166, and gemcitabine produced 69, 50, and 97% reduction in the volume of pancreatic tumors, respectively. Administration of protein tyrosine kinase inhibitors and gemcitabine also significantly decreased the incidence of lymph node and liver metastasis. The therapeutic efficacy directly correlated with a decrease in circulating proangiogenic molecules (VEGF, interleukin-8), a decrease in microvessel density, a decrease in proliferating cell nuclear antigen staining, and an increase in apoptosis of tumor cells and endothelial cells. Therapies produced by combining gemcitabine with either PKI 166 or PTK 787 were similar to those produced by combining gemcitabine with both PKI 166 and PTK 787. These results suggest that blockade of either epidermal growth factor receptor or VEGF receptor signaling combined with chemotherapy provides an effective approach to the therapy of pancreatic cancer.

  18. Using Manipulatives To Teach Quantitative Concepts in Ecology.

    ERIC Educational Resources Information Center

    Eyster, Linda S.; Tashiro, Jay Shiro

    1997-01-01

    Describes the use of manipulatives to teach the fundamental concept of limiting factors and presents a series of questions that can be used to test whether students are harboring some of the most common misconceptions about limiting factors. Includes applications to discussions of cultural eutrophication and vegetarianism. (JRH)

  19. A virally inactivated functional growth factor preparation from human platelet concentrates.

    PubMed

    Su, C-Y; Kuo, Y P; Lin, Y C; Huang, C-T; Tseng, Y H; Burnouf, T

    2009-08-01

    Human platelet growth factors (HPGF) are essential for tissue regeneration and may replace fetal bovine serum (FBS) in cell therapy. No method for the manufacture of standardized virally inactivated HPGF has been developed yet. Platelet concentrates (PC) were subjected to solvent/detergent (S/D) treatment (1% TnBP/1% Triton X-45), oil extraction, hydrophobic interaction chromatography and sterile filtration. Platelet-derived growth factor (PDGF)-AB, -BB and -AA, transforming growth factor-beta1 (TGF-beta1), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1) and vascular endothelium growth factor (VEGF) were measured by ELISA. Composition in proteins and lipids was determined, protein profiles were obtained by SDS-PAGE, and TnBP and Triton X-45 were assessed by gas chromatography and high-performance liquid chromatography, respectively. Cell growth promoting activity of HPGF was evaluated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay using human embryonic kidney (HEK293A) fibroblast and Statens Seruminstitute rabbit corneal (SIRC) epithelial cell lines. The GF preparation contained a mean of 16.66, 2.04, 1.53, 72.19, 0.33, 48.59 and 0.44 ng/ml of PDGF-AB, -BB, -AA, TGF-beta1, EGF, IGF-1 and VEGF, respectively. The protein profile was typical of platelet releasates and had less than 2 p.p.m. of residual S/D agents. MTS assay of HEK293A and SIRC cultures showed that the GF preparation at 10% and 0.1% (v/v), respectively, could successfully replace 10% FBS for cell proliferation. Cell-stimulating activity of HPGF on HEK293A was over twice that of PC releasates. STANDARDIZED and functional virally inactivated HPGF can be prepared from human PC for possible applications in cell therapy and regenerative medicine.

  20. Sustained release of nerve growth factor from biodegradable polymer microspheres.

    PubMed

    Camarata, P J; Suryanarayanan, R; Turner, D A; Parker, R G; Ebner, T J

    1992-03-01

    Although grafted adrenal medullary tissue to the striatum has been used both experimentally and clinically in parkinsonism, there is a definite need to augment long-term survival. Infusion of nerve growth factor (NGF) or implantation of NGF-rich tissue into the area of the graft prolongs survival and induces differentiation into neural-like cells. To provide for prolonged, site-specific delivery of this growth factor to the grafted tissue in a convenient manner, we fabricated biodegradable polymer microspheres of poly(L-lactide)co-glycolide (70:30) containing NGF. Biologically active NGF was released from the microspheres, as assayed by neurite outgrowth in a dorsal root ganglion tissue culture system. Anti-NGF could block this outgrowth. An enzyme-linked immunosorbent assay detected NGF still being released in vitro for longer than 5 weeks. In vivo immunohistochemical studies showed release over a 4.5-week period. This technique should prove useful for incorporating NGF and other growth factors into polymers and delivering proteins and other macromolecules intracerebrally over a prolonged time period. These growth factor-containing polymer microspheres can be used in work aimed at prolonging graft survival, treating experimental Alzheimer's disease, and augmenting peripheral nerve regeneration.

  1. Concentrated Growth Factor Enhanced Fat Graft Survival: A Comparative Study.

    PubMed

    Hu, Yun; Jiang, Yichen; Wang, Muyao; Tian, Weidong; Wang, Hang

    2018-06-08

    Concentrated growth factors (CGFs) belong to a new generation biomaterials that concentrate large number of growth factors and CD34 stem cells in small volume of plasma. The purpose of this study was to evaluate the impact of the new technique, CGF, on fat graft survival, which compared with platelet-rich plasma (PRP) and platelet-rich fibrin (PRF). Nude mice received fat graft were divided into PRP group, PRF group, CGF group, and saline. The grafts were volumetrically and histologically evaluated at 4, 8, and 12 weeks after fat grafting. In vitro growth factor levels in PRP, PRF, and CGF were compared using enzyme-linked immunoassay method. Cell count and real-time polymerase chain reaction were used to evaluate the impact of CGF in medium on human adipose-derived stem cell (hADSC) proliferation and vascular differentiation, respectively. Fat graft weight was significantly higher in the CGF group than those in the other groups, and histologic evaluation revealed greater vascularity, fewer cysts, and less fibrosis. Adding CGF to the medium maximally promoted hADSC proliferation and expressing vascular endothelial growth factor and PECAM-1. In this preliminary study, CGF treatment improved the survival and quality of fat grafts.

  2. Platelet Activating Factor: A Growth Factor for Breast Cancer

    DTIC Science & Technology

    2006-09-01

    synthase (ADS) increases ether lipid content, growth and PAF synthesis in MCF-7 cells. 4. Eicosapentaenoic acid (EPA) inhibits the synthesis of PAF...Schmitt, J. D., Bullock, B. C. Wykle, R. L. Reacylation of platelet activating factor with eicosapentaenoic acid in fish-oil-enriched monkey...breast cancer. Recent studies have shown that the ratio of two families of essential fatty acids is important in regulating many cellular processes

  3. Role of Fibroblast Growth Factor Binding Protein-1 in Mammary Development and Tumorigenesis

    DTIC Science & Technology

    2009-10-01

    AD_________________ Award Number: W81XWH-06-1-0763 TITLE: Role of Fibroblast Growth Factor ...2009 4. TITLE AND SUBTITLE Role of Fibroblast Growth Factor Binding Protein-1 in Mammary Development 5a. CONTRACT NUMBER and Tumorigenesis...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS Fibroblast Growth Factor Binding Protein-1

  4. ROLES OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF-A) IN MEDIATION OF DIOXIN (TCDD)-INDUCED DELAYS IN DEVELOPMENT OF THE MOUSE MAMMARY GLAND

    EPA Science Inventory

    Roles of Epidermal Growth Factor (EGF) and Transforming Growth Factor-alpha (TGF-a) in Mediation of Dioxin (TCDD)-Induced Delays in Development of the Mouse Mammary Gland.
    Suzanne E. Fenton, Barbara Abbott, Lamont Bryant, and Angela Buckalew. U.S. EPA, NHEERL, Reproductive Tox...

  5. Novel Growth Factor as Prognostic Marker for Estrogen-Independence in Breast Cancer

    DTIC Science & Technology

    2002-08-01

    factor (PCDGF, also known as progranulin ) is a novel autocrine growth factor shown to be overexpressed and to be mitogenic in human breast cancer cell...kDa glycoprotein originally purified from the highly tumorigenic mouse teratoma-derived cell line PC (1, 2). PCDGF (also known as progranulin ) is the...requirement for the insulin-like growth factor 1 receptor for growth in vitro. J Biol Chem, 273: 20078-20083, 1998. 6. He, Z. and Bateman, A. Progranulin gene

  6. Plant-Produced Human Recombinant Erythropoietic Growth Factors Support Erythroid Differentiation In Vitro

    PubMed Central

    Musiychuk, Konstantin; Sivalenka, Rajarajeswari; Jaje, Jennifer; Bi, Hong; Flores, Rosemary; Shaw, Brenden; Jones, R. Mark; Golovina, Tatiana; Schnipper, Jacob; Khandker, Luipa; Sun, Ruiqiang; Li, Chang; Kang, Lin; Voskinarian-Berse, Vanessa; Zhang, Xiaokui; Streatfield, Stephen; Hambor, John; Abbot, Stewart

    2013-01-01

    Clinically available red blood cells (RBCs) for transfusions are at high demand, but in vitro generation of RBCs from hematopoietic stem cells requires significant quantities of growth factors. Here, we describe the production of four human growth factors: erythropoietin (EPO), stem cell factor (SCF), interleukin 3 (IL-3), and insulin-like growth factor-1 (IGF-1), either as non-fused proteins or as fusions with a carrier molecule (lichenase), in plants, using a Tobacco mosaic virus vector-based transient expression system. All growth factors were purified and their identity was confirmed by western blotting and peptide mapping. The potency of these plant-produced cytokines was assessed using TF1 cell (responsive to EPO, IL-3 and SCF) or MCF-7 cell (responsive to IGF-1) proliferation assays. The biological activity estimated here for the cytokines produced in plants was slightly lower or within the range cited in commercial sources and published literature. By comparing EC50 values of plant-produced cytokines with standards, we have demonstrated that all four plant-produced growth factors stimulated the expansion of umbilical cord blood-derived CD34+ cells and their differentiation toward erythropoietic precursors with the same potency as commercially available growth factors. To the best of our knowledge, this is the first report on the generation of all key bioactive cytokines required for the erythroid development in a cost-effective manner using a plant-based expression system. PMID:23517237

  7. Gene therapy with growth factors for periodontal tissue engineering–A review

    PubMed Central

    Gupta, Shipra; Mahendra, Aneet

    2012-01-01

    The treatment of oral and periodontal diseases and associated anomalies accounts for a significant proportion of the healthcare burden, with the manifestations of these conditions being functionally and psychologically debilitating. A challenge faced by periodontal therapy is the predictable regeneration of periodontal tissues lost as a consequence of disease. Growth factors are critical to the development, maturation, maintenance and repair of oral tissues as they establish an extra-cellular environment that is conducive to cell and tissue growth. Tissue engineering principles aim to exploit these properties in the development of biomimetic materials that can provide an appropriate microenvironment for tissue development. The aim of this paper is to review emerging periodontal therapies in the areas of materials science, growth factor biology and cell/gene therapy. Various such materials have been formulated into devices that can be used as vehicles for delivery of cells, growth factors and DNA. Different mechanisms of drug delivery are addressed in the context of novel approaches to reconstruct and engineer oral and tooth supporting structure. Key words: Periodontal disease, gene therapy, regeneration, tissue repair, growth factors, tissue engineering. PMID:22143705

  8. A novel mechanism of vascular endothelial growth factor, leptin and transforming growth factor-beta2 sequestration in a subpopulation of human ovarian follicle cells.

    PubMed

    Antczak, M; Van Blerkom, J; Clark, A

    1997-10-01

    This study describes the occurrence of a highly specialized subpopulation of granulosa and cumulus oophorus cells that accumulate and sequester specific growth factors by a novel mechanism. These cells are characterized by multiple balloon-like processes tethered to the cell by means of a slender stalk of plasma membrane. Time-lapse analyses demonstrate that these tethered structures (TS) form in minutes and frequently detach from the cell with the bulbous portion remaining motile on the cell surface. Serial section reconstruction of transmission electron microscopic images shows a specific and stable intracellular organization in which an apparent secretory compartment composed of densely packed vacuoles, vesicles, and cisternae is separated by a thick filamentous network from a nuclear compartment containing mitochondria, polyribosomes, lipid inclusions, and rough-surfaced endoplasmic reticulum. Immunofluorescent analysis performed during the formation of these structures showed a progressive accumulation of vascular endothelial growth factor, leptin, and transforming growth factor-beta2 in the bulbous region. TS were identified in newly aspirated masses of granulosa and cumulus oophorus, and their production persists for months in culture. Observations of TS-forming cells made over several days of culture indicates that their production is episodic and factor release from these cells may be pulsatile. The findings suggest that a novel method of growth factor storage and release by an apparent apocrine-like mechanism occurs in the human ovarian follicle. The results are discussed with respect to possible roles in pre- and post-ovulatory follicular development.

  9. Manipulability, force, and compliance analysis for planar continuum manipulators

    NASA Technical Reports Server (NTRS)

    Gravagne, Ian A.; Walker, Ian D.

    2002-01-01

    Continuum manipulators, inspired by the natural capabilities of elephant trunks and octopus tentacles, may find niche applications in areas like human-robot interaction, multiarm manipulation, and unknown environment exploration. However, their true capabilities will remain largely inaccessible without proper analytical tools to evaluate their unique properties. Ellipsoids have long served as one of the foremost analytical tools available to the robotics researcher, and the purpose of this paper is to first formulate, and then to examine, three types of ellipsoids for continuum robots: manipulability, force, and compliance.

  10. Manipulability, force, and compliance analysis for planar continuum manipulators.

    PubMed

    Gravagne, Ian A; Walker, Ian D

    2002-06-01

    Continuum manipulators, inspired by the natural capabilities of elephant trunks and octopus tentacles, may find niche applications in areas like human-robot interaction, multiarm manipulation, and unknown environment exploration. However, their true capabilities will remain largely inaccessible without proper analytical tools to evaluate their unique properties. Ellipsoids have long served as one of the foremost analytical tools available to the robotics researcher, and the purpose of this paper is to first formulate, and then to examine, three types of ellipsoids for continuum robots: manipulability, force, and compliance.

  11. FGF19 functions as autocrine growth factor for hepatoblastoma

    PubMed Central

    Elzi, David J.; Song, Meihua; Blackman, Barron; Weintraub, Susan T.; López-Terrada, Dolores; Chen, Yidong; Tomlinson, Gail E.; Shiio, Yuzuru

    2016-01-01

    Hepatoblastoma is the most common liver cancer in children, accounting for over 65% of all childhood liver malignancies. Hepatoblastoma is distinct from adult liver cancer in that it is not associated with hepatitis virus infection, cirrhosis, or other underlying liver pathology. The paucity of appropriate cell and animal models has been hampering the mechanistic understanding of hepatoblastoma pathogenesis. Consequently, there is no molecularly targeted therapy for hepatoblastoma. To gain insight into cytokine signaling in hepatoblastoma, we employed mass spectrometry to analyze the proteins secreted from Hep293TT hepatoblastoma cell line we established and identified the specific secretion of fibroblast growth factor 19 (FGF19), a growth factor for liver cells. We determined that silencing FGF19 by shRNAs or neutralizing secreted FGF19 by anti-FGF19 antibody inhibits the proliferation of hepatoblastoma cells. Furthermore, blocking FGF19 signaling by an FGF receptor kinase inhibitor suppressed hepatoblastoma growth. RNA expression analysis in hepatoblastoma tumors revealed that the high expression of FGF19 signaling pathway components as well as the low expression of FGF19 signaling repression targets correlates with the aggressiveness of the tumors. These results suggest the role of FGF19 as autocrine growth factor for hepatoblastoma. PMID:27382436

  12. Design and characteristics of cytotoxic fibroblast growth factor 1 conjugate for fibroblast growth factor receptor-targeted cancer therapy.

    PubMed

    Szlachcic, Anna; Zakrzewska, Malgorzata; Lobocki, Michal; Jakimowicz, Piotr; Otlewski, Jacek

    2016-01-01

    Fibroblast growth factor receptors (FGFRs) are attractive candidate cancer therapy targets as they are overexpressed in multiple types of tumors, such as breast, prostate, bladder, and lung cancer. In this study, a natural ligand of FGFR, an engineered variant of fibroblast growth factor 1 (FGF1V), was conjugated to a potent cytotoxic drug, monomethyl auristatin E (MMAE), and used as a targeting agent for cancer cells overexpressing FGFRs, similar to antibodies in antibody-drug conjugates. The FGF1V-valine-citrulline-MMAE conjugate showed a favorable stability profile, bound FGFRs on the cell surface specifically, and efficiently released the drug (MMAE) upon cleavage by the lysosomal protease cathepsin B. Importantly, the conjugate showed a prominent cytotoxic effect toward cell lines expressing FGFR. FGF1V-vcMMAE was highly cytotoxic at concentrations even an order of magnitude lower than those found for free MMAE. This effect was FGFR-specific as cells lacking FGFR did not show any increased mortality.

  13. Design and characteristics of cytotoxic fibroblast growth factor 1 conjugate for fibroblast growth factor receptor-targeted cancer therapy

    PubMed Central

    Szlachcic, Anna; Zakrzewska, Malgorzata; Lobocki, Michal; Jakimowicz, Piotr; Otlewski, Jacek

    2016-01-01

    Fibroblast growth factor receptors (FGFRs) are attractive candidate cancer therapy targets as they are overexpressed in multiple types of tumors, such as breast, prostate, bladder, and lung cancer. In this study, a natural ligand of FGFR, an engineered variant of fibroblast growth factor 1 (FGF1V), was conjugated to a potent cytotoxic drug, monomethyl auristatin E (MMAE), and used as a targeting agent for cancer cells overexpressing FGFRs, similar to antibodies in antibody–drug conjugates. The FGF1V–valine–citrulline–MMAE conjugate showed a favorable stability profile, bound FGFRs on the cell surface specifically, and efficiently released the drug (MMAE) upon cleavage by the lysosomal protease cathepsin B. Importantly, the conjugate showed a prominent cytotoxic effect toward cell lines expressing FGFR. FGF1V–vcMMAE was highly cytotoxic at concentrations even an order of magnitude lower than those found for free MMAE. This effect was FGFR-specific as cells lacking FGFR did not show any increased mortality. PMID:27563235

  14. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma

    PubMed Central

    Snuderl, Matija; Batista, Ana; Kirkpatrick, Nathaniel D.; de Almodovar, Carmen Ruiz; Riedemann, Lars; Walsh, Elisa C.; Anolik, Rachel; Huang, Yuhui; Martin, John D.; Kamoun, Walid; Knevels, Ellen; Schmidt, Thomas; Farrar, Christian T.; Vakoc, Benjamin J.; Mohan, Nishant; Chung, Euiheon; Roberge, Sylvie; Peterson, Teresa; Bais, Carlos; Zhelyazkova, Boryana H.; Yip, Stephen; Hasselblatt, Martin; Rossig, Claudia; Niemeyer, Elisabeth; Ferrara, Napoleone; Klagsbrun, Michael; Duda, Dan G.; Fukumura, Dai; Xu, Lei; Carmeliet, Peter; Jain, Rakesh K.

    2013-01-01

    SUMMARY Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastases, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1—and not vascular endothelial growth factor receptor 1 (VEGFR1)—to promote tumor cell survival. This critical tumor-stroma interaction—mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes—supports the development of therapies targeting PlGF/Nrp1 pathway. PMID:23452854

  15. Origin of platelet-derived growth factor in megakaryocytes in guinea pigs.

    PubMed Central

    Chernoff, A; Levine, R F; Goodman, D S

    1980-01-01

    Growth factor activity, as determined by the stimulation of [3H]thymidine incorporation into the DNA of quiescent 3T3 cells in culture, was found in lysates of guinea pig platelets and megakaryocytes. Quantitative dilution studies demonstrated that, of the cells present in the guinea pig bone marrow, only the megakaryocyte possessed quantitatively significant growth factor activity. The amount of activity present in one megakaryocyte was equivalent to that present in 1,000-5,000 platelets, a value approximately comparable to the number of platelets shed from a single megakaryocyte. It is suggested that guinea pig platelet-derived growth factor has its origin in the megakaryocyte. PMID:7358851

  16. Role Of Expectancy Manipulation In Systematic Desensitization

    ERIC Educational Resources Information Center

    Brown, H. Alan

    1973-01-01

    Expectancy, relaxation, and hierarchy content were manipulated. Findings did not support the hypothesis that expectancy was the only factor in desensitization, but did clarify the role of expectancy vis-a-vis the counterconditioning elements typically discussed in the literature. (Author)

  17. Role of Fibroblast Growth Factor Binding Protein-1 in Mammary Development and Tumorigenesis

    DTIC Science & Technology

    2008-10-01

    AD_________________ AWARD NUMBER: W81XWH-06-1-0763 TITLE: Role of Fibroblast Growth Factor ...Role of Fibroblast Growth Factor Binding Protein-1 in Mammary Development and Tumorigenesis 5b. GRANT NUMBER W81XWH-06-1-0763 5c. PROGRAM...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Fibroblast growth factors (FGFs) are vital modulators of development as well as

  18. On the dimensionality of the stress-related growth scale: one, three, or seven factors?

    PubMed

    Roesch, Scott C; Rowley, Anthony A; Vaughn, Allison A

    2004-06-01

    We examined the factorial validity and dimensionality of the Stress-Related Growth Scale (SRGS; Park, Cohen, & Murch, 1996) using a large multiethnic sample (n = 1,070). Exploratory and confirmatory factor analyses suggested that a multidimensional representation of the SRGS fit better than a unidimensional representation. Specifically, we cross-validated both a 3-factor model and a 7-factor model using confirmatory factor analysis and were shown to be invariant across gender and ethnic groups. The 3-factor model was represented by global dimensions of growth that included rational/mature thinking, affective/emotional growth, and religious/spiritual growth. We replicated the 7-factor model of Armeli, Gunthert, and Cohen (2001) and it represented more specific components of growth such as Self-Understanding and Treatment of Others. However, some factors of the 7-factor model had questionable internal consistency and were strongly intercorrelated, suggesting redundancy. The findings support the notion that the factor structure of both the original 1-factor and revised 7-factor models are unstable and that the 3-factor model developed in this research has more reliable psychometric properties and structure.

  19. Growth factor delivery for oral and periodontal tissue engineering

    PubMed Central

    Kaigler, Darnell; Cirelli, Joni A; Giannobile, William V

    2008-01-01

    The treatment of oral and periodontal diseases and associated anomalies accounts for a significant proportion of the healthcare burden, with the manifestations of these conditions being functionally and psychologically debilitating. Growth factors are critical to the development, maturation, maintenance and repair of craniofacial tissues, as they establish an extracellular environment that is conducive to cell and tissue growth. Tissue-engineering principles aim to exploit these properties in the development of biomimetic materials that can provide an appropriate microenvironment for tissue development. These materials have been constructed into devices that can be used as vehicles for delivery of cells, growth factors and DNA. In this review, different mechanisms of drug delivery are addressed in the context of novel approaches to reconstruct and engineer oral- and tooth-supporting structures, namely the periodontium and alveolar bone. PMID:16948560

  20. Casein kinase 2 and the cell response to growth factors.

    PubMed

    Filhol-Cochet, O; Loue-Mackenbach, P; Cochet, C; Chambaz, E M

    1994-01-01

    Different approaches have been followed with the aim of delineating a possible role of casein kinase 2 (CK2) in the mitogenic signalling in response to cell growth factors. (a) Immunocytochemical detection of CK2 showed that while the kinase is evenly distributed throughout cycle arrested cells, it becomes preferentially associated with the nuclear compartment in activity growing cells; (b) CK2 biosynthesis is activated as an early response of quiescent cells to growth factors. The newly synthesized CK2 steadily accumulates as the cells progress through the G1 phase. This growth factor-induced CK2 biosynthesis involves in parallel the two alpha and beta subunits of the kinase, with no detectable preferential subcellular localization of the newly synthesized enzyme; and (c) In addition to substrate phosphorylation, CK2 may form molecular complexes with cell components of functional significance. Such is the case with the protein p53, a major negative regulator of the cell cycle. CK2 forms a high affinity association (Kd 70 nM) with p53, through its beta subunit. The complex dissociates in the presence of adenosine triphosphate (ATP). These observations suggest that CK2 and p53 may play a coordinated regulatory role in the cell response to growth factors.

  1. Serum placental growth factor, vascular endothelial growth factor, soluble vascular endothelial growth factor receptor-1 and -2 levels in periodontal disease, and adverse pregnancy outcomes.

    PubMed

    Sert, Tuba; Kırzıoğlu, F Yeşim; Fentoğlu, Ozlem; Aylak, Firdevs; Mungan, Tamer

    2011-12-01

    The aim of this study is the evaluation of levels of serum interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), placental growth factor (PIGF), and soluble VEGF receptor (sVEGFR)-1 and -2 in the association between periodontal disease and adverse pregnancy outcomes. One hundred and nine mothers, who recently gave birth, and 51 women who were not recently pregnant, aged 18 to 35 years, were included in this study. The mothers were classified as term birth, preterm birth (PTB), and preterm low birth weight (PLBW) in respect to their gestational age and baby's birth weight. The birth mothers were grouped as having gingivitis or periodontitis. The non-pregnant group also included periodontally healthy patients. Venous blood samples were collected to evaluate serum IL-1β, IL-6, IL-10, TNF-α, VEGF, PIGF, and sVEGFR-1 and -2 levels. Mother's weight, education, and income level were significantly associated with pregnancy outcomes. Serum levels of IL-1β, TNF-α, IL-6, VEGF, and sVEGFR-1 and -2 showed an increase in significance when related to pregnancy. Whereas in the PLBW group IL-1β, VEGF, and sVEGFR-2 levels were increased, in the PTB group sVEGFR-1 levels were increased. Additionally, the patients in the PLBW group with periodontitis had higher serum levels of IL-1β, VEGF, sVEGFR-2, and IL-1β/IL-10. The serum levels of IL-1β, VEGF, and sVEGFR-1 and -2 may have a potential effect on the mechanism of the association between periodontal disease and adverse pregnancy outcomes.

  2. UV-B Inhibits Leaf Growth through Changes in Growth Regulating Factors and Gibberellin Levels1[OPEN

    PubMed Central

    Fina, Julieta; AbdElgawad, Hamada; Prinsen, Els

    2017-01-01

    Ultraviolet-B (UV-B) radiation affects leaf growth in a wide range of species. In this work, we demonstrate that UV-B levels present in solar radiation inhibit maize (Zea mays) leaf growth without causing any other visible stress symptoms, including the accumulation of DNA damage. We conducted kinematic analyses of cell division and expansion to understand the impact of UV-B radiation on these cellular processes. Our results demonstrate that the decrease in leaf growth in UV-B-irradiated leaves is a consequence of a reduction in cell production and a shortened growth zone (GZ). To determine the molecular pathways involved in UV-B inhibition of leaf growth, we performed RNA sequencing on isolated GZ tissues of control and UV-B-exposed plants. Our results show a link between the observed leaf growth inhibition and the expression of specific cell cycle and developmental genes, including growth-regulating factors (GRFs) and transcripts for proteins participating in different hormone pathways. Interestingly, the decrease in the GZ size correlates with a decrease in the concentration of GA19, the immediate precursor of the active gibberellin, GA1, by UV-B in this zone, which is regulated, at least in part, by the expression of GRF1 and possibly other transcription factors of the GRF family. PMID:28400494

  3. [Fibroblast growth factors and their effects in pancreas organogenesis].

    PubMed

    Gnatenko, D A; Kopantzev, E P; Sverdlov, E D

    2017-05-01

    Fibroblast growth factors (FGF) - growth factors that regulate many important biological processes, including proliferation and differentiation of embryonic cells during organogenesis. In this review, we will summarize current information about the involvement of FGFs in the pancreas organogenesis. Pancreas organogenesis is a complex process, which involves constant signaling from mesenchymal tissue. This orchestrates the activation of various regulator genes at specific stages, determining the specification of progenitor cells. Alterations in FGF/FGFR signaling pathway during this process lead to incorrect activation of the master genes, which leads to different pathologies during pancreas development. Understanding the full picture about role of FGF factors in pancreas development will make it possible to more accurately understand their role in other pathologies of this organ, including carcinogenesis.

  4. Quantification of various growth factors in different demineralized bone matrix preparations.

    PubMed

    Wildemann, B; Kadow-Romacker, A; Haas, N P; Schmidmaier, G

    2007-05-01

    Besides autografts, allografts, and synthetic materials, demineralized bone matrix (DBM) is used for bone defect filling and treatment of non-unions. Different DBM formulations are introduced in clinic since years. However, little is known about the presents and quantities of growth factors in DBM. Aim of the present study was the quantification of eight growth factors important for bone healing in three different "off the shelf" DBM formulations, which are already in human use: DBX putty, Grafton DBM putty, and AlloMatrix putty. All three DBM formulations are produced from human donor tissue but they differ in the substitutes added. From each of the three products 10 different lots were analyzed. Protein was extracted from the samples with Guanidine HCL/EDTA method and human ELISA kits were used for growth factor quantification. Differences between the three different products were seen in total protein contend and the absolute growth factor values but also a large variability between the different lots was found. The order of the growth factors, however, is almost comparable between the materials. In the three investigated materials FGF basic and BMP-4 were not detectable in any analyzed sample. BMP-2 revealed the highest concentration extractable from the samples with approximately 3.6 microg/g tissue without a significant difference between the three DBM formulations. In DBX putty significantly more TGF-beta1 and FGFa were measurable compared to the two other DBMs. IGF-I revealed the significantly highest value in the AlloMatrix and PDGF in Grafton. No differences were accessed for VEGF. Due to the differences in the growth factor concentration between the individual samples, independently from the product formulation, further analyzes are required to optimize the clinical outcome of the used demineralized bone matrix. Copyright 2006 Wiley Periodicals, Inc.

  5. Rearing Mozambique tilapia in tidally-changing salinities: Effects on growth and the growth hormone/insulin-like growth factor I axis.

    PubMed

    Moorman, Benjamin P; Yamaguchi, Yoko; Lerner, Darren T; Grau, E Gordon; Seale, Andre P

    2016-08-01

    The growth hormone (GH)/insulin-like growth factor (IGF) axis plays a central role in the regulation of growth in teleosts and has been shown to be affected by acclimation salinity. This study was aimed at characterizing the effects of rearing tilapia, Oreochromis mossambicus, in a tidally-changing salinity on the GH/IGF axis and growth. Tilapia were raised in fresh water (FW), seawater (SW), or in a tidally-changing environment, in which salinity is switched between FW (TF) and SW (TS) every 6h, for 4months. Growth was measured over all time points recorded and fish reared in a tidally-changing environment grew significantly faster than other groups. The levels of circulating growth hormone (GH), insulin-like growth factor I (IGF-I), pituitary GH mRNA, gene expression of IGF-I, IGF-II, and growth hormone receptor 2 (GHR) in the muscle and liver were also determined. Plasma IGF-I was higher in FW and TS than in SW and TF tilapia. Pituitary GH mRNA was higher in TF and TS than in FW and SW tilapia. Gene expression of IGF-I in the liver and of GHR in both the muscle and liver changed between TF and TS fish. Fish growth was positively correlated with GH mRNA expression in the pituitary, and GHR mRNA expression in muscle and liver tissues. Our study indicates that rearing fish under tidally-changing salinities elicits a distinct pattern of endocrine regulation from that observed in fish reared in steady-state conditions, and may provide a new approach to increase tilapia growth rate and study the regulation of growth in euryhaline fish. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Bone morphogenetic protein-4 strongly potentiates growth factor-induced proliferation of mammary epithelial cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Montesano, Roberto; Sarkoezi, Rita; Schramek, Herbert

    2008-09-12

    Bone morphogenetic proteins (BMPs) are multifunctional cytokines that elicit pleiotropic effects on biological processes such as cell proliferation, cell differentiation and tissue morphogenesis. With respect to cell proliferation, BMPs can exert either mitogenic or anti-mitogenic activities, depending on the target cells and their context. Here, we report that in low-density cultures of immortalized mammary epithelial cells, BMP-4 did not stimulate cell proliferation by itself. However, when added in combination with suboptimal concentrations of fibroblast growth factor (FGF)-2, FGF-7, FGF-10, epidermal growth factor (EGF) or hepatocyte growth factor (HGF), BMP-4 potently enhanced growth factor-induced cell proliferation. These results reveal a hithertomore » unsuspected interplay between BMP-4 and growth factors in the regulation of mammary epithelial cell proliferation. We suggest that the ability of BMP-4 to potentiate the mitogenic activity of multiple growth factors may contribute to mammary gland ductal morphogenesis as well as to breast cancer progression.« less

  7. Extracellular Matrix-Inspired Growth Factor Delivery Systems for Skin Wound Healing

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Briquez, Priscilla S.; Hubbell, Jeffrey A.; Martino, Mikaël M.

    2015-08-01

    Blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular, the spatial localizationmore » of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.« less

  8. Phosphorylation of hepatocyte growth factor receptor and epidermal growth factor receptor of human hepatocytes can be maintained in a (3D) collagen sandwich culture system.

    PubMed

    Engl, Tobias; Boost, Kim A; Leckel, Kerstin; Beecken, Wolf-Dietrich; Jonas, Dietger; Oppermann, Elsie; Auth, Marcus K H; Schaudt, André; Bechstein, Wolf-Otto; Blaheta, Roman A

    2004-08-01

    In vitro culture models that employ human liver cells could be potent tools for predictive studies on drug toxicity and metabolism in the pharmaceutical industry. However, an adequate receptor responsiveness is necessary to allow intracellular signalling and metabolic activity. We tested the ability of three-dimensionally arranged human hepatocytes to respond to the growth factors hepatocyte growth factor (HGF) or epidermal growth factor (EGF). Isolated adult human hepatocytes were cultivated within a three-dimensional collagen gel (sandwich) or on a two-dimensional collagen matrix. Cells were treated with HGF or EGF and expression and phosphorylative activity of HGF receptors (HGFr, c-met) or EGF receptors (EGFr) were measured by flow cytometry and Western blot. Increasing HGFr and EGFr levels were detected in hepatocytes growing two-dimensionally. However, both receptors were not activated in presence of growth factors. In contrast, when hepatocytes were plated within a three-dimensional matrix, HGFr and EGFr levels remained constantly low. However, both receptors became strongly phosphorylated by soluble HGF or EGF. We conclude that cultivation of human hepatocytes in a three-dimensionally arranged in vitro system allows the maintenance of specific functional activities. The necessity of cell dimensionality for HGFr and EGFr function should be considered when an adequate in vitro system has to be introduced for drug testing.

  9. R7 Photoreceptor Axon Growth Is Temporally Controlled by the Transcription Factor Ttk69, Which Inhibits Growth in Part by Promoting Transforming Growth Factor-β/Activin Signaling

    PubMed Central

    Kniss, Jonathan S.; Holbrook, Scott

    2013-01-01

    Work on axon growth has classically focused on understanding how extrinsic cues control growth cone dynamics independent of the cell body. However, more recently, neuron-intrinsic transcription factors have been shown to influence both normal and regenerative axon growth, suggesting that understanding their mechanism of action is of clinical importance. We are studying axon targeting in the Drosophila visual system and here show that the BTB/POZ zinc-finger transcription factor Tramtrack69 (Ttk69) plays an instructive role in inhibiting the growth of R7 photoreceptor axon terminals. Although ttk69 mutant R7 axons project to the correct medullar target layer, M6, their terminals fail to remain retinotopically restricted and instead grow laterally within M6. This overgrowth is not caused by an inability to be repelled by neighboring R7 axons or by an inability to recognize and initiate synapse formation with postsynaptic targets. The overgrowth is progressive and occurs even if contact between ttk69 mutant R7 axons and their normal target layer is disrupted. Ttk69 is first expressed in wild-type R7s after their axons have reached the medulla; ttk69 mutant R7 axon terminal overgrowth begins shortly after this time point. We find that expressing Ttk69 prematurely in R7s collapses their growth cones and disrupts axon extension, indicating that Ttk69 plays an instructive role in this process. A TGF-β/Activin pathway was shown previously to inhibit R7 axon terminal growth. We find that Ttk69 is required for normal activation of this pathway but that Ttk69 likely also inhibits R7 axon growth by a TGF-β/Activin-independent mechanism. PMID:23345225

  10. Genetic polymorphisms and protein structures in growth hormone, growth hormone receptor, ghrelin, insulin-like growth factor 1 and leptin in Mehraban sheep.

    PubMed

    Bahrami, A; Behzadi, Sh; Miraei-Ashtiani, S R; Roh, S-G; Katoh, K

    2013-09-15

    The somatotropic axis, the control system for growth hormone (GH) secretion and its endogenous factors involved in the regulation of metabolism and energy partitioning, has promising potentials for producing economically valuable traits in farm animals. Here we investigated single nucleotide polymorphisms (SNPs) of the genes of factors involved in the somatotropic axis for growth hormone (GH1), growth hormone receptor (GHR), ghrelin (GHRL), insulin-like growth factor 1 (IGF-I) and leptin (LEP), using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods in 452 individual Mehraban sheep. A nonradioactive method to allow SSCP detection was used for genomic DNA and PCR amplification of six fragments: exons 4 and 5 of GH1; exon 10 of GH receptor (GHR); exon 1 of ghrelin (GHRL); exon 1 of insulin-like growth factor-I (IGF-I), and exon 3 of leptin (LEP). Polymorphisms were detected in five of the six PCR products. Two electrophoretic patterns were detected for GH1 exon 4. Five conformational patterns were detected for GH1 exon 5 and LEP exon 3, and three for IGF-I exon 1. Only GHR and GHRL were monomorphic. Changes in protein structures due to variable SNPs were also analyzed. The results suggest that Mehraban sheep, a major breed that is important for the animal industry in Middle East countries, has high genetic variability, opening interesting prospects for future selection programs and preservation strategies. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. The growth hormone–insulin-like growth factor-I axis in the diagnosis and treatment of growth disorders

    PubMed Central

    Blum, Werner F; Alherbish, Abdullah; Alsagheir, Afaf; El Awwa, Ahmed; Kaplan, Walid; Koledova, Ekaterina; Savage, Martin O

    2018-01-01

    The growth hormone (GH)–insulin-like growth factor (IGF)-I axis is a key endocrine mechanism regulating linear growth in children. While paediatricians have a good knowledge of GH secretion and assessment, understanding and use of measurements of the components of the IGF system are less current in clinical practice. The physiological function of this axis is to increase the anabolic cellular processes of protein synthesis and mitosis, and reduction of apoptosis, with each being regulated in the appropriate target tissue. Measurement of serum IGF-I and IGF-binding protein (IGFBP)-3 concentrations can complement assessment of GH status in the investigation of short stature and contribute to prediction of growth response during GH therapy. IGF-I monitoring during GH therapy also informs the clinician about adherence and provides a safety reference to avoid over-dosing during long-term management. PMID:29724795

  12. The growth hormone-insulin-like growth factor-I axis in the diagnosis and treatment of growth disorders.

    PubMed

    Blum, Werner; Alherbish, Abdullah; Alsagheir, Afaf; El Awwa, Ahmed; Kaplan, Walid; Koledova, Ekaterina; Savage, Martin O

    2018-05-03

    The growth hormone (GH)-insulin-like growth factor (IGF)-I axis is a key endocrine mechanism regulating linear growth in children. While paediatricians have a good knowledge of GH secretion and assessment, understanding and use of measurements of the components of the IGF system are less current in clinical practice. The physiological function of this axis is to increase the anabolic cellular processes of protein synthesis and mitosis, and reduction of apoptosis, with each being regulated in the appropriate target tissue. Measurement of serum IGF-I and IGFBP-3 concentrations can complement assessment of GH status in the investigation of short stature and contribute to prediction of growth response during GH therapy. IGF-I monitoring during GH therapy also informs the clinician about adherence and provides a safety reference to avoid over-dosing during long-term management.

  13. Tissular growth factors profile after teduglutide administration on an animal model of intestinal anastomosis.

    PubMed

    Costa, Beatriz Pinto; Gonçalves, Ana Cristina; Abrantes, Ana Margarida; Alves, Raquel; Matafome, Paulo; Seiça, Raquel; Sarmento-Ribeiro, Ana Bela; Botelho, Maria Filomena; Castro-Sousa, Francisco

    2018-01-16

    Teduglutide is an enterotrophic analogue of glucagon-like peptide-2, with an indirect and poorly understood mechanism of action, approved for the rehabilitation of short-bowel syndrome. This study aims to analyze the response of tissue growth factors to surgical injury and teduglutide administration on an animal model of intestinal anastomosis. Wistar rats (n = 59) were distributed into four groups: "ileal resection" or "laparotomy", each one subdivided into "postoperative teduglutide administration" or "no treatment"; and sacrificed at the third or the seventh day, with ileal sample harvesting. Gene expression of insulin-like growth factor 1 (Igf1), vascular endothelial growth factor a (Vegfa), transforming growth factor β1 (Tgfβ1), connective tissue growth factor (Ctgf), fibroblast growth factor 2 (Fgf2), fibroblast growth factor 7 (Fgf7), epidermal growth factor (Egf), heparin-binding epidermal-like growth factor (Hbegf), platelet-derived growth factor b (Pdgfb) and glucagon-like peptide 2 receptor (Glp2r)was studied by real-time polymerase chain reaction. Upregulation of Fgf7, Fgf2, Egf, Vegfaand Glp2rat the third day and of Pdgfat the seventh day was verified in the perianastomotic segment. Teduglutide administration was associated with higher fold-change of relative gene expression of Vegfa(3.6 ± 1.3 vs.1.9 ± 2.0, p = 0.0001), Hbegf(2.2 ± 2.3 vs. 1.1 ± 0.9, p = 0.001), Igf1(1.6 ± 7.6 vs. 0.9 ± 0.7, p = 0.002) and Ctgf(1.1 ± 2.1 vs. 0.6 ± 2.0, p = 0.013); and lower fold-change of Tgfβ1, Fgf7and Glp2r. Those results underscore the recognized role of Igf1and Hbegfas molecular mediators of the effects of teduglutide and suggest that other humoral factors, like Vegfand Ctgf, may also be relevant in the perioperative context. Induction of Vegfa, Igf1and Ctgfgene expressions might indicate a favorable influence of teduglutide on the intestinal anastomotic healing.

  14. Effects of different growth factors and carriers on bone regeneration: a systematic review.

    PubMed

    Khojasteh, Arash; Behnia, Hossein; Naghdi, Navid; Esmaeelinejad, Mohammad; Alikhassy, Zahra; Stevens, Mark

    2013-12-01

    The application and subsequent investigations in the use of varied osteogenic growth factors in bone regeneration procedures have grown dramatically over the past several years. Owing to this rapid gain in popularity and documentation, a review was undertaken to evaluate the in vivo effects of growth factors on bone regeneration. Using related key words, electronic databases (Medline, Embase, and Cochrane) were searched for articles published from 1999 to April 2010 to find growth factor application in bone regeneration in human or animal models. A total of 63 articles were matched with the inclusion criteria of this study. Bone morphogenetic protein 2 (BMP-2) was the most studied growth factor. Carriers for the delivery, experimental sites, and methods of evaluation were different, and therefore articles did not come to a general agreement. Within the limitations of this review, BMP-2 may be an appropriate growth factor for osteogenesis. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Mesenchymal Stem Cells Suppress Chronic Rejection in Heterotopic Small Intestine Transplant Rat Models Via Inhibition of CD68, Transforming Growth Factor- β1, and Platelet-Derived Growth Factor Expression.

    PubMed

    Li, Fuxin; Cao, Jisen; Zhao, Zhicheng; Li, Chuan; Qi, Feng; Liu, Tong

    2017-04-01

    Mesenchymal stem cells are easy to obtain and expand, with characteristics of low immunogenicity and strong tissue repair capacity. In this study, our aim was to investigate the role of mesenchymal stem cells in chronic immune rejection of heterotopic small intestine transplant in rats. After successfully constructing a rat chronic immune rejection model of heterotopic small intestine transplant, we infused mesenchymal stem cells into the animal recipients. We observed mesenchymal stem cell location in the recipients, recipient survival, pathology changes, and the expression of CD68, transforming growth factor β1, and platelet-derived growth factor C in the donor intestine. Mesenchymal stem cells inhibited the lymphocyte proliferation caused by concanavalin A in vitro. After stem cells were infused into recipients, they were mainly located in the donor intestine, as well as in the spleen and thymus. Recovery after transplant and pathology changes of the donor intestine in rats with stem cell infusion were better than in the control group; however, we observed no differences in survival time, accompanied by downregulated expression of CD68, transforming growth factor β1, and platelet-derived growth factor C. Mesenchymal stem cells, to a certain extent, could inhibit the process of chronic rejection. The mechanisms may include the inhibited function of these cells on lymphocyte proliferation, reduced infiltration of macrophages, and reduced expression of transforming growth factor β1 and platelet-derived growth factor C.

  16. Insulin-like growth factors and insulin: at the crossroad between tumor development and longevity.

    PubMed

    Novosyadlyy, Ruslan; Leroith, Derek

    2012-06-01

    Numerous lines of evidence indicate that insulin-like growth factor signaling plays an important role in the regulation of life span and tumor development. In the present paper, the role of individual components of insulin-like growth factor signaling in aging and tumor development has been extensively analyzed. The molecular mechanisms underlying aging and tumor development are frequently overlapping. Although the link between reduced insulin-like growth factor signaling and suppressed tumor growth and development is well established, it remains unclear whether extended life span results from direct suppression of insulin-like growth factor signaling or this effect is caused by indirect mechanisms such as improved insulin sensitivity.

  17. Controllable mineral coatings on PCL scaffolds as carriers for growth factor release

    PubMed Central

    Suárez-González, Darilis; Barnhart, Kara; Migneco, Francesco; Flanagan, Colleen; Hollister, Scott J.; Murphy, William L.

    2011-01-01

    In this study, we have developed mineral coatings on polycaprolactone scaffolds to serve as templates for growth factor binding and release. Mineral coatings were formed using a biomimetic approach that consisted in the incubation of scaffolds in modified simulated body fluids (mSBF). To modulate the properties of the mineral coating, which we hypothesized would dictate growth factor release, we used carbonate (HCO3) concentration in mSBF of 4.2 mM, 25mM, and 100mM. Analysis of the mineral coatings formed using scanning electron microscopy indicated growth of a continuous layer of mineral with different morphologies. X-ray diffraction analysis showed peaks associated with hydroxyapatite, the major inorganic constituent of human bone tissue in coatings formed in all HCO3 concentrations. Mineral coatings with increased HCO3 substitution showed more rapid dissolution kinetics in an environment deficient in calcium and phosphate but showed re-precipitation in an environment with the aforementioned ions. The mineral coating provided an effective mechanism for growth factor binding and release. Peptide versions of vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2) were bound with efficiencies up to 90% to mineral mineral-coated PCL scaffolds. We also demonstrated sustained release of all growth factors with release kinetics that were strongly dependent in the solubility of the mineral coating. PMID:22014948

  18. L-ascorbic acid 2-phosphate and fibroblast growth factor-2 treatment maintains differentiation potential in bone marrow-derived mesenchymal stem cells through expression of hepatocyte growth factor.

    PubMed

    Bae, Sung Hae; Ryu, Hoon; Rhee, Ki-Jong; Oh, Ji-Eun; Baik, Soon Koo; Shim, Kwang Yong; Kong, Jee Hyun; Hyun, Shin Young; Pack, Hyun Sung; Im, Changjo; Shin, Ha Cheol; Kim, Yong Man; Kim, Hyun Soo; Eom, Young Woo; Lee, Jong In

    2015-04-01

    l-ascorbic acid 2-phosphate (Asc-2P) acts as an antioxidant and a stimulator of hepatocyte growth factor (HGF) production. Previously, we reported that depletion of growth factors such as fibroblast growth factor (FGF)-2, epidermal growth factor (EGF), FGF-4 and HGF during serial passage could induce autophagy, senescence and down-regulation of stemness (proliferation via FGF-2/-4 and differentiation via HGF). In this study, we investigated the proliferation and differentiation potential of BMSCs by FGF-2 and Asc-2P. Co-treatment with FGF-2 and Asc-2P induced optimal proliferation of BMSCs and increased the accumulation rate of BMSC numbers during a 2-month culture period. Moreover, differentiation potential was maintained by co-treatment with FGF-2 and Asc-2P via HGF expression. Adipogenic differentiation potential by FGF-2 and Asc-2P was dramatically suppressed by c-Met inhibitors (SU11274). These data suggest that co-treatment with FGF-2 and Asc-2P would be beneficial in obtaining BMSCs that possess "stemness" during long-term culture.

  19. Insulin-like growth factor-I and insulin-like growth factor binding protein-3 cotreatment versus insulin-like growth factor-I alone in two brothers with growth hormone insensitivity syndrome: effects on insulin sensitivity, body composition and linear growth.

    PubMed

    Ekström, Klas; Carlsson-Skwirut, Christine; Ritzén, E Martin; Bang, Peter

    2011-01-01

    Growth hormone insensitivity syndrome (GHIS) is caused by a defective growth hormone receptor (GHR) and is associated with insulin-like growth factor-I (IGF-I) deficiency, severely short stature and, from adolescence, fasting hyperglycemia and obesity. We studied the effects of treatment with IGF-I in either a 1:1 molar complex with IGFBP-3 (IGF-I/BP-3-Tx) or with IGF-I alone (IGF-I-Tx) on metabolism and linear growth. Two brothers, compound heterozygous for a GHR gene defect, were studied. After 8 months without treatment, we examined the short- and long-term effects of IGF-I/BP-3-Tx and, subsequently, IGF-I-Tx on 12-hour overnight levels of IGF-I, GH, insulin, IGFBP-1, insulin sensitivity by hyperinsulinemic euglycemic clamp, body composition by dual-energy X-ray absorptiometry and linear growth. Mean overnight levels of insulin decreased and IGFBP-1, a measure of hepatic insulin sensitivity, increased on both regimens, but was more pronounced on IGF-I-Tx. Insulin sensitivity by clamp showed no consistent changes. Lean body mass increased and abdominal fat mass decreased in both subjects on IGF-I-Tx. However, the changes were inconsistent during IGF-I/BP-3-Tx. Height velocity was low without treatment, increased slightly on IGF-I/BP-3-Tx and doubled on IGF-I-Tx. Both modalities of IGF-I improved determinants of hepatic insulin sensitivity, body composition and linear growth rate; however, IGF-I alone seemed to be more efficient. Copyright © 2011 S. Karger AG, Basel.

  20. Haplotypes of heparin-binding epidermal-growth-factor-like growth factor gene are associated with pre-eclampsia.

    PubMed

    Harendra, Galhenagey Gayani; Jayasekara, Rohan W; Dissanayake, Vajira H W

    2012-01-01

    Heparin-binding epidermal-growth-factor-like growth factor (HBEGF) plays an important role in placentation, including impaired placentation, the primary defect seen in pre-eclampsia. We carried out a case-control disease-association study to examine the association of single nucleotide polymorphisms (SNP) in the HBEGF gene and haplotypes defined by them with pre-eclampsia in a Sinhalese population in Sri Lanka. A total of 175 women with pre-eclampsia and 171 matched normotensive controls were genotyped for six SNP selected in silico as having putative functional effects using mass array Sequenom iplex methodology and a newly designed polymerase chain reaction-restriction fragment length polymorphism assay. The individual SNP were not associated with pre-eclampsia. The haplotypes defined by them, however, showed both predisposing (rs13385T,rs2074613G,rs2237076G,rs2074611C,rs4150196A,rs1862176A; odds ratio,1.65; 95% confidence interval1.04-2.60; P=0.032) and protective (rs13385C,rs2074613G,rs2237076A,rs2074611C,rs4150196A,rs1862176A; odds ratio,0.20; 95% confidence interval, 0.04-0.89; P=0.034) effects. These results confirm that polymorphisms in the HGEGF gene are associated with pre-eclampsia. The haplotypes are likely to exert their effects through the numerous transcription regulation factors binding to the polymorphic sites, namely GATA-1, GATA-3, MZF-1 and AML-1a. © 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.

  1. Characteristics of manipulative in mathematics laboratory

    NASA Astrophysics Data System (ADS)

    Istiandaru, A.; Istihapsari, V.; Prahmana, R. C. I.; Setyawan, F.; Hendroanto, A.

    2017-12-01

    A manipulative is a teaching aid designed such that students could understand mathematical concepts by manipulating it. This article aims to provide an insight to the characteristics of manipulatives produced in the mathematics laboratory of Universitas Ahmad Dahlan, Indonesia. A case study was conducted to observe the existing manipulatives produced during the latest three years and classified the manipulatives based on the characteristics found. There are four kinds of manipulatives: constructivism manipulative, virtual manipulative, informative manipulative, and game-based manipulative. Each kinds of manipulative has different characteristics and impact towards the mathematics learning.

  2. Localized delivery of growth factors for periodontal tissue regeneration: role, strategies, and perspectives.

    PubMed

    Chen, Fa-Ming; Shelton, Richard M; Jin, Yan; Chapple, Iain L C

    2009-05-01

    Difficulties associated with achieving predictable periodontal regeneration, means that novel techniques need to be developed in order to regenerate the extensive soft and hard tissue destruction that results from periodontitis. Localized delivery of growth factors to the periodontium is an emerging and versatile therapeutic approach, with the potential to become a powerful tool in future regenerative periodontal therapy. Optimized delivery regimes and well-defined release kinetics appear to be logical prerequisites for safe and efficacious clinical application of growth factors and to avoid unwanted side effects and toxicity. While adequate concentrations of growth factor(s) need to be appropriately localized, delivery vehicles are also expected to possess properties such as protein protection, precision in controlled release, biocompatibility and biodegradability, self-regulated therapeutic activity, potential for multiple delivery, and good cell/tissue penetration. Here, current knowledge, recent advances, and future possibilities of growth factor delivery strategies are outlined for periodontal regeneration. First, the role of those growth factors that have been implicated in the periodontal healing/regeneration process, general requirements for their delivery, and the different material types available are described. A detailed discussion follows of current strategies for the selection of devices for localized growth factor delivery, with particular emphasis placed upon their advantages and disadvantages and future prospects for ongoing studies in reconstructing the tooth supporting apparatus.

  3. Neurodevelopmental effects of insulin-like growth factor signaling

    PubMed Central

    O’Kusky, John; Ye, Ping

    2012-01-01

    Insulin-like growth factor (IGF) signaling greatly impacts the development and growth of the central nervous system (CNS). IGF-I and IGF-II, two ligands of the IGF system, exert a wide variety of actions both during development and in adulthood, promoting the survival and proliferation of neural cells. The IGFs also influence the growth and maturation of neural cells, augmenting dendritic growth and spine formation, axon outgrowth, synaptogenesis, and myelination. Specific IGF actions, however, likely depend on cell type, developmental stage, and local microenvironmental milieu within the brain. Emerging research also indicates that alterations in IGF signaling likely contribute to the pathogenesis of some neurological disorders. This review summarizes experimental studies and shed light on the critical roles of IGF signaling, as well as its mechanisms, during CNS development. PMID:22710100

  4. The importance of neuronal growth factors in the ovary.

    PubMed

    Streiter, S; Fisch, B; Sabbah, B; Ao, A; Abir, R

    2016-01-01

    The neurotrophin family consists of nerve growth factor (NGF), neurotrophin 3 (NT3) and neurotrophin 4/5 (NT4/5), in addition to brain-derived neurotrophic factor (BDNF) and the neuronal growth factors, glial cell line-derived neurotrophic factor (GDNF) and vasointestinal peptide (VIP). Although there are a few literature reviews, mainly of animal studies, on the importance of neurotrophins in the ovary, we aimed to provide a complete review of neurotrophins as well as neuronal growth factors and their important roles in normal and pathological processes in the ovary. Follicular assembly is probably stimulated by complementary effects of NGF, NT4/5 and BDNF and their receptors. The neurotrophins, GDNF and VIP and their receptors have all been identified in preantral and antral follicles of mammalian species, including humans. Transgenic mice with mutations in the genes encoding for Ngf, Nt4/5 and Bdnf and their tropomyosin-related kinase β receptor showed a reduction in preantral follicles and an abnormal ovarian morphology, whereas NGF, NT3, GDNF and VIP increased the in vitro activation of primordial follicles in rats and goats. Additionally, NGF, NT3 and GDNF promoted follicular cell proliferation; NGF, BDNF and VIP were shown to be involved in ovulation; VIP inhibited follicular apoptosis; NT4/5, BDNF and GDNF promoted oocyte maturation and NGF, NT3 and VIP stimulated steroidogenesis. NGF may also exert a stimulatory effect in ovarian cancer and polycystic ovarian syndrome (PCOS). Low levels of NGF and BDNF in follicular fluid may be associated with diminished ovarian reserve and high levels with endometriosis. More knowledge of the roles of neuronal growth factors in the ovary has important implications for the development of new therapeutic drugs (such as anti-NGF agents) for ovarian cancer and PCOS as well as various infertility problems, warranting further research. © The Author 2015. Published by Oxford University Press on behalf of the European Society

  5. Does L-arginine induce intestinal adaptation by epithelial growth factor?

    PubMed

    Camli, Alparslan; Barlas, Meral; Yagmurlu, Aydin

    2005-01-01

    To evaluate whether L-Arginine has an effect on endogenous epidermal growth factor secretion and intestinal adaptation in massive small bowel resection an experimental study was performed. Fourteen albino Wistar rats weighing 250-300 g were used for the study. After performing 50% small bowel resection and anastomosis the rats were randomly divided into two groups. The first group received 500 mg/kg/day of L-Arginine intraperitoneally for 14 days just after the surgical procedure. The control group received isotonic saline instead. Body weight measurement was preformed daily. At the end of the second postoperative week all rats underwent relaparotomy. Small bowel was resected for histopathological examination. Levels of epidermal growth factor were measured by enzyme-linked immunosorbent assay in serum, saliva, and urine at the end of second postoperative week in both groups. The weight gain was higher in the L-Arginine treated group (P < 0.05). Serum, saliva and urinary epidermal growth factor levels were significantly higher at the end of the second week compared to the control group (P < 0.05). The villus height was higher on histopathological examination in L-Arginine treated group compared to the control group (P < 0.05). L-Arginine resulted in a better intestinal adaptation after massive bowel resection. The high levels of epidermal growth factor in body fluids of L-Arginine treated rats could be the explanation for this effect.

  6. Extrinsic Factors Influencing Fetal Deformations and Intrauterine Growth Restriction

    PubMed Central

    Moh, Wendy; Graham, John M.; Wadhawan, Isha; Sanchez-Lara, Pedro A.

    2012-01-01

    The causes of intrauterine growth restriction (IUGR) are multifactorial with both intrinsic and extrinsic influences. While many studies focus on the intrinsic pathological causes, the possible long-term consequences resulting from extrinsic intrauterine physiological constraints merit additional consideration and further investigation. Infants with IUGR can exhibit early symmetric or late asymmetric growth abnormality patterns depending on the fetal stage of development, of which the latter is most common occurring in 70–80% of growth-restricted infants. Deformation is the consequence of extrinsic biomechanical factors interfering with normal growth, functioning, or positioning of the fetus in utero, typically arising during late gestation. Biomechanical forces play a critical role in the normal morphogenesis of most tissues. The magnitude and direction of force impact the form of the developing fetus, with a specific tissue response depending on its pliability and stage of development. Major uterine constraining factors include primigravida, small maternal size, uterine malformation, uterine fibromata, early pelvic engagement of the fetal head, aberrant fetal position, oligohydramnios, and multifetal gestation. Corrective mechanical forces similar to those that gave rise to the deformation to reshape the deformed structures are often used and should take advantage of the rapid postnatal growth to correct form. PMID:22888434

  7. Expression of transforming growth factor alpha and epidermal growth factor receptor messenger RNA in neoplastic and nonneoplastic human kidney tissue.

    PubMed

    Mydlo, J H; Michaeli, J; Cordon-Cardo, C; Goldenberg, A S; Heston, W D; Fair, W R

    1989-06-15

    Using Northern blot analysis, we have demonstrated that mRNA for transforming growth factor alpha (TGF-alpha) was expressed in five malignant kidney tissue specimens but was not detected in their autologous nonneoplastic homologues. In addition, the expression of epidermal growth factor (EGF) receptor mRNA in these malignant tissues was 2- to 3-fold greater than in nontransformed tissues. In two cases examined using immunohistochemistry, we were able to correlate the increased expression of the mRNA with an increase in protein expression. Since TGF-alpha is known to bind to the EGF receptor, the finding of an increased expression of both TGF-alpha and EGF receptor mRNA in kidney tumor tissue suggests that interaction between TGF-alpha and the EGF receptor may play a role in promoting transformation and/or proliferation of kidney neoplasms, perhaps by an autocrine mechanism.

  8. Expression of Epidermal Growth Factor Receptor and Transforming Growth Factor Alpha in Cancer Bladder: Schistosomal and Non-Schistosomal

    PubMed Central

    Badawy, Afkar A.; El-Hindawi, Ali; Hammam, Olfat; Moussa, Mona; Helal, Noha S.; Kamel, Amira

    2017-01-01

    Introduction Overexpression of epidermal growth factor receptor (EGFR) has been described in several solid tumors including bladder cancer. Transforming growth factor alpha (TGFα) is frequently deregulated in neoplastic cells and plays a role in the development of bladder cancer. TGFα-EGFR ligand-receptor combination constitutes an important event in multistep tumorigenesis. Methods This study was done on 30 bladder biopsies from patients with urothelial carcinoma, 15 with squamous cell carcinoma, 10 with cystitis and 5 normal control bladder specimens. All were immuohistochemically stained with EGFR and TGFα antibodies. Results EGFR and TGFα were over-expressed in higher grades and late stages of bladder cancer. Moreover, they show higher expression in squamous cell carcinoma compared to urothelial carcinoma and in schistosomal associated lesions than in non-schistosomal associated lesions. Conclusion EGFR and TGFα could be used as prognostic predictors in early stage and grade of bladder cancer cases, especially those with schistosomal association. In addition they can help in selecting patients who can get benefit from anti-EGFR molecular targeted therapy. PMID:28413380

  9. Assessing the Factors of Regional Growth Decline of Sugar Maple

    NASA Astrophysics Data System (ADS)

    Bishop, D. A.; Beier, C. M.; Pederson, N.; Lawrence, G. B.; Stella, J. C.; Sullivan, T. J.

    2014-12-01

    Sugar maple (Acer saccharum Marsh) is among the most ecologically, economically and culturally important trees in North America, but has experienced a decline disease across much of its range. We investigated the climatic and edaphic factors associated with A. saccharum growth in the Adirondack Mountains (USA) using a well-replicated tree-ring network incorporating a range of soil fertility (base cation availability). We found that nearly 3 in 4 A. saccharum trees exhibited declining growth rates during the last several decades, regardless of tree age or size. Although diameter growth was consistently higher on base-rich soils, the negative trends in growth were largely consistent across the soil chemistry gradient. Sensitivity of sugar maple growth to climatic variability was overall weaker than expected, but were also non-stationary during the 20th century. We observed increasingly positive responses to late-winter precipitation, increasingly negative responses to growing season temperatures, and strong positive responses to moisture availability during the 1960s drought that became much weaker during the recent pluvial. Further study is needed of these factors and their interactions as potential mechanisms for sugar maple growth decline.

  10. Insulin-like growth factor-binding protein 7 alters the sensitivity to interferon-based anticancer therapy in hepatocellular carcinoma cells.

    PubMed

    Tomimaru, Y; Eguchi, H; Wada, H; Noda, T; Murakami, M; Kobayashi, S; Marubashi, S; Takeda, Y; Tanemura, M; Umeshita, K; Doki, Y; Mori, M; Nagano, H

    2010-05-11

    A striking efficiency of interferon (IFN)-based anticancer therapy for advanced hepatocellular carcinoma (HCC) has been reported. Because its clinical efficiency greatly depends on each patient's local response, prediction of local response is crucial. Continuous exposure of IFN-alpha to parental PLC/PRF/5 cells (PLC-P) and a limiting dilution method resulted in the establishment of IFN-resistant cell clones (PLC-Rs). Microarray analyses of PLC-P and PLC-Rs identified insulin-like growth factor-binding protein 7 (IGFBP7) as one of the most significantly downregulated genes in PLC-Rs. Changes in anticancer effects of IFN-alpha were examined in HCC cells after genetic manipulation of IGFBP7 expression. The correlation between immunohistochemically determined IGFBP7 expression and the response to IFN-alpha/5-fluorouracil (5-FU) therapy was investigated in surgically resected HCC specimens. PLC-R cells showed a remarkable downregulation of IGFBP7 and resistance to IFN-alpha, compared with PLC-P. Parental PLC/PRF/5 cells transfected with short hairpin RNA against IGFBP7 showed a significant resistance to IFN-alpha relative to control cells (IC(50) fold increase=14.38 times). Insulin-like growth factor-binding protein 7 transfection into PLC-R restored sensitivity to IFN-alpha. In resected specimens, IGFBP7 expression significantly correlated with the response to IFN-alpha/5-FU therapy. IGFBP7 could be a useful predictor of the response to IFN-based therapy in advanced HCC.

  11. Some growth factors stimulate cultured adult rabbit ventricular myocyte hypertrophy in the absence of mechanical loading

    NASA Technical Reports Server (NTRS)

    Decker, R. S.; Cook, M. G.; Behnke-Barclay, M.; Decker, M. L.

    1995-01-01

    Cultured adult rabbit cardiac myocytes treated with recombinant growth factors display enhanced rates of protein accumulation (ie, growth) in response to insulin and insulin-like growth factors (IGFs), but epidermal growth factor, acidic or basic fibroblast growth factor, and platelet-derived growth factor failed to increase contractile protein synthesis or growth of the heart cells. Insulin and IGF-1 increased growth rates by stimulating anabolic while simultaneously inhibiting catabolic pathways, whereas IGF-2 elevated growth modestly by apparently inhibiting lysosomal proteolysis. Neutralizing antibodies directed against either IGF-1 or IGF-2 or IGF binding protein 3 blocked protein accumulation. A monoclonal antibody directed against the IGF-1 receptor also inhibited changes in protein turnover provoked by recombinant human IGF-1 but not IGF-2. Of the other growth factors tested, only transforming growth factor-beta 1 increased the fractional rate of myosin heavy chain (MHC) synthesis, with beta-MHC synthesis being elevated and alpha-MHC synthesis being suppressed. However, the other growth factors were able to modestly stimulate the rate of DNA synthesis in this preparation. Bromodeoxyuridine labeling revealed that these growth factors increased DNA synthesis in myocytes and nonmyocytes alike, but the heart cells displayed neither karyokinesis or cytokinesis. In contrast, cocultures of cardiac myocytes and nonmyocytes and nonmyocyte-conditioned culture medium failed to enhance the rate of cardiac MHC synthesis or its accumulation, implying that quiescent heart cells do not respond to "conditioning" by cardiac nonmyocytes. These findings demonstrated that insulin and the IGFs promote passively loaded cultured adult rabbit heart cells to hypertrophy but suggest that other growth factors tested may be limited in this regard.

  12. Basic fibroblast growth factor in an animal model of spontaneous mammary tumor progression.

    PubMed

    Kao, Steven; Mo, Jeffrey; Baird, Andrew; Eliceiri, Brian P

    2012-06-01

    Although basic fibroblast growth factor (FGF2) was the first pro-angiogenic molecule discovered, it has numerous activities on the growth and differentiation of non-vascular cell types. FGF2 is both stimulatory and inhibitory, depending on the cell type evaluated, the experimental design used and the context in which it is tested. Here, we investigated the effects of manipulating endogenous FGF2 on the development of mammary cancer to determine whether its endogenous contribution in vivo is pro- or anti-tumorigenic. Specifically, we examined the effects of FGF2 gene dosing in a cross between a spontaneous breast tumor model (PyVT+ mice) and FGF2-/- (FGF KO) mice. Using these mice, the onset and progression of mammary tumors was determined. As predicted, female FGF2 WT mice developed mammary tumors starting around 60 days after birth and by 80 days, 100% of FGF2 WT female mice had mammary tumors. In contrast, 80% of FGF2 KO female mice had no palpable tumors until nearly three weeks later (85 days) at times when 100% of the WT cohort was tumor positive. All FGF KO mice were tumor-bearing by 115 days. When we compared the onset of mammary tumor development and the tumor progression curves between FGF het and FGF KO mice, we observed a difference, which suggested a gene dosing effect. Analysis of the tumors demonstrated that there were significant differences in tumor size depending on FGF2 status. The delay in tumor onset supports a functional role for FGF2 in mammary tumor progression, but argues against an essential role for FGF2 in overall mammary tumor progression.

  13. Hematopoietic growth factors and human acute leukemia.

    PubMed

    Löwenberg, B; Touw, I

    1988-10-22

    The study of myelopoietic maturation arrest in acute myeloblastic leukemia (AML) has been eased by availability of the human recombinant hemopoietic growth factors, macrophage colony stimulating factor (M-CSF), granulocyte-(G-CSF), granulocyte-macrophage-(GM-CSF) and multilineage stimulating factor (IL-3). Nonphysiological expansion of the leukemic population is not due to escape from control by these factors. Proliferation in vitro of AML cells is dependent on the presence of one or several factors in most cases. The pattern of factor-dependency does not correlate with morphological criteria in individual cases, and may thus offer a new tool for classification of AML. Overproduction of undifferentiated cells is not due to abnormal expression of receptors for the stimulating factors acting at an immature level. Rather, autocrine secretion of early acting lymphokines maintains proliferation of the leukemic clone. When looking at causes of leukemic dysregulation, yet undefined inhibitors of differentiation probably are of equal importance as dysequilibrated stimulation by lymphokines.

  14. The effect of pasteurization on transforming growth factor alpha and transforming growth factor beta 2 concentrations in human milk.

    PubMed

    McPherson, R J; Wagner, C L

    2001-01-01

    Transforming growth factor alpha (TGF-alpha) and beta 2 (TGF-beta2) are present in human milk and are involved in growth differentiation and repair of neonatal intestinal epithelia. Heat treatment at 56 degrees C has been shown effective for providing safe banked donor milk, with good retention of other biologically active factors. The purpose of our study was to determine the effect of heat sterilization on TGF-alpha and TGF-beta2 concentrations in human milk. Twenty milk samples were collected from 20 lactating mothers in polypropylene containers and frozen at -20 degrees C for transport or storage. Before heat treatment by holder pasteurization, the frozen milk was thawed and divided into 1-mL aliquots. All samples were heated in an accurately regulated water bath until a holding temperature was achieved, then held for 30 minutes using constant agitation. Holding temperature ranged from 56.5 degrees C to 56.9 degrees C. The milk was then stored at 4 degrees C overnight for analysis the following day. The concentration of TGF-alpha was measured by radioimmunoassay. Mean concentration +/- SD of TGF-alpha in raw milk samples was 119+/-50 pg/mL, range 57 to 234. The mean concentration +/- SD of TGF-alpha in heat treated samples was 113+/-50 pg/mL, range 51 to 227. TGF-alpha concentration was minimally affected by pasteurization, with an overall loss of 6.1%. Of 19 samples, 4 had increased and 15 had decreased concentrations after pasteurization (mean percent SEM: 94%+/-7% of raw milk, range 72%+/-107%). The concentration of acid-activated TGF-beta2 was measured by enzyme-linked immunosorbent assay. Mean concentration +/- SD of TGF-beta2 in raw milk samples was 5624+/-5038 pg/mL, range 195 to 15480. The mean concentration +/- SD of TGF-beta2 in heat-treated samples was 5073+/-4646 pg/mL, range 181 to 15140. TGF-beta2 survived with relatively little loss (0.6%): of 18 samples, 11 had increased and 7 had decreased concentrations after pasteurization (mean percent

  15. Hepatocyte growth factor induces resistance to anti-epidermal growth factor receptor antibody in lung cancer.

    PubMed

    Yamada, Tadaaki; Takeuchi, Shinji; Kita, Kenji; Bando, Hideaki; Nakamura, Takahiro; Matsumoto, Kunio; Yano, Seiji

    2012-02-01

    Epidermal growth factor receptor (EGFR) is an attractive drug target in lung cancer, with several anti-EGFR antibodies and small-molecule inhibitors showing efficacy in lung cancer patients. Patients, however, may develop resistance to EGFR inhibitors. We demonstrated previously that hepatocyte growth factor (HGF) induced resistance to EGFR tyrosine kinase inhibitors in lung cancers harboring EGFR mutations. We therefore determined whether HGF could induce resistance to the anti-EGFR antibody (EGFR Ab) cetuximab in lung cancer cells, regardless of EGFR gene status. Cetuximab sensitivity and signal transduction in lung cancer cells were examined in the presence or absence of HGF, HGF-producing fibroblasts, and cells tranfected with the HGF gene in vitro and in vivo. HGF induced resistance to cetuximab in H292 (EGFR wild) and Ma-1(EGFR mutant) cells. Western blotting showed that HGF-induced resistance was mediated by the Met/Gab1/Akt signaling pathway. Resistance of H292 and Ma-1 cells to cetuximab was also induced by coculture with lung fibroblasts producing high levels of HGF and by cells stably transfected with the HGF gene. This resistance was abrogated by treatment with anti-HGF neutralizing antibody. HGF-mediated resistance is a novel mechanism of resistance to EGFR Ab in lung cancers, with fibroblast-derived HGF inducing cetuximab resistance in H292 tumors in vivo. The involvement of HGF-Met-mediated signaling should be assessed in acquired resistance to EGFR Ab in lung cancer, regardless of EGFR gene status.

  16. Growth factor deprivation induces cytosolic translocation of SIRT1

    NASA Astrophysics Data System (ADS)

    Meng, Chengbo; Xing, Da; Wu, Shengnan; Huang, Lei

    2010-02-01

    Sirtuin type 1 (SIRT1), a NAD+-dependent histone deacetylases, plays a critical role in cellular senescence, aging and longevity. In general, SIRT1 is localized in nucleus and is believed as a nuclear protein. Though overexpression of SIRT1 delays senescence, SIRT1-protein levels decline naturally in thymus and heart during aging. In the present studies, we investigated the subcellular localization of SIRT1 in response to growth factor deprivation in African green monkey SV40-transformed kidney fibroblast cells (COS-7). Using SIRT1-EGFP fluorescence reporter, we found that SIRT1 localized to nucleus in physiological conditions. We devised a model enabling cell senescence via growth factor deprivation, and we found that SIRT1 partially translocated to cytosol under the treatment, suggesting a reduced level of SIRT1's activity. We found PI3K/Akt pathway was involved in the inhibition of SIRT1's cytosolic translocation, because inhibition of these kinases significantly decreased the amount of SIRT1 maintained in nucleus. Taken together, we demonstrated that growth factor deprivation induces cytosolic translocation of SIRT1, which suggesting a possible connection between cytoplasm-localized SIRT1 and the aging process.

  17. Gene Manipulation Strategies to Identify Molecular Regulators of Axon Regeneration in the Central Nervous System

    PubMed Central

    Ribas, Vinicius T.; Costa, Marcos R.

    2017-01-01

    Limited axon regeneration in the injured adult mammalian central nervous system (CNS) usually results in irreversible functional deficits. Both the presence of extrinsic inhibitory molecules at the injury site and the intrinsically low capacity of adult neurons to grow axons are responsible for the diminished capacity of regeneration in the adult CNS. Conversely, in the embryonic CNS, neurons show a high regenerative capacity, mostly due to the expression of genes that positively control axon growth and downregulation of genes that inhibit axon growth. A better understanding of the role of these key genes controlling pro-regenerative mechanisms is pivotal to develop strategies to promote robust axon regeneration following adult CNS injury. Genetic manipulation techniques have been widely used to investigate the role of specific genes or a combination of different genes in axon regrowth. This review summarizes a myriad of studies that used genetic manipulations to promote axon growth in the injured CNS. We also review the roles of some of these genes during CNS development and suggest possible approaches to identify new candidate genes. Finally, we critically address the main advantages and pitfalls of gene-manipulation techniques, and discuss new strategies to promote robust axon regeneration in the mature CNS. PMID:28824380

  18. Growth hormone and insulin-like growth factors in fish: Where we are and where to go

    USGS Publications Warehouse

    Reinecke, M.; Bjornsson, Bjorn Thrandur; Dickhoff, Walton W.; McCormick, S.D.; Navarro, I.; Power, D.M.; Gutierrez, J.

    2005-01-01

    This communication summarizes viewpoints, discussion, perspectives, and questions, put forward at a workshop on "Growth hormone and insulin-like growth factors in fish" held on September 7th, 2004, at the 5th International Symposium on Fish Endocrinology in Castello??n, Spain. ?? 2005 Elsevier Inc. All rights reserved.

  19. Collagen and Stretch Modulate Autocrine Secretion of Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Proteins from Differentiated Skeletal Muscle Cells

    NASA Technical Reports Server (NTRS)

    Perrone, Carmen E.; Fenwick-Smith, Daniela; Vandenburgh, Herman H.

    1995-01-01

    Stretch-induced skeletal muscle growth may involve increased autocrine secretion of insulin-like growth factor-1 (IGF-1) since IGF-1 is a potent growth factor for skeletal muscle hypertrophy, and stretch elevates IGF-1 mRNA levels in vivo. In tissue cultures of differentiated avian pectoralis skeletal muscle cells, nanomolar concentrations of exogenous IGF-1 stimulated growth in mechanically stretched but not static cultures. These cultures released up to 100 pg of endogenously produced IGF-1/micro-g of protein/day, as well as three major IGF binding proteins of 31, 36, and 43 kilodaltons (kDa). IGF-1 was secreted from both myofibers and fibroblasts coexisting in the muscle cultures. Repetitive stretch/relaxation of the differentiated skeletal muscle cells stimulated the acute release of IGF-1 during the first 4 h after initiating mechanical activity, but caused no increase in the long-term secretion over 24-72 h of IGF-1, or its binding proteins. Varying the intensity and frequency of stretch had no effect on the long-term efflux of IGF-1. In contrast to stretch, embedding the differentiated muscle cells in a three-dimensional collagen (Type I) matrix resulted in a 2-5-fold increase in long-term IGF-1 efflux over 24-72 h. Collagen also caused a 2-5-fold increase in the release of the IGF binding proteins. Thus, both the extracellular matrix protein type I collagen and stretch stimulate the autocrine secretion of IGF-1, but with different time kinetics. This endogenously produced growth factor may be important for the growth response of skeletal myofibers to both types of external stimuli.

  20. Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival.

    PubMed

    Tiong, Kai Hung; Tan, Boon Shing; Choo, Heng Lungh; Chung, Felicia Fei-Lei; Hii, Ling-Wei; Tan, Si Hoey; Khor, Nelson Tze Woei; Wong, Shew Fung; See, Sze-Jia; Tan, Yuen-Fen; Rosli, Rozita; Cheong, Soon-Keng; Leong, Chee-Onn

    2016-09-06

    Basal-like breast cancer is an aggressive tumor subtype with poor prognosis. The discovery of underlying mechanisms mediating tumor cell survival, and the development of novel agents to target these pathways, is a priority for patients with basal-like breast cancer. From a functional screen to identify key drivers of basal-like breast cancer cell growth, we identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of cell survival. We found that FGFR4 mediates cancer cell survival predominantly via activation of PI3K/AKT. Importantly, a subset of basal-like breast cancer cells also secrete fibroblast growth factor 19 (FGF19), a canonical ligand specific for FGFR4. siRNA-mediated silencing of FGF19 or neutralization of extracellular FGF19 by anti-FGF19 antibody (1A6) decreases AKT phosphorylation, suppresses cancer cell growth and enhances doxorubicin sensitivity only in the FGFR4+/FGF19+ breast cancer cells. Consistently, FGFR4/FGF19 co-expression was also observed in 82 out of 287 (28.6%) primary breast tumors, and their expression is strongly associated with AKT phosphorylation, Ki-67 staining, higher tumor stage and basal-like phenotype. In summary, our results demonstrated the presence of an FGFR4/FGF19 autocrine signaling that mediates the survival of a subset of basal-like breast cancer cells and suggest that inactivation of this autocrine loop may potentially serve as a novel therapeutic intervention for future treatment of breast cancers.

  1. Underwater manipulator

    DOEpatents

    Schrum, Phillip B.; Cohen, George H.

    1993-01-01

    Self-contained, waterproof, water-submersible, remote-controlled apparatus is provided for manipulating a device, such as an ultrasonic transducer for measuring crack propagation on an underwater specimen undergoing shock testing. The subject manipulator includes metal bellows for transmittal of angular motions without the use of rotating shaft seals or O-rings. Inside the manipulator, a first stepper motor controls angular movement. In the preferred embodiment, the bellows permit the first stepper motor to move an ultrasonic transducer .+-.45 degrees in a first plane and a second bellows permit a second stepper motor to move the transducer .+-.10 degrees in a second plane orthogonal to the first. In addition, an XY motor-driven table provides XY motion.

  2. Improving In Vitro Generated Cartilage-Carrier-Constructs by Optimizing Growth Factor Combination

    PubMed Central

    Wiegandt, Katharina; Goepfert, Christiane; Pörtner, Ralf

    2007-01-01

    The presented study is focused on the generation of osteochondral implants for cartilage repair, which consist of bone substitutes covered with in vitro engineered cartilage. Re-differentiation of expanded porcine cells was performed in alginate gel followed by cartilage formation in high-density cell cultures. In this work, different combinations of growth factors for the stimulation of re-differentiation and cartilage formation have been tested to improve the quality of osteochondral implants. It has been demonstrated that supplementation of the medium with growth factors has significant effects on the properties of the matrix. The addition of the growth factors IGF-I (100 ng/mL) and TGF-β1 (10 ng/mL) during the alginate culture and the absence of any growth factors during the high-density cell culture led to significantly higher GAG to DNA ratios and Young’s Moduli of the constructs compared to other combinations. The histological sections showed homogenous tissue and intensive staining for collagen type II. PMID:19662133

  3. Transforming growth factor (TGF. beta. ) decreases the proliferation of human bone marrow fibroblasts by inhibiting the platelet-derived growth factor (PDGF) binding

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bryckaert, M.C.; Tobelem, G.; Lindroth, M.

    1988-12-01

    Human bone marrow fibroblasts were cultivated and characterized by immunofluorescent staining and electron microscopy. Their interactions with PDGF and TGF{beta} were studied. While a positive intracellular antifibronectin staining was observed, the cultured cells were not labeled with specific antibodies toward factor VIII von Willebrand factor (F VIII/vWF), desmin, and macrophage antigen. The binding of pure human PDGF to the cultured bone marrow fibroblasts was investigated. Addition of an excess of unlabeled PDGF decreased the binding to 75 and 80%, which means that the nonspecific binding represented 20-25% of total binding, whereas epidermal growth factor (EGF) had no effect. Two classesmore » of sites were detected by Scatchard analysis. The stimulation of DNA synthesis of PDGF was quantified by ({sup 3}H)thymidine incorporation. The results suggested that PDGF and TGF{beta} could modulate the growth of bone marrow fibroblasts.« less

  4. Inhibition of Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Phosphorylation on Tumor-Associated Endothelial Cells Leads to Treatment of Orthotopic Human Colon Cancer in Nude Mice1

    PubMed Central

    Sasaki, Takamitsu; Kitadai, Yasuhiko; Nakamura, Toru; Kim, Jang-Seong; Tsan, Rachel Z; Kuwai, Toshio; Langley, Robert R; Fan, Dominic; Kim, Sun-Jin; Fidler, Isaiah J

    2007-01-01

    The purpose of our study was to determine whether the dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) signaling pathways in tumor-associated endothelial cells can inhibit the progressive growth of human colon carcinoma in the cecum of nude mice. SW620CE2 human colon cancer cells growing in culture and orthotopically in the cecum of nude mice expressed a high level of transforming growth factor alpha (TGF-α) and vascular endothelial growth factor (VEGF) but were negative for EGFR, human epidermal growth factor receptor 2 (HER2), and VEGFR. Double immunofluorescence staining revealed that tumor-associated endothelial cells expressed EGFR, VEGFR2, phosphorylated EGFR (pEGFR), and phosphorylated VEGFR (pVEGFR). Treatment of mice with either 7H-pyrrolo [2,3-d]-pyrimidine lead scaffold (AEE788; an inhibitor of EGFR and VEGFR tyrosine kinase) or CPT-11 as single agents significantly inhibited the growth of cecal tumors (P < .01); this decrease was even more pronounced with AEE788 combined with CPT-11 (P < .001). AEE788 alone or combined with CPT-11 also inhibited the expression of pEGFR and pVEGFR on tumor-associated endothelial cells, significantly decreased vascularization and tumor cell proliferation, and increased the level of apoptosis in both tumor-associated endothelial cells and tumor cells. These data demonstrate that targeting EGFR and VEGFR signaling on tumor-associated endothelial cells provides a viable approach for the treatment of colon cancer. PMID:18084614

  5. [Metabolic and hemodynamic effects of the growth hormone system - insulin-like growth factor].

    PubMed

    Manhylova, T A; Gafarova, N H

    2015-01-01

    Significant congenital deficiency of growth factor (GF) results in pituitary nanism (dwarfism) and its substantial excess is accompanied by the development of gigantism or acromegaly. Its impact on the growth of the whole body or its individual parts is impossible without affecting metabolic processes and hemodynamic parameters. A number of investigations have proven that GF has a direct lipolytic effect: adequate replacement therapy for pituitary nanism gives rise to a reduction in fat depots. Since the concentration of GF is lower in obesity, Whether it may be used to treat this abnormality is considered.

  6. Autocrine and/or paracrine insulin-like growth factor-I activity in skeletal muscle

    NASA Technical Reports Server (NTRS)

    Adams, Gregory R.

    2002-01-01

    Similar to bone, skeletal muscle responds and adapts to changes in loading state via mechanisms that appear to be intrinsic to the muscle. One of the mechanisms modulating skeletal muscle adaptation it thought to involve the autocrine and/or paracrine production of insulinlike growth factor-I. This brief review outlines components of the insulinlike growth factor-I system as it relates to skeletal muscle and provides the rationale for the theory that insulinlike growth factor-I is involved with muscle adaptation.

  7. Osteopathic Manipulative Treatment

    MedlinePlus

    ... Library Osteopathic Manipulative Treatment Becoming a DO Video Library What is Osteopathic Medicine? Osteopathic Manipulative Treatment Page Content Nearly every day, medical science unveils new discoveries from brain scans to anti- ...

  8. Modeling invasive breast cancer: growth factors propel progression of HER2-positive premalignant lesions

    PubMed Central

    Pradeep, C-R; Zeisel, A; Köstler, WJ; Lauriola, M; Jacob-Hirsch, J; Haibe-Kains, B; Amariglio, N; Ben-Chetrit, N; Emde, A; Solomonov, I; Neufeld, G; Piccart, M; Sagi, I; Sotiriou, C; Rechavi, G; Domany, E; Desmedt, C; Yarden, Y

    2013-01-01

    The HER2/neu oncogene encodes a receptor-like tyrosine kinase whose overexpression in breast cancer predicts poor prognosis and resistance to conventional therapies. However, the mechanisms underlying aggressiveness of HER2 (human epidermal growth factor receptor 2)-overexpressing tumors remain incompletely understood. Because it assists epidermal growth factor (EGF) and neuregulin receptors, we overexpressed HER2 in MCF10A mammary cells and applied growth factors. HER2-overexpressing cells grown in extracellular matrix formed filled spheroids, which protruded outgrowths upon growth factor stimulation. Our transcriptome analyses imply a two-hit model for invasive growth: HER2-induced proliferation and evasion from anoikis generate filled structures, which are morphologically and transcriptionally analogous to preinvasive patients’ lesions. In the second hit, EGF escalates signaling and transcriptional responses leading to invasive growth. Consistent with clinical relevance, a gene expression signature based on the HER2/EGF-activated transcriptional program can predict poorer prognosis of a subgroup of HER2-overexpressing patients. In conclusion, the integration of a three-dimensional cellular model and clinical data attributes progression of HER2-overexpressing lesions to EGF-like growth factors acting in the context of the tumor's microenvironment. PMID:22139081

  9. [Pathogenetic and Prognostic Role of Growth Factors in the Development of Chronic Heart Failure].

    PubMed

    Teplyakov, A T; Berezikova, E N; Shilov, S N; Efremova, A V; Pustovetova, M G; Popova, A A; Grakova, E V; Torim, Y Y; Safronov, I D; Andriyanova, A V

    2017-10-01

    To study the role of growth factors ((vascular endothelial growth factor (VEGF), platelet derived growth factor AB (PDGF-AB) and basic fibroblast growth factor (FGF-basic)) in the development and progression of chronic heart failure (CHF) in patients with ishcemic heart disease (IHD). We included in this study 94 patients with CHF. The control group comprised 32 persons. Blood serum levels of growth factors were determined at baseline and after 12 months of observation by enzyme-linked immunosorbent assay. VEGF, PDGF-AB and FGF-basic play an important role in the pathogenesis and progression of heart failure in patients with IHD, determining the increased risk of adverse cardiovascular events in this pathology. Serum activity of growth factors characterizes the severity and course of CHF: with disease progression levels of VEGF and FGF-basic decrease and PDGF-AB concentration increases. Initial low level of VEGF expression regardless of the sex of the patient's sex, significantly low level of FGF-basic and significantly high PDGF-AB in men characterizes unfavorable course of CHF. A correlation has been established between blood serum levels of VEGF, PDGF-AB and FGF-basic and severity and course of CHF.

  10. Inhibition of platelet-derived growth factor signaling prevents muscle fiber growth during skeletal muscle hypertrophy.

    PubMed

    Sugg, Kristoffer B; Korn, Michael A; Sarver, Dylan C; Markworth, James F; Mendias, Christopher L

    2017-03-01

    The platelet-derived growth factor receptors alpha and beta (PDGFRα and PDGFRβ) mark fibroadipogenic progenitor cells/fibroblasts and pericytes in skeletal muscle, respectively. While the role that these cells play in muscle growth and development has been evaluated, it was not known whether the PDGF receptors activate signaling pathways that control transcriptional and functional changes during skeletal muscle hypertrophy. To evaluate this, we inhibited PDGFR signaling in mice subjected to a synergist ablation muscle growth procedure, and performed analyses 3 and 10 days after induction of hypertrophy. The results from this study indicate that PDGF signaling is required for fiber hypertrophy, extracellular matrix production, and angiogenesis that occur during muscle growth. © 2017 Federation of European Biochemical Societies.

  11. Underwater manipulator

    DOEpatents

    Schrum, P.B.; Cohen, G.H.

    1993-04-20

    Self-contained, waterproof, water-submersible, remote-controlled apparatus is described for manipulating a device, such as an ultrasonic transducer for measuring crack propagation on an underwater specimen undergoing shock testing. The subject manipulator includes metal bellows for transmittal of angular motions without the use of rotating shaft seals or O-rings. Inside the manipulator, a first stepper motor controls angular movement. In the preferred embodiment, the bellows permit the first stepper motor to move an ultrasonic transducer [plus minus]45 degrees in a first plane and a second bellows permit a second stepper motor to move the transducer [plus minus]10 degrees in a second plane orthogonal to the first. In addition, an XY motor-driven table provides XY motion.

  12. Controllable mineral coatings on scaffolds as carriers for growth factor release for bone tissue engineering

    NASA Astrophysics Data System (ADS)

    Saurez-Gonzalez, Darilis

    The work presented in this document, focused on the development and characterization of mineral coatings on scaffold materials to serve as templates for growth factor binding and release. Mineral coatings were formed using a biomimetic approach that consisted in the incubation of scaffolds in modified simulated body fluids (mSBF). To modulate the properties of the mineral coating, which we hypothesized would dictate growth factor release, we used carbonate (HCO3) concentration in mSBF of 4.2 mM, 25mM, and 100mM. Analysis of the mineral coatings formed using scanning electron microscopy indicated growth of a continuous layer of mineral with different morphologies. X-ray diffraction analysis showed peaks associated with hydroxyapatite. FTIR data confirmed the substitution of HCO3 in the mineral. As the extent of HCO3 substitution increased, the coating exhibited more rapid dissolution kinetics in an environment deficient in calcium and phosphate. The mineral coatings provided an effective mechanism for bioactive growth factor binding and release. Peptide versions of vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2) were bound with efficiencies up to 90% to mineral-coated PCL scaffolds. Recombinant human vascular endothelial growth factor (rhVEGF) also bound to mineral coated scaffolds with lower efficiency (20%) and released with faster release kinetics compared to peptides growth factor. Released rhVEGF induced human umbilical vein endothelial cell (HUVEC) proliferation in vitro and enhanced blood vessel formation in vivo in an intramuscular sheep model. In addition to the use the mineral coatings for single growth factor release, we expanded the concept and bound both an angiogenic (rhVEGF) and osteogenic (mBMP2) growth factor by a simple double dipping process. Sustained release of both growth factors was demonstrated for over 60 days. Released rhVEGF enhanced blood vessel formation in vivo in sheep and its biological activity was

  13. Extracellular Matrix and Growth Factors Improve the Efficacy of Intramuscular Islet Transplantation.

    PubMed

    Tsuchiya, Haruyuki; Sakata, Naoaki; Yoshimatsu, Gumpei; Fukase, Masahiko; Aoki, Takeshi; Ishida, Masaharu; Katayose, Yu; Egawa, Shinichi; Unno, Michiaki

    2015-01-01

    The efficacy of intramuscular islet transplantation is poor despite being technically simple, safe, and associated with reduced rates of severe complications. We evaluated the efficacy of combined treatment with extracellular matrix (ECM) and growth factors in intramuscular islet transplantation. Male BALB/C mice were used for the in vitro and transplantation studies. The following three groups were evaluated: islets without treatment (islets-only group), islets embedded in ECM with growth factors (Matrigel group), and islets embedded in ECM without growth factors [growth factor-reduced (GFR) Matrigel group]. The viability and insulin-releasing function of islets cultured for 96 h were significantly improved in Matrigel and GFR Matrigel groups compared with the islets-only group. Blood glucose and serum insulin levels immediately following transplantation were significantly improved in the Matrigel and GFR Matrigel groups and remained significantly improved in the Matrigel group at postoperative day (POD) 28. On histological examination, significantly decreased numbers of TdT-mediated deoxyuridine triphosphate-biotin nick end labeling-positive islet cells and significantly increased numbers of Ki67-positive cells were observed in the Matrigel and GFR Matrigel groups at POD 3. Peri-islet revascularization was most prominent in the Matrigel group at POD 14. The efficacy of intramuscular islet transplantation was improved by combination treatment with ECM and growth factors through the inhibition of apoptosis, increased proliferation of islet cells, and promotion of revascularization.

  14. Mechanisms of integrin-vascular endothelial growth factor receptor cross-activation in angiogenesis.

    PubMed

    Mahabeleshwar, Ganapati H; Feng, Weiyi; Reddy, Kumar; Plow, Edward F; Byzova, Tatiana V

    2007-09-14

    The functional responses of endothelial cells are dependent on signaling from peptide growth factors and the cellular adhesion receptors, integrins. These include cell adhesion, migration, and proliferation, which, in turn, are essential for more complex processes such as formation of the endothelial tube network during angiogenesis. This study identifies the molecular requirements for the cross-activation between beta3 integrin and tyrosine kinase receptor 2 for vascular endothelial growth factor (VEGF) receptor (VEGFR-2) on endothelium. The relationship between VEGFR-2 and beta3 integrin appears to be synergistic, because VEGFR-2 activation induces beta3 integrin tyrosine phosphorylation, which, in turn, is crucial for VEGF-induced tyrosine phosphorylation of VEGFR-2. We demonstrate here that adhesion- and growth factor-induced beta3 integrin tyrosine phosphorylation are directly mediated by c-Src. VEGF-stimulated recruitment and activation of c-Src and subsequent beta3 integrin tyrosine phosphorylation are critical for interaction between VEGFR-2 and beta3 integrin. Moreover, c-Src mediates growth factor-induced beta3 integrin activation, ligand binding, beta3 integrin-dependent cell adhesion, directional migration of endothelial cells, and initiation of angiogenic programming in endothelial cells. Thus, the present study determines the molecular mechanisms and consequences of the synergism between 2 cell surface receptor systems, growth factor receptor and integrins, and opens new avenues for the development of pro- and antiangiogenic strategies.

  15. Tissue Engineering Using Transfected Growth-Factor Genes

    NASA Technical Reports Server (NTRS)

    Madry, Henning; Langer, Robert S.; Freed, Lisa E.; Trippel, Stephen; Vunjak-Novakovic, Gordana

    2005-01-01

    A method of growing bioengineered tissues includes, as a major component, the use of mammalian cells that have been transfected with genes for secretion of regulator and growth-factor substances. In a typical application, one either seeds the cells onto an artificial matrix made of a synthetic or natural biocompatible material, or else one cultures the cells until they secrete a desired amount of an extracellular matrix. If such a bioengineered tissue construct is to be used for surgical replacement of injured tissue, then the cells should preferably be the patient s own cells or, if not, at least cells matched to the patient s cells according to a human-leucocyteantigen (HLA) test. The bioengineered tissue construct is typically implanted in the patient's injured natural tissue, wherein the growth-factor genes enhance metabolic functions that promote the in vitro development of functional tissue constructs and their integration with native tissues. If the matrix is biodegradable, then one of the results of metabolism could be absorption of the matrix and replacement of the matrix with tissue formed at least partly by the transfected cells. The method was developed for articular chondrocytes but can (at least in principle) be extended to a variety of cell types and biocompatible matrix materials, including ones that have been exploited in prior tissue-engineering methods. Examples of cell types include chondrocytes, hepatocytes, islet cells, nerve cells, muscle cells, other organ cells, bone- and cartilage-forming cells, epithelial and endothelial cells, connective- tissue stem cells, mesodermal stem cells, and cells of the liver and the pancreas. Cells can be obtained from cell-line cultures, biopsies, and tissue banks. Genes, molecules, or nucleic acids that secrete factors that influence the growth of cells, the production of extracellular matrix material, and other cell functions can be inserted in cells by any of a variety of standard transfection techniques.

  16. [Growth Factors and Interleukins in Amniotic Membrane Tissue Homogenate].

    PubMed

    Stachon, T; Bischoff, M; Seitz, B; Huber, M; Zawada, M; Langenbucher, A; Szentmáry, N

    2015-07-01

    Application of amniotic membrane homogenate eye drops may be a potential treatment alternative for therapy resistant corneal epithelial defects. The purpose of this study was to determine the concentrations of epidermal growth factor (EGF), fibroblast growth factor basic (bFGF), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), interleukin-6 (IL-6) and interleukin-8 (IL-8) in amniotic membrane homogenates. Amniotic membranes of 8 placentas were prepared and thereafter stored at - 80 °C using the standard methods of the LIONS Cornea Bank Saar-Lor-Lux, Trier/Westpfalz. Following defreezing, amniotic membranes were cut in two pieces and homogenized in liquid nitrogen. One part of the homogenate was prepared in cell-lysis buffer, the other part was prepared in PBS. The tissue homogenates were stored at - 20 °C until enzyme-linked immunosorbent assay (ELISA) analysis for EGF, bFGF, HGF, KGF, IL-6 and IL-8 concentrations. Concentrations of KGF, IL-6 and IL-8 were below the detection limit using both preparation techniques. The EGF concentration in tissue homogenates treated with cell-lysis buffer (2412 pg/g tissue) was not significantly different compared to that of tissue homogenates treated with PBS (1586 pg/g tissue, p = 0.72). bFGF release was also not significantly different using cell-lysis buffer (3606 pg/g tissue) or PBS treated tissue homogenates (4649 pg/g tissue, p = 0.35). HGF release was significantly lower using cell-lysis buffer (23,555 pg/g tissue), compared to PBS treated tissue (47,766 pg/g tissue, p = 0.007). Containing EGF, bFGF and HGF, and lacking IL-6 and IL-8, the application of amniotic membrane homogenate eye drops may be a potential treatment alternative for therapy-resistant corneal epithelial defects. Georg Thieme Verlag KG Stuttgart · New York.

  17. Hydraulic manipulator research at ORNL

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kress, R.L.; Jansen, J.F.; Love, L.J.

    1997-03-01

    Recently, task requirements have dictated that manipulator payload capacity increase to accommodate greater payloads, greater manipulator length, and larger environmental interaction forces. General tasks such as waste storage tank cleanup and facility dismantlement and decommissioning require manipulator life capacities in the range of hundreds of pounds rather than tens of pounds. To meet the increased payload capacities demanded by present-day tasks, manipulator designers have turned once again to hydraulics as a means of actuation. In order to successfully design, build, and deploy a new hydraulic manipulator (or subsystem), sophisticated modeling, analysis, and control experiments are usually needed. Oak Ridge Nationalmore » Laboratory (ORNL) has a history of projects that incorporate hydraulics technology, including mobile robots, teleoperated manipulators, and full-scale construction equipment. In addition, to support the development and deployment of new hydraulic manipulators, ORNL has outfitted a significant experimental laboratory and has developed the software capability for research into hydraulic manipulators, hydraulic actuators, hydraulic systems, modeling of hydraulic systems, and hydraulic controls. The purpose of this article is to describe the past hydraulic manipulator developments and current hydraulic manipulator research capabilities at ORNL. Included are example experimental results from ORNL`s flexible/prismatic test stand.« less

  18. Understanding the role of growth factors in embryonic development: insights from the lens

    PubMed Central

    Lovicu, F. J.; McAvoy, J. W.; de Iongh, R. U.

    2011-01-01

    Growth factors play key roles in influencing cell fate and behaviour during development. The epithelial cells and fibre cells that arise from the lens vesicle during lens morphogenesis are bathed by aqueous and vitreous, respectively. Vitreous has been shown to generate a high level of fibroblast growth factor (FGF) signalling that is required for secondary lens fibre differentiation. However, studies also show that FGF signalling is not sufficient and roles have been identified for transforming growth factor-β and Wnt/Frizzled families in regulating aspects of fibre differentiation. In the case of the epithelium, key roles for Wnt/β-catenin and Notch signalling have been demonstrated in embryonic development, but it is not known if other factors are required for its formation and maintenance. This review provides an overview of current knowledge about growth factor regulation of differentiation and maintenance of lens cells. It also highlights areas that warrant future study. PMID:21402581

  19. A nanoparticulate injectable hydrogel as a tissue engineering scaffold for multiple growth factor delivery for bone regeneration.

    PubMed

    Dyondi, Deepti; Webster, Thomas J; Banerjee, Rinti

    2013-01-01

    Gellan xanthan gels have been shown to be excellent carriers for growth factors and as matrices for several tissue engineering applications. Gellan xanthan gels along with chitosan nanoparticles of 297 ± 61 nm diameter, basic fibroblast growth factor (bFGF), and bone morphogenetic protein 7 (BMP7) were employed in a dual growth factor delivery system to promote the differentiation of human fetal osteoblasts. An injectable system with ionic and temperature gelation was optimized and characterized. The nanoparticle loaded gels showed significantly improved cell proliferation and differentiation due to the sustained release of growth factors. A differentiation marker study was conducted, analyzed, and compared to understand the effect of single vs dual growth factors and free vs encapsulated growth factors. Dual growth factor loaded gels showed a higher alkaline phosphatase and calcium deposition compared to single growth factor loaded gels. The results suggest that encapsulation and stabilization of growth factors within nanoparticles and gels are promising for bone regeneration. Gellan xanthan gels also showed antibacterial effects against Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis, the common pathogens in implant failure.

  20. Discerning environmental factors affecting current tree growth in Central Europe.

    PubMed

    Cienciala, Emil; Russ, Radek; Šantrůčková, Hana; Altman, Jan; Kopáček, Jiří; Hůnová, Iva; Štěpánek, Petr; Oulehle, Filip; Tumajer, Jan; Ståhl, Göran

    2016-12-15

    We examined the effect of individual environmental factors on the current spruce tree growth assessed from a repeated country-level statistical landscape (incl. forest) survey in the Czech Republic. An extensive set of variables related to tree size, competition, site characteristics including soil texture, chemistry, N deposition and climate was tested within a random-effect model to explain growth in the conditions of dominantly managed forest ecosystems. The current spruce basal area increment was assessed from two consecutive landscape surveys conducted in 2008/2009 and six years later in 2014/2015. Tree size, age and competition within forest stands were found to be the dominant explanatory variables, whereas the expression of site characteristics, environmental and climatic drives was weaker. The significant site variables affecting growth included soil C/N ratio and soil exchangeable acidity (pH KCl; positive response) reflecting soil chemistry, long-term N-deposition (averaged since 1975) in combination with soil texture (clay content) and Standardized Precipitation Index (SPI), a drought index expressing moisture conditions. Sensitivity of growth to N-deposition was positive, although weak. SPI was positively related to and significant in explaining tree growth when expressed for the growth season. Except SPI, no significant relation of growth was determined to altitude-related variables (temperature, growth season length). We identified the current spruce growth optimum at elevations about 800ma.s.l. or higher in the conditions of the country. This suggests that at lower elevations, limitation by a more pronounced water deficit dominates, whereas direct temperature limitation may concern the less frequent higher elevations. The mixed linear model of spruce tree growth explained 55 and 65% of the variability with fixed and random effects included, respectively, and provided new insights on the current spruce tree growth and factors affecting it within the

  1. Chronic alterations in growth hormone/insulin-like growth factor-I signaling lead to changes in mouse tendon structure.

    PubMed

    Nielsen, R H; Clausen, N M; Schjerling, P; Larsen, J O; Martinussen, T; List, E O; Kopchick, J J; Kjaer, M; Heinemeier, K M

    2014-02-01

    The growth hormone/insulin-like growth factor-I (GH/IGF-I) axis is an important stimulator of collagen synthesis in connective tissue, but the effect of chronically altered GH/IGF-I levels on connective tissue of the muscle-tendon unit is not known. We studied three groups of mice; 1) giant transgenic mice that expressed bovine GH (bGH) and had high circulating levels of GH and IGF-I, 2) dwarf mice with a disrupted GH receptor gene (GHR-/-) leading to GH resistance and low circulating IGF-I, and 3) a wild-type control group (CTRL). We measured the ultra-structure, collagen content and mRNA expression (targets: GAPDH, RPLP0, IGF-IEa, IGF-IR, COL1A1, COL3A1, TGF-β1, TGF-β2, TGF-β3, versican, scleraxis, tenascin C, fibronectin, fibromodulin, decorin) in the Achilles tendon, and the mRNA expression was also measured in calf muscle (same targets as tendon plus IGF-IEb, IGF-IEc). We found that GHR-/- mice had significantly lower collagen fibril volume fraction in Achilles tendon, as well as decreased mRNA expression of IGF-I isoforms and collagen types I and III in muscle compared to CTRL. In contrast, the mRNA expression of IGF-I isoforms and collagens in bGH mice was generally high in both tendon and muscle compared to CTRL. Mean collagen fibril diameter was significantly decreased with both high and low GH/IGF-I signaling, but the GHR-/- mouse tendons were most severely affected with a total loss of the normal bimodal diameter distribution. In conclusion, chronic manipulation of the GH/IGF-I axis influenced both morphology and mRNA levels of selected genes in the muscle-tendon unit of mice. Whereas only moderate structural changes were observed with up-regulation of GH/IGF-I axis, disruption of the GH receptor had pronounced effects upon tendon ultra-structure. © 2013.

  2. Purification and Refolding of Overexpressed Human Basic Fibroblast Growth Factor in Escherichia coli

    PubMed Central

    Alibolandi, Mona; Mirzahoseini, Hasan

    2011-01-01

    This work describes the integration of expanded bed adsorption (EBA) and adsorptive protein refolding operations used to recover purified and biologically active human basic fibroblast growth factor from inclusion bodies expressed in E. coli. Insoluble overexpressed human basic fibroblast growth factor has been purified on CM Hyper Z matrix by expanded bed adsorption after isolation and solubilization in 8 M urea. The adsorption was made in expanded bed without clarification steps such as centrifugation. Column refolding was done by elimination of urea and elution with NaCl. The human basic fibroblast growth factor was obtained as a highly purified soluble monomer form with similar behavior in circular dichroism and fluorescence spectroscopy as native protein. A total of 92.52% of the available human basic fibroblast growth factor was recovered as biologically active and purified protein using the mentioned purification and refolding process. This resulted in the first procedure describing high-throughput purification and refolding of human basic fibroblast growth factor in one step and is likely to have the greatest benefit for proteins that tend to aggregate when refolded by dilution. PMID:21837279

  3. Fibroblast growth factor 20 is protective towards dopaminergic neurons in vivo in a paracrine manner.

    PubMed

    Boshoff, Eugene L; Fletcher, Edward J R; Duty, Susan

    2018-04-23

    Neuroprotective strategies are an unmet medical need for Parkinson's disease. Fibroblast growth factor 20 (FGF20) enhances survival of cultured dopaminergic neurons but little is known about its in vivo potential. We set out to examine whether manipulation of the FGF20 system affected nigrostriatal tract integrity in rats, to identify which fibroblast growth factor receptors (FGFRs) might reside on dopaminergic neurons and to discover the source of endogenous FGF20 in the substantia nigra (SN). Male Sprague Dawley rats were subject to a partial 6-OHDA lesion alongside treatment with exogenous FGF20 or an FGFR antagonist. Behavioural readouts and tyrosine-hydroxylase (TH) immunohistochemistry were used to evaluate nigrostriatal tract integrity. Fluorescent immunohistochemistry was used to examine FGFR subtype expression on TH-positive dopamine neurons and FGF20 cellular localisation within the SN. FGF20 (2.5 μg/day) significantly protected TH-positive cells in the SN and terminals in the striatum, while reducing the development of motor asymmetry at 5, 8 and 11 days post lesion. Conversely, the FGFR antagonist PD173074 (2 mg/kg) significantly worsened both the 6-OHDA lesion and resultant motor asymmetry. Within the SN, TH-positive cells expressed FGFR1, 3 and 4 while FGF20 co-localised with GFAP-positive astrocytes. In conclusion, FGF20 protects dopaminergic neurons in vivo, an action likely mediated through activation of FGFRs1, 3 or 4 found on these neurons. Given FGF20 is localised to astrocytes in the adult SN, endogenous FGF20 provides its protection of dopamine neurons through a paracrine action. Boosting the endogenous FGF20 production might offer potential as a future therapeutic strategy in Parkinson's disease. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  4. Placental growth factor expression is reversed by antivascular endothelial growth factor therapy under hypoxic conditions.

    PubMed

    Zhou, Ai-Yi; Bai, Yu-Jing; Zhao, Min; Yu, Wen-Zhen; Huang, Lv-Zhen; Li, Xiao-Xin

    2014-08-01

    Clinical trials have revealed that the antivascular endothelial growth factor (VEGF) therapies are effective in retinopathy of prematurity (ROP). But the low level of VEGF was necessary as a survival signal in healthy conditions, and endogenous placental growth factor (PIGF) is redundant for development. The purpose of this study was to elucidate the PIGF expression under hypoxia as well as the influence of anti-VEGF therapy on PIGF. CoCl2-induced hypoxic human umbilical vein endothelial cells (HUVECs) were used for an in vitro study, and oxygen-induced retinopathy (OIR) mice models were used for an in vivo study. The expression patterns of PIGF under hypoxic conditions and the influence of anti-VEGF therapy on PIGF were evaluated by quantitative reverse transcription-polymerase chain reaction (RTPCR). The retinal avascular areas and neovascularization (NV) areas of anti-VEGF, anti-PIGF and combination treatments were calculated. Retina PIGF concentration was evaluated by ELISA after treatment. The vasoactive effects of exogenous PIGF on HUVECs were investigated by proliferation and migration studies. PIGF mRNA expression was reduced by hypoxia in OIR mice, in HUVECs under hypoxia and anti-VEGF treatment. However, PIGF expression was reversed by anti-VEGF therapy in the OIR model and in HUVECs under hypoxia. Exogenous PIGF significantly inhibited HUVECs proliferation and migration under normal conditions, but it stimulated cell proliferation and migration under hypoxia. Anti-PIGF treatment was effective for neovascular tufts in OIR mice (P<0.05). The finding that PIGF expression is iatrogenically up-regulated by anti-VEGF therapy provides a consideration to combine it with anti-PIGF therapy.

  5. A Prodomain Fragment from the Proteolytic Activation of Growth Differentiation Factor 11 Remains Associated with the Mature Growth Factor and Keeps It Soluble.

    PubMed

    Pepinsky, Blake; Gong, Bang-Jian; Gao, Yan; Lehmann, Andreas; Ferrant, Janine; Amatucci, Joseph; Sun, Yaping; Bush, Martin; Walz, Thomas; Pederson, Nels; Cameron, Thomas; Wen, Dingyi

    2017-08-22

    Growth differentiation factor 11 (GDF11), a member of the transforming growth factor β (TGF-β) family, plays diverse roles in mammalian development. It is synthesized as a large, inactive precursor protein containing a prodomain, pro-GDF11, and exists as a homodimer. Activation requires two proteolytic processing steps that release the prodomains and transform latent pro-GDF11 into active mature GDF11. In studying proteolytic activation in vitro, we discovered that a 6-kDa prodomain peptide containing residues 60-114, PDP 60-114 , remained associated with the mature growth factor. Whereas the full-length prodomain of GDF11 is a functional antagonist, PDP 60-114 had no impact on activity. The specific activity of the GDF11/PDP 60-114 complex (EC 50 = 1 nM) in a SMAD2/3 reporter assay was identical to that of mature GDF11 alone. PDP 60-114 improved the solubility of mature GDF11 at neutral pH. As the growth factor normally aggregates/precipitates at neutral pH, PDP 60-114 can be used as a solubility-enhancing formulation. Expression of two engineered constructs with PDP 60-114 genetically fused to the mature domain of GDF11 through a 2x or 3x G4S linker produced soluble monomeric products that could be dimerized through redox reactions. The construct with a 3x G4S linker retained 10% activity (EC 50 = 10 nM), whereas the construct connected with a 2x G4S linker could only be activated (EC 50 = 2 nM) by protease treatment. Complex formation with PDP 60-114 represents a new strategy for stabilizing GDF11 in an active state that may translate to other members of the TGF-β family that form latent pro/mature domain complexes.

  6. Endothelial Heparan Sulfate 6-O-Sulfation Levels Regulate Angiogenic Responses of Endothelial Cells to Fibroblast Growth Factor 2 and Vascular Endothelial Growth Factor*

    PubMed Central

    Ferreras, Cristina; Rushton, Graham; Cole, Claire L.; Babur, Muhammad; Telfer, Brian A.; van Kuppevelt, Toin H.; Gardiner, John M.; Williams, Kaye J.; Jayson, Gordon C.; Avizienyte, Egle

    2012-01-01

    Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor 165 (VEGF165) are potent pro-angiogenic growth factors that play a pivotal role in tumor angiogenesis. The activity of these growth factors is regulated by heparan sulfate (HS), which is essential for the formation of FGF2/FGF receptor (FGFR) and VEGF165/VEGF receptor signaling complexes. However, the structural characteristics of HS that determine activation or inhibition of such complexes are only partially defined. Here we show that ovarian tumor endothelium displays high levels of HS sequences that harbor glucosamine 6-O-sulfates when compared with normal ovarian vasculature where these sequences are also detected in perivascular area. Reduced HS 6-O-sulfotransferase 1 (HS6ST-1) or 6-O-sulfotransferase 2 (HS6ST-2) expression in endothelial cells impacts upon the prevalence of HS 6-O-sulfate moieties in HS sequences, which consist of repeating short, highly sulfated S domains interspersed by transitional N-acetylated/N-sulfated domains. 1–40% reduction in 6-O-sulfates significantly compromises FGF2- and VEGF165-induced endothelial cell sprouting and tube formation in vitro and FGF2-dependent angiogenesis in vivo. Moreover, HS on wild-type neighboring endothelial or smooth muscle cells fails to restore endothelial cell sprouting and tube formation. The affinity of FGF2 for HS with reduced 6-O-sulfation is preserved, although FGFR1 activation is inhibited correlating with reduced receptor internalization. These data show that 6-O-sulfate moieties in endothelial HS are of major importance in regulating FGF2- and VEGF165-dependent endothelial cell functions in vitro and in vivo and highlight HS6ST-1 and HS6ST-2 as potential targets of novel antiangiogenic agents. PMID:22927437

  7. Heparin-binding growth factor isolated from human prostatic extracts.

    PubMed

    Mydlo, J H; Bulbul, M A; Richon, V M; Heston, W D; Fair, W R

    1988-01-01

    Prostatic tissue extracts from patients with benign prostatic hyperplasia (BPH) and prostatic carcinoma were fractionated using heparin-Sepharose chromatography. The mitogenic activity of eluted fractions on quiescent subconfluent Swiss Albino 3T3 fibroblasts was tested employing a tritiated-thymidine-incorporation assay. Two peaks of activity were consistently noted--one in the void volume and a second fraction which eluted with 1.3-1.6 M NaCl and contained the majority of the mitogenic activity. Both non-heparin- and heparin-binding fractions increased tritiated incorporation into a mouse osteoblast cell line (MC3T3), while only the heparin-binding fractions stimulated a human umbilical vein endothelial cell line (HUV). No increased uptake of thymidine was seen using a human prostatic carcinoma cell line (PC-3). Sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE) of lyophilized active fractions showed a persistent band at 17,500 daltons. The purified protein demonstrated angiogenic properties using the chick embryo chorioallantoic membrane (CAM) assay. Western blot analysis using antibodies specific to basic fibroblast growth factor (bFGF) or acidic FGF (aFGF) demonstrated that the former, but not the latter, bound to prostatic growth factor (PrGF), and inhibited its mitogenic activity as well. It appears that PrGF shares homology with basic fibroblast growth factors.

  8. Autonomous manipulation on a robot: Summary of manipulator software functions

    NASA Technical Reports Server (NTRS)

    Lewis, R. A.

    1974-01-01

    A six degree-of-freedom computer-controlled manipulator is examined, and the relationships between the arm's joint variables and 3-space are derived. Arm trajectories using sequences of third-degree polynomials to describe the time history of each joint variable are presented and two approaches to the avoidance of obstacles are given. The equations of motion for the arm are derived and then decomposed into time-dependent factors and time-independent coefficients. Several new and simplifying relationships among the coefficients are proven. Two sample trajectories are analyzed in detail for purposes of determining the most important contributions to total force in order that relatively simple approximations to the equations of motion can be used.

  9. A review of the influence of growth factors and cytokines in in vitro human keratinocyte migration.

    PubMed

    Peplow, Philip V; Chatterjee, Marissa P

    2013-04-01

    Keratinocyte migration from the wound edge is a crucial step in the reepithelization of cutaneous wounds. Growth factors and cytokines, released from cells that invade the wound matrix, play an important role, and several in vitro assays have been performed to elucidate this. The purposes of this study were to review in vitro human studies on keratinocyte migration to identify those growth factors or cytokines that stimulate keratinocyte migration and whether these assays might serve as a screening procedure prior to testing combinations of growth factors or cytokines to promote wound closure in vivo. Research papers investigating effect of growth factors and cytokines on human keratinocyte migration in vitro were retrieved from library sources, PubMed databases, reference lists of papers, and searches of relevant journals. Fourteen different growth factors and cytokines enhanced migration in scratch wound assay and HGF together with TGF-β, and IGF-1 with EGF, were more stimulatory than either growth factor alone. HGF with TGF-β1 had a greater chemokinetic effect than either growth factor alone in transmigration assay. TGF-β1, FGF-7, FGF-2 and AGF were chemotactic to keratinocytes. EGF, TGF-α, IL-1α, IGF and MGSA enhanced cell migration on ECM proteins. Many growth factors and cytokines enhanced migration of keratinocytes in vitro, and certain combinations of growth factors were more stimulatory than either alone. These and other combinations that stimulate keratinocyte migration in vitro should be tested for effect on wound closure and repair in vivo. The scratch wound assay provides a useful, inexpensive and easy-to-perform screening method for testing individual or combinations of growth factors or cytokines, or growth factors combined with other modalities such as laser irradiation, prior to performing wound healing studies with laboratory animals. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Fibroblast growth factor 8 is expressed at higher levels in lactating human breast and in breast cancer.

    PubMed

    Zammit, C; Coope, R; Gomm, J J; Shousha, S; Johnston, C L; Coombes, R C

    2002-04-08

    Fibroblast growth factor 8 can transform NIH3T3 cells and its expression has been found to be associated with breast and prostate cancer. Following our finding that fibroblast growth factor 8 mRNA expression is increased in breast cancer, we have undertaken an immunohistochemistry study of fibroblast growth factor 8 expression in a series of human breast tissues and other normal tissues. Our findings confirm increased expression of fibroblast growth factor 8 in malignant breast tissue but also show significant fibroblast growth factor 8 expression in non-malignant breast epithelial cells. No significant difference in fibroblast growth factor 8 expression was found between different grades of ductal carcinoma, lobular carcinoma and ductal carcinoma in-situ or cancer of different oestrogen receptor, progesterone receptor or nodal status. The highest levels of fibroblast growth factor 8 expression were found in lactating breast tissues and fibroblast growth factor 8 was also detected in human milk. A survey of other normal tissues showed that fibroblast growth factor 8 is expressed in the proliferative cells of the dermis and epithelial cells in colon, ovary fallopian tube and uterus. Fibroblast growth factor 8 appears to be expressed in several organs in man and appears to have an importance in lactation.

  11. Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine

    DOE PAGES

    Martino, Mikael M.; Brkic, Sime; Bovo, Emmanuela; ...

    2015-04-01

    In this study, blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular,more » the spatial localization of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.« less

  12. Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Martino, Mikael M.; Brkic, Sime; Bovo, Emmanuela

    In this study, blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular,more » the spatial localization of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.« less

  13. Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine.

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Martino, Mikael M.; Brkic, Sime; Bovo, Emmanuela

    Blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular, the spatial localizationmore » of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.« less

  14. Fibroblast Growth Factor 23 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

    PubMed

    Chonchol, Michel; Gitomer, Berenice; Isakova, Tamara; Cai, Xuan; Salusky, Isidro; Pereira, Renata; Abebe, Kaleab; Torres, Vicente; Steinman, Theodor I; Grantham, Jared J; Chapman, Arlene B; Schrier, Robert W; Wolf, Myles

    2017-09-07

    Increases in fibroblast growth factor 23 precede kidney function decline in autosomal dominant polycystic kidney disease; however, the role of fibroblast growth factor 23 in autosomal dominant polycystic kidney disease has not been well characterized. We measured intact fibroblast growth factor 23 levels in baseline serum samples from 1002 participants in the HALT-PKD Study A ( n =540; mean eGFR =91±17 ml/min per 1.73 m 2 ) and B ( n =462; mean eGFR =48±12 ml/min per 1.73 m 2 ). We used linear mixed and Cox proportional hazards models to test associations between fibroblast growth factor 23 and eGFR decline, percentage change in height-adjusted total kidney volume, and composite of time to 50% reduction in eGFR, onset of ESRD, or death. Median (interquartile range) intact fibroblast growth factor 23 was 44 (33-56) pg/ml in HALT-PKD Study A and 69 (50-93) pg/ml in Study B. In adjusted models, annualized eGFR decline was significantly faster in the upper fibroblast growth factor 23 quartile (Study A: quartile 4, -3.62; 95% confidence interval, -4.12 to -3.12 versus quartile 1, -2.51; 95% confidence interval, -2.71 to -2.30 ml/min per 1.73 m 2 ; P for trend <0.001; Study B: quartile 4, -3.74; 95% confidence interval, -4.14 to -3.34 versus quartile 1, -2.78; 95% confidence interval, -2.92 to -2.63 ml/min per 1.73 m 2 ; P for trend <0.001). In Study A, higher fibroblast growth factor 23 quartiles were associated with greater longitudinal percentage increase in height-adjusted total kidney volume in adjusted models (quartile 4, 6.76; 95% confidence interval, 5.57 to 7.96 versus quartile 1, 6.04; 95% confidence interval, 5.55 to 6.54; P for trend =0.03). In Study B, compared with the lowest quartile, the highest fibroblast growth factor 23 quartile was associated with elevated risk for the composite outcome (hazard ratio, 3.11; 95% confidence interval, 1.84 to 5.25). Addition of fibroblast growth factor 23 to a model of annualized decline in eGFR≥3.0 ml/min per 1.73 m

  15. Non-manipulation quantitative designs.

    PubMed

    Rumrill, Phillip D

    2004-01-01

    The article describes non-manipulation quantitative designs of two types, correlational and causal comparative studies. Both of these designs are characterized by the absence of random assignment of research participants to conditions or groups and non-manipulation of the independent variable. Without random selection or manipulation of the independent variable, no attempt is made to draw causal inferences regarding relationships between independent and dependent variables. Nonetheless, non-manipulation studies play an important role in rehabilitation research, as described in this article. Examples from the contemporary rehabilitation literature are included. Copyright 2004 IOS Press

  16. A highly versatile adaptor protein for the tethering of growth factors to gelatin-based biomaterials.

    PubMed

    Addi, Cyril; Murschel, Frédéric; Liberelle, Benoît; Riahi, Nesrine; De Crescenzo, Gregory

    2017-03-01

    In the field of tissue engineering, the tethering of growth factors to tissue scaffolds in an oriented manner can enhance their activity and increase their half-life. We chose to investigate the capture of the basic Fibroblast Growth Factor (bFGF) and the Epidermal Growth Factor (EGF) on a gelatin layer, as a model for the functionalization of collagen-based biomaterials. Our strategy relies on the use of two high affinity interactions, that is, the one between two distinct coil peptides as well as the one occurring between a collagen-binding domain (CBD) and gelatin. We expressed a chimeric protein to be used as an adaptor that comprises one of the coil peptides and a CBD derived from the human fibronectin. We proved that it has the ability to bind simultaneously to a gelatin substrate and to form a heterodimeric coiled-coil domain with recombinant growth factors being tagged with the complementary coil peptide. The tethering of the growth factors was characterized by ELISA and surface plasmon resonance-based biosensing. The bioactivity of the immobilized bFGF and EGF was evaluated by a human umbilical vein endothelial cell proliferation assay and a vascular smooth muscle cell survival assay. We found that the tethering of EGF preserved its mitogenic and anti-apoptotic activity. In the case of bFGF, when captured via our adaptor protein, changes in its natural mode of interaction with gelatin were observed. In an effort to functionalize collagen/gelatin-based biomaterials with growth factors, we have designed an adaptor protein corresponding to a collagen-binding domain fused to a coil peptide. In our strategy, this adaptor protein captures growth factors being tagged with the partner coil peptide in a specific, stable and oriented manner. We have found that the tethering of the Epidermal Growth Factor preserved its mitogenic and anti-apoptotic activity. In the case of the basic Fibroblast Growth Factor, the captured growth factor remained bioactive although its

  17. Problem-Solving Test: The Role of Ubiquitination in Epidermal Growth Factor Receptor Trafficking

    ERIC Educational Resources Information Center

    Szeberenyi, Jozsef

    2012-01-01

    Terms to be familiar with before you start to solve the test: growth factor signaling, epidermal growth factor, tyrosine protein kinase, tyrosine phosphorylation, ubiquitin, monoubiquitination, polyubiquitination, site-directed mutagenesis, transfection, expression vector, cDNA, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, Western…

  18. Region-specific role of growth differentiation factor-5 in the establishment of sympathetic innervation.

    PubMed

    O'Keeffe, Gerard W; Gutierrez, Humberto; Howard, Laura; Laurie, Christopher W; Osorio, Catarina; Gavaldà, Núria; Wyatt, Sean L; Davies, Alun M

    2016-02-15

    Nerve growth factor (NGF) is the prototypical target-derived neurotrophic factor required for sympathetic neuron survival and for the growth and ramification of sympathetic axons within most but not all sympathetic targets. This implies the operation of additional target-derived factors for regulating terminal sympathetic axon growth and branching. Here report that growth differentiation factor 5 (GDF5), a widely expressed member of the transforming growth factor beta (TGFβ) superfamily required for limb development, promoted axon growth from mouse superior cervical ganglion (SCG) neurons independently of NGF and enhanced axon growth in combination with NGF. GDF5 had no effect on neuronal survival and influenced axon growth during a narrow window of postnatal development when sympathetic axons are ramifying extensively in their targets in vivo. SCG neurons expressed all receptors capable of participating in GDF5 signaling at this stage of development. Using compartment cultures, we demonstrated that GDF5 exerted its growth promoting effect by acting directly on axons and by initiating retrograde canonical Smad signalling to the nucleus. GDF5 is synthesized in sympathetic targets, and examination of several anatomically circumscribed tissues in Gdf5 null mice revealed regional deficits in sympathetic innervation. There was a marked, highly significant reduction in the sympathetic innervation density of the iris, a smaller though significant reduction in the trachea, but no reduction in the submandibular salivary gland. There was no reduction in the number of neurons in the SCG. These findings show that GDF5 is a novel target-derived factor that promotes sympathetic axon growth and branching and makes a distinctive regional contribution to the establishment of sympathetic innervation, but unlike NGF, plays no role in regulating sympathetic neuron survival.

  19. Recent research on the growth plate: Advances in fibroblast growth factor signaling in growth plate development and disorders.

    PubMed

    Xie, Yangli; Zhou, Siru; Chen, Hangang; Du, Xiaolan; Chen, Lin

    2014-08-01

    Skeletons are formed through two distinct developmental actions, intramembranous ossification and endochondral ossification. During embryonic development, most bone is formed by endochondral ossification. The growth plate is the developmental center for endochondral ossification. Multiple signaling pathways participate in the regulation of endochondral ossification. Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling has been found to play a vital role in the development and maintenance of growth plates. Missense mutations in FGFs and FGFRs can cause multiple genetic skeletal diseases with disordered endochondral ossification. Clarifying the molecular mechanisms of FGFs/FGFRs signaling in skeletal development and genetic skeletal diseases will have implications for the development of therapies for FGF-signaling-related skeletal dysplasias and growth plate injuries. In this review, we summarize the recent advances in elucidating the role of FGFs/FGFRs signaling in growth plate development, genetic skeletal disorders, and the promising therapies for those genetic skeletal diseases resulting from FGFs/FGFRs dysfunction. Finally, we also examine the potential important research in this field in the future. © 2014 Society for Endocrinology.

  20. Characterization of the growth of murine fibroblasts that express human insulin receptors. II. Interaction of insulin with other growth factors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Randazzo, P.A.; Jarett, L.

    1990-09-01

    The effects of insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and insulin on DNA synthesis were studied in murine fibroblasts transfected with an expression vector containing human insulin receptor cDNA (NIH 3T3/HIR) and the parental NIH 3T3 cells. In NIH 3T3/HIR cells, individual growth factors in serum-free medium stimulated DNA synthesis with the following relative efficacies: insulin greater than or equal to 10% fetal calf serum greater than PDGF greater than IGF-1 much greater than EGF. In comparison, the relative efficacies of these factors in stimulating DNA synthesis by NIH 3T3 cells were 10% fetalmore » calf serum greater than PDGF greater than EGF much greater than IGF-1 = insulin. In NIH 3T3/HIR cells, EGF was synergistic with 1-10 ng/ml insulin but not with 100 ng/ml insulin or more. Synergy of PDGF or IGF-1 with insulin was not detected. In the parental NIH 3T3 cells, insulin and IGF-1 were found to be synergistic with EGF (1 ng/ml), PDGF (100 ng/ml), and PDGF plus EGF. In NIH 3T3/HIR cells, the lack of interaction of insulin with other growth factors was also observed when the percentage of cells synthesizing DNA was examined. Despite insulin's inducing only 60% of NIH 3T3/HIR cells to incorporate thymidine, addition of PDGF, EGF, or PDGF plus EGF had no further effect. In contrast, combinations of growth factors resulted in 95% of the parental NIH 3T3 cells synthesizing DNA. The independence of insulin-stimulated DNA synthesis from other mitogens in the NIH 3T3/HIR cells is atypical for progression factor-stimulated DNA synthesis and is thought to be partly the result of insulin receptor expression in an inappropriate context or quantity.« less

  1. Understanding the factors that limit restoration success on a recreation-impacted subalpine site

    Treesearch

    Catherine Zabinski; David Cole

    2000-01-01

    Factors that limit successful revegetation of a subalpine site were studied through a combination of soil assays, greenhouse studies, and field manipulations. Campsite soils had higher available nitrogen, lower microbial community diversity, and lower seed bank density than undisturbed soils. In the greenhouse, there was no significant difference in plant growth on...

  2. Root growth dynamics linked to above-ground growth in walnut (Juglans regia).

    PubMed

    Contador, Maria Loreto; Comas, Louise H; Metcalf, Samuel G; Stewart, William L; Porris Gomez, Ignacio; Negron, Claudia; Lampinen, Bruce D

    2015-07-01

    Examination of plant growth below ground is relatively scant compared with that above ground, and is needed to understand whole-plant responses to the environment. This study examines whether the seasonal timing of fine root growth and the spatial distribution of this growth through the soil profile varies in response to canopy manipulation and soil temperature. Plasticity in the seasonal timing and vertical distribution of root production in response to canopy and soil water manipulation was analysed in field-grown walnut (Juglans regia 'Chandler') using minirhizotron techniques. Root production in walnuts followed a unimodal curve, with one marked flush of root growth starting in mid-May, with a peak in mid-June. Root production declined later in the season, corresponding to increased soil temperature, as well as to the period of major carbohydrate allocation to reproduction. Canopy and soil moisture manipulation did not influence the timing of root production, but did influence the vertical distribution of roots through the soil profile. Water deficit appeared to promote root production in deeper soil layers for mining soil water. Canopy removal appeared to promote shallow root production. The findings of this study add to growing evidence that root growth in many ecosystems follows a unimodal curve with one marked flush of root growth in coordination with the initial leaf flush of the season. Root vertical distribution appeared to have greater plasticity than timing of root production in this system, with temperature and/or carbohydrate competition constraining the timing of root growth. Effects on root distribution can have serious impacts on trees, with shallow rooting having negative impacts in years with limited soil water or positive impacts in years with wet springs, and deep rooting having positive impacts on soil water mining from deeper soil layers but negative impacts in years with wet springs. © The Author 2015. Published by Oxford University Press

  3. Growth Factors and COX2 Expression in Canine Perivascular Wall Tumors.

    PubMed

    Avallone, G; Stefanello, D; Boracchi, P; Ferrari, R; Gelain, M E; Turin, L; Tresoldi, E; Roccabianca, P

    2015-11-01

    Canine perivascular wall tumors (PWTs) are a group of subcutaneous soft tissue sarcomas developing from vascular mural cells. Mural cells are involved in angiogenesis through a complex crosstalk with endothelial cells mediated by several growth factors and their receptors. The evaluation of their expression may have relevance since they may represent a therapeutic target in the control of canine PWTs. The expression of vascular endothelial growth factor (VEGF) and receptors VEGFR-I/II, basic fibroblast growth factor (bFGF) and receptor Flg, platelet-derived growth factor B (PDGFB) and receptor PDGFRβ, transforming growth factor β1 (TGFβ1) and receptors TGFβR-I/II, and cyclooxygenase 2 (COX2) was evaluated on frozen sections of 40 PWTs by immunohistochemistry and semiquantitatively scored to identify their potential role in PWT development. Statistical analysis was performed to analyze possible correlations between Ki67 labeling index and the expression of each molecule. Proteins of the VEGF-, PDGFB-, and bFGF-mediated pathways were highly expressed in 27 (67.5%), 30 (75%), and 19 (47.5%) of 40 PWTs, respectively. Proteins of the TGFβ1- and COX2-mediated pathways were highly expressed in 4 (10%) and 14 (35%) of 40 cases. Statistical analysis identified an association between VEGF and VEGFR-I/II (P = .015 and .003, respectively), bFGF and Flg (P = .038), bFGF and PDGFRβ (P = .003), and between TGFβ1 and COX2 (P = .006). These findings were consistent with the mechanisms that have been reported to play a role in angiogenesis and in tumor development. No association with Ki67 labeling index was found. VEGF-, PDGFB-, and bFGF-mediated pathways seem to have a key role in PWT development and growth. Blockade of tyrosine kinase receptors after surgery could represent a promising therapy with the aim to reduce the PWT relapse rate and prolong the time to relapse. © The Author(s) 2015.

  4. Methods to Manipulate and Monitor Wnt Signaling in Human Pluripotent Stem Cells.

    PubMed

    Huggins, Ian J; Brafman, David; Willert, Karl

    2016-01-01

    Human pluripotent stem cells (hPSCs) may revolutionize medical practice by providing: (a) a renewable source of cells for tissue replacement therapies, (b) a powerful system to model human diseases in a dish, and (c) a platform for examining efficacy and safety of novel drugs. Furthermore, these cells offer a unique opportunity to study early human development in vitro, in particular, the process by which a seemingly uniform cell population interacts to give rise to the three main embryonic lineages: ectoderm, endoderm. and mesoderm. This process of lineage allocation is regulated by a number of inductive signals that are mediated by growth factors, including FGF, TGFβ, and Wnt. In this book chapter, we introduce a set of tools, methods, and protocols to specifically manipulate the Wnt signaling pathway with the intention of altering the cell fate outcome of hPSCs.

  5. The effect of growth factors on both collagen synthesis and tensile strength of engineered human ligaments.

    PubMed

    Hagerty, Paul; Lee, Ann; Calve, Sarah; Lee, Cassandra A; Vidal, Martin; Baar, Keith

    2012-09-01

    Growth factors play a central role in the development and remodelling of musculoskeletal tissues. To determine which growth factors optimized in vitro ligament formation and mechanics, a Box-Behnken designed array of varying concentrations of growth factors and ascorbic acid were applied to engineered ligaments and the collagen content and mechanics of the grafts were determined. Increasing the amount of transforming growth factor (TGF) β1 and insulin-like growth factor (IGF)-1 led to an additive effect on ligament collagen and maximal tensile load (MTL). In contrast, epidermal growth factor (EGF) had a negative effect on both collagen content and MTL. The predicted optimal growth media (50 μg/ml TGFβ, IGF-1, and GDF-7 and 200 μM ascorbic acid) was then validated in two separate trials: showing a 5.7-fold greater MTL and 5.2-fold more collagen than a minimal media. Notably, the effect of the maximized growth media was scalable such that larger constructs developed the same material properties, but larger MTL. These results show that optimizing the interactions between growth factors and engineered ligament volume results in an engineered ligament of clinically relevant function. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Multifunctional mesoporous bioactive glasses for effective delivery of therapeutic ions and drug/growth factors.

    PubMed

    Wu, Chengtie; Chang, Jiang

    2014-11-10

    Regeneration of large-size bone defects represents a significant challenge clinically, which requires the use of scaffolds with multifunction, such as anti-bacterial activity, and stimulation of osteogenesis and angiogenesis. It is known that functional ions or drug/growth factors play an important role to stimulate tissue regeneration. Mesoporous bioactive glasses (MBG) possess excellent bioactivity and drug-delivery ability as well as effective ionic release in the body fluids microenvironment due to its specific mesoporous structure and large surface area. For these reasons, functional ions (e.g. lithium (Li), strontium (Sr), Copper (Cu) and Boron (B)) and drug/growth factors (e.g. dexamethasone, vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)) have been incorporated into MBG, which shows high loading efficiency and effective release. The release of therapeutic ions and drug/growth factors from MBG offers it multifunctional properties, such as improved osteogenesis, angiogenesis, anti-bacterial/cancer activity. However, there is no a systematic review about delivery of therapeutic ions and drugs/growth factors from MBG for the functional effect on the tissue regeneration despite that significant progress has been achieved in the past five years. Therefore, in this review, we mainly focused on the new advances for the functional effect of delivering therapeutic ions and drugs/growth factors on the ostegeogenesis, angiogenesis and antibacterial activity. It is expected that the review will offer new concept to develop multifunctional biomaterials for bone regeneration by the synergistic effect of therapeutic ions and drug/growth factors. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Overexpression of Heparin-Binding Epidermal Growth Factor-Like Growth Factor Mediates Liver Fibrosis in Transgenic Mice.

    PubMed

    Guo, Yongze; Ding, Qian; Chen, Lei; Ji, Chenguang; Hao, Huiyao; Wang, Jia; Qi, Wei; Xie, Xiaoli; Ma, Junji; Li, Aidi; Jiang, Xiaoyu; Li, Xiaotian; Jiang, Huiqing

    2017-08-01

    The role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in liver fibrosis is not clear and is sometimes even contradictory. To clarify this role, a HB-EGF transgenic (Tg) mouse model was, for the first time, used to evaluate the functions of HB-EGF in liver fibrosis. For the in vivo study, carbon tetrachloride injection and bile duct ligation treatment were used to induce liver fibrosis in HB-EGF Tg mice and wild-type (WT) mice, respectively. Primary hepatic satellite cells (HSCs) were isolated from HB-EGF Tg and WT mice for the in vitro study. Compared with the WT mice, HB-EGF Tg mice were shown to develop more severe liver fibrosis when treated with carbon tetrachloride or bile duct ligation, with increased matrix metalloproteinases 13 activity and enhanced expression of fibrogenic genes including α-smooth muscle actin and collagen I. HB-EGF gene transfer led to an increase in proliferation and a decrease in apoptosis in primary HSCs. The ERK signaling pathway was more highly activated in primary HSCs from HB-EGF Tg mice than in those from WT mice. Our investigation confirmed the profibrotic effect of HB-EGF on the liver using a Tg mouse model. This result may contribute to the elucidation of HB-EGF as a therapeutic target in liver fibrosis. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  8. Recombinant Human Acidic Fibroblast Growth Factor (aFGF) Expressed in Nicotiana benthamiana Potentially Inhibits Skin Photoaging.

    PubMed

    Ha, Jang-Ho; Kim, Ha-Neul; Moon, Ki-Beom; Jeon, Jae-Heung; Jung, Dai-Hyun; Kim, Su-Jung; Mason, Hugh S; Shin, Seo-Yeon; Kim, Hyun-Soon; Park, Kyung-Mok

    2017-07-01

    Responding to the need for recombinant acidic fibroblast growth factor in the pharmaceutical and cosmetic industries, we established a scalable expression system for recombinant human aFGF using transient and a DNA replicon vector expression in Nicotiana benthamiana . Recombinant human-acidic fibroblast growth factor was recovered following Agrobacterium infiltration of N. benthamiana . The optimal time point at which to harvest recombinant human acidic fibroblast growth factor expressing leaves was found to be 4 days post-infiltration, before necrosis was evident. Commassie-stained SDS-PAGE gels of His-tag column eluates, concentrated using a 10 000 molecular weight cut-off column, showed an intense band at the expected molecular weight for recombinant human acidic fibroblast growth factor. An immunoblot confirmed that this band was recombinant human acidic fibroblast growth factor. Up to 10 µg recombinant human-acidic fibroblast growth factor/g of fresh leaves were achieved by a simple affinity purification protocol using protein extract from the leaves of agroinfiltrated N. benthamiana . The purified recombinant human acidic fibroblast growth factor improved the survival rate of UVB-irradiated HaCaT and CCD-986sk cells approximately 89 and 81 %, respectively. N. benthamiana -derived recombinant human acidic fibroblast growth factor showed similar effects on skin cell proliferation and UVB protection compared to those of Escherichia coli -derived recombinant human acidic fibroblast growth factor. Additionally, N. benthamiana- derived recombinant human acidic fibroblast growth factor increased type 1 procollagen synthesis up to 30 % as well as reduced UVB-induced intracellular reactive oxygen species generation in fibroblast (CCD-986sk) cells.UVB is a well-known factor that causes various types of skin damage and premature aging. Therefore, the present study demonstrated that N. benthamiana -derived recombinant human acidic fibroblast growth factor

  9. Soil-Site Factors Affecting Southern Upland Oak Managment and Growth

    Treesearch

    John K. Francis

    1980-01-01

    Soil supplies trees with physical support, moisture, oxygen, and nutrients. Amount of moisture most limits tree growth; and soil and topographic factors such as texture and aspect, which influence available soil moisture. are most useful in predicting growth. Equations that include soil and topographic variables can be used to predict site index. Foresters can also...

  10. A nematode that can manipulate the behaviour of slugs.

    PubMed

    Morris, Alex; Green, Michael; Martin, Hayley; Crossland, Katie; Swaney, William T; Williamson, Sally M; Rae, Robbie

    2018-06-01

    The ability of parasites to manipulate the behaviour of their hosts has evolved multiple times, and has a clear fitness benefit to the parasite in terms of facilitating growth, reproduction and transfer to suitable hosts. The mechanisms by which these behavioural changes are induced are poorly understood, but in many cases parasite manipulation of serotonergic signalling in the host brain is implicated. Here we report that Phasmarhabditis hermaphrodita, a parasite of terrestrial gastropod molluscs, can alter the behaviour of slugs. Uninfected slugs (Deroceras panormitanum, Arion subfuscus and Arion hortensis) avoid areas where P. hermaphrodita is present, but slugs infected with P. hermaphrodita are more likely to be found where the nematodes are present. This ability is specific to P. hermaphrodita and other nematodes (Steinernema carpocapsae and Heterorhabditis bacteriophora) do not induce this behavioural change. To investigate how P. hermaphrodita changes slug behaviour we exposed slugs to fluoxetine (a selective serotonin reuptake inhibitor) and cyproheptadine (a serotonin receptor antagonist). Uninfected slugs fed fluoxetine no longer avoided areas where P. hermaphrodita was present; and conversely, infected slugs fed cyproheptadine showed no increased attraction to areas with nematodes. These findings suggest that a possible mechanism by which P. hermaphrodita is able to manipulate parasite avoidance behaviour in host slugs is by manipulating serotonergic signalling in the brain, and that increased serotonin levels are potentially associated with a reduction in parasite avoidance. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Rac regulates vascular endothelial growth factor stimulated motility.

    PubMed

    Soga, N; Connolly, J O; Chellaiah, M; Kawamura, J; Hruska, K A

    2001-01-01

    During angiogenesis endothelial cells migrate towards a chemotactic stimulus. Understanding the mechanism of endothelial cell migration is critical to the therapeutic manipulation of angiogenesis and ultimately cancer prevention. Vascular endothelial growth factor (VEGF) is a potent chemotactic stimulus of endothelial cells during angiogenesis. The endothelial cell signal transduction pathway of VEGF represents a potential target for cancer therapy, but the mechanisms of post-receptor signal transduction including the roles of rho family GTPases in regulating the cytoskeletal effects of VEGF in endothelial cells are not understood. Here we analyze the mechanisms of cell migration in the mouse brain endothelial cell line (bEND3). Stable transfectants containing a tetracycline repressible expression vector were used to induce expression of Rac mutants. Endothelial cell haptotaxis was stimulated by constitutively active V12Rac on collagen and vitronectin coated supports, and chemotaxis was further stimulated by VEGF. Osteopontin coated supports were the most stimulatory to bEND3 haptotaxis, but VEGF was not effective in further increasing migration on osteopontin coated supports. Haptotaxis on support coated with collagen, vitronectin, and to a lesser degree osteopontin was inhibited by N17 Rac. N17 Rac expression blocked stimulation of endothelial cell chemotaxis by VEGF. As part of the chemotactic stimulation, VEGF caused a loss of actin organization at areas of cell-cell contact and increased stress fiber expression in endothelial cells which were directed towards pores in the transwell membrane. N17 Rac prevented the stimulation of cell-cell contact disruption and the stress fiber stimulation by VEGF. These data demonstrate two pathways of regulating endothelial cell motility, one in which Rac is activated by matrix/integrin stimulation and is a crucial modulator of endothelial cell haptotaxis. The other pathway, in the presence of osteopontin, is Rac independent

  12. Fibroblast Growth Factor 23 in Long-Duration Spaceflight

    NASA Technical Reports Server (NTRS)

    Bokhari, R.; Zwart, S. R.; Fields, E.; Heer, M.; Sibonga, J.; Smith, S. M.

    2015-01-01

    Many nutritional factors influence bone, from the basics of calcium and vitamin D, to factors which influence bone through acid/base balance, including protein, sodium, and more. Fibroblast growth factor 23 (FGF23) is a recently identified factor, secreted from osteocytes, which is involved in classic (albeit complex) feedback loops controlling phosphorus homeostasis through both vitamin D and parathyroid hormone (PTH) (1, 2). As osteocytes are gravity sensing cells, it is important to determine if there are changes in FGF23 during spaceflight. In extreme cases, such as chronic kidney disease, FGF23 levels are highly elevated. FGF23 imbalances, secondary to dietary influences, may contribute to skeletal demineralization and kidney stone risk during spaceflight.

  13. Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer.

    PubMed

    Liu, Junjun; Chen, Xiaosong; Ward, Toby; Mao, Yan; Bockhorn, Jessica; Liu, Xiaofei; Wang, Gen; Pegram, Mark; Shen, Kunwei

    2016-02-01

    Acquired resistance to lapatinib, a human epidermal growth factor receptor 2 kinase inhibitor, remains a clinical problem for women with human epidermal growth factor receptor 2-positive advanced breast cancer, as metastasis is commonly observed in these patients. Niclosamide, an anti-helminthic agent, has recently been shown to exhibit cytotoxicity to tumor cells with stem-like characteristics. This study was designed to identify the mechanisms underlying lapatinib resistance and to determine whether niclosamide inhibits lapatinib resistance by reversing epithelial-mesenchymal transition. Here, two human epidermal growth factor receptor 2-positive breast cancer cell lines, SKBR3 and BT474, were exposed to increasing concentrations of lapatinib to establish lapatinib-resistant cultures. Lapatinib-resistant SKBR3 and BT474 cells exhibited up-regulation of the phenotypic epithelial-mesenchymal transition markers Snail, vimentin and α-smooth muscle actin, accompanied by activation of nuclear factor-кB and Src and a concomitant increase in stem cell marker expression (CD44(high)/CD24(low)), compared to naive lapatinib-sensitive SKBR3 and BT474 cells, respectively. Interestingly, niclosamide reversed epithelial-mesenchymal transition, induced apoptosis and inhibited cell growth by perturbing aberrant signaling pathway activation in lapatinib-resistant human epidermal growth factor receptor 2-positive cells. The ability of niclosamide to alleviate stem-like phenotype development and invasion was confirmed. Collectively, our results demonstrate that lapatinib resistance correlates with epithelial-mesenchymal transition and that niclosamide inhibits lapatinib-resistant cell viability and epithelial-mesenchymal transition. These findings suggest a role of niclosamide or derivatives optimized for more favorable bioavailability not only in reversing lapatinib resistance but also in reducing metastatic potential during the treatment of human epidermal growth factor receptor

  14. Enhancing hair growth in male androgenetic alopecia by a combination of fractional CO2 laser therapy and hair growth factors.

    PubMed

    Huang, Yue; Zhuo, Fenglin; Li, Linfeng

    2017-11-01

    Laser therapy and growth factors have been used as alternative treatments for male androgenetic alopecia (MAA). The aim of this study is to determine the efficacy and safety of hair growth factors alone or combined with ablative carbon dioxide (CO 2 ) fractional laser therapy in MAA. Twenty-eight men were enrolled in this randomized half-split study based on a left-head to right-head pattern. Fractional CO 2 laser treatment was unilaterally performed; hair growth factors were bilaterally applied. Six sessions with 2-week intervals were performed. Global photographs and dermoscopy assessments were performed at the baseline and 4 months after first treatment. Global photographs underwent blinded review by three independent dermatologists. Scanning electron microscopy was used to compare changes in hair-follicle phase and hair-shaft diameter. Twenty-seven participants completed the 4-month treatment schedule. One patient was lost. Mean hair density increased from 114 ± 27 to 143 ± 25/cm 2 (P < 0.001) in the combined group and from 113 ± 24 to 134 ± 19/cm 2 in the growth factor group (P < 0.001). The mean change from baseline between two groups was also compared (P = 0.003). Global photographs showed improvement in 93% (25/27) patients in the combined group and 67% (18/27) patients in the growth factor group. Under scanning electron microscopy, hair follicles appeared to transition from telogen to anagen, and hair-shaft diameter increased in five randomly selected patients. Ablative fractional CO 2 laser combined with hair growth factors may serve as an alternative treatment for MAA in individuals unwilling/unable to undergo medical or surgical treatment.

  15. Chemical environment manipulation for pest insects control

    NASA Astrophysics Data System (ADS)

    Greenblatt, J. A.; Lewis, W. J.

    1983-01-01

    The chemical environment of pest species may be considered a habitat susceptible to management Management may be by means of manipulation of the environment of the pest for population suppression or for enhancement of natural enemies Examples of each are reviewed here Chemical stimuli influencing the behavior of phytophagous insects include host plant originated stimuli and pheromones The latter, especially sex pheromones, have proved most successful as tools for manipulation of pest population dynamics Factors influencing search behavior of natural enemies include habitat characteristics such as crop, associated plants and plant assemblages, host plant characteristics, influence of associated organisms, and characteristics of the searching entomophage Recent studies have shown potential for simultaneous management of a pest species and enhancement of natural enemies using pest pheromones

  16. Surgical intestinal manipulation increases gene expression of TrkA, CGRP, and PAR-2 IN dorsal root ganglia in the rat.

    PubMed

    Berdún, S; Rychter, J; Vergara, P

    2016-06-01

    Surgical handling of the bowel evokes degranulation of peritoneal mast cells (PMC). Nonetheless, role of PMCs in postoperative ileus (POI) is somewhat controversial. We aimed to investigate if intestinal manipulation elicits changes in afferent mediators related to MC activation and alteration of gastrointestinal (GI) motility. Postoperative ileus was induced by intestinal manipulation in Sprague-Dawley rats. Additionally, compound 48/80 (C48/80) and ketotifen were used to modulate MC activity. Rat mast cell protease 6 (RMCP-6, ELISA) release was determined in peritoneal lavage 20 min after intestinal manipulation. At 24 h, GI transit was determined. Gene expression of calcitonin gene-related peptide (CGRP), protease-activated receptor-2 (PAR-2), nerve growth factor (NGF), and TrkA receptor was determined (PCR) in dorsal root ganglia (DRG). Ileal wall inflammation was assessed by myeloperoxidase (MPO) activity, interleukin-6 expression (IL-6). Intestinal manipulation and exposure to C48/80-induced degranulation of PMCs delayed GI transit and up-regulated IL-6 and MPO activity. Intestinal manipulation, but not C48/80, up-regulated CGRP, PAR-2, and NGF/TrkA in DRGs. Ketotifen only improved gastric emptying and fecal output. Up-regulation of CGRP and TrkA expression in DRG was not prevented by ketotifen. Postoperative ileus is accompanied by activation of CGRP, NGF-TrkA, and PAR-2 in DRGs. Our results suggest that these mediators could be a target in further POI studies in order to find new therapeutic targets for this medical condition. © 2016 John Wiley & Sons Ltd.

  17. Preserving sparseness in multivariate polynominal factorization

    NASA Technical Reports Server (NTRS)

    Wang, P. S.

    1977-01-01

    Attempts were made to factor these ten polynomials on MACSYMA. However it did not get very far with any of the larger polynomials. At that time, MACSYMA used an algorithm created by Wang and Rothschild. This factoring algorithm was also implemented for the symbolic manipulation system, SCRATCHPAD of IBM. A closer look at this old factoring algorithm revealed three problem areas, each of which contribute to losing sparseness and intermediate expression growth. This study led to effective ways of avoiding these problems and actually to a new factoring algorithm. The three problems are known as the extraneous factor problem, the leading coefficient problem, and the bad zero problem. These problems are examined separately. Their causes and effects are set forth in detail; the ways to avoid or lessen these problems are described.

  18. The Manipulation of Pace within Endurance Sport

    PubMed Central

    Skorski, Sabrina; Abbiss, Chris R.

    2017-01-01

    In any athletic event, the ability to appropriately distribute energy is essential to prevent premature fatigue prior to the completion of the event. In sport science literature this is termed “pacing.” Within the past decade, research aiming to better understand the underlying mechanisms influencing the selection of an athlete's pacing during exercise has dramatically increased. It is suggested that pacing is a combination of anticipation, knowledge of the end-point, prior experience and sensory feedback. In order to better understand the role each of these factors have in the regulation of pace, studies have often manipulated various conditions known to influence performance such as the feedback provided to participants, the starting strategy or environmental conditions. As with all research there are several factors that should be considered in the interpretation of results from these studies. Thus, this review aims at discussing the pacing literature examining the manipulation of: (i) energy expenditure and pacing strategies, (ii) kinematics or biomechanics, (iii) exercise environment, and (iv) fatigue development. PMID:28289392

  19. Peripheral blood "endothelial progenitor cells" are derived from monocyte/macrophages and secrete angiogenic growth factors.

    PubMed

    Rehman, Jalees; Li, Jingling; Orschell, Christie M; March, Keith L

    2003-03-04

    Endothelial progenitor cells (EPCs) have been isolated from peripheral blood and can enhance angiogenesis after infusion into host animals. It is not known whether the proangiogenic effects are a result of such events as endothelial differentiation and subsequent proliferation of EPCs or secondary to secretion of angiogenic growth factors. Human EPCs were isolated as previously described, and their phenotypes were confirmed by uptake of acetylated LDL and binding of ulex-lectin. EPC proliferation and surface marker expression were analyzed by flow cytometry, and conditioned medium was assayed for growth factors. The majority of EPCs expressed monocyte/macrophage markers such as CD14 (95.7+/-0.3%), Mac-1 (57.6+/-13.5%), and CD11c (90.8+/-4.9%). A much lower percentage of cells expressed the specific endothelial marker VE-cadherin (5.2+/-0.7%) or stem/progenitor-cell markers AC133 (0.16+/-0.05%) and c-kit (1.3+/-0.7%). Compared with circulating monocytes, cultured EPCs showed upregulation of monocyte activation and macrophage differentiation markers. EPCs did not demonstrate any significant proliferation but did secrete the angiogenic growth factors vascular endothelial growth factor, hepatocyte growth factor, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor. Our findings suggest that acetylated LDL(+)ulex-lectin(+) cells, commonly referred to as EPCs, do not proliferate but release potent proangiogenic growth factors. The majority of acetylated LDL(+)ulex-lectin(+) cells are derived from monocyte/macrophages. The findings of low proliferation and endothelial differentiation suggest that their angiogenic effects are most likely mediated by growth factor secretion. These findings may allow for development of novel angiogenic therapies relying on secreted growth factors or on recruitment of endogenous monocytes/macrophages to sites of ischemia.

  20. Differential growth factor control of bone formation through osteoprogenitor differentiation.

    PubMed

    Chaudhary, L R; Hofmeister, A M; Hruska, K A

    2004-03-01

    The osteogenic factors bone morphogenetic protein (BMP-7), platelet-derived growth factor (PDGF)-BB, and fibroblast growth factor (FGF-2) regulate the recruitment of osteoprogenitor cells and their proliferation and differentiation into mature osteoblasts. However, their mechanisms of action on osteoprogenitor cell growth, differentiation, and bone mineralization remain unclear. Here, we tested the hypothesis that these osteogenic agents were capable of regulating osteoblast differentiation and bone formation in vitro. Normal human bone marrow stromal (HBMS) cells were treated with BMP-7 (40 ng ml(-1)), PDGF-BB (20 ng ml(-1)), FGF-2 (20 ng ml(-1)), or FGF-2 plus BMP-7 for 28 days in a serum-containing medium with 10 mM beta-glycerophosphate and 50 microg ml(-1) ascorbic acid. BMP-7 stimulated a morphological change to cuboidal-shaped cells, increased alkaline phosphatase (ALKP) activity, bone sialoprotein (BSP) gene expression, and alizarin red S positive nodule formation. Hydroxyapatite (HA) crystal deposition in the nodules was demonstrated by Fourier transform infrared (FTIR) spectroscopy only in BMP-7- and dexamethasone (DEX)-treated cells. DEX-treated cells appeared elongated and fibroblast-like compared to BMP-7-treated cells. FGF-2 did not stimulate ALKP, and cell morphology was dystrophic. PDGF-BB had little or no effect on ALKP activity and biomineralization. Alizarin Red S staining of cells and calcium assay indicated that BMP-7, DEX, and FGF-2 enhanced calcium mineral deposition, but FTIR spectroscopic analysis demonstrated no formation of HA similar to human bone in control, PDGF-BB-, and FGF-2-treated samples. Thus, FGF-2 stimulated amorphous octacalcium phosphate mineral deposition that failed to mature into HA. Interestingly, FGF-2 abrogated BMP-7-induced ALKP activity and HA formation. Results demonstrate that BMP-7 was competent as a sole factor in the differentiation of human bone marrow stromal cells to bone-forming osteoblasts confirmed by FTIR

  1. The statistical mechanics of complex signaling networks: nerve growth factor signaling

    NASA Astrophysics Data System (ADS)

    Brown, K. S.; Hill, C. C.; Calero, G. A.; Myers, C. R.; Lee, K. H.; Sethna, J. P.; Cerione, R. A.

    2004-10-01

    The inherent complexity of cellular signaling networks and their importance to a wide range of cellular functions necessitates the development of modeling methods that can be applied toward making predictions and highlighting the appropriate experiments to test our understanding of how these systems are designed and function. We use methods of statistical mechanics to extract useful predictions for complex cellular signaling networks. A key difficulty with signaling models is that, while significant effort is being made to experimentally measure the rate constants for individual steps in these networks, many of the parameters required to describe their behavior remain unknown or at best represent estimates. To establish the usefulness of our approach, we have applied our methods toward modeling the nerve growth factor (NGF)-induced differentiation of neuronal cells. In particular, we study the actions of NGF and mitogenic epidermal growth factor (EGF) in rat pheochromocytoma (PC12) cells. Through a network of intermediate signaling proteins, each of these growth factors stimulates extracellular regulated kinase (Erk) phosphorylation with distinct dynamical profiles. Using our modeling approach, we are able to predict the influence of specific signaling modules in determining the integrated cellular response to the two growth factors. Our methods also raise some interesting insights into the design and possible evolution of cellular systems, highlighting an inherent property of these systems that we call 'sloppiness.'

  2. Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib.

    PubMed

    Wiedmann, Marcus; Feisthammel, Jürgen; Blüthner, Thilo; Tannapfel, Andrea; Kamenz, Thomas; Kluge, Annett; Mössner, Joachim; Caca, Karel

    2006-08-01

    Aberrant activation of the epidermal growth factor receptor is frequently observed in neoplasia, notably in tumors of epithelial origin. Attempts to treat such tumors with epidermal growth factor receptor antagonists resulted in remarkable success in recent studies. Little is known, however, about the efficacy of this therapy in biliary tract cancer. Protein expression of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 was assessed in seven human biliary tract cancer cell lines by immunoblotting. In addition, histological sections from 19 patients with extrahepatic cholangiocarcinoma were analyzed for epidermal growth factor receptor, ErbB-2 and vascular endothelial growth factor receptor-2 expression by immunohistochemistry. Moreover, we sequenced the cDNA products representing the entire epidermal growth factor receptor coding region of the seven cell lines, and searched for genomic epidermal growth factor receptor amplifications and polysomy by fluorescence in-situ hybridization. Cell growth inhibition by gefitinib erlotinib and NVP-AEE788 was studied in vitro by automated cell counting. In addition, the anti-tumoral effect of erlotinib and NVP-AEE788 was studied in a chimeric mouse model. The anti-tumoral drug mechanism in this model was assessed by MIB-1 antibody staining, terminal deoxynucleotidyl transfer-mediated dUTP nick end-labelling assay, von Willebrand factor staining, and immunoblotting for p-p42/44 (p-Erk1/2, p-MAPK) and p-AKT. Immunoblotting revealed expression of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 in all biliary tract cancer cell lines. EGFR was detectable in six of 19 (32%) extrahepatic human cholangiocarcinoma tissue samples, ErbB-2 in 16 of 19 (84%), and vascular endothelial growth factor receptor-2 in nine of 19 (47%). Neither epidermal growth factor receptor mutations nor amplifications or polysomy were found in the seven biliary tract cancer

  3. A high ratio of insulin-like growth factor II/insulin-like growth factor binding protein 2 messenger RNA as a marker for anaplasia in meningiomas.

    PubMed

    Nordqvist, A C; Peyrard, M; Pettersson, H; Mathiesen, T; Collins, V P; Dumanski, J P; Schalling, M

    1997-07-01

    Insulin-like growth factors (IGFs) I and II have been implicated as autocrine or paracrine growth promoters. These growth factors bind to specific receptors, and the response is modulated by interaction with IGF-binding proteins (IGFBPs). We observed a strong correlation between anaplastic/atypical histopathology and a high IGF-II/IGFBP-2 mRNA ratio in a set of 68 sporadic meningiomas. A strong correlation was also found between clinical outcome and IGF-II/IGFBP-2 ratio, whereas previously used histochemical markers were less correlated to outcome. We suggest that a high IGF-II/IGFBP-2 mRNA ratio may be a sign of biologically aggressive behavior in meningiomas that can influence treatment strategies. We propose that low IGFBP-2 levels in combination with increased levels of IGF-II would result in more free IGF-II and consequently greater stimulation of proliferation.

  4. Understanding pharmaceutical research manipulation in the context of accounting manipulation.

    PubMed

    Brown, Abigail

    2013-01-01

    The problem of the manipulation of data that arises when there is both opportunity and incentive to mislead is better accepted and studied - though by no means solved - in financial accounting than in medicine. This article analyzes pharmaceutical company manipulation of medical research as part of a broader problem of corporate manipulation of data in the creation of accounting profits. The article explores how our understanding of accounting fraud and misinformation helps us understand the risk of similar information manipulation in the medical sciences. This understanding provides a framework for considering how best to improve the quality of medical research and analysis in light of the current system of medical information production. I offer three possible responses: (1) use of the Dodd-Frank whistleblower provisions to encourage reporting of medical research fraud; (2) a two-step academic journal review process for clinical trials; and (3) publicly subsidized trial-failure insurance. These would improve the release of negative information about drugs, thereby increasing the reliability of positive information. © 2013 American Society of Law, Medicine & Ethics, Inc.

  5. Can insulin-like growth factor 1 (IGF-1), IGF-1 receptor connective tissue growth factor and Ki-67 labelling index have a prognostic role in pulmonary carcinoids?

    PubMed

    Kanakis, Georgios A; Grimelius, Lars; Papaioannou, Dimitrios; Kaltsas, Gregory; Tsolakis, Apostolos V

    2018-04-27

    Altered expression of Insulin-like Growth Factor-1 (IGF-1), its receptor (IGF-1R), Connective Tissue Growth Factor (CTGF) and Hypoxia Inducible Factor-1 (HIF-1), has been implicated in tumorigenesis. So far, these factors have not been studied systematically in Pulmonary Carcinoids (PCs). To examine IGF-1, IGF-1R, CTGF and HIF-1 expression in PCs, and assess their prognostic value over established factors. Retrospective study of 121 PCs (104 Typical and 17 Atypical). The expression of growth factors was studied immunohistochemically and tumors were considered positive if immunoreactivity appeared in >50% of cells. All studied parameters were expressed in the majority of tumors (IGF-1, IGF-1R, CTGF and HIF-1, in 78.5%, 67%, 72% and 78%, respectively). Their expression tended to be more frequent in TCs and in tumors with Ki-67≤2% (significant only for HIF-1; 82 vs. 53%; p=0.023 and 83 vs. 63%; p=0.025 respectively). CTGF was the only factor correlated with more extensive disease (larger size; presence of lymph node and distant metastases). According to logistic regression analysis, only advanced age, Ki-67≥3.4% and lymph node involvement could predict the development of distant metastases. IGF-1, IGF-1R, CTGF and HIF-1 are avidly expressed in PCs; however, their presence did not appear to be of statistically significant value over established prognostic factors.

  6. ISCHEMIC CENTRAL RETINAL VEIN OCCLUSION IN THE ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR ERA.

    PubMed

    Tam, Emily K; Golchet, Pamela; Yung, Madeline; DeCroos, Francis C; Spirn, Marc; Lehmann-Clarke, Lydia; Ambresin, Aude; Tsui, Irena

    2018-02-01

    Anti-vascular endothelial growth factor therapy has improved the prognosis for patients with central retinal vein occlusion (CRVO). However, most studies published to date exclude ischemic CRVO. The purpose of this study was to describe the outcome in eyes with ischemic CRVO treated with anti-vascular endothelial growth factor therapy. Thirty-seven patients with ischemic CRVO from 3 centers were followed for at least 6 months. Data on patient demographic, vision status, and anti-vascular endothelial growth factor treatments were collected. Average number of injections during the study period was 5. Younger age was associated with improved vision (P = 0.006). Patients with improved visual outcomes tended to have macular edema as the primary indication for treatment, whereas patients with worse outcomes tended to have neovascularization as the primary indication for treatment. This study highlights significant variability in the use of anti-vascular endothelial growth factor therapy for ischemic CRVO and underscores that eyes with neovascularization tend to have worse visual outcomes.

  7. Mouse Balb/c3T3 cell mutant with low epidermal growth factor receptor activity: induction of stable anchorage-independent growth by transforming growth factor. beta

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kuratomi, Y.; Ono, M.; Yasutake, C.

    1987-01-01

    A mutant clone (MO-5) was originally isolated as a clone resistant to Na/sup +//K/sup +/ ionophoric antibiotic monensin from mouse Balb/c3T3 cells. MO-5 was found to show low receptor-endocytosis activity for epidermal growth factor (EGF):binding activity for EGF in MO-5 was less than one tenth of that in Balb/c3T3. Anchorage-independent growth of MO-5 was compared to that of Balb/c3T3 when assayed by colony formation capacity in soft agar. Coadministration of EGF and TGF-..beta.. efficiently enhanced anchorage-independent growth of normal rat kidney (NRK) cells, but neither factor alone was competent to promote the anchorage-independent growth. The frequency of colonies appearing inmore » soft agar of MO-5 or Balb/c3T3 was significantly enhanced by TGF-..beta.. while EGF did not further enhance that of MO-5 or Balb/c3T3. Colonies of Balb/c3T3 formed in soft agar in the presence of TGF-..beta.. showed low colony formation capacity in soft agar in the absence of TGF-..beta... Colonies of MO-5 formed by TGF-..beta.. in soft agar, however, showed high colony formation capacity in soft agar in the absence of TGF-..beta... Pretreatment of MO-5 with TGF-..beta.. induced secretion of TGF-..beta..-like activity from the cells, while the treatment of Balb/c3T3 did not induce the secretion of a significant amount of TGF-..beta..-like activity. The loss of EGF-receptor activity in the stable expression and maintenance of the transformed phenotype in MO-5 is discussed.« less

  8. Ligand-Independent Epidermal Growth Factor Receptor Overexpression Correlates with Poor Prognosis in Colorectal Cancer.

    PubMed

    Yun, Sumi; Kwak, Yoonjin; Nam, Soo Kyung; Seo, An Na; Oh, Heung-Kwon; Kim, Duck-Woo; Kang, Sung-Bum; Lee, Hye Seung

    2018-01-17

    Molecular treatments targeting epidermal growth factor receptors (EGFRs) are important strategies for advanced colorectal cancer (CRC). However, clinicopathologic implications of EGFRs and EGFR ligand signaling have not been fully evaluated. We evaluated the expression of EGFR ligands and correlation with their receptors, clinicopathologic factors, and patients' survival with CRC. The expression of EGFR ligands, including heparin binding epidermal growth factor like growth factor (HBEGF), transforming growth factor (TGF), betacellulin, and epidermal growth factor (EGF), were evaluated in 331 consecutive CRC samples using mRNA in situ hybridization (ISH). We also evaluated the expression status of EGFR, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 using immunohistochemistry and/or silver ISH. Unlike low incidences of TGF (38.1%), betacellulin (7.9%), and EGF (2.1%), HBEGF expression was noted in 62.2% of CRC samples. However, the expression of each EGFR ligand did not reveal significant correlations with survival. The combined analyses of EGFR ligands and EGFR expression indicated that the ligands‒/EGFR+ group showed a significant association with the worst disease-free survival (DFS, p=0.018) and overall survival (OS, p=0.005). It was also an independent, unfavorable prognostic factor for DFS (p=0.026) and OS (p=0.007). Additionally, HER4 nuclear expression, regardless of ligand expression, was an independent, favorable prognostic factor for DFS (p=0.034) and OS (p=0.049), by multivariate analysis. Ligand-independent EGFR overexpression was suggested to have a significant prognostic impact; thus, the expression status of EGFR ligands, in addition to EGFR, might be necessary for predicting patients' outcome in CRC.

  9. Emerging growth factor receptor antagonists for the treatment of renal cell carcinoma.

    PubMed

    Zahoor, Haris; Rini, Brian I

    2016-12-01

    The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials. Areas covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials which led to their approval, is presented. This is followed by reviewing the limitations of these therapeutic options, medical need to develop new treatments and major goals of ongoing research. We then discuss two recently approved growth factor receptor antagonists i.e. cabozantinib and lenvatinib, and a recently approved checkpoint inhibitor, nivolumab, and issues pertaining to drug development, and future directions in treatment of metastatic RCC. Expert opinion: Recently approved growth factor receptor antagonists have shown encouraging survival benefit but associated drug toxicity is a major issue. Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, has similarly shown survival benefit and is well tolerated. With multiple options now available in this patient population, the right sequence of these agents remains to be determined.

  10. The effect of platelet rich fibrin on growth factor levels in urethral repair.

    PubMed

    Soyer, Tutku; Ayva, Şebnem; Boybeyi, Özlem; Aslan, Mustafa Kemal; Çakmak, Murat

    2013-12-01

    Platelet rich fibrin (PRF) is an autologous source of growth factors and promotes wound healing. An experimental study was performed to evaluate the effect of PRF on growth factor levels in urethral repair. Eighteen Wistar albino rats were included in the study. Rats were allocated in three groups (n:6): control (CG), sham (SG), and PRF (PRFG). In SG, a 5 mm vertical incision was performed in the penile urethra and repaired with 10/0 Vicryl® under a microscope. In PRFG, during the urethral repair as described in SG, 1 cc of blood was sampled from each rat and centrifuged for 10 minutes at 2400 rpm. PRF obtained from the centrifugation was placed on the repair site during closure. Penile urethras were sampled 24 hours after PRF application in PRFG and after urethral repair in SG. Transforming growth factor beta receptor (TGF-β-R-CD105), vascular endothelial growth factor (VEGF) and its receptor (VEGF-R), as well as endothelial growth factor receptor (EGFR), were evaluated in subepithelia of the penile skin and urethra. Groups were compared for growth factor levels and growth factor receptor expression with the Kruskal Wallis test. TGF-β-R levels were significantly decreased in SG when compared to CG (p<0.05). In PRFG, TGF-β-R was increased in both subepithelia of penile skin and urethra with respect to SG (p<0.05). When VEGF levels and its receptor expression were compared between SG and PRFG, VEGF levels were found to be increased in penile skin subepithelium, whereas VEGF-R expressions were decreased in urethral subepithelia in PRFG (p<0.05). There was no difference between groups for EGFR levels (p>0.05). Use of PRF after urethral repair increases TGF-β-R and VEGF expressions in urethral tissue. PRF can be considered as an alternative measure to improve the success of urethral repair. © 2013.

  11. Multiple Mechanisms are Responsible for Transactivation of the Epidermal Growth Factor Receptor in Mammary Epithelial Cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rodland, Karin D.; Bollinger, Nikki; Ippolito, Danielle L.

    2008-11-14

    REVIEW ENTIRE DOCUMENT AT: https://pnlweb.pnl.gov/projects/bsd/ERICA%20Manuscripts%20for%20Review/KD%20Rodland%20D7E80/HMEC_transactivation_ms01_15+Figs.pdf ABSTRACT: Using a single nontransformed strain of human mammary epithelial cells, we found that the ability of multiple growth factors and cytokines to induce ERK phosphorylation was dependent on EGFR activity. These included lysophosphatidic acid (LPA), uridine triphosphate, growth hormone, vascular endothelial growth factor, insulin-like growth factor-1 (IGF-1), and tumor necrosis factoralpha. In contrast, hepatocyte growth factor could stimulate ERK phosphorylation independent of EGFR activity...

  12. Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: A review.

    PubMed

    Frater, Julanne; Lie, David; Bartlett, Perry; McGrath, John J

    2018-03-01

    Insulin-like Growth Factor 1 (IGF-1) and its signaling pathway play a primary role in normal growth and ageing, however serum IGF-1 is known to reduce with advancing age. Recent findings suggest IGF-1 is essential for neurogenesis in the adult brain, and this reduction of IGF-1 with ageing may contribute to age-related cognitive decline. Experimental studies have shown manipulation of the GH/GF-1 axis can slow rates of cognitive decline in animals, making IGF-1 a potential biomarker of cognition, and/or its signaling pathway a possible therapeutic target to prevent or slow age-related cognitive decline. A systematic literature review and qualitative narrative summary of current evidence for IGF-1 as a biomarker of cognitive decline in the ageing brain was undertaken. Results indicate IGF-1 concentrations do not confer additional diagnostic information for those with cognitive decline, and routine clinical measurement of IGF-1 is not currently justified. In cases of established cognitive impairment, it remains unclear whether increasing circulating or brain IGF-1 may reverse or slow down the rate of further decline. Advances in neuroimaging, genetics, neuroscience and the availability of large well characterized biobanks will facilitate research exploring the role of IGF-1 in both normal ageing and age-related cognitive decline. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Torque-Limiting Manipulation Device

    NASA Technical Reports Server (NTRS)

    Moetteli, John B. (Inventor)

    1999-01-01

    A device for manipulating a workpiece in space includes a fixture, a stanchion assembly, a manipulation mechanism, an actuation mechanism, and a reaction mechanism. The fixture has an end onto which the workpiece affixes. The stanchion assembly has an upper and a lower end. The manipulation mechanism connects the fixture and the upper end of the stanchion assembly. The lower end of the stanchion assembly mounts, via probe and a socket, to a structure. The actuation mechanism operably connects to the manipulation mechanism, and moves the fixture in space. The reaction mechanism provides a point through which force inputs into the actuation mechanism may react.

  14. PLACENTAL GROWTH FACTOR ADMINISTRATION ABOLISHES PLACENTAL ISCHEMIA-INDUCED HYPERTENSION

    PubMed Central

    Spradley, Frank T.; Tan, Adelene Y.; Joo, Woo S.; Daniels, Garrett; Kussie, Paul; Karumanchi, S. Ananth; Granger, Joey P.

    2016-01-01

    Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia as placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and VEGF are both natural ligands for sFlt-1, VEGF also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to four groups: normal pregnant (NP) or RUPP ± infusion of rhPlGF (180 μg/kg/day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than NP rats. Infusion of rhPlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that rhPlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. PMID:26831193

  15. Manipulation of Fgf and Bmp signaling in teleost fishes suggests potential pathways for the evolutionary origin of multicuspid teeth

    PubMed Central

    Jackman, William R; Davies, Shelby H; Lyons, David B; Stauder, Caitlin K; Denton-Schneider, Benjamin R; Jowdry, Andrea; Aigler, Sharon R; Vogel, Scott A; Stock, David W

    2014-01-01

    Teeth with two or more cusps have arisen independently from an ancestral unicuspid condition in a variety of vertebrate lineages, including sharks, teleost fishes, amphibians, lizards, and mammals. One potential explanation for the repeated origins of multicuspid teeth is the existence of multiple adaptive pathways leading to them, as suggested by their different uses in these lineages. Another is that the addition of cusps required only minor changes in genetic pathways regulating tooth development. Here we provide support for the latter hypothesis by demonstrating that manipulation of the levels of Fibroblast growth factor (Fgf) or Bone morphogenetic protein (Bmp) signaling produces bicuspid teeth in the zebrafish (Danio rerio), a species lacking multicuspid teeth in its ancestry. The generality of these results for teleosts is suggested by the conversion of unicuspid pharyngeal teeth into bicuspid teeth by similar manipulations of the Mexican Tetra (Astyanax mexicanus). That these manipulations also produced supernumerary teeth in both species supports previous suggestions of similarities in the molecular control of tooth and cusp number. We conclude that despite their apparent complexity, the evolutionary origin of multicuspid teeth is positively constrained, likely requiring only slight modifications of a pre-existing mechanism for patterning the number and spacing of individual teeth. PMID:25098636

  16. Manipulation of Fgf and Bmp signaling in teleost fishes suggests potential pathways for the evolutionary origin of multicuspid teeth.

    PubMed

    Jackman, William R; Davies, Shelby H; Lyons, David B; Stauder, Caitlin K; Denton-Schneider, Benjamin R; Jowdry, Andrea; Aigler, Sharon R; Vogel, Scott A; Stock, David W

    2013-01-01

    Teeth with two or more cusps have arisen independently from an ancestral unicuspid condition in a variety of vertebrate lineages, including sharks, teleost fishes, amphibians, lizards, and mammals. One potential explanation for the repeated origins of multicuspid teeth is the existence of multiple adaptive pathways leading to them, as suggested by their different uses in these lineages. Another is that the addition of cusps required only minor changes in genetic pathways regulating tooth development. Here we provide support for the latter hypothesis by demonstrating that manipulation of the levels of Fibroblast growth factor (Fgf) or Bone morphogenetic protein (Bmp) signaling produces bicuspid teeth in the zebrafish (Danio rerio), a species lacking multicuspid teeth in its ancestry. The generality of these results for teleosts is suggested by the conversion of unicuspid pharyngeal teeth into bicuspid teeth by similar manipulations of the Mexican Tetra (Astyanax mexicanus). That these manipulations also produced supernumerary teeth in both species supports previous suggestions of similarities in the molecular control of tooth and cusp number. We conclude that despite their apparent complexity, the evolutionary origin of multicuspid teeth is positively constrained, likely requiring only slight modifications of a pre-existing mechanism for patterning the number and spacing of individual teeth. © 2013 Wiley Periodicals, Inc.

  17. Growth factor-induced morphological, physiological and molecular characteristics in cerebral endothelial cells.

    PubMed

    Krizbai, I A; Bauer, H; Amberger, A; Hennig, B; Szabó, H; Fuchs, R; Bauer, H C

    2000-09-01

    The capacity of vascular endothelial cells to modulate their phenotype in response to changes in environmental conditions is one of the most important characteristics of this cell type. Since different growth factors may play an important signalling role in this adaptive process we have investigated the effect of endothelial cell growth factor (ECGF) on morphological, physiological and molecular characteristics of cerebral endothelial cells (CECs). CECs grown in the presence of ECGF and its cofactor heparin exhibit an epithelial-like morphology (type I CECs). Upon removal of growth factors, CECs develop an elongated spindle-like shape (type II CECs) which is accompanied by the reorganization of actin filaments and the induction of alpha-actin expression. Since one of the most important functions of CECs is the creation of a selective diffusion barrier between the blood and the central nervous system (CNS), we have studied the expression of junction-related proteins in both cell types. We have found that removal of growth factors from endothelial cultures leads to the downregulation of cadherin and occludin protein levels. The loss of junctional proteins was accompanied by a significant increase in the migratory activity and an altered protease activity profile of the cells. TGF-beta1 suppressed endothelial migration in all experiments. Our data provide evidence to suggest that particular endothelial functions are largely controlled by the presence of growth factors. The differences in adhesiveness and migration may play a role in important physiological and pathological processes of endothelial cells such as vasculogenesis or tumor progression.

  18. Cycles of Ubiquitination and Deubiquitination Critically Regulate Growth Factor-Mediated Activation of Akt Signaling

    PubMed Central

    Yang, Wei-Lei; Jin, Guoxiang; Li, Chien-Feng; Jeong, Yun Seong; Moten, Asad; Xu, Dazhi; Feng, Zizhen; Chen, Wei; Cai, Zhen; Darnay, Bryant; Gu, Wei; Lin, Hui-Kuan

    2013-01-01

    K63-linked ubiquitination of Akt is a posttranslational modification that plays a critical role in growth factor-mediated membrane recruitment and activation of Akt. Although E3 ligases involved in growth factor-induced Akt ubiquitination have been defined, the deubiquitinating enzyme (DUB) that triggers deubiquitination of Akt and the function of Akt deubiquitination remain largely unclear. Here, we showed that CYLD was a DUB for Akt and suppressed growth factor-mediated Akt ubiquitination and activation. CYLD directly removed ubiquitin moieties on Akt under serum-starved conditions. CYLD dissociated from Akt upon growth factor stimulation, thereby allowing E3 ligases to induce ubiquitination and activation of Akt. CYLD deficiency also promoted cancer cell proliferation, survival, glucose uptake and growth of prostate tumors. Our findings reveal the crucial role of cycles of ubiquitination and deubiquitination of Akt in its membrane recruitment and activation, and further identifies CYLD as a molecular switch for these processes. PMID:23300340

  19. Vascular endothelial growth factors: A comparison between invertebrates and vertebrates.

    PubMed

    Kipryushina, Yulia O; Yakovlev, Konstantin V; Odintsova, Nelly A

    2015-12-01

    This review aims to summarize recent data concerning the structure and role of the members of the vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) families in the context of early development, organogenesis and regeneration, with a particular emphasis on the role of these factors in the development of invertebrates. Homologs of VEGF and/or VEGFR have been found in all Eumetazoa, in both Radiata and Bilateria, where they are expressed in the descendants of different germ layers and play a pivotal role in the development of animals with and without a vascular system. VEGF is a well-known angiogenesis regulator, but this factor also control cell migration during neurogenesis and the development of branching organs (the trachea) in invertebrate and vertebrate species. A possible explanation for the origin of Vegf/Vegfr in the animal kingdom and a pathway of Vegf/Vegfr evolution are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. A History of Manipulative Therapy

    PubMed Central

    Pettman, Erland

    2007-01-01

    Manipulative therapy has known a parallel development throughout many parts of the world. The earliest historical reference to the practice of manipulative therapy in Europe dates back to 400 BCE. Over the centuries, manipulative interventions have fallen in and out of favor with the medical profession. Manipulative therapy also was initially the mainstay of the two leading alternative health care systems, osteopathy and chiropractic, both founded in the latter part of the 19th century in response to shortcomings in allopathic medicine. With medical and osteopathic physicians initially instrumental in introducing manipulative therapy to the profession of physical therapy, physical therapists have since then provided strong contributions to the field, thereby solidifying the profession's claim to have manipulative therapy within in its legally regulated scope of practice. PMID:19066664

  1. Biological properties of human skeletal myoblasts genetically modified to simultaneously overexpress the pro-angiogenic factors vascular endothelial growth factor-A and fibroblast growth factor-4.

    PubMed

    Zimna, A; Janeczek, A; Rozwadowska, N; Fraczek, M; Kucharzewska, P; Rucinski, M; Mietkiewski, T; Kurpisz, M

    2014-04-01

    Myocardial infarction results in cardiomyocyte loss and may eventually lead to cardiac failure. Skeletal myoblast transplantation into the scar area may compensate for this observed cell loss by strengthening the weakened myocardium and inducing myogenesis. Moreover, skeletal myoblasts may serve as potential transgene carriers for the myocardium (i.e., delivering pro-angiogenic factors, which may potentially improve blood perfusion in infarcted heart). We examined the influence of the simultaneous overexpression of two potent pro-angiogenic factors, fibroblast growth factor-4 (FGF-4) and vascular endothelial growth factor (VEGF), on human primary myoblast proliferation, cell cycle, resistance to hypoxic stress conditions and myogenic gene expression, as well as the induction of pro-angiogenic activities. We used a bicistronic plasmid vector encoding two factors introduced via an efficient myoblast electroporation method. The levels of overexpressed proteins were assessed, and their functionality at capillary formation was evaluated. This combined approach led to a high level of non-viral transient overexpression of both pro-angiogenic proteins, which proved to be potent regulators of blood vessel development assayed in capillary formation tests. We demonstrated in in vitro conditions that the transfection of human skeletal myoblasts with both FGF-4 and VEGF did not affect their basic biological properties such as the cell cycle, proliferation or expression of myogenic lineage-specific genes, and the modified cells adapted to oxidative stress conditions. Overall, the results obtained suggest that the applied combined approach with the use of two pro-angiogenic genes overexpressed in skeletal muscle stem cells may be an interesting alternative for the effective therapy of myocardial infarction in animal models and/or prospective clinical trials.

  2. Selenoprotein W controls epidermal growth factor receptor surface expression, activation and degradation via receptor ubiquitination

    USDA-ARS?s Scientific Manuscript database

    Epidermal growth factor (EGF) receptor (EGFR) is the founding member of the ErbB family of growth factor receptors that modulate a complex network of intracellular signaling pathways controlling growth, proliferation and differentiation. Selenoprotein W (SEPW1) is a diet-regulated, highly conserved...

  3. Manipulation, salience, and nudges.

    PubMed

    Noggle, Robert

    2018-03-01

    Cass Sunstein and Richard Thaler recommend helping people make better decisions by employing 'nudges', which they define as noncoercive methods of influencing choice for the better. Not surprisingly, healthcare practitioners and public policy professionals have become interested in whether nudges might be a promising method of improving health-related behaviors without resorting to heavy-handed methods such as coercion, deception, or government regulation. Many nudges seem unobjectionable as they merely improve the quality and quantity available for the decision-maker. However, other nudges influence decision-making in ways that do not involve providing more and better information. Nudges of this sort raise concerns about manipulation. This paper will focus on noninformational nudges that operate by changing the salience of various options. It will survey two approaches to understanding manipulation, one which sees manipulation as a kind of pressure, and one that sees it as a kind of trickery. On the pressure view, salience nudges do not appear to be manipulative. However, on the trickery view (which the author favors), salience nudges will be manipulative if they increase the salience so that it is disproportionate to that fact's true relevance and importance for the decision at hand. By contrast, salience nudges will not be manipulative if they merely highlight some fact that is true and important for the decision at hand. The paper concludes by providing examples of both manipulative and nonmanipulative salience nudges. © 2017 John Wiley & Sons Ltd.

  4. Expression of basic fibroblast growth factor mRNA in benign prostatic hyperplasia and prostatic carcinoma.

    PubMed

    Mydlo, J H; Michaeli, J; Heston, W D; Fair, W R

    1988-01-01

    In our previous work we demonstrated that prostate-derived growth factor (PrGF) is homologous to basic fibroblast growth factor (bFGF), not acidic fibroblast growth factor (aFGF). Using Northern blot analysis we now show that the messenger RNA for bFGF but not aFGF is expressed in benign prostatic hyperplastic (BPH) tissue as well as in carcinoma of the prostate (CAP). This not only corroborates our previous results, but suggests that PrGF is produced locally and not merely stored in the prostate. The demonstration of local production of bFGF by prostate tissue may indicate that this growth factor plays a role, either alone or in conjunction with other factors, in the etiology of benign hyperplasia or prostatic cancer.

  5. On Motion Planning and Control of Multi-Link Lightweight Robotic Manipulators

    NASA Technical Reports Server (NTRS)

    Cetinkunt, Sabri

    1987-01-01

    A general gross and fine motion planning and control strategy is needed for lightweight robotic manipulator applications such as painting, welding, material handling, surface finishing, and spacecraft servicing. The control problem of lightweight manipulators is to perform fast, accurate, and robust motions despite the payload variations, structural flexibility, and other environmental disturbances. Performance of the rigid manipulator model based computed torque and decoupled joint control methods are determined and simulated for the counterpart flexible manipulators. A counterpart flexible manipulator is defined as a manipulator which has structural flexibility, in addition to having the same inertial, geometric, and actuation properties of a given rigid manipulator. An adaptive model following control (AMFC) algorithm is developed to improve the performance in speed, accuracy, and robustness. It is found that the AMFC improves the speed performance by a factor of two over the conventional non-adaptive control methods for given accuracy requirements while proving to be more robust with respect to payload variations. Yet there are clear limitations on the performance of AMFC alone as well, which are imposed by the arm flexibility. In the search to further improve speed performance while providing a desired accuracy and robustness, a combined control strategy is developed. Furthermore, the problem of switching from one control structure to another during the motion and implementation aspects of combined control are discussed.

  6. Targeting Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer by Inducing Epidermal Growth Factor Receptor Degradation via Methionine 790 Oxidation

    PubMed Central

    Leung, Elaine Lai-Han; Fan, Xing-Xing; Wong, Maria Pik; Jiang, Zhi-Hong; Liu, Zhong-Qiu; Yao, Xiao-Jun; Lu, Lin-Lin; Zhou, Yan-Ling; Yau, Li-Fong; Tin, Vicky Pui-Chi

    2016-01-01

    Abstract Aims: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat non-small cell lung cancer (NSCLC) patients with EGFR mutation, but TKI resistance is common. Almost half of the acquired resistance patients are due to additional T790M mutation on EGFR (EGFRT790M), thus overcoming TKI resistance is important. In this study, we aim to investigate the role of reactive oxygen species (ROS) in TKI resistance as well as the molecular and biological effects of EGFRT790M after redox manipulation. Results: The basal ROS levels in EGFRT790M-containing TKI-resistant NSCLC cell lines were substantially high. Sixty-three human lung tumors showed higher NADPH oxidase isoform 2 (NOX2) expression than normal lung tissues, which may contribute to high basal ROS in cancer and poor survival. Interestingly, only NOX3 was upregulated by sanguinarine, a pharmacological agent to elevate ROS, and resulted in EGFR overoxidation, degradation, and apoptosis. By contrast, such responses were lacking in EGFRWT cells. Selective EGFRT790M degradation was manipulated by redox imbalance between NOX3 and methionine reductase A (MsrA). Furthermore, the in vivo tumor suppression effect of sanguinarine, NOX3 upregulation, and EGFR degradation were confirmed. Innovation: We have found a new treatment strategy to overcome TKI resistance by selectively inducing EGFRT790M degradation via specific stimulation of methionine 790 (M790) oxidation. It can be achieved via manipulating redox imbalance between NOX3 and MsrA. Conclusion: Targeting EGFR by elevating ROS and redox imbalance is a potential new strategy to develop a new EGFR inhibitor for TKI-resistant patients with a wide therapeutic window between EGFRT790M and EGFRWT. Antioxid. Redox Signal. 24, 263–279. PMID:26528827

  7. Circulating growth factors data associated with insulin secretagogue use in women with incident breast cancer.

    PubMed

    Wintrob, Zachary A P; Hammel, Jeffrey P; Nimako, George K; Gaile, Dan P; Forrest, Alan; Ceacareanu, Alice C

    2017-04-01

    Oral drugs stimulating insulin production may impact growth factor levels. The data presented shows the relationship between pre-existing insulin secretagogues use, growth factor profiles at the time of breast cancer diagnosis and subsequent cancer outcomes in women diagnosed with breast cancer and type 2 diabetes mellitus. A Pearson correlation analysis evaluating the relationship between growth factors stratified by diabetes pharmacotherapy and controls is also provided.

  8. Steroid hormone and epidermal growth factor receptors in meningiomas.

    PubMed

    Horsfall, D J; Goldsmith, K G; Ricciardelli, C; Skinner, J M; Tilley, W D; Marshall, V R

    1989-11-01

    A prospective study of steroid hormone and epidermal growth factor receptor expression in 57 meningiomas is presented. Scatchard analysis of radioligand binding identified 20% of meningiomas as expressing classical oestrogen receptors (ER) at levels below that normally accepted for positivity, the remainder being negative. ER could not be visualized in any meningioma using immunocytochemistry. Alternatively, 74% of meningiomas demonstrated the presence of progesterone receptors (PR) by Scatchard analysis, the specificity of which could not be attributed to glucocorticoid or androgen receptors. Confirmation of classical PR presence was determined by immunocytochemical staining. The presence of epidermal growth factor receptor (EGFR) was demonstrated in 100% of meningiomas using immunocytochemical staining. These data are reviewed in the context of previously reported results and are discussed in relation to the potential for medical therapy as an adjunct to surgery.

  9. Conditioned media from a renal cell carcinoma cell line demonstrates the presence of basic fibroblast growth factor.

    PubMed

    Mydlo, J H; Zajac, J; Macchia, R J

    1993-09-01

    In a previous report, we demonstrated the isolation and purification of a heparin binding growth factor from human renal carcinoma, and suggested that this growth factor may play a role in the neovascularity and growth of the tumor. In this report, we demonstrate that the growth of the renal cell carcinoma cell line RC29 is stimulated by the addition of exogenous fibroblast growth factor (FGF), epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha). Also, media conditioned by this cell line was able to stimulate growth of the A431 vulvar tumor cell line, known for its high concentration of EGF receptors, 3T3 fibroblasts, human umbilical vein (HUV) cells and RC29 cells. Using heparin-sepharose chromatography and then SDS polyacrylamide gel electrophoresis (PAGE), we were able to demonstrate several proteins in the conditioned media of the RC29 cell line. Using Western blot analysis, we detected that at least one of the proteins expressed in this conditioned media was FGF and that it belongs to the basic, not acidic, family of fibroblast growth factors. These findings suggest that renal tumors may express growth factors that may play a direct role in maintaining their unrestricted proliferation.

  10. Visualizing Motion Patterns in Acupuncture Manipulation.

    PubMed

    Lee, Ye-Seul; Jung, Won-Mo; Lee, In-Seon; Lee, Hyangsook; Park, Hi-Joon; Chae, Younbyoung

    2016-07-16

    Acupuncture manipulation varies widely among practitioners in clinical settings, and it is difficult to teach novice students how to perform acupuncture manipulation techniques skillfully. The Acupuncture Manipulation Education System (AMES) is an open source software system designed to enhance acupuncture manipulation skills using visual feedback. Using a phantom acupoint and motion sensor, our method for acupuncture manipulation training provides visual feedback regarding the actual movement of the student's acupuncture manipulation in addition to the optimal or intended movement, regardless of whether the manipulation skill is lifting, thrusting, or rotating. Our results show that students could enhance their manipulation skills by training using this method. This video shows the process of manufacturing phantom acupoints and discusses several issues that may require the attention of individuals interested in creating phantom acupoints or operating this system.

  11. Cell manipulation in microfluidics.

    PubMed

    Yun, Hoyoung; Kim, Kisoo; Lee, Won Gu

    2013-06-01

    Recent advances in the lab-on-a-chip field in association with nano/microfluidics have been made for new applications and functionalities to the fields of molecular biology, genetic analysis and proteomics, enabling the expansion of the cell biology field. Specifically, microfluidics has provided promising tools for enhancing cell biological research, since it has the ability to precisely control the cellular environment, to easily mimic heterogeneous cellular environment by multiplexing, and to analyze sub-cellular information by high-contents screening assays at the single-cell level. Various cell manipulation techniques in microfluidics have been developed in accordance with specific objectives and applications. In this review, we examine the latest achievements of cell manipulation techniques in microfluidics by categorizing externally applied forces for manipulation: (i) optical, (ii) magnetic, (iii) electrical, (iv) mechanical and (v) other manipulations. We furthermore focus on history where the manipulation techniques originate and also discuss future perspectives with key examples where available.

  12. Growth status of children in well-baby outpatient clinics and related factors.

    PubMed

    Çelik, Sercan Bulut; Şahin, Figen; Beyazova, Ufuk; Can, Hüseyin

    2014-06-01

    The aim of this study was to determine the state of growth during follow-up of healthy children and the factors affecting growth. The patient cards of the infants who were born in 2002 and followed up in the well-baby outpatient clinic in Gazi University, Medical Faculty regularly for at least 18 months were examined retrospectively. Their sociodemographic properties including age, education level, occupation of the parents, if the mother was working, caretakers and gender, gestational week, birth weight, birth height and mode of nutrition (breastmilk, formula, cow's milk, period of feeding, etc.) and growth of the babies (month, percentile) were recorded. Number of siblings and ages of the siblings were also recorded and the children with and without growth problems were compared in terms of these properties. It was found that 290 (39.3%) of 739 children who were followed up continued to grow up in the percentile in which they started (normal growth), 188 (25.4%) lost 2 or more percentiles in any month (growth retardation) and 261 (35.3%) lost less than 2 percentiles (decelerated growth). Deceleration/retardation in growth was observed most commonly in the 9(th) month. Deceleration in growth was found in the 6(th) month in 23.6% of the group with deceleration in growth, in the 9(th) month in 50.2%, in the 12(th) month in 15.8% and in the 18(th) month in 3.9%. Growth retardation was found in the 6(th) month in 35.8% of the group with growth retardation, in the 9(th) month in 38.0% and in the 18(th) month in 4.3%. It was found that receiving formula and presence of infection were the main risk factors in terms of deceleration of growth and unemployed mother, the lenght of the total time of breastfeeding and presence of infection were the main risk factors in terms of growth retardation. This study shows the importance of follow-up of growth of children in outpatient clinics for healthy children. It was found that detailed examination and recording of non

  13. 3D axon growth by exogenous electrical stimulus and soluble factors.

    PubMed

    Tang-Schomer, Min D

    2018-01-01

    Axon growth and alignment are fundamental processes during nervous system development and neural regeneration after injury. The present study investigates the effects of exogenous stimulus of electrical signals and soluble factors on axon 3D growth, using a silk protein material-based 3D brain tissue model. Electrical stimulus was delivered via embedded gold wires positioned at the interface of the scaffold region and the center matrix gel-filled region, spanning the axon growth area. This setup delivered applied electrical field directly to growing axons, and the effects were compared to micro-needle assisted local delivery of soluble factors of extracellular (ECM) components and neurotrophins. Dissociated rat cortical neurons were exposed to an alternating field of 80 mV/mm at 0.5 Hz to 2 kHz or soluble factors for up to 4 days, and evaluated by of β III-tubulin immunostaining, confocal imaging and 3D neurite tracing. 0.5-20 Hz were found to promote axon growth, with 2 Hz producing the biggest effect of ∼30% axon length increase compared to control cultures. Delivery of ECM components of laminin and fibronectin resulted significantly greater axon initial length increases compared to neurotrophic factors, such as BDNF, GDNF, NGF and NT3 (all at 1 μM). Though axon lengths under 2 Hz stimulation and LN or FN exposure were statistically similar, significant AC-induced axon alignment was found under all frequencies tested. The effects included perpendicular orientation of axons trespassing an electrode, large populations of aligned axon tracts in parallel to the field direction with a few perpendicularly aligned along the middle point of the EF. These findings are consistent with the hypothesis that an electrode in AC field could act as an alternating cathode that attracts the growing tip of the axon. These results demonstrate the use of alternating electric field stimulation to direct axon 3D length growth and orientation. Our study provides basis

  14. A combined model of human erythropoiesis and granulopoiesis under growth factor and chemotherapy treatment

    PubMed Central

    2014-01-01

    Background Haematotoxicity of conventional chemotherapies often results in delays of treatment or reduction of chemotherapy dose. To ameliorate these side-effects, patients are routinely treated with blood transfusions or haematopoietic growth factors such as erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF). For the latter ones, pharmaceutical derivatives are available, which differ in absorption kinetics, pharmacokinetic and -dynamic properties. Due to the complex interaction of cytotoxic effects of chemotherapy and the stimulating effects of different growth factor derivatives, optimal treatment is a non-trivial task. In the past, we developed mathematical models of thrombopoiesis, granulopoiesis and erythropoiesis under chemotherapy and growth-factor applications which can be used to perform clinically relevant predictions regarding the feasibility of chemotherapy schedules and cytopenia prophylaxis with haematopoietic growth factors. However, interactions of lineages and growth-factors were ignored so far. Results To close this gap, we constructed a hybrid model of human granulopoiesis and erythropoiesis under conventional chemotherapy, G-CSF and EPO applications. This was achieved by combining our single lineage models of human erythropoiesis and granulopoiesis with a common stem cell model. G-CSF effects on erythropoiesis were also implemented. Pharmacodynamic models are based on ordinary differential equations describing proliferation and maturation of haematopoietic cells. The system is regulated by feedback loops partly mediated by endogenous and exogenous EPO and G-CSF. Chemotherapy is modelled by depletion of cells. Unknown model parameters were determined by fitting the model predictions to time series data of blood counts and cytokine profiles. Data were extracted from literature or received from cooperating clinical study groups. Our model explains dynamics of mature blood cells and cytokines after growth-factor applications in

  15. Cardiac Regeneration using Growth Factors: Advances and Challenges.

    PubMed

    Rebouças, Juliana de Souza; Santos-Magalhães, Nereide Stela; Formiga, Fabio Rocha

    2016-09-01

    Myocardial infarction is the most significant manifestation of ischemic heart disease and is associated with high morbidity and mortality. Novel strategies targeting at regenerating the injured myocardium have been investigated, including gene therapy, cell therapy, and the use of growth factors. Growth factor therapy has aroused interest in cardiovascular medicine because of the regeneration mechanisms induced by these biomolecules, including angiogenesis, extracellular matrix remodeling, cardiomyocyte proliferation, stem-cell recruitment, and others. Together, these mechanisms promote myocardial repair and improvement of the cardiac function. This review aims to address the strategic role of growth factor therapy in cardiac regeneration, considering its innovative and multifactorial character in myocardial repair after ischemic injury. Different issues will be discussed, with emphasis on the regeneration mechanisms as a potential therapeutic resource mediated by growth factors, and the challenges to make these proteins therapeutically viable in the field of cardiology and regenerative medicine. Resumo O infarto do miocárdio representa a manifestação mais significativa da cardiopatia isquêmica e está associado a elevada morbimortalidade. Novas estratégias vêm sendo investigadas com o intuito de regenerar o miocárdio lesionado, incluindo a terapia gênica, a terapia celular e a utilização de fatores de crescimento. A terapia com fatores de crescimento despertou interesse em medicina cardiovascular, devido aos mecanismos de regeneração induzidos por essas biomoléculas, incluindo angiogênese, remodelamento da matriz extracelular, proliferação de cardiomiócitos e recrutamento de células-tronco, dentre outros. Em conjunto, tais mecanismos promovem a reparação do miocárdio e a melhora da função cardíaca. Esta revisão pretende abordar o papel estratégico da terapia, com fatores de crescimento, para a regeneração cardíaca, considerando seu car

  16. Update: Biochemistry of Genetic Manipulation.

    ERIC Educational Resources Information Center

    Barker, G. R.

    1983-01-01

    Various topics on the biochemistry of genetic manipulation are discussed. These include genetic transformation and DNA; genetic expression; DNA replication, repair, and mutation; technology of genetic manipulation; and applications of genetic manipulation. Other techniques employed are also considered. (JN)

  17. Subglottic injury, gastric juice, corticosteroids, and peptide growth factors in a porcine model.

    PubMed

    Yellon, R F; Szeremeta, W; Grandis, J R; Diguisseppe, P; Dickman, P S

    1998-06-01

    To study the effects of mucosal injury, gastric juice, and corticosteroids and to determine the presence of peptide growth factors in the subglottic mucosa in a porcine model. Prospective cohort animal study. In this model of subglottic injury, five groups (n = 5 each) of piglets were used. Injury was induced by electrocautery (acute), electrocautery plus repeated saline application (chronic), electrocautery plus repeated gastric juice application (chronic plus gastric juice), or repeated gastric juice application (gastric). Control piglets had normal saline applied repeatedly. Histopathologic findings for the gastric juice group included basal cell hyperplasia (80%), squamous metaplasia (80%), and mucosal ulceration (40%). Control piglets showed squamous metaplasia (80%) but no basilar hyperplasia or ulceration. Immunohistochemistry detected peptide growth factors and epidermal growth factor receptor (EGFR) in all groups. Decreased staining was most frequent in the acute injury group. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) documented lower expression of EGFR in the gastric juice group (P = .01). These findings suggest that peptide growth factors and EGFR are part of normal subglottic mucosal turnover. Noxious stimuli decrease production of these factors. Gastric juice had adverse effects documented by histopathology and molecular techniques.

  18. Prohormone convertase and autocrine growth factor mRNAs are coexpressed in small cell lung carcinoma.

    PubMed

    Rounseville, M P; Davis, T P

    2000-08-01

    A hallmark of small cell lung carcinoma (SCLC) is the expression of autocrine growth factors such as neurotensin and gastrin-releasing peptide, which bind to cellular receptors and stimulate cell division. The biological activity of autocrine growth factors requires the concurrent expression of prohormone convertases that cleave the growth factors to their active form, suggesting the expression of these genes is linked in SCLCs. RNase protection assays were used to detect the expression of autocrine growth factor and prohormone convertase mRNAs in a panel of lung cancer cell lines. These mRNAs are coexpressed in SCLC and lung carcinoid cell lines, but not in normal lung epithelium or in non-small cell lung cancers. These findings, together with earlier results from our laboratory, suggest the expression of prohormone convertases has an important role in the development and maintenance of the SCLC phenotype and that autocrine growth factor and prohormone convertase genes respond to a common transcriptional activator in SCLC.

  19. Effects of temperature and drought manipulations on seedlings of Scots pine provenances.

    PubMed

    Taeger, S; Sparks, T H; Menzel, A

    2015-03-01

    Rising temperatures and more frequent and severe climatic extremes as a consequence of climate change are expected to affect growth and distribution of tree species that are adapted to current local conditions. Species distribution models predict a considerable loss of habitats for Pinus sylvestris. These models do not consider possible intraspecific differences in response to drought and warming that could buffer those impacts. We tested 10 European provenances of P. sylvestris, from the southwestern to the central European part of the species distribution, for their response to warming and to drought using a factorial design. In this common-garden experiment the air surrounding plants was heated directly to prevent excessive soil heating, and drought manipulation, using a rain-out shelter, permitted almost natural radiation, including high light stress. Plant responses were assessed as changes in phenology, growth increment and biomass allocation. Seedlings of P. sylvestris revealed a plastic response to drought by increased taproot length and root-shoot ratios. Strongest phenotypic plasticity of root growth was found for southwestern provenances, indicating a specific drought adaptation at the cost of overall low growth of aboveground structures even under non-drought conditions. Warming had a minor effect on growth but advanced phenological development and had a contrasting effect on bud biomass and diameter increment, depending on water availability. The intraspecific variation of P. sylvestris provenances could buffer climate change impacts, although additional factors such as the adaptation to other climatic extremes have to be considered before assisted migration could become a management option. © 2014 German Botanical Society and The Royal Botanical Society of the Netherlands.

  20. All about running: synaptic plasticity, growth factors and adult hippocampal neurogenesis.

    PubMed

    Vivar, Carmen; Potter, Michelle C; van Praag, Henriette

    2013-01-01

    Accumulating evidence from animal and human research shows exercise benefits learning and memory, which may reduce the risk of neurodegenerative diseases, and could delay age-related cognitive decline. Exercise-induced improvements in learning and memory are correlated with enhanced adult hippocampal neurogenesis and increased activity-dependent synaptic plasticity. In this present chapter we will highlight the effects of physical activity on cognition in rodents, as well as on dentate gyrus (DG) neurogenesis, synaptic plasticity, spine density, neurotransmission and growth factors, in particular brain-derived nerve growth factor (BDNF).

  1. Platelet-rich plasma preparation for regenerative medicine: optimization and quantification of cytokines and growth factors.

    PubMed

    Amable, Paola Romina; Carias, Rosana Bizon Vieira; Teixeira, Marcus Vinicius Telles; da Cruz Pacheco, Italo; Corrêa do Amaral, Ronaldo José Farias; Granjeiro, José Mauro; Borojevic, Radovan

    2013-06-07

    Platelet-rich plasma (PRP) is nowadays widely applied in different clinical scenarios, such as orthopedics, ophthalmology and healing therapies, as a growth factor pool for improving tissue regeneration. Studies into its clinical efficiency are not conclusive and one of the main reasons for this is that different PRP preparations are used, eliciting different responses that cannot be compared. Platelet quantification and the growth factor content definition must be defined in order to understand molecular mechanisms behind PRP regenerative strength. Standardization of PRP preparations is thus urgently needed. PRP was prepared by centrifugation varying the relative centrifugal force, temperature, and time. Having quantified platelet recovery and yield, the two-step procedure that rendered the highest output was chosen and further analyzed. Cytokine content was determined in different fractions obtained throughout the whole centrifugation procedure. Our method showed reproducibility when applied to different blood donors. We recovered 46.9 to 69.5% of total initial platelets and the procedure resulted in a 5.4-fold to 7.3-fold increase in platelet concentration (1.4 × 10(6) to 1.9 × 10(6) platelets/μl). Platelets were highly purified, because only <0.3% from the initial red blood cells and leukocytes was present in the final PRP preparation. We also quantified growth factors, cytokines and chemokines secreted by the concentrated platelets after activation with calcium and calcium/thrombin. High concentrations of platelet-derived growth factor, endothelial growth factor and transforming growth factor (TGF) were secreted, together with the anti-inflammatory and proinflammatory cytokines interleukin (IL)-4, IL-8, IL-13, IL-17, tumor necrosis factor (TNF)-α and interferon (IFN)-α. No cytokines were secreted before platelet activation. TGF-β3 and IFNγ were not detected in any studied fraction. Clots obtained after platelet coagulation retained a high concentration

  2. Nerve Growth Factor: Early Studies And Recent Clinical Trials.

    PubMed

    Rocco, Maria Luisa; Soligo, Marzia; Manni, Luigi; Aloe, Luigi

    2018-04-11

    Since its discovery, nerve growth factor (NGF) has long occupied a critical role in developmental and adult neurobiology for its many important regulatory functions on the survival, growth and differentiation of nerve cells in the peripheral and central nervous system. NGF is the first discovered member of a family of neurotrophic factors, collectively indicated as neurotrophins, (which include brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin 4/5). NGF was discovered for its action on the survival and differentiation of selected populations of peripheral neurons. Since then, an enormous number of basic and human studies were undertaken to explore the role of purified NGF to prevent the death of NGF-receptive cells. These studies revealed that NGF possesses important therapeutic properties, after topical administration, on human cutaneous pressure ulcer, corneal ulcers, glaucoma, retinal maculopathy, Retinitis Pigmentosa and in pediatric optic gliomas and brain traumas. The aim of this review is to present our previous, recent and ongoing clinical studies on the therapeutic properties of NGF. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Comparison between tocotrienol and omeprazole on gastric growth factors in stress-exposed rats.

    PubMed

    Nur Azlina, Mohd Fahami; Qodriyah, Hj Mohd Saad; Chua, Kien Hui; Kamisah, Yusof

    2017-08-28

    To investigate and compare the effects of tocotrienol and omeprazole on gastric growth factors in rats exposed to water-immersion restraint stress (WIRS). Twenty-eight male Wistar rats were randomly assigned to four groups of seven rats. The two control groups were administered vitamin-free palm oil (vehicle) and the two treatment groups were given omeprazole (20 mg/kg) or tocotrienol (60 mg/kg) by oral gavage. After 28 d of treatment, rats from one control group and both treated groups were subjected to WIRS one time for 3.5 h. Gastric lesions were measured and gastric tissues were obtained to measure vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and transforming growth factor-alpha (TGF-α) mRNA expression. Rats exposed to WIRS for 3.5 h demonstrated the presence of considerable ulcers in the form of gastric erosion. The lesion index in the stressed control (S) group was increased ( P < 0.001) compared to the tocotrienol treated and omeprazole treated groups. Stress led to a decrease in gastric VEGF ( P < 0.001), bFGF ( P < 0.001) and TGF-α ( P < 0.001) mRNA levels and caused an increase in EGF mRNA ( P < 0.001) that was statistically significant compared to the non-stressed control group. Although both treatment agents exerted similar ulcer reducing ability, only treatment with tocotrienol led to increased expression of VEGF ( P = 0.008), bFGF ( P = 0.001) and TGF-α ( P = 0.002) mRNA. Tocotrienol provides gastroprotective effects in WIRS-induced ulcers. Compared to omeprazole, tocotrienol exerts a similar protective effect, albeit through multiple mechanisms of protection, particularly through up-regulation of growth factors that assist in repair of gastric tissue injuries.

  4. Higher growth rate and gene expression in male zebra finch embryos are independent of manipulation of maternal steroids in the eggs.

    PubMed

    Lutyk, Dorota; Tagirov, Makhsud; Drobniak, Szymon; Rutkowska, Joanna

    2017-12-01

    Sexual dimorphism in prenatal development is widespread among vertebrates, including birds. Its mechanism remains unclear, although it has been attributed to the effect of maternal steroid hormones. The aim of this study was to investigate how increased levels of steroid hormones in the eggs influence early embryonic development of male and female offspring. We also asked whether maternal hormones take part in the control of sex-specific expression of the genes involved in prenatal development. We experimentally manipulated hormones' concentrations in the egg yolk by injecting zebra finch females prior to ovulation with testosterone or corticosterone. We assessed growth rate and expression levels of CDK7, FBP1 and GHR genes in 37h-old embryos. We found faster growth and higher expression of two studied genes in male compared to female embryos. Hormonal treatment, despite clearly differentiating egg steroid levels, had no effect on the sex-specific pattern of the embryonic gene expression, even though we confirmed expression of receptors of androgens and glucocorticoids at such an early stage of development. Thus, our study shows high stability of the early sex differences in the embryonic development before the onset of sexual differentiation and indicates their independence of maternal hormones in the egg. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Identification of interleukin-6 as an autocrine growth factor for Epstein-Barr virus-immortalized B cells.

    PubMed Central

    Tosato, G; Tanner, J; Jones, K D; Revel, M; Pike, S E

    1990-01-01

    Autocrine growth factors are believed to be important for maintenance of an immortalized state by Epstein-Barr virus (EBV), because cell-free supernatants of EBV-immortalized cell lines promote the proliferation of autologous cells and permit their growth at low cell density. In this study, we provide evidence for the existence of two autocrine growth factor activities produced by EBV-immortalized lines distinguished by size and biological activities. Much of the autocrine growth factor activity in lymphoblastoid cell line supernatants resided in a low-molecular-weight (less than 5,000) fraction. However, up to 20 to 30% of the autocrine growth factor activity resided in the high-molecular-weight (greater than 5,000) fraction. While the nature of the low-molecular-weight growth factor activity remains undefined, the high-molecular-weight growth factor activity was identified as interleukin-6 (IL-6). Culture supernatants from six EBV-induced lymphoblastoid cell lines tested contained IL-6 activity, because they promoted proliferation in the IL-6-dependent hybridoma cell line B9. In addition, a rabbit antibody to human IL-6 neutralized the capacity of the high-molecular-weight (greater than 5,000) fraction of a lymphoblastoid cell line supernatant to promote growth both in autologous EBV-immortalized cells and in B9 cells. Similarly, this high-molecular-weight autocrine growth factor activity was neutralized by a monoclonal antibody to human IL-6. Furthermore, characteristic bands, attributable to IL-6, were visualized in supernatants of each of four EBV-induced lymphoblastoid cell lines after immunoprecipitation with a rabbit antiserum to human IL-6. Thus, in addition to its previously reported properties, IL-6 is an autocrine growth factor for EBV-immortalized B cells cultured under serum-free conditions. Images PMID:2159561

  6. Demographic Responses To Climate Manipulations Across a Species Range

    NASA Astrophysics Data System (ADS)

    Oldfather, M. F.

    2016-12-01

    Species biogeographic responses to climate change will occur through the local extinction and establishment of populations. The overall performance of populations across a species range is shaped by the idiosyncratic sensitivities of demographic rates to the changing climate conditions. Heterogeneous topography partially decouples temperature and soil moisture presenting an opportunity to disentangle demographic sensitivity to multiple local climate variables and refine range shift predictions in response to complex climate change. Since 2013, I have monitored 16 populations of a long-lived alpine plant, Ivesia lycopodioides var. scandularis (Rosaceae) across the entirety of its altitudinal range in the arid White Mountains, CA (3350 - 4420m). I quantified microclimatic soil moisture and temperature, and the demographic rates of over 4,000 individuals. Demographic rates exhibited sensitivity to accumulated degree-days (ex. reproduction), soil volumetric water content (ex. germination), or the interaction between these climate variables (ex. survival). These observations motivated an experimental test of the relationship between demography and local climate with manipulations of increased summertime temperature and precipitation in nine populations. All demographic rates were sensitive to the climate manipulations and the magnitude of the demographic response depended on the population's location within the range. However, the modeled population growth rate was only minimally affected by the manipulations in most populations. The inverse responses of many of the demographic rates may allow populations to demographically buffer against the climate manipulations. However, in one low elevation edge population the negative effect of heating on survival overwhelmed the positive effect on germination, indicating that the capacity of populations to demographically buffer may have a limit.

  7. Preclinical and clinical studies on the use of growth factors for bone repair: a systematic review.

    PubMed

    Fisher, Daniel Mark; Wong, James Min-Leong; Crowley, Conor; Khan, Wasim S

    2013-05-01

    Bone healing is a complex process. Whilst the majority of fractures heal with conventional treatment, open fractures, large bone defects and non unions still provide great challenges to Orthopaedic Surgeons. Whilst autologous bone graft is seen as the gold standard, the use of growth factors is a growing area of research to find an effective alternative with lower side effects such as donor site morbidity and the finite amount available. This systematic review aims to summarize the pre clinical in-vivo studies and examine the clinical studies on the use of growth factors in bone healing. Databases: PubMed, Medline, OVID, and Cochrane library. The following key words and search terms were used: Growth Factors, Bone Healing, Bone Morphogenic Protein, Transforming Growth Factor Beta, Insulin Like Growth Factor, Platelet Derived Growth Factor, Fracture. All articles were screened based on title with abstracts and full text articles reviewed as appropriate. Reference lists were reviewed from relevant articles to ensure comprehensive and systematic review. Three tables of studies were constructed focussing on Bone Morphogenic Proteins, Platelet Rich Plasma and Growth Factors and Tissue Engineering. Bone Morphogenic Proteins and Platelet Rich Plasma, which contains multiple growth factors, have been shown in preclinical and clinical trials to be an effective alternative to autologous bone graft. Bone Morphogenic Proteins have been shown to be effective in fracture non union, and in open tibial fractures. Platelet Rich Plasma has shown promise in preclinical trials and some small clinical trials, however numbers are limited. Bone Morphogenic Proteins have been shown to be superior to Platelet Rich Protein in one trial. Combining these growth factors with tissue engineering techniques is the focus of ongoing research, and through further clinical trials the most effective techniques for enhancing bone healing will be revealed.

  8. Partial characterization of a putative new growth factor present in pathological human vitreous.

    PubMed

    Pombo, C; Bokser, L; Casabiell, X; Zugaza, J; Capeans, M; Salorio, M; Casanueva, F

    1996-03-01

    Several growth factors have been implicated in the development of proliferative eye diseases, and some of those are present in human vitreous (HV). The effects of HV on cellular responses which modulate proliferative cell processes were studied. This study describes the partial characterization of a vitreous factor activity which does not correspond to any of the previously reported growth factors in pathological HV. Vitreous humour was obtained from medical vitrectomies, from patients with PDR and PVR. The biological activity of the vitreous factor was determined by its ability to increase cytosolic calcium concentration ([Ca2+]i), increase production of inositol phosphates, and induce cell proliferation in the cell line EGFR T17. In some experiments other cell lines, such as NIH 3T3, 3T3-L1, FRTL5, A431, PC12, Y79, and GH3, were also employed. Measurement of [Ca2+]i in cell suspensions was performed using the fluorescent Ca2+ indicator fura-2. The activity of the factor present in HV was compared with other growth factors by means of: (a) [Ca2+]i mobilization pattern, (b) sequential homologous and heterologous desensitization of receptors, (c) effects of phorbol esters on their action, and (d) inactivation after treatment with different proteolytic enzymes. The HV-induced cell proliferation and increases in [Ca2+]i concentration were characterized by a peculiar time pattern. The different approaches used ruled out its identity with PDGF, bFGF, EGF, TGF-beta, IGFs, TNF-alpha, NGF, and other compounds such as ATP, angiotensin I, and bradykinin. Vitreous factor actions are mediated by specific receptors apparently regulated by PKC. This factor is able to induce [Ca2+]i mobilization in most of the cell lines studied, indicating that its effects are not tissue specific. These results suggest the presence of a growth factor activity in pathological HV which may be due to the presence of an undescribed growth factor in the eye.

  9. Membrane type 1-matrix metalloproteinase cleaves off the NH2-terminal portion of heparin-binding epidermal growth factor and converts it into a heparin-independent growth factor.

    PubMed

    Koshikawa, Naohiko; Mizushima, Hiroto; Minegishi, Tomoko; Iwamoto, Ryo; Mekada, Eisuke; Seiki, Motoharu

    2010-07-15

    Epidermal growth factor (EGF) receptors (ErbB) and EGF family members represent promising targets for cancer therapy. Heparin-binding EGF (HB-EGF) is a member of the EGF family and is an important target for therapy in some types of human cancers. Processing of HB-EGF by proprotein convertases, and successively, by ADAM family proteases, generates a soluble growth factor that requires heparin as a cofactor. Although heparin potentiates HB-EGF activity in vitro, it is not clear how the heparin-binding activity of HB-EGF is regulated. Here, we show that membrane type 1-matrix metalloproteinase (MT1-MMP; MMP14), a potent invasion-promoting protease, markedly enhances HB-EGF-dependent tumor formation in mice. MT1-MMP additionally cleaves HB-EGF and removes the NH(2)-terminal 20 amino acids that are important for binding heparin. Consequently, the processing of HB-EGF by MT1-MMP converts HB-EGF into a heparin-independent growth factor with enhanced mitogenic activity, and thereby, expression of both proteins costimulates tumor cell growth in vitro and in vivo. The ErbB family of receptors expressed in human gastric carcinoma cells play a role in mediating enhanced HB-EGF activity by MT1-MMP during invasive cell growth in collagen. Thus, we shed light on a new mechanism whereby HB-EGF activity is regulated that should be considered when designing HB-EGF-targeted cancer therapy. (c)2010 AACR.

  10. Diagnostic Usefulness of Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor Binding Protein 3 in Children with Suspected Pituitary Dwarfism.

    PubMed

    Zelazowska-Rutkowska, Beata; Trusiak, Marta; Bossowski, Artur; Cylwik, Bogdan

    2018-05-01

    Pituitary dwarfism (also known as short stature) is a medical condition in which the pituitary gland does not produce enough growth hormone (GH). To confirm the diagnosis of growth hormone deficiency the overnight profile of GH secretion and GH provocative tests are usually performed; however, due to wide GH fluctuations throughout the day and night and the invasiveness of stimulation tests, their clinical utility is limited. Therefore, screening for IGF-1 (insulin-like growth factor 1) and IGFBP-3 (insulin-like growth factor binding protein type 3) is proposed, suggesting that these tests provide a more accurate reflection of the mean plasma GH level, although the results of these tests are still problematic. In this context, the aim of this study was to assess the diagnostic usefulness of IGF-1 and IGFBP-3 in children with suspected pituitary dwarfism. Studies were carried out in 127 children with abnormal growth and low spontaneous 24-hour plasma GH profiles and abnormal results of GH stimulation tests. Fasting serum IGF-1 and IGFBP-3 were determined by chemiluminescent quantitative measurement using the IMMULITE 1000 IGF-1 and IGFBP-3 kits (Siemens Healthcare Diagnostics, United Kingdom) on the IMMULITE 1000 analyzer (Siemens Healthcare Diagnostics, USA). Results were compared to the normal range by children's age. Mean serum IGF-1 concentrations were within the lower normal range (41.7% cases), and 58.3% results were below the normal reference range in the study group. The average serum IGFBP-3 levels were within the lower normal range. We conclude that IGF-1 test can be a useful tool in the diagnosis of pituitary dwarfism in children suspected of this condition, but due to relatively poor sensitivity the testing cannot be performed alone, but in combination with other tests. The IGFBP-3 test is not useful for the diagnosis of this disease.

  11. Nerve Growth Factor Inhibits Sympathetic Neurons' Response to an Injury Cytokine

    NASA Astrophysics Data System (ADS)

    Shadiack, Annette M.; Vaccariello, Stacey A.; Sun, Yi; Zigmond, Richard E.

    1998-06-01

    Axonal damage to adult peripheral neurons causes changes in neuronal gene expression. For example, axotomized sympathetic, sensory, and motor neurons begin to express galanin mRNA and protein, and recent evidence suggests that galanin plays a role in peripheral nerve regeneration. Previous studies in sympathetic and sensory neurons have established that galanin expression is triggered by two consequences of nerve transection: the induction of leukemia inhibitory factor (LIF) and the reduction in the availability of the target-derived factor, nerve growth factor. It is shown in the present study that no stimulation of galanin expression occurs following direct application of LIF to intact neurons in the superior cervical sympathetic ganglion. Injection of animals with an antiserum to nerve growth factor concomitant with the application of LIF, on the other hand, does stimulate galanin expression. The data suggest that the response of neurons to an injury factor, LIF, is affected by whether the neurons still receive trophic signals from their targets.

  12. Growth differentiation factor-15 (GDF-15) suppresses in vitro angiogenesis through a novel interaction with connective tissue growth factor (CCN2).

    PubMed

    Whitson, Ramon J; Lucia, Marshall Scott; Lambert, James R

    2013-06-01

    Growth differentiation factor-15 (GDF-15) and the CCN family member, connective tissue growth factor (CCN2), are associated with cardiac disease, inflammation, and cancer. The precise role and signaling mechanism for these factors in normal and diseased tissues remains elusive. Here we demonstrate an interaction between GDF-15 and CCN2 using yeast two-hybrid assays and have mapped the domain of interaction to the von Willebrand factor type C domain of CCN2. Biochemical pull down assays using secreted GDF-15 and His-tagged CCN2 produced in PC-3 prostate cancer cells confirmed a direct interaction between these proteins. To investigate the functional consequences of this interaction, in vitro angiogenesis assays were performed. We demonstrate that GDF-15 blocks CCN2-mediated tube formation in human umbilical vein endothelial (HUVEC) cells. To examine the molecular mechanism whereby GDF-15 inhibits CCN2-mediated angiogenesis, activation of αV β3 integrins and focal adhesion kinase (FAK) was examined. CCN2-mediated FAK activation was inhibited by GDF-15 and was accompanied by a decrease in αV β3 integrin clustering in HUVEC cells. These results demonstrate, for the first time, a novel signaling pathway for GDF-15 through interaction with the matricellular signaling molecule CCN2. Furthermore, antagonism of CCN2 mediated angiogenesis by GDF-15 may provide insight into the functional role of GDF-15 in disease states. Copyright © 2012 Wiley Periodicals, Inc.

  13. Adaptive control of robotic manipulators

    NASA Technical Reports Server (NTRS)

    Seraji, H.

    1987-01-01

    The author presents a novel approach to adaptive control of manipulators to achieve trajectory tracking by the joint angles. The central concept in this approach is the utilization of the manipulator inverse as a feedforward controller. The desired trajectory is applied as an input to the feedforward controller which behaves as the inverse of the manipulator at any operating point; the controller output is used as the driving torque for the manipulator. The controller gains are then updated by an adaptation algorithm derived from MRAC (model reference adaptive control) theory to cope with variations in the manipulator inverse due to changes of the operating point. An adaptive feedback controller and an auxiliary signal are also used to enhance closed-loop stability and to achieve faster adaptation. The proposed control scheme is computationally fast and does not require a priori knowledge of the complex dynamic model or the parameter values of the manipulator or the payload.

  14. Lactoferrin – A Novel Bone Growth Factor

    PubMed Central

    Naot, Dorit; Grey, Andrew; Reid, Ian R; Cornish, Jillian

    2005-01-01

    Lactoferrin is an iron-binding glycoprotein that belongs to the transferrin family. It is present in breast milk, in epithelial secretions, and in the secondary granules of neutrophils. In healthy subjects lactoferrin circulates at concentrations of 2–7 x 10−6 g/ml. Lactoferrin is a pleiotropic factor with potent antimicrobial and immunomodulatory activities. Recently, we have shown that lactoferrin can also promote bone growth. At physiological concentrations, lactoferrin potently stimulates the proliferation and differentiation of primary osteoblasts and also acts as a survival factor inhibiting apoptosis induced by serum withdrawal. Lactoferrin also affects osteoclast formation and, in murine bone marrow culture, lactoferrin potently inhibits osteoclastogenesis. In vivo, local injection of lactoferrin above the hemicalvaria of adult mice results in substantial increases in the dynamic histomorphometric indices of bone formation and bone area. The mitogenic effect of lactoferrin in osteoblast-like cells is mediated mainly through LRP1, a member of the family of low-density lipoprotein receptor-related proteins that are primarily known as endocytic receptors. Using confocal laser scanning microscopy, we demonstrated that fluorescently labeled lactoferrin is endocytosed and can be visualized in the cytoplasm of primary osteoblastic cells. Lactoferrin also induces activation of p42/44 MAPK signaling in primary osteoblasts, but the two pathways seem to operate independently as activation of MAPK signaling, but not endocytosis, is necessary for the mitogenic effect of lactoferrin. We conclude that lactoferrin may have a physiological role in bone growth and healing, and a potential therapeutic role as an anabolic factor in osteoporosis. PMID:16012127

  15. Comparison of human dermal fibroblasts (HDFs) growth rate in culture media supplemented with or without basic fibroblast growth factor (bFGF).

    PubMed

    Abdian, Narges; Ghasemi-Dehkordi, Payam; Hashemzadeh-Chaleshtori, Morteza; Ganji-Arjenaki, Mahbobe; Doosti, Abbas; Amiri, Beheshteh

    2015-12-01

    Basic fibroblast growth factor (bFGF or FGF-2) is a member of the FGF family secreted by different kinds of cells like HDFs and it is an important nutritional factor for cell growth and differentiation. The HDFs release bFGF in culture media at very low. The present study aims to investigate the HDFs growth rate in culture media supplemented either with or without bFGF. In brief, HDFs were isolated from human foreskin sample and were cultured in vitro in media containing bFGF and lack of this factor. The cells growth rate was calculated by trypan blue. The karyotyping was performed using G-banding to investigate the chromosomal abnormality of HDFs in both groups. Total RNA of each groups were extracted and cDNA samples were synthesized then, real-time Q-PCR was used to measure the expression level of p27kip1 and cyclin D1 genes normalized to internal control gene (GAPDH). The karyotype analysis showed that HDFs cultured in media or without bFGF had normal karyotype (46 chromosomes, XY) and chromosomal abnormalities were not observed. The cell growth rates in both groups were normal with proliferated exponentially but the slope of growth curve in HDFs cultured in media containing bFGF was increased. Karyotyp test showed that bFGF does not affect on cytogenetic stability of cells. The survey of p27kip1 and cyclin D1 genes by real-time Q-PCR showed that the expression level of these genes were up-regulated when adding bFGF in culture media (p < 0.05). The findings of the present study demonstrate that appropriate supplementation of culture media with growth factor like bFGF could enhance the proliferation and differentiation capacity of cells and improve cells growth rate. Similarly, fibroblast growth factors did not induce any chromosomal abnormality in cells. Furthermore, in HDFs cultured in bFGF supplemented media, the p27kip1 and cyclin D1 genes were up-regulated and suggesting an important role for bFGF in cell-cycle regulation and progression and fibroblast

  16. Fibroblast growth factors: key players in regeneration and tissue repair.

    PubMed

    Maddaluno, Luigi; Urwyler, Corinne; Werner, Sabine

    2017-11-15

    Tissue injury initiates a complex repair process, which in some organisms can lead to the complete regeneration of a tissue. In mammals, however, the repair of most organs is imperfect and results in scar formation. Both regeneration and repair are orchestrated by a highly coordinated interplay of different growth factors and cytokines. Among the key players are the fibroblast growth factors (FGFs), which control the migration, proliferation, differentiation and survival of different cell types. In addition, FGFs influence the expression of other factors involved in the regenerative response. Here, we summarize current knowledge on the roles of endogenous FGFs in regeneration and repair in different organisms and in different tissues and organs. Gaining a better understanding of these FGF activities is important for appropriate modulation of FGF signaling after injury to prevent impaired healing and to promote organ regeneration in humans. © 2017. Published by The Company of Biologists Ltd.

  17. Alginate Sulfates Mitigate Binding Kinetics of Proangiogenic Growth Factors with Receptors toward Revascularization.

    PubMed

    Schmidt, John; Lee, Min Kyung; Ko, Eunkyung; Jeong, Jae Hyun; DiPietro, Luisa A; Kong, Hyunjoon

    2016-07-05

    Ever since proangiogenic growth factors have been used as a vascular medicine to treat tissue ischemia, efforts have been increasingly made to develop a method to enhance efficacy of growth factors in recreating microvascular networks, especially at low dose. To this end, we hypothesized that polysaccharides substituted with sulfate groups would amplify growth factor receptor activation and stimulate phenotypic activities of endothelial cells involved in neovascularization. We examined this hypothesis by modifying alginate with a controlled number of sulfates and using it to derive a complex with vascular endothelial growth factor (VEGF), as confirmed with fluorescence resonance energy transfer (FRET) assay. Compared with the bare VEGF and with a mixture of VEGF and unmodified alginates, the VEGF complexed with alginate sulfates significantly reduced the dissociation rate with the VEGFR-2, elevated VEGFR-2 phosphorylation level, and increased the number of endothelial sprouts in vitro. Furthermore, the VEGF-alginate sulfate complex improved recovery of perfusion in an ischemic hindlimb of a mouse due to the increase of the capillary density. Overall, this study not only demonstrates an important cofactor of VEGF but also uncovers an underlying mechanism by which the cofactor mitigates the VEGF-induced signaling involved in the binding kinetics and activation of VEGFR. We therefore believe that the results of this study will be highly useful in improving the therapeutic efficacy of various growth factors and expediting their uses in clinical treatments of wounds and tissue defects.

  18. Increased and correlated expression of connective tissue growth factor and transforming growth factor beta 1 in surgically removed periodontal tissues with chronic periodontitis.

    PubMed

    Mize, T W; Sundararaj, K P; Leite, R S; Huang, Y

    2015-06-01

    Both gingival tissue destruction and regeneration are associated with chronic periodontitis, although the former overwhelms the latter. Studies have shown that transforming growth factor beta 1 (TGF-β1), a growth factor largely involved in tissue regeneration and remodeling, is upregulated in chronic periodontitis. However, the gingival expression of connective tissue growth factor (CTGF or CCN2), a TGF-β1-upregulated gene, in patients with periodontitis remains undetermined. Although both CTGF/CCN2 and TGF-b1 increase the production of extracellular matrix, they have many different biological functions. Therefore, it is important to delineate the impact of periodontitis on gingival CTGF/CCN2 expression. Periodontal tissue specimens were collected from seven individuals without periodontitis (group 1) and from 14 with periodontitis (group 2). The expression of CTGF and TGFβ1 mRNAs were quantified using real-time PCR. Analysis using the nonparametric Mann-Whitney U-test showed that the levels of expression of both CTGF/CCN2 and TGFβ1 mRNAs were significantly increased in individuals with periodontitis compared with individuals without periodontitis. Furthermore, analysis using a nonparametric correlation (Spearman r) test showed a positive correlation between TGFβ1 and CTGF/CCN2 mRNAs. The gingival expression levels of CTGF/CCN2 and TGFβ1 mRNAs in individuals with periodontitis are upregulated and correlated. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Phenotypic differences between oral and skin fibroblasts in wound contraction and growth factor expression.

    PubMed

    Shannon, Diane B; McKeown, Scott T W; Lundy, Fionnuala T; Irwin, Chris R

    2006-01-01

    Wounds of the oral mucosa heal in an accelerated fashion with reduced scarring compared with cutaneous wounds. The differences in healing outcome between oral mucosa and skin could be because of phenotypic differences between the respective fibroblast populations. This study compared paired mucosal and dermal fibroblasts in terms of collagen gel contraction, alpha-smooth muscle actin expression (alpha-SMA), and production of the epithelial growth factors: keratinocyte growth factor (KGF) and hepatocyte growth factor/scatter factor (HGF). The effects of transforming growth factor -beta1 and -beta3 on each parameter were also determined. Gel contraction in floating collagen lattices was determined over a 7-day period. alpha-SMA expression by fibroblasts was determined by Western blotting. KGF and HGF expression were determined by an enzyme-linked immunosorbent assay. Oral fibroblasts induced accelerated collagen gel contraction, yet surprisingly expressed lower levels of alpha-SMA. Oral cells also produced significantly greater levels of both KGF and HGF than their dermal counterparts. Transforming growth factor-beta1 and -beta3, over the concentration range of 0.1-10 ng/mL, had similar effects on cell function, stimulating both gel contraction and alpha-SMA production, but inhibiting KGF and HGF production by both cell types. These data indicate phenotypic differences between oral and dermal fibroblasts that may well contribute to the differences in healing outcome between these two tissues.

  20. Expression of insulin-like growth factor-2 receptors on EL4 lymphoma cells overexpressing growth hormone.

    PubMed

    Farmer, John T; Weigent, Douglas A

    2007-01-01

    In the present study, we report the upregulation of functional IGF-2Rs in cells overexpressing growth hormone (GH). EL4 lymphoma cells stably transfected with an rGH cDNA overexpression vector (GHo) exhibited an increase in the binding of (125)I-IGF-2 with no change in the binding affinity compared to vector alone controls. An increase in the expression of the insulin-like growth factor-2 receptor (IGF-2R) in cells overexpressing GH was confirmed by Western blot analysis and IGF-2R promoter luciferase assays. EL4 cells produce insulin-like growth factor-2 (IGF-2) as detected by the reverse transcription-polymerase chain reaction (RT-PCR); however, no IGF-2 protein was detected by Western analysis. The increase in the expression of the IGF-2R resulted in greater levels of IGF-2 uptake in GHo cells compared to vector alone controls. The data suggest that one of the consequences of the overexpression of GH is an increase in the expression of the IGF-2R.

  1. Adult-Directed and Peer-Directed Respect for Authority: Relationships With Aggressive and Manipulative Behavior.

    PubMed

    Clemans, Katherine H; Graber, Julia A; Bettencourt, Amie F

    2012-09-01

    This study investigated whether respect for adult and peer authority are separate attitudes which have distinct relationships with aggressive and manipulative behavior. Items assessing admiration for and obedience toward parents, teachers, popular students, and friend group leaders were administered to 286 middle school students (M age = 12.6 yrs). Factor analysis revealed two primary factors which corresponded to adult-directed and peer-directed respect orientations. Results suggested that adult-directed respect was associated with lower levels of aggression and social manipulation, whereas peer-directed respect was associated with higher levels of these behaviors. The role of peer-directed respect as a risk factor for negative social behavior in adolescence is discussed.

  2. Connective tissue growth factor is expressed in bone marrow stromal cells and promotes interleukin-7-dependent B lymphopoiesis.

    PubMed

    Cheung, Laurence C; Strickland, Deborah H; Howlett, Meegan; Ford, Jette; Charles, Adrian K; Lyons, Karen M; Brigstock, David R; Goldschmeding, Roel; Cole, Catherine H; Alexander, Warren S; Kees, Ursula R

    2014-07-01

    Hematopoiesis occurs in a complex bone marrow microenvironment in which bone marrow stromal cells provide critical support to the process through direct cell contact and indirectly through the secretion of cytokines and growth factors. We report that connective tissue growth factor (Ctgf, also known as Ccn2) is highly expressed in murine bone marrow stromal cells. In contrast, connective tissue growth factor is barely detectable in unfractionated adult bone marrow cells. While connective tissue growth factor has been implicated in hematopoietic malignancies, and is known to play critical roles in skeletogenesis and regulation of bone marrow stromal cells, its role in hematopoiesis has not been described. Here we demonstrate that the absence of connective tissue growth factor in mice results in impaired hematopoiesis. Using a chimeric fetal liver transplantation model, we show that absence of connective tissue growth factor has an impact on B-cell development, in particular from pro-B to more mature stages, which is linked to a requirement for connective tissue growth factor in bone marrow stromal cells. Using in vitro culture systems, we demonstrate that connective tissue growth factor potentiates B-cell proliferation and promotes pro-B to pre-B differentiation in the presence of interleukin-7. This study provides a better understanding of the functions of connective tissue growth factor within the bone marrow, showing the dual regulatory role of the growth factor in skeletogenesis and in stage-specific B lymphopoiesis. Copyright© Ferrata Storti Foundation.

  3. Connective tissue growth factor is expressed in bone marrow stromal cells and promotes interleukin-7-dependent B lymphopoiesis

    PubMed Central

    Cheung, Laurence C.; Strickland, Deborah H.; Howlett, Meegan; Ford, Jette; Charles, Adrian K.; Lyons, Karen M.; Brigstock, David R.; Goldschmeding, Roel; Cole, Catherine H.; Alexander, Warren S.; Kees, Ursula R.

    2014-01-01

    Hematopoiesis occurs in a complex bone marrow microenvironment in which bone marrow stromal cells provide critical support to the process through direct cell contact and indirectly through the secretion of cytokines and growth factors. We report that connective tissue growth factor (Ctgf, also known as Ccn2) is highly expressed in murine bone marrow stromal cells. In contrast, connective tissue growth factor is barely detectable in unfractionated adult bone marrow cells. While connective tissue growth factor has been implicated in hematopoietic malignancies, and is known to play critical roles in skeletogenesis and regulation of bone marrow stromal cells, its role in hematopoiesis has not been described. Here we demonstrate that the absence of connective tissue growth factor in mice results in impaired hematopoiesis. Using a chimeric fetal liver transplantation model, we show that absence of connective tissue growth factor has an impact on B-cell development, in particular from pro-B to more mature stages, which is linked to a requirement for connective tissue growth factor in bone marrow stromal cells. Using in vitro culture systems, we demonstrate that connective tissue growth factor potentiates B-cell proliferation and promotes pro-B to pre-B differentiation in the presence of interleukin-7. This study provides a better understanding of the functions of connective tissue growth factor within the bone marrow, showing the dual regulatory role of the growth factor in skeletogenesis and in stage-specific B lymphopoiesis. PMID:24727816

  4. [Analysis of optimal plan of multiple acupuncture manipulations for shoulder pain after stroke at different stages].

    PubMed

    Chen, Dachun; Gao, Jianyu; Chen, Lu; Hao, Zhuanzhuan; Fan, Gangqi

    2015-12-01

    To observe the effects between acupuncture combined with rehabilitation and simple rehabilitation for shoulder pain after stroke, and to select the best plan of acupuncture manipulations at different stages by orthogonal design. Ninety patients were treated with comprehensive rehabilitation, and nine cases without acupuncture were arranged into a control group. Eighty-one patients of orthogonal design were applied by acupuncture with the same acupoints and course. The VAS score and its weighted value were regarded as the observation indices,and the effects between the acupuncture group and the control group were compared. The optimal plans of acupuncture manipulations of the early stage and the later stage were chosen after the first course treatment and the third course treatment separately. The acupuncture depth (factor A:A: shallow depth less than 25 mm, A(II): modest depth 25-40 mm, A(III): deep depth 40-50 mm), the acupuncture angle (factor B:B(I): perpendicular insertion, B(II): horizontal insertion, B(III): oblique insertion), needle manipulated frequency (factor C: C(I): zero time, C(II): one time, C(III): three times) and needle retained time(factor D:D(I):20 min, D(II): 30 min, D(III): 60 min) were studied. The differences among all factors and the diversity among major factors at different stages were analyzed. (1) Acupuncture combined with rehabilitation at the early and the later stage acquired better improvement than simple rehabilitation (all P < 0.01). (2) The optimal acupuncture manipulation plan at the early stage was A(III) B(III) C(I) D(I), which was deep acupuncture and oblique insertion for 20 min with zero-time manipulation; the optimal acupuncture manipulation plan at the later stage was A(III) B(III) C(III) D(I), which was deep acupuncture and oblique insertion for 20 min with three-time manipulation. (3) There was significance for acupuncture depth and angle at the early stage (both P < 0.01) and there was significance for insertion depth

  5. Real-space Wigner-Seitz Cells Imaging of Potassium on Graphite via Elastic Atomic Manipulation

    PubMed Central

    Yin, Feng; Koskinen, Pekka; Kulju, Sampo; Akola, Jaakko; Palmer, Richard E.

    2015-01-01

    Atomic manipulation in the scanning tunnelling microscopy, conventionally a tool to build nanostructures one atom at a time, is here employed to enable the atomic-scale imaging of a model low-dimensional system. Specifically, we use low-temperature STM to investigate an ultra thin film (4 atomic layers) of potassium created by epitaxial growth on a graphite substrate. The STM images display an unexpected honeycomb feature, which corresponds to a real-space visualization of the Wigner-Seitz cells of the close-packed surface K atoms. Density functional simulations indicate that this behaviour arises from the elastic, tip-induced vertical manipulation of potassium atoms during imaging, i.e. elastic atomic manipulation, and reflects the ultrasoft properties of the surface under strain. The method may be generally applicable to other soft e.g. molecular or biomolecular systems. PMID:25651973

  6. Mediation of wound-related Rous sarcoma virus tumorigenesis by TFG (transforming growth factor)-. beta

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sieweke, M.H.; Bissell, M.J.; Thompson, N.L.

    1990-06-29

    In Rous sarcoma virus (RSV)-infected chickens, wounding leads to tumor formation with nearly 100% frequency in tissues that would otherwise remain tumor-free. Identifying molecular mediators of this phenomenon should yield important clues to the mechanisms involved in RSV tumorigenesis. Immunohistochemical staining showed that TGF-{beta} is present locally shortly after wounding, but not in unwounded controls. In addition, subcutaneous administration of recombinant transforming growth factor {beta}1 (TGF-{beta}1) could substitute completely for wounding in tumor induction. A treatment protocol of four doses of 800 nanograms of TGF-{beta} resulted in v-src-expressing tumors with 100% frequency; four doses of only 10 nanograms still ledmore » to tumor formation in 80% of the animals. This effect was specific, as other growth factors with suggested roles in would healing did not elicit the same response. Epidermal growth factor (EGF) or TGF-{alpha} had no effect, and platelet-derived growth factor (PDGF) or insulin-like growth factor-1 (IGF-1) yielded only occasional tumors after longer latency. TGF-{beta} release during the would-healing response may thus be a critical event that creates a conducive environment for RSV tumorigenesis and may act as a cofactor for transformation in this system. 31 refs., 3 figs., 2 tabs.« less

  7. Promotion of human early embryonic development and blastocyst outgrowth in vitro using autocrine/paracrine growth factors.

    PubMed

    Kawamura, Kazuhiro; Chen, Yuan; Shu, Yimin; Cheng, Yuan; Qiao, Jie; Behr, Barry; Pera, Renee A Reijo; Hsueh, Aaron J W

    2012-01-01

    Studies using animal models demonstrated the importance of autocrine/paracrine factors secreted by preimplantation embryos and reproductive tracts for embryonic development and implantation. Although in vitro fertilization-embryo transfer (IVF-ET) is an established procedure, there is no evidence that present culture conditions are optimal for human early embryonic development. In this study, key polypeptide ligands known to be important for early embryonic development in animal models were tested for their ability to improve human early embryo development and blastocyst outgrowth in vitro. We confirmed the expression of key ligand/receptor pairs in cleavage embryos derived from discarded human tri-pronuclear zygotes and in human endometrium. Combined treatment with key embryonic growth factors (brain-derived neurotrophic factor, colony-stimulating factor, epidermal growth factor, granulocyte macrophage colony-stimulating factor, insulin-like growth factor-1, glial cell-line derived neurotrophic factor, and artemin) in serum-free media promoted >2.5-fold the development of tri-pronuclear zygotes to blastocysts. For normally fertilized embryos, day 3 surplus embryos cultured individually with the key growth factors showed >3-fold increases in the development of 6-8 cell stage embryos to blastocysts and >7-fold increase in the proportion of high quality blastocysts based on Gardner's criteria. Growth factor treatment also led to a 2-fold promotion of blastocyst outgrowth in vitro when day 7 surplus hatching blastocysts were used. When failed-to-be-fertilized oocytes were used to perform somatic cell nuclear transfer (SCNT) using fibroblasts as donor karyoplasts, inclusion of growth factors increased the progression of reconstructed SCNT embryos to >4-cell stage embryos. Growth factor supplementation of serum-free cultures could promote optimal early embryonic development and implantation in IVF-ET and SCNT procedures. This approach is valuable for infertility

  8. Diminished survival of human cytotrophoblast cells exposed to hypoxia/reoxygenation injury and associated reduction of heparin-binding epidermal growth factor-like growth factor.

    PubMed

    Leach, Richard E; Kilburn, Brian A; Petkova, Anelia; Romero, Roberto; Armant, D Randall

    2008-04-01

    The antiapoptotic action of heparin-binding epidermal growth factor (HBEGF)-like growth factor and its regulation by O(2) constitutes a key factor for trophoblast survival. The hypothesis that cytotrophoblast survival is compromised by exposure to hypoxia-reoxygenation (H/R) injury, which may contribute to preeclampsia and some missed abortions, prompted us to investigate HBEGF regulation and its role as a survival factor during H/R in cytotrophoblast cells. A transformed human first-trimester cytotrophoblast cell line HTR-8/SVneo was exposed to H/R (2% O(2) followed by 20% O(2)) and assessed for HBEGF expression and cell death. Cellular HBEGF declined significantly within 30 minutes of reoxygenation after culture at 2% O(2). H/R significantly reduced proliferation and increased cell death when compared with trophoblast cells cultured continuously at 2% or 20% O(2). Restoration of cell survival also was achieved by adding recombinant HBEGF during reoxygenation. HBEGF inhibited apoptosis through its binding to either human epidermal receptor (HER)-1 or HER4, its cognate receptors. These results provide evidence that cytotrophoblast exposure to H/R induces apoptosis and decreased cell proliferation. HBEGF accumulation is diminished under these conditions, whereas restoration of HBEGF signaling improves trophoblast survival.

  9. Inhibitory effects of hepatocyte growth factor and interleukin-6 on transforming growth factor-beta1 mediated vocal fold fibroblast-myofibroblast differentiation.

    PubMed

    Vyas, Bimal; Ishikawa, Keiko; Duflo, Suzy; Chen, Xia; Thibeault, Susan L

    2010-05-01

    The role of myofibroblasts in vocal fold scarring has not been extensively studied, partly because of the lack of a robust in vitro model. The objective of this investigation was to develop and characterize a myofibroblast in vitro model that could be utilized to investigate the molecular mechanism of myofibroblast differentiation and function in injured vocal fold tissue. Differentiation of human primary vocal fold fibroblasts (hVFFs) to myofibroblasts was stimulated with 5, 10, or 20 ng/mL of recombinant transforming growth factor-beta1 (TGF-beta1). Cultures were analyzed by immunofluorescence and Western blotting, with an alpha-smooth muscle actin (alpha-SMA) antibody used as a myofibroblast marker. Normal rabbit vocal folds were treated with 10 ng/mL of TGF-beta1 for 7 days for in vivo corroboration. The effects of interleukin-6 (IL-6) and hepatocyte growth factor (HGF) on myofibroblast differentiation were studied with Western blots. The hVFFs demonstrated positive alpha-SMA labeling in cells stimulated by 10 and 20 ng/mL TGF-beta1, indicating that hVFFs were capable of differentiation to myofibroblasts. Transforming growth factor-beta1 induced the largest increase in alpha-SMA at 10 ng/mL on day 5 of treatment. Both HGF and IL-6 suppressed the expression of TGF-beta1-induced alpha-SMA. Our work characterizes a useful in vitro model of TGF-beta1-mediated vocal fold fibroblast-myofibroblast differentiation. The extent of differentiation appears to be attenuated by HGF, suggesting a potential mechanism to support prior work indicating that HGF plays a protective role in reducing scar formation in vocal fold injuries. Paradoxically, IL-6, which has been shown to play a profibrotic role in dermal studies, also attenuated the TGF-beta1 response.

  10. Diversification of the insulin-like growth factor 1 gene in mammals.

    PubMed

    Rotwein, Peter

    2017-01-01

    Insulin-like growth factor 1 (IGF1), a small, secreted peptide growth factor, is involved in a variety of physiological and patho-physiological processes, including somatic growth, tissue repair, and metabolism of carbohydrates, proteins, and lipids. IGF1 gene expression appears to be controlled by several different signaling cascades in the few species in which it has been evaluated, with growth hormone playing a major role by activating a pathway involving the Stat5b transcription factor. Here, genes encoding IGF1 have been evaluated in 25 different mammalian species representing 15 different orders and ranging over ~180 million years of evolutionary diversification. Parts of the IGF1 gene have been fairly well conserved. Like rat Igf1 and human IGF1, 21 of 23 other genes are composed of 6 exons and 5 introns, and all 23 also contain recognizable tandem promoters, each with a unique leader exon. Exon and intron lengths are similar in most species, and DNA sequence conservation is moderately high in orthologous exons and proximal promoter regions. In contrast, putative growth hormone-activated Stat5b-binding enhancers found in analogous locations in rodent Igf1 and in human IGF1 loci, have undergone substantial variation in other mammals, and a processed retro-transposed IGF1 pseudogene is found in the sloth locus, but not in other mammalian genomes. Taken together, the fairly high level of organizational and nucleotide sequence similarity in the IGF1 gene among these 25 species supports the contention that some common regulatory pathways had existed prior to the beginning of mammalian speciation.

  11. Manipulation strategies for massive space payloads

    NASA Technical Reports Server (NTRS)

    Book, Wayne J.

    1991-01-01

    Motion planning and control for the joints of flexible manipulators are discussed. Specific topics covered include control of a flexible braced manipulator, control of a small working robot on a large flexible manipulator to suppress vibrations, control strategies for ensuring cooperation among disparate manipulators, and motion planning for robots in free-fall.

  12. ACTINOMYCES NEUII ENDOPHTHALMITIS AFTER INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTION.

    PubMed

    Sahni, Sakshi; Watson, Randee Miller; Sheth, Veeral S

    2017-01-01

    To describe a case of acute endophthalmitis caused by Actinomyces neuii after intravitreal anti-vascular endothelial growth factor injection. Observational case report, review of published literature. A 67-year-old white man with wet age-related macular degeneration developed endophthalmitis secondary to A. neuii on the 10th day after intravitreal anti-vascular endothelial growth factor injection. Both anterior chamber and vitreous cultures were positive for A. neuii. He was treated successfully with intravitreal injection of vancomycin and ceftazidime. This is the first published report of culture-positive endophthalmitis caused by A. neuii after intravitreal injection.

  13. Direct Manipulation in Virtual Reality

    NASA Technical Reports Server (NTRS)

    Bryson, Steve

    2003-01-01

    Virtual Reality interfaces offer several advantages for scientific visualization such as the ability to perceive three-dimensional data structures in a natural way. The focus of this chapter is direct manipulation, the ability for a user in virtual reality to control objects in the virtual environment in a direct and natural way, much as objects are manipulated in the real world. Direct manipulation provides many advantages for the exploration of complex, multi-dimensional data sets, by allowing the investigator the ability to intuitively explore the data environment. Because direct manipulation is essentially a control interface, it is better suited for the exploration and analysis of a data set than for the publishing or communication of features found in that data set. Thus direct manipulation is most relevant to the analysis of complex data that fills a volume of three-dimensional space, such as a fluid flow data set. Direct manipulation allows the intuitive exploration of that data, which facilitates the discovery of data features that would be difficult to find using more conventional visualization methods. Using a direct manipulation interface in virtual reality, an investigator can, for example, move a data probe about in space, watching the results and getting a sense of how the data varies within its spatial volume.

  14. Role of fibroblast growth factor receptor signaling in kidney development.

    PubMed

    Bates, Carlton M

    2007-03-01

    Fibroblast growth factor receptors (Fgfrs) are expressed in the ureteric bud and metanephric mesenchyme of the developing kidney. Furthermore, in vitro and in vivo studies have shown that exogenous fibroblast growth factors (Fgfs) increase growth and maturation of the metanephric mesenchyme and ureteric bud. Deletion of fgf7, fgf10, and fgfr2IIIb (the receptor isoform that binds Fgf7 and Fgf10) in mice lead to smaller kidneys with fewer collecting ducts and nephrons. Overexpression of a dominant negative receptor isoform in transgenic mice has revealed more striking defects including renal aplasia or severe dysplasia. Moreover, deletion of many fgf ligands and receptors in mice results in early embryonic lethality, making it difficult to determine their roles in kidney development. Recently, conditional targeting approaches revealed that deletion of fgf8 from the metanephric mesenchyme interrupts nephron formation. Furthermore, deletion of fgfr2 from the ureteric bud resulted in both ureteric bud branching and stromal mesenchymal patterning defects. Deletion of both fgfr1 and fgfr2 in the metanephric mesenchyme resulted in renal aplasia, characterized by defects in metanephric mesenchyme formation and initial ureteric bud elongation and branching. Thus, Fgfr signaling is critical for growth and patterning of all renal lineages at early and later stages of kidney development.

  15. Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of uterine leiomyomata.

    PubMed

    Sozen, Ibrahim; Arici, Aydin

    2002-07-01

    To review the available information regarding the role of cytokines, growth factors, and the extracellular matrix in the pathophysiology of uterine leiomyomata and to integrate this information in a suggested model of disease at the cellular level. A thorough literature and MEDLINE search was conducted to identify the relevant studies in the English literature published between January, 1966 and October, 2001. A model of disease at the cellular level was developed using the most likely cytokines to be involved in the pathogenesis of leiomyomata as determined by our assessment of the available literature. A number of cytokines and growth factors, including transforming growth factor-beta (TGF-beta), epidermal growth factor, monocyte chemotactic protein-1, insulin-like growth factors 1 and 2, prolactin, parathyroid-hormone-related peptide, basic fibroblast growth factor, platelet-derived growth factor, interleukin-8, and endothelin, have been investigated in myometrium and leiomyoma. Among these cytokines, TGF-beta appears to be the only growth factor that has been shown to be overexpressed in leiomyoma vs. myometrium, be hormonally-regulated both in vivo and in vitro, and be both mitogenic and fibrogenic in these tissues. In addition to the cytokines, extracellular matrix components such as collagen, fibronectin, proteoglycans, matrix metalloproteinases, and tissue inhibitors of metalloproteinases seem to play pivotal roles in the pathogenesis of leiomyomata. We believe that, given the extent and depth of the current research on the cellular biology of leiomyomata, the cellular mechanisms responsible in the pathogenesis of leiomyomata will be identified clearly within the foreseeable future. This will enable researchers to develop therapy directed against the molecules and mechanisms at the cellular level.

  16. Assessment of insulin-like growth factor-1 (IGF-I) level in patients with rheumatic mitral stenosis.

    PubMed

    Deveci, Onur S; Yavuz, Bunyamin; Sen, Omer; Deniz, Ali; Ozkan, Selcuk; Dal, Kursat; Ata, Naim; Baser, Salih; Akin, Kadir O; Kucukazman, Metin; Beyan, Esin; Ertugrul, Derun T

    2015-03-01

    Insulin-like growth factor-1 may serve some regulatory function in the immune system. Rheumatic mitral stenosis is related to autoimmune heart valve damage after streptococcal infection. The aim of this study was to assess the level of insulin-like growth factor-1 and its correlation with the Wilkins score in patients with rheumatic mitral stenosis. A total of 65 patients with rheumatic mitral stenosis and 62 age- and sex-matched control subjects were enrolled in this study. All subjects underwent transthoracic echocardiography. The mitral valve area and Wilkins score were evaluated for all patients. Biochemical parameters and serum insulin-like growth factor-1 levels were measured. Demographic data were similar in the rheumatic mitral stenosis and control groups. The mean mitral valve area was 1.6±0.4 cm2 in the rheumatic mitral stenosis group. The level of insulin-like growth factor-1 was significantly higher in the rheumatic mitral stenosis group than in the control group (104 (55.6-267) versus 79.1 (23.0-244.0) ng/ml; p=0.039). There was a significant moderate positive correlation between insulin-like growth factor-1 and thickening of leaflets score of Wilkins (r=0.541, p<0.001). The present study demonstrated that serum insulin-like growth factor-1 levels were significantly higher in the rheumatic mitral stenosis group compared with control subjects and that insulin-like growth factor-1 level was also correlated with the Wilkins score. It can be suggested that there may be a link between insulin-like growth factor-1 level and immune pathogenesis of rheumatic mitral stenosis.

  17. Insulin-like growth factor I gene deletion causing intrauterine growth retardation and severe short stature.

    PubMed

    Woods, K A; Camacho-Hübner, C; Barter, D; Clark, A J; Savage, M O

    1997-11-01

    The first human case of a homozygous molecular defect in the gene encoding insulin-like growth factor I (IGF-I) is described. The patient was a 15-year-old boy from a consanguineous pedigree who presented with severe intrauterine growth failure, sensorineural deafness and mild mental retardation. Endocrine evaluation of the growth hormone (GH)--IGF-I axis revealed elevated GH secretion, undetectable serum IGF-I and normal serum IGF-binding protein-3, acid-labile subunit, and GH-binding activity. Analysis of the IGF-I gene revealed a homozygous partial IGF-I gene deletion involving exons 4 and 5, which encodes a severely truncated mature IGF-I peptide. This patient demonstrates that complete disruption of the IGF-I gene in man is compatible with life, and indicates a major role for IGF-I in human fetal growth. In addition, his neurological abnormalities suggest that IGF-I may be involved in central nervous system development.

  18. The diagnostic value of plasma N-terminal connective tissue growth factor levels in children with heart failure.

    PubMed

    Li, Gang; Song, Xueqing; Xia, Jiyi; Li, Jing; Jia, Peng; Chen, Pengyuan; Zhao, Jian; Liu, Bin

    2017-01-01

    The aim of this study was to assess the diagnostic value of plasma N-terminal connective tissue growth factor in children with heart failure. Methods and results Plasma N-terminal connective tissue growth factor was determined in 61 children, including 41 children with heart failure, 20 children without heart failure, and 30 healthy volunteers. The correlations between plasma N-terminal connective tissue growth factor levels and clinical parameters were investigated. Moreover, the diagnostic value of N-terminal connective tissue growth factor levels was evaluated. Compared with healthy volunteers and children without heart failure, plasma N-terminal connective tissue growth factor levels were significantly elevated in those with heart failure (p0.05), but it obviously improved the ability of diagnosing heart failure in children, as demonstrated by the integrated discrimination improvement (6.2%, p=0.013) and net re-classification improvement (13.2%, p=0.017) indices. Plasma N-terminal connective tissue growth factor is a promising diagnostic biomarker for heart failure in children.

  19. Kisspeptin regulates the somatic growth-related factors of the cinnamon clownfish Amphiprion melanopus.

    PubMed

    Kim, Na Na; Choi, Young-Ung; Park, Heung-Sik; Choi, Cheol Young

    2015-01-01

    This study aimed to test the effects of kisspeptin (Kiss) on somatic growth in the cinnamon clownfish Amphiprion melanopus. We investigated the effects of Kiss treatment on the growth by measuring the mRNA expressions of the growth hormone (GH), insulin-like growth hormone factor (IGF-I), somatolactin (SL), and melatonin receptor (MT). The expression levels of GH and SL of the pituitary gland and IGF-I of the liver increased after Kiss treatment (in vivo and in vitro). In addition, the MT mRNA expression increased in the pituitary gland and brain after Kiss treatment (in vivo and in vitro). These results support the hypothesis that Kiss directly regulates the somatic growth-related factors, such as GH, SL, and MT, and IGF-I in the cinnamon clownfish. Further, injection of Kiss resulted in significantly higher levels of plasma melatonin than that in the control. We, therefore, conclude that Kiss plays a role in modulating growth and artificially induced rapid growth in cinnamon clownfish. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Cropping practices manipulate abundance patterns of root and soil microbiome members paving the way to smart farming.

    PubMed

    Hartman, Kyle; van der Heijden, Marcel G A; Wittwer, Raphaël A; Banerjee, Samiran; Walser, Jean-Claude; Schlaeppi, Klaus

    2018-01-16

    Harnessing beneficial microbes presents a promising strategy to optimize plant growth and agricultural sustainability. Little is known to which extent and how specifically soil and plant microbiomes can be manipulated through different cropping practices. Here, we investigated soil and wheat root microbial communities in a cropping system experiment consisting of conventional and organic managements, both with different tillage intensities. While microbial richness was marginally affected, we found pronounced cropping effects on community composition, which were specific for the respective microbiomes. Soil bacterial communities were primarily structured by tillage, whereas soil fungal communities responded mainly to management type with additional effects by tillage. In roots, management type was also the driving factor for bacteria but not for fungi, which were generally determined by changes in tillage intensity. To quantify an "effect size" for microbiota manipulation, we found that about 10% of variation in microbial communities was explained by the tested cropping practices. Cropping sensitive microbes were taxonomically diverse, and they responded in guilds of taxa to the specific practices. These microbes also included frequent community members or members co-occurring with many other microbes in the community, suggesting that cropping practices may allow manipulation of influential community members. Understanding the abundance patterns of cropping sensitive microbes presents the basis towards developing microbiota management strategies for smart farming. For future targeted microbiota management-e.g., to foster certain microbes with specific agricultural practices-a next step will be to identify the functional traits of the cropping sensitive microbes.

  1. High altitude hypoxia as a factor that promotes tibial growth plate development in broiler chickens

    PubMed Central

    Huang, Shucheng; Zhang, Lihong; Rehman, Mujeeb Ur; Iqbal, Muhammad Kashif; Lan, Yanfang; Mehmood, Khalid; Zhang, Hui; Qiu, Gang; Nabi, Fazul; Yao, Wangyuan; Wang, Meng; Li, Jiakui

    2017-01-01

    Tibial dyschondroplasia (TD) is one of the most common problems in the poultry industry and leads to lameness by affecting the proximal growth plate of the tibia. However, due to the unique environmental and geographical conditions of Tibet, no case of TD has been reported in Tibetan chickens (TBCs). The present study was designed to investigate the effect of high altitude hypoxia on blood parameters and tibial growth plate development in chickens using the complete blood count, morphology, and histological examination. The results of this study showed an undesirable impact on the overall performance, body weight, and mortality of Arbor Acres chickens (AACs) exposed to a high altitude hypoxic environment. However, AACs raised under hypoxic conditions showed an elevated number of red blood cells (RBCs) and an increase in hemoglobin and hematocrit values on day 14 compared to the hypobaric normoxia group. Notably, the morphology and histology analyses showed that the size of tibial growth plates in AACs was enlarged and that the blood vessel density was also higher after exposure to the hypoxic environment for 14 days, while no such change was observed in TBCs. Altogether, our results revealed that the hypoxic environment has a potentially new role in increasing the blood vessel density of proximal tibial growth plates to strengthen and enhance the size of the growth plates, which may provide new insights for the therapeutic manipulation of hypoxia in poultry TD. PMID:28282429

  2. Control of a flexible bracing manipulator: Integration of current research work to realize the bracing manipulator

    NASA Technical Reports Server (NTRS)

    Kwon, Dong-Soo

    1991-01-01

    All research results about flexible manipulator control were integrated to show a control scenario of a bracing manipulator. First, dynamic analysis of a flexible manipulator was done for modeling. Second, from the dynamic model, the inverse dynamic equation was derived, and the time domain inverse dynamic method was proposed for the calculation of the feedforward torque and the desired flexible coordinate trajectories. Third, a tracking controller was designed by combining the inverse dynamic feedforward control with the joint feedback control. The control scheme was applied to the tip position control of a single link flexible manipulator for zero and non-zero initial condition cases. Finally, the contact control scheme was added to the position tracking control. A control scenario of a bracing manipulator is provided and evaluated through simulation and experiment on a single link flexible manipulator.

  3. The in vitro release of cytokines and growth factors from fibrin membranes produced through horizontal centrifugation.

    PubMed

    Lourenço, Emanuelle Stellet; Mourão, Carlos Fernando de Almeida Barros; Leite, Paulo Emílio Corrêa; Granjeiro, José Mauro; Calasans-Maia, Mônica Diuana; Alves, Gutemberg Gomes

    2018-05-01

    Platelet-rich fibrin membranes are biomaterials widely used for therapeutic purposes, and canonically produced through the processing of peripheral blood with fixed-angle rotor centrifuges. In this work, we evaluate the in vitro stability and release of cytokines and growth factors when these biomaterials are produced with a horizontal swing-out clinical centrifuge. Membranes produced from the blood of 14 donors were morphologically evaluated by scanning electron microscopy and fluorescence microscopy, and their stability was assessed by photographic recording after incubation in culture medium for up to 28 days. The release of 27 cytokines and growth factors was monitored for three weeks through a multiparametric immunoassay. The fibrin membranes presented complex three-dimensional structure with a high density of nucleated cells. A large release of growth factors [platelet derived growth factor, fibroblastic growth factor (bFGF), and vascular endothelial growth factor] was detected in the first 24 h, followed by time-dependent decay, maintaining significant concentrations after three weeks. Both anti-inflammatory and pro-inflammatory cytokines presented different release peaks, maintaining high rates of elution for up to 21 days. Chemokines of relevance in tissue repair [RANTES, granulocyte colony-stimulating factor (G-CSF)] were also produced in large quantities throughout the experimental period. The present results demonstrate that blood-derived fibrin membranes with high structural stability and cell content can be generated by horizontal centrifugation, being able of a prolonged production/release of growth factors and pro- and anti-inflammatory cytokines. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1373-1380, 2018. © 2018 Wiley Periodicals, Inc.

  4. Role of fibroblast growth factor receptor signaling in kidney development.

    PubMed

    Bates, Carlton M

    2011-08-01

    Fibroblast growth factor receptors (Fgfrs) consist of four signaling family members and one nonsignaling "decoy" receptor, Fgfr-like 1 (Fgfrl1), all of which are expressed in the developing kidney. Several studies have shown that exogenous fibroblast growth factors (Fgfs) affect growth and maturation of the metanephric mesenchyme (MM) and ureteric bud (UB) in cultured tissues. Transgenic and conditional knockout approaches in whole animals have shown that Fgfr1 and Fgfr2 (predominantly the IIIc isoform) in kidney mesenchyme are critical for early MM and UB formation. Conditional deletion of the ligand, Fgf8, in nephron precursors or global deletion of Fgfrl1 interrupts nephron formation. Fgfr2 (likely the IIIb isoform signaling downstream of Fgf7 and Fgf10) is critical for ureteric morphogenesis. Moreover, Fgfr2 appears to act independently of Frs2α (the major signaling adapter for Fgfrs) in regulating UB branching. Loss of Fgfr2 in the MM leads to many kidney and urinary tract anomalies, including vesicoureteral reflux. Thus Fgfr signaling is critical for patterning of virtually all renal lineages at early and later stages of development.

  5. Plant defences limit herbivore population growth by changing predator-prey interactions.

    PubMed

    Kersch-Becker, Mônica F; Kessler, André; Thaler, Jennifer S

    2017-09-13

    Plant quality and predators are important factors affecting herbivore population growth, but how they interact to regulate herbivore populations is not well understood. We manipulated jasmonate-induced plant resistance, exposure to the natural predator community and herbivore density to test how these factors jointly and independently affect herbivore population growth. On low-resistance plants, the predator community was diverse and abundant, promoting high predator consumption rates. On high-resistance plants, the predator community was less diverse and abundant, resulting in low predator consumption rate. Plant resistance only directly regulated aphid population growth on predator-excluded plants. When predators were present, plant resistance indirectly regulated herbivore population growth by changing the impact of predators on the herbivorous prey. A possible mechanism for the interaction between plant resistance and predation is that methyl salicylate, a herbivore-induced plant volatile attractive to predators, was more strongly induced in low-resistance plants. Increased plant resistance reduced predator attractant lures, preventing predators from locating their prey. Low-resistance plants may regulate herbivore populations via predators by providing reliable information on prey availability and increasing the effectiveness of predators. © 2017 The Author(s).

  6. Trajectories of physical growth and personality dimensions of the Five-Factor Model.

    PubMed

    Lahti, Marius; Räikkönen, Katri; Lemola, Sakari; Lahti, Jari; Heinonen, Kati; Kajantie, Eero; Pesonen, Anu-Katriina; Osmond, Clive; Barker, David J P; Eriksson, Johan G

    2013-07-01

    Although physical growth in early life is associated with the risk of somatic illnesses and psychological disorders in adulthood, few studies have focused upon the associations between growth and dimensional personality traits. We examined the associations between pre- and postnatal growth in height, weight, and body mass index (BMI) and Five-Factor Model dimensions in adulthood. From the Helsinki Birth Cohort Study, 1,682 participants completed the NEO Personality Inventory (NEO-PI) at an average age of 63 years. Growth estimates were derived based on medical records. Adjusting for gestational length and sociodemographic variables, birth weight showed a quadratic association with neuroticism; participants with low birth weight scored the highest on neuroticism. Larger ponderal index at birth predicted higher agreeableness, while average ponderal index predicted higher conscientiousness. BMI and weight growth trajectories from birth to adulthood were associated with agreeableness and conscientiousness. More specifically, less BMI and weight gain between 7 and 11 years and/or between 11 years and adulthood were associated with higher conscientiousness and higher agreeableness. Height and weight growth trajectories from birth to adulthood were associated with extraversion: faster height and weight growth between birth and 6 months, slower height growth between 7 and 11 years, and faster weight gain between 11 years and adulthood were associated with higher extraversion. Openness to experience was not associated with growth. This longitudinal study supports an association between pre- and postnatal physical growth and 4 of the Five-Factor Model personality dimensions in adulthood. PsycINFO Database Record (c) 2013 APA, all rights reserved.

  7. Delivering heparin-binding insulin-like growth factor 1 with self-assembling peptide hydrogels.

    PubMed

    Florine, Emily M; Miller, Rachel E; Liebesny, Paul H; Mroszczyk, Keri A; Lee, Richard T; Patwari, Parth; Grodzinsky, Alan J

    2015-02-01

    Heparin-binding insulin-like growth factor 1 (HB-IGF-1) is a fusion protein of IGF-1 with the HB domain of heparin-binding epidermal growth factor-like growth factor. A single dose of HB-IGF-1 has been shown to bind specifically to cartilage and to promote sustained upregulation of proteoglycan synthesis in cartilage explants. Achieving strong integration between native cartilage and tissue-engineered cartilage remains challenging. We hypothesize that if a growth factor delivered by the tissue engineering scaffold could stimulate enhanced matrix synthesis by both the cells within the scaffold and the adjacent native cartilage, integration could be enhanced. In this work, we investigated methods for adsorbing HB-IGF-1 to self-assembling peptide hydrogels to deliver the growth factor to encapsulated chondrocytes and cartilage explants cultured with growth factor-loaded hydrogels. We tested multiple methods for adsorbing HB-IGF-1 in self-assembling peptide hydrogels, including adsorption prior to peptide assembly, following peptide assembly, and with/without heparan sulfate (HS, a potential linker between peptide molecules and HB-IGF-1). We found that HB-IGF-1 and HS were retained in the peptide for all tested conditions. A subset of these conditions was then studied for their ability to stimulate increased matrix production by gel-encapsulated chondrocytes and by chondrocytes within adjacent native cartilage. Adsorbing HB-IGF-1 or IGF-1 prior to peptide assembly was found to stimulate increased sulfated glycosaminoglycan per DNA and hydroxyproline content of chondrocyte-seeded hydrogels compared with basal controls at day 10. Cartilage explants cultured adjacent to functionalized hydrogels had increased proteoglycan synthesis at day 10 when HB-IGF-1 was adsorbed, but not IGF-1. We conclude that delivery of HB-IGF-1 to focal defects in cartilage using self-assembling peptide hydrogels is a promising technique that could aid cartilage repair via enhanced matrix

  8. Bradykinin-induced growth inhibition of normal rat kidney (NRK) cells is paralleled by a decrease in epidermal-growth-factor receptor expression.

    PubMed Central

    Van Zoelen, E J; Peters, P H; Afink, G B; Van Genesen, S; De Roos, D G; Van Rotterdam, W; Theuvenet, A P

    1994-01-01

    Normal rat kidney fibroblasts, grown to density arrest in the presence of epidermal growth factor (EGF), can be induced to undergo phenotypic transformation by treatment with transforming growth factor beta or retinoic acid. Here we show that bradykinin blocks this growth-stimulus-induced loss of density-dependent growth arrest by a specific receptor-mediated mechanism. The effects of bradykinin are specific, and are not mimicked by other phosphoinositide-mobilizing agents such as prostaglandin F2 alpha. Northern-blot analysis and receptor-binding studies demonstrate that bradykinin also inhibits the retinoic acid-induced increase in EGF receptor levels in these cells. These studies provide additional evidence that EGF receptor levels modulate EGF-induced expression of the transformed phenotype in these cells. Images Figure 5 PMID:8135739

  9. Response to Growth Hormone Treatment in a Patient with Insulin-Like Growth Factor 1 Receptor Deletion

    PubMed Central

    Mahmoud, Ranim; Naidu, Ajanta; Risheg, Hiba; Kimonis, Virginia

    2017-01-01

    We report a six-year-old boy who presented with short stature, microcephaly, dysmorphic features, and developmental delay and who was identified with a terminal deletion of 15q26.2q26.3 containing the insulin-like growth factor receptor (IGF1R) gene in addition to a terminal duplication of the 4q35.1q35.2 region. We compare our case with other reports of deletions and mutations affecting the IGF1R gene associated with pre-and postnatal growth restriction. We report the dramatic response to growth hormone therapy in this patient which highlights the importance of identifying patients with IGF1R deletion and treating them early. PMID:28720553

  10. Response to Growth Hormone Treatment in a Patient with Insulin-Like Growth Factor 1 Receptor Deletion.

    PubMed

    Mahmoud, Ranim; Naidu, Ajanta; Risheg, Hiba; Kimonis, Virginia

    2017-12-15

    We report a six-year-old boy who presented with short stature, microcephaly, dysmorphic features, and developmental delay and who was identified with a terminal deletion of 15q26.2q26.3 containing the insulin-like growth factor receptor (IGF1R) gene in addition to a terminal duplication of the 4q35.1q35.2 region. We compare our case with other reports of deletions and mutations affecting the IGF1R gene associated with pre-and postnatal growth restriction. We report the dramatic response to growth hormone therapy in this patient which highlights the importance of identifying patients with IGF1R deletion and treating them early.

  11. Genetic and environmental factors in associations between infant growth and adult cardiometabolic risk profile in twins.

    PubMed

    Touwslager, Robbert N H; Gielen, Marij; Mulder, Antonius L M; Gerver, Willem J M; Zimmermann, Luc J; Dagnelie, Pieter C; Houben, Alfons J H M; Stehouwer, Coen D A; Derom, Catherine; Vlietinck, Robert; Loos, Ruth J F; Zeegers, Maurice P

    2013-10-01

    Accelerated infant growth is associated with an altered, mostly adverse adult cardiometabolic risk profile. The importance of genetic and environmental factors to these associations is unclear. The objective was to examine the importance of genetic and environmental factors in the associations between infant growth and adult cardiometabolic risk factors (anthropometric characteristics, lipids, insulin sensitivity, leptin, blood pressure, and fibrinogen) in twins. Cardiometabolic risk factors were assessed in 240 twin pairs (aged 18-34 y) from the East Flanders Prospective Twin Survey. Infant growth was defined as change in weight z score. We regressed intrapair differences in growth during 4 growth windows (0-1, 1-6, 6-12, and 12-24 mo) against intrapair differences in the risk factors in monozygotic and dizygotic twins separately. Within monozygotic twin pairs only, associations between infant growth and most adult lipids, glucose, leptin, and blood pressure (eg, systolic blood pressure: b = 5.95 mm Hg per change in z score, P = 0.01 in monozygotic twins; b = -1.64, P = 0.82 in dizygotic twins from 12 to 24 mo) were found. Within dizygotic twin pairs only, associations between growth and triglycerides and fibrinogen (eg, fibrinogen: b = 0.07 ln mg/dL per change in z score, P = 0.31 in monozygotic twins; b = 0.79, P = 0.01 in dizygotic twins from 0 to 1 mo) were identified. Most associations showed a detrimental effect of accelerated growth, but beneficial associations were also identified (eg, total-to-high-density-lipoprotein cholesterol ratio: b = -0.22 per change in z score from 1 to 6 mo, P = 0.008 in monozygotic twins). Our data showed that environmental factors play a role in the associations between infant growth and most adult lipids, glucose, leptin, and blood pressure, whereas genetic factors are involved regarding triglycerides and fibrinogen.

  12. Protein deficiency and intestinal nematode infection in pregnant mice differentially impact fetal growth through specific stress hormones, growth factors, and cytokines.

    PubMed

    Starr, Lisa M; Scott, Marilyn E; Koski, Kristine G

    2015-01-01

    Protein deficiency (PD) and intestinal nematode infections commonly co-occur during pregnancy and impair fetal growth, but the complex network of signals has not been explored. Our objective was to assess those stress hormones, growth factors, and cytokines affected by maternal PD and nematode infection and associated with fetal growth. Using a 2 × 2 factorial design, CD-1 mice, fed protein-sufficient (PS; 24%) or protein-deficient (PD; 6%) isoenergetic diets, were either uninfected or infected every 5 d with Heligmosomoides bakeri, beginning on gestational day (GD) 5. Biomarker concentrations were measured on GD 18 in maternal serum (m), fetal serum (f), and amniotic fluid (af) by using Luminex. Maternal PD lowered fetal body mass (PS/uninfected 1.25 ± 0.02 g, PS/infected 1.19 ± 0.02 g vs. PD/uninfected 1.11 ± 0.02 g, PD/infected 0.97 ± 0.02 g; P = 0.02), fetal lung (P = 0.005), and liver (P = 0.003) but not brain mass, whereas maternal infection lowered fetal length (PS/uninfected 2.28 ± 0.02 cm, PD/uninfected 2.27 ± 0.03 cm vs. PS/infected 2.21 ± 0.03 cm, PD/infected 2.11 ± 0.02 cm; P = 0.05) and kidney mass (P = 0.04). PD elevated stress hormones (m-adrenocortiotropic hormone, f-corticosterone, af-corticosterone) and reduced insulin-like growth factor 1 in all compartments (P ≤ 0.01), but these were unassociated with fetal mass or length. Fetal mass was positively associated with f-leptin (R(2) = 0.71, P = 0.0001) and negatively with fetal cytokines [tumor necrosis factor-α: R(2) = 0.62, P = 0.001; interleukin-4 (IL-4): R(2) = 0.63, P = 0.0004]. In contrast, maternal infection lowered f-prolactin (P = 0.02) that was positively associated with fetal length (R(2) = 0.43; P = 0.03); no other biomarker was affected by infection. Regression analyses showed associations between organ growth, cytokines, and growth factors: 1) thymus, spleen, heart, and brain with m-IL-10; 2) brain and kidney with f-vascular endothelial growth factor, af

  13. Non-identical distribution pattern of epidermal growth factor and platelet-derived growth factor in the mouse uterus during the oestrous cycle and early pregnancy.

    PubMed

    Jaber, L; Kan, F W

    1998-10-01

    In the present study, we examined by immunohistochemistry the cell-specific distribution of epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) in the mouse uterus during the oestrous cycle and throughout the first 7 days of pregnancy. Paraffin-embedded tissue samples were immunostained using the avidin-biotin peroxidase technique and then examined by light microscopy. Our results showed that immunostaining for EGF was detected in the stroma but not in the luminal or glandular epithelium. A high concentration of EGF was detected in the stroma around the time of embryo implantation at days 3, 4 and 5 of pregnancy. The implanted embryo at day 7 of gestation showed immunostaining for EGF between the ectoderm and endoderm layers. The cell distribution pattern for PDGF was found to be different from that observed with EGF. Luminal and glandular epithelia displayed PDGF immunostaining throughout the first 7 days of pregnancy, with the highest intensity at days 4 and 5 of gestation. In contrast, no immunostaining was observed in the luminal and glandular epithelia at post-oestrus, dioestrus and pro-oestrus stages. However, a weak reaction started to appear at oestrus. The embryo at the blastocyst stage displayed a strong immunoreaction for antibody against PDGF. In addition, the decidual boundary zone surrounding the implanted embryo at days 5, 6 and 7 of gestation also showed an immunostaining for PDGF. The present observations demonstrate clearly the presence of EGF and PDGF in the mouse uterus in high concentrations at the peri-implantation period. Thus, our results, together with what is known about the effect of EGF and PDGF in controlling the growth, differentiation and activation of a variety of cell types, suggest a possible role for these growth factors during the preparation of the endometrium for implantation in controlling the proliferation activity of stromal and/or epithelial cells.

  14. Fuzzy logic control of telerobot manipulators

    NASA Technical Reports Server (NTRS)

    Franke, Ernest A.; Nedungadi, Ashok

    1992-01-01

    Telerobot systems for advanced applications will require manipulators with redundant 'degrees of freedom' (DOF) that are capable of adapting manipulator configurations to avoid obstacles while achieving the user specified goal. Conventional methods for control of manipulators (based on solution of the inverse kinematics) cannot be easily extended to these situations. Fuzzy logic control offers a possible solution to these needs. A current research program at SRI developed a fuzzy logic controller for a redundant, 4 DOF, planar manipulator. The manipulator end point trajectory can be specified by either a computer program (robot mode) or by manual input (teleoperator). The approach used expresses end-point error and the location of manipulator joints as fuzzy variables. Joint motions are determined by a fuzzy rule set without requiring solution of the inverse kinematics. Additional rules for sensor data, obstacle avoidance and preferred manipulator configuration, e.g., 'righty' or 'lefty', are easily accommodated. The procedure used to generate the fuzzy rules can be extended to higher DOF systems.

  15. Double emulsion electrospun nanofibers as a growth factor delivery vehicle for salivary gland regeneration

    NASA Astrophysics Data System (ADS)

    Foraida, Zahraa I.; Sharikova, Anna; Peerzada, Lubna N.; Khmaladze, Alexander; Larsen, Melinda; Castracane, James

    2017-08-01

    Sustained delivery of growth factors, proteins, drugs and other biologically active molecules is necessary for tissue engineering applications. Electrospun fibers are attractive tissue engineering scaffolds as they partially mimic the topography of the extracellular matrix (ECM). However, they do not provide continuous nourishment to the tissue. In search of a biomimetic scaffold for salivary gland tissue regeneration, we previously developed a blend nanofiber scaffold composed of the protein elastin and the synthetic polymer polylactic-co-glycolic acid (PLGA). The nanofiber scaffold promoted in vivo-like salivary epithelial cell tissue organization and apicobasal polarization. However, in order to enhance the salivary cell proliferation and biomimetic character of the scaffold, sustained growth factor delivery is needed. The composite nanofiber scaffold was optimized to act as a growth factor delivery system using epidermal growth factor (EGF) as a model protein. The nanofiber/EGF hybrid nanofibers were synthesized by double emulsion electrospinning where EGF is emulsified within a water/oil/water (w/o/w) double emulsion system. Successful incorporation of EGF was confirmed using Raman spectroscopy. EGF release profile was characterized using enzyme-linked immunosorbent assay (ELIZA) of the EGF content. Double emulsion electrospinning resulted in slower release of EGF. We demonstrated the potential of the proposed double emulsion electrospun nanofiber scaffold for the delivery of growth factors and/or drugs for tissue engineering and pharmaceutical applications.

  16. Immobilization of Growth Factors to Collagen Surfaces Using Pulsed Visible Light.

    PubMed

    Fernandes-Cunha, Gabriella M; Lee, Hyun Jong; Kumar, Alisha; Kreymerman, Alexander; Heilshorn, Sarah; Myung, David

    2017-10-09

    In the treatment of traumatic injuries, burns, and ulcers of the eye, inadequate epithelial tissue healing remains a major challenge. Wound healing is a complex process involving the temporal and spatial interplay between cells and their extracellular milieu. It can be impaired by a variety of causes including infection, poor circulation, loss of critical cells, and/or proteins, and a deficiency in normal neural signaling (e.g., neurotrophic ulcers). Ocular anatomy is particularly vulnerable to lasting morbidity from delayed healing, whether it be scarring or perforation of the cornea, destruction of the conjunctival mucous membrane, or cicatricial changes to the eyelids and surrounding skin. Therefore, there is a major clinical need for new modalities for controlling and accelerating wound healing, particularly in the eye. Collagen matrices have long been explored as scaffolds to support cell growth as both two-dimensional coatings and substrates, as well as three-dimensional matrices. Meanwhile, the immobilization of growth factors to various substrates has also been extensively studied as a way to promote enhanced cellular adhesion and proliferation. Herein we present a new strategy for photochemically immobilizing growth factors to collagen using riboflavin as a photosensitizer and exposure to visible light (∼458 nm). Epidermal growth factor (EGF) was successfully bound to collagen-coated surfaces as well as directly to endogenous collagen from porcine corneas. The initial concentration of riboflavin and EGF as well as the blue light exposure time were keys to the successful binding of growth factors to these surfaces. The photocrosslinking reaction increased EGF residence time on collagen surfaces over 7 days. EGF activity was maintained after the photocrosslinking reaction with a short duration of pulsed blue light exposure. Bound EGF accelerated in vitro corneal epithelial cell proliferation and migration and maintained normal cell phenotype. Additionally

  17. Growth factor and proteinase profile of Vivostat® platelet-rich fibrin linked to tissue repair.

    PubMed

    Agren, M S; Rasmussen, K; Pakkenberg, B; Jørgensen, B

    2014-07-01

    Autologous platelet-rich fibrin (PRF(®)) is prepared by the automatic Vivostat(®) system. Conflicting results with Vivostat PRF in acute wound healing prompted us to examine its cellular and biomolecular composition. Specifically, platelets, selected growth factors and matrix metalloproteinase (MMP)-9 were quantified using novel analytical methods. Ten healthy non-thrombocytopenic volunteers donated blood for generation of intermediate fibrin-I and final PRF. Anticoagulated whole blood and serum procured in parallel served as baseline controls. Leucocyte, erythrocyte and platelet counts in whole blood and fibrin-I were determined by automated haematology analyser. Platelet concentration in PRF was quantified manually by stereologic analysis of Giemsa-stained tissue sections, and the total content of five growth factors and MMP-9 by enzyme-linked immunosorbent assays. The number of leucocytes and erythrocytes was reduced (P < 0·001), whereas platelets increased (P < 0·001) in fibrin-I versus whole blood. PRF contained 982 ± 206 × 10(9) platelets/l representing 3·9-fold (P < 0·001) enrichment relative to whole blood. Growth factor abundance in Vivostat PRF and serum was in descending order: transforming growth factor-β1 [5·1-fold higher in PRF than serum, P < 0·001] > platelet-derived growth factor (PDGF)-AB [2·5-fold, P < 0·01] > PDGF-BB [1·6-fold, P < 0·05] > vascular endothelial growth factor > basic fibroblast growth factor [75-fold, P < 0·001]. MMP-9 was reduced 139-fold (P < 0·001) compared with serum, reflecting leucocyte depletion in PRF. The gained knowledge on platelet enrichment and biomolecular constituents may guide clinicians in their optimal use of Vivostat PRF for tissue regenerative applications. © 2013 International Society of Blood Transfusion.

  18. The chemokine CXCL12 mediates the anti-amyloidogenic action of painless human nerve growth factor.

    PubMed

    Capsoni, Simona; Malerba, Francesca; Carucci, Nicola Maria; Rizzi, Caterina; Criscuolo, Chiara; Origlia, Nicola; Calvello, Mariantonietta; Viegi, Alessandro; Meli, Giovanni; Cattaneo, Antonino

    2017-01-01

    Nerve growth factor is a therapeutic candidate for Alzheimer's disease. Due to its pain-inducing activity, in current clinical trials nerve growth factor is delivered locally into the brain by neurosurgery, but data on the efficacy of local nerve growth factor delivery in decreasing amyloid-β deposition are not available. To reduce the nerve growth factor pain-inducing side effects, thus avoiding the need for local brain injection, we developed human painless nerve growth factor (hNGFp), inspired by the human genetic disease hereditary sensory and autonomic neuropathy type V. hNGFp has identical neurotrophic potency as wild-type human nerve growth factor, but a 10-fold lower pain sensitizing activity. In this study we first mimicked, in the 5xFAD mouse model, the intraparenchymal delivery of hNGFp used in clinical trials and found it to be ineffective in decreasing amyloid-β plaque load. On the contrary, the same dose of hNGFp delivered intranasally, which was widely biodistributed in the brain and did not induce pain, showed a potent anti-amyloidogenic action and rescued synaptic plasticity and memory deficits. We found that hNGFp acts on glial cells, modulating inflammatory proteins such as the soluble TNFα receptor II and the chemokine CXCL12. We further established that the rescuing effect by hNGFp is mediated by CXCL12, as pharmacological inhibition of CXCL12 receptor CXCR4 occludes most of hNGFp effects. These findings have significant therapeutic implications: (i) we established that a widespread exposure of the brain is required for nerve growth factor to fully exert its neuroprotective actions; and (ii) we have identified a new anti-neurodegenerative pathway as a broad target for new therapeutic opportunities for neurodegenerative diseases. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

  19. Insulin-like growth factor-I, physical activity, and control of cellular anabolism.

    PubMed

    Nindl, Bradley C

    2010-01-01

    The underlying mechanisms responsible for mediating the beneficial outcomes of exercise undoubtedly are many, but the insulin-like growth factor-I (IGF-I) system is emerging as an important and central hormonal axis that plays a significant role concerning cellular anabolism. This introductory article summarizes the intent and the content for papers presented as part of a 2008 American College of Sports Medicine national symposium entitled "Insulin-like Growth Factor-I, Physical Activity, and Control of Cellular Anabolism." The individual authors and their papers are as follows: Jan Frystyk authoring "The relationship between exercise and the growth hormone/insulin-like growth factor-I axis," Greg Adams authoring "IGF-I signaling in skeletal muscle and the potential for cytokine interactions," and Brad Nindl authoring "Insulin-like growth factor-I as a biomarker of health, fitness, and training status." These papers focus on 1) different assay methodologies for IGF-I within the paradigm of exercise studies, 2) research demonstrating that intracellular signaling components associated with several proinflammatory cytokines have the potential to interact with anabolic signaling processes in skeletal muscle, and 3) an overview of IGF-I as a biomarker related to exercise training, muscle and bone remodeling, body composition, cognition, and cancer. When summed in total, the contribution that these papers will make will undoubtedly involve bringing attention to the vast regulatory complexity of the IGF-I system and will hopefully convince the reader that the IGF-I system warrants further detailed scientific inquiry to resolve many unanswered questions and paradoxical experimental findings. The IGF-I system remains one of the most intriguing and captivating marvels of human physiology that seems central in mediating numerous adaptations from physical activity.

  20. Regulation of gene expression by manipulating transcriptional repressor activity using a novel CoSRI technology.

    PubMed

    Xu, Yue; Li, Song Feng; Parish, Roger W

    2017-07-01

    Targeted gene manipulation is a central strategy for studying gene function and identifying related biological processes. However, a methodology for manipulating the regulatory motifs of transcription factors is lacking as these factors commonly possess multiple motifs (e.g. repression and activation motifs) which collaborate with each other to regulate multiple biological processes. We describe a novel approach designated conserved sequence-guided repressor inhibition (CoSRI) that can specifically reduce or abolish the repressive activities of transcription factors in vivo. The technology was evaluated using the chimeric MYB80-EAR transcription factor and subsequently the endogenous WUS transcription factor. The technology was employed to develop a reversible male sterility system applicable to hybrid seed production. In order to determine the capacity of the technology to regulate the activity of endogenous transcription factors, the WUS repressor was chosen. The WUS repression motif could be inhibited in vivo and the transformed plants exhibited the wus-1 phenotype. Consequently, the technology can be used to manipulate the activities of transcriptional repressor motifs regulating beneficial traits in crop plants and other eukaryotic organisms. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  1. Modeling Vascularized Bone Regeneration Within a Porous Biodegradable CaP Scaffold Loaded with Growth Factors

    PubMed Central

    Sun, X; Kang, Y; Bao, J; Zhang, Y; Yang, Y; Zhou, X

    2013-01-01

    Osteogenetic microenvironment is a complex constitution in which extracellular matrix (ECM) molecules, stem cells and growth factors each interact to direct the coordinate regulation of bone tissue development. Importantly, angiogenesis improvement and revascularization are critical for osteogenesis during bone tissue regeneration processes. In this study, we developed a three-dimensional (3D) multi-scale system model to study cell response to growth factors released from a 3D biodegradable porous calcium phosphate (CaP) scaffold. Our model reconstructed the 3D bone regeneration system and examined the effects of pore size and porosity on bone formation and angiogenesis. The results suggested that scaffold porosity played a more dominant role in affecting bone formation and angiogenesis compared with pore size, while the pore size could be controlled to tailor the growth factor release rate and release fraction. Furthermore, a combination of gradient VEGF with BMP2 and Wnt released from the multi-layer scaffold promoted angiogenesis and bone formation more readily than single growth factors. These results demonstrated that the developed model can be potentially applied to predict vascularized bone regeneration with specific scaffold and growth factors. PMID:23566802

  2. Manipulation of Magnetic Textures in Thin Films and Devices

    NASA Astrophysics Data System (ADS)

    Tolley, Robert Douglas

    Control and manipulation of magnetic textures is promising for the development of next-generation data storage, memory and processing technologies. Towards this goal, domain wall manipulation in two materials systems are presented here and thoroughly evaluated. Domain walls in ferrimagnetic Cobalt-Terbium alloys and multilayers are created, moved and stabilized via thermal gradients and a static magnetic field and exploit the unique properties of the system across the magnetic compensation point. The response of the systems to thermal gradients is observed via Kerr microscopy and used to determine the positioning of domain walls within patterned devices. Magnetic skyrmions are discovered in thin-film multilayered stacks using an Pt/Co/Os/Pt heterostructures where the thin Osmium layer is used to break interfacial symmetry and enhance the Dzyaloshinskii-Moriya interaction. The resulting skyrmions are manipulated using temperature, magnetic field, and electric current, and special attention is paid to their motion and nucleation behavior. Skyrmions are observed to be formed by low applied currents from nucleation sites and by collapse of stripe textures. Patterned wires allow for the observation of skyrmion nucleation behavior in free space, as well as defect sites, and real-time Kerr microscopy imaging is presented of skyrmion and stripe dynamics. These systems are evaluated from a perspective of their growth, patterning, measurement, and the novel behavior of the magnetic textures.

  3. Role of G protein-coupled receptors (GPCR), matrix metalloproteinases 2 and 9 (MMP2 and MMP9), heparin-binding epidermal growth factor-like growth factor (hbEGF), epidermal growth factor receptor (EGFR), erbB2, and insulin-like growth factor 1 receptor (IGF-1R) in trenbolone acetate-stimulated bovine satellite cell proliferation.

    PubMed

    Thornton, K J; Kamange-Sollo, E; White, M E; Dayton, W R

    2015-09-01

    Implanting cattle with steroids significantly enhances feed efficiency, rate of gain, and muscle growth. However, the mechanisms responsible for these improvements in muscle growth have not been fully elucidated. Trenbolone acetate (TBA), a testosterone analog, has been shown to increase proliferation rate in bovine satellite cell (BSC) cultures. The classical genomic actions of testosterone have been well characterized; however, our results indicate that TBA may also initiate a quicker, nongenomic response that involves activation of G protein-coupled receptors (GPCR) resulting in activation of matrix metalloproteinases 2 and 9 (MMP2 and MMP9) that release membrane-bound heparin-binding epidermal growth factor-like growth factor (hbEGF), which then binds to and activates the epidermal growth factor receptor (EGFR) and/or erbB2. Furthermore, the EGFR has been shown to regulate expression of the IGF-1 receptor (IGF-1R), which is well known for its role in modulating muscle growth. To determine whether this nongenomic pathway is potentially involved in TBA-stimulated BSC proliferation, we analyzed the effects of treating BSC with guanosine 5'-O-2-thiodiphosphate (GDPβS), an inhibitor of all GPCR; a MMP2 and MMP9 inhibitor (MMPI); CRM19, a specific inhibitor of hbEGF; AG1478, a specific EGFR tyrosine kinase inhibitor; AG879, a specific erbB2 kinase inhibitor; and AG1024, an IGF-1R tyrosine kinase inhibitor on TBA-stimulated proliferation rate (H-thymidine incorporation). Assays were replicated at least 9 times for each inhibitor experiment using BSC cultures obtained from at least 3 different animals. Bovine satellite cell cultures were obtained from yearling steers that had no previous exposure to androgenic or estrogenic compounds. As expected, BSC cultures treated with 10 n TBA showed ( < 0.05) increased proliferation rate when compared with control cultures. Additionally, treatment with 5 ng hbEGF/mL stimulated proliferation in BSC cultures ( < 0.05). Treatment

  4. Platelet-derived growth factor receptors differentially inform intertumoral and intratumoral heterogeneity

    PubMed Central

    Kim, Youngmi; Kim, Eunhee; Wu, Qiulian; Guryanova, Olga; Hitomi, Masahiro; Lathia, Justin D.; Serwanski, David; Sloan, Andrew E.; Weil, Robert J.; Lee, Jeongwu; Nishiyama, Akiko; Bao, Shideng; Hjelmeland, Anita B.; Rich, Jeremy N.

    2012-01-01

    Growth factor-mediated proliferation and self-renewal maintain tissue-specific stem cells and are frequently dysregulated in cancers. Platelet-derived growth factor (PDGF) ligands and receptors (PDGFRs) are commonly overexpressed in gliomas and initiate tumors, as proven in genetically engineered models. While PDGFRα alterations inform intertumoral heterogeneity toward a proneural glioblastoma (GBM) subtype, we interrogated the role of PDGFRs in intratumoral GBM heterogeneity. We found that PDGFRα is expressed only in a subset of GBMs, while PDGFRβ is more commonly expressed in tumors but is preferentially expressed by self-renewing tumorigenic GBM stem cells (GSCs). Genetic or pharmacological targeting of PDGFRβ (but not PDGFRα) attenuated GSC self-renewal, survival, tumor growth, and invasion. PDGFRβ inhibition decreased activation of the cancer stem cell signaling node STAT3, while constitutively active STAT3 rescued the loss of GSC self-renewal caused by PDGFRβ targeting. In silico survival analysis demonstrated that PDGFRB informed poor prognosis, while PDGFRA was a positive prognostic factor. Our results may explain mixed clinical responses of anti-PDGFR-based approaches and suggest the need for integration of models of cancer as an organ system into development of cancer therapies. PMID:22661233

  5. Adult-Directed and Peer-Directed Respect for Authority: Relationships With Aggressive and Manipulative Behavior

    PubMed Central

    Clemans, Katherine H.; Graber, Julia A.; Bettencourt, Amie F.

    2012-01-01

    This study investigated whether respect for adult and peer authority are separate attitudes which have distinct relationships with aggressive and manipulative behavior. Items assessing admiration for and obedience toward parents, teachers, popular students, and friend group leaders were administered to 286 middle school students (M age = 12.6 yrs). Factor analysis revealed two primary factors which corresponded to adult-directed and peer-directed respect orientations. Results suggested that adult-directed respect was associated with lower levels of aggression and social manipulation, whereas peer-directed respect was associated with higher levels of these behaviors. The role of peer-directed respect as a risk factor for negative social behavior in adolescence is discussed. PMID:23329877

  6. Soft computing prediction of economic growth based in science and technology factors

    NASA Astrophysics Data System (ADS)

    Marković, Dušan; Petković, Dalibor; Nikolić, Vlastimir; Milovančević, Miloš; Petković, Biljana

    2017-01-01

    The purpose of this research is to develop and apply the Extreme Learning Machine (ELM) to forecast the gross domestic product (GDP) growth rate. In this study the GDP growth was analyzed based on ten science and technology factors. These factors were: research and development (R&D) expenditure in GDP, scientific and technical journal articles, patent applications for nonresidents, patent applications for residents, trademark applications for nonresidents, trademark applications for residents, total trademark applications, researchers in R&D, technicians in R&D and high-technology exports. The ELM results were compared with genetic programming (GP), artificial neural network (ANN) and fuzzy logic results. Based upon simulation results, it is demonstrated that ELM has better forecasting capability for the GDP growth rate.

  7. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) expression in colorectal cancer.

    PubMed

    Nagano, Hideki; Goi, Takanori; Koneri, Kenji; Hirono, Yasuo; Katayama, Kanji; Yamaguchi, Akio

    2007-12-01

    Vascular endothelial growth factor (VEGF) is known as an important factor in the growth and metastasis of cancer cells. In 2001, a novel angiogenesis factor, endocrine gland-derived vascular endothelial growth factor (EG-VEGF), was cloned. In this study, we investigated the expression of EG-VEGF in colorectal cancer, the relationship between its expression and clinicopathological factors, and the in vitro activity of EG-VEGF transfectants. We determined expression levels of EG-VEGF in 113 advanced colorectal cancers resected in our hospital by quantitative PCR, and compared the expression levels and clinicopathological findings by multivariate analyses. The expression of EG-VEGF mRNA was positive in 31 cancers and negative in 82 cancers. We found that compared with the negative expression of the EG-VEGF gene, its positive expression was more frequently associated with hematogenous metastasis, and was associated with a poorer survival rate. In addition, EG-VEGF transfectants showed a higher degree of in vitro tubular formation than control cells. We speculate that, in colorectal cancers, the EG-VEGF gene functions as an important factor in angiogenesis in primary and metastatic lesions, and consider that it is useful as a novel prognostic factor. EG-VEGF molecule-targeted therapy has the potential for improving survival rates.

  8. Hematological and hepatic effects of vascular epidermal growth factor (VEGF) used to stimulate hair growth in an animal model

    PubMed Central

    2013-01-01

    Background Alopecia areata is the hair loss usually reversible, in sharply defined areas. The treatment of alopecia using growth factors shows interesting activity in promoting hair growth. In this concept, VEGF (vascular endothelial growth factor) is a marker of angiogenesis, stimulating hair growth by facilitating the supply of nutrients to the hair follicle, increasing follicular diameter. The aim of this study was the evaluation of a topical gel enriched with VEGF liposomes on the hair growth stimulation and its toxicological aspects. Methods Mesocricetus auratus were randomly divided into three groups. Control group was treated with Aristoflex® gel, 1% group with the same gel but added 1% VEGF and 3% group with 3% VEGF. Biochemical, hematological and histological analyses were done. Results At the end of the experiment (15th day of VEGF treatment) efficacy was determined macroscopically by hair density dermatoscopy analysis, and microscopically by hair diameter analysis. They both demonstrated that hair of the VEGF group increased faster and thicker than control. On the other hand, biochemical and hematological results had shown that VEGF was not 100% inert. Conclusions VEGF increased hair follicle area, but more studies are necessary to confirm its toxicity. PMID:24168457

  9. Hematological and hepatic effects of vascular epidermal growth factor (VEGF) used to stimulate hair growth in an animal model.

    PubMed

    Gnann, Laís Angelo; Castro, Rafael Ferreira; Azzalis, Ligia Ajaime; Feder, David; Perazzo, Fabio Ferreira; Pereira, Edimar Cristiano; Rosa, Paulo César Pires; Junqueira, Virginia Berlanga Campos; Rocha, Katya Cristina; Machado, Carlos D' Aparecida; Paschoal, Francisco Camargo; de Abreu, Luiz Carlos; Valenti, Vitor Engrácia; Fonseca, Fernando Luiz Affonso

    2013-10-29

    Alopecia areata is the hair loss usually reversible, in sharply defined areas. The treatment of alopecia using growth factors shows interesting activity in promoting hair growth. In this concept, VEGF (vascular endothelial growth factor) is a marker of angiogenesis, stimulating hair growth by facilitating the supply of nutrients to the hair follicle, increasing follicular diameter. The aim of this study was the evaluation of a topical gel enriched with VEGF liposomes on the hair growth stimulation and its toxicological aspects. Mesocricetus auratus were randomly divided into three groups. Control group was treated with Aristoflex® gel, 1% group with the same gel but added 1% VEGF and 3% group with 3% VEGF. Biochemical, hematological and histological analyses were done. At the end of the experiment (15th day of VEGF treatment) efficacy was determined macroscopically by hair density dermatoscopy analysis, and microscopically by hair diameter analysis. They both demonstrated that hair of the VEGF group increased faster and thicker than control. On the other hand, biochemical and hematological results had shown that VEGF was not 100% inert. VEGF increased hair follicle area, but more studies are necessary to confirm its toxicity.

  10. Experimental manipulation of dietary arsenic levels in great tit nestlings: Accumulation pattern and effects on growth, survival and plasma biochemistry.

    PubMed

    Sánchez-Virosta, Pablo; Espín, Silvia; Ruiz, Sandra; Salminen, Juha-Pekka; García-Fernández, Antonio J; Eeva, Tapio

    2018-02-01

    Arsenic (As) is a ubiquitous metalloid classified as one of the most hazardous substances, but information about its exposure and effects in free-living passerines is lacking. The aim of this study is to elucidate the effect of an As manipulation experiment on survival, growth and physiology of great tits (Parus major). Wild P. major nestlings inhabiting an unpolluted area were dosed with water, 0.2 or 1 μg g -1  d -1 of sodium arsenite (Control, Low and High As groups), whereas those living in a metal-polluted area were dosed with water (Smelter group). Birds accumulated As in tissues (liver, bone and feathers) in a dose-dependent way. Nestlings exposed to 1 μg g -1  d -1 of sodium arsenite showed reduced number of fledglings per successful nest, and those exposed to 0.2 μg g -1  d -1 had reduced wing growth, which could have post-fledging consequences such as increased predation risk. These results suggest that the LOAEL for effects on nestling survival and development in great tits is likely equal to or below 1 μg g -1  d -1 . However, limited effects on the biochemical parameters evaluated were found. It has been shown that As may produce oxidative stress and tissue damage, so further research exploring this issue will be carried out in a future study. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Randomized Clinical Trial of Sevelamer Carbonate on Serum Klotho and Fibroblast Growth Factor 23 in CKD.

    PubMed

    Liabeuf, Sophie; Ryckelynck, Jean-Philippe; El Esper, Najeh; Ureña, Pablo; Combe, Christian; Dussol, Bertrand; Fouque, Denis; Vanhille, Philippe; Frimat, Luc; Thervet, Eric; Mentaverri, Romuald; Prié, Dominique; Choukroun, Gabriel

    2017-12-07

    Epidemiologic studies suggest that higher serum phosphaturic hormone fibroblast growth factor 23 levels are associated with increase morbidity and mortality. The aim of the FGF23 Reduction Efficacy of a New Phosphate Binder in CKD Trial was to evaluate the effect of sevelamer carbonate on serum C-terminal fibroblast growth factor 23 levels in normophosphatemic patients with CKD stage 3b/4. Patients with CKD, eGFR between 45 and 15 ml/min per 1.73 m 2 , fasting serum phosphate concentration >3.1 mg/dl, and serum C-terminal fibroblast growth factor 23 >80 relative units/ml were included in our double-blind, placebo-controlled, randomized multicenter study. All patients received 100,000 IU cholecalciferol at time of randomization. Participants received either placebo or sevelamer carbonate 4.8 g daily during a 12-week period. Biologic parameters, including serum C-terminal fibroblast growth factor 23, intact fibroblast growth factor 23, and α -klotho, were evaluated at baseline and 12 weeks after inclusion. Of 96 screened patients, 78 (mean±SD age: 63±13 years old; 70% men; mean eGFR: 27±9 ml/min per 1.73 m 2 ) met the inclusion criteria. At baseline, mean eGFR was 27±9 ml/min per 1.73 m 2 , mean serum phosphate level was 3.8±0.5 mg/dl, and median (interquartile range) serum C-terminal fibroblast growth factor 23 level was 157 (120-241) relative units/ml. After 12 weeks of treatment, urinary phosphate-to-creatinine ratio fell significantly in the sevelamer group. The sevelamer and placebo groups did not differ significantly in terms of median change in serum C-terminal fibroblast growth factor 23 levels: the median (interquartile range) change was 38 (-13-114) relative units/ml in the placebo group and 37 (-1-101) relative units/ml in the sevelamer group ( P =0.77). There was no significant difference in serum intact fibroblast growth factor 23, α -klotho, or phosphate levels changes between the two groups. Serum total and LDL cholesterol levels fell

  12. Understanding Cytokine and Growth Factor Receptor Activation Mechanisms

    PubMed Central

    Atanasova, Mariya; Whitty, Adrian

    2012-01-01

    Our understanding of the detailed mechanism of action of cytokine and growth factor receptors – and particularly our quantitative understanding of the link between structure, mechanism and function – lags significantly behind our knowledge of comparable functional protein classes such as enzymes, G protein-coupled receptors, and ion channels. In particular, it remains controversial whether such receptors are activated by a mechanism of ligand-induced oligomerization, versus a mechanism in which the ligand binds to a pre-associated receptor dimer or oligomer that becomes activated through subsequent conformational rearrangement. A major limitation to progress has been the relative paucity of methods for performing quantitative mechanistic experiments on unmodified receptors expressed at endogenous levels on live cells. In this article we review the current state of knowledge on the activation mechanisms of cytokine and growth factor receptors, critically evaluate the evidence for and against the different proposed mechanisms, and highlight other key questions that remain unanswered. New approaches and techniques have led to rapid recent progress in this area, and the field is poised for major advances in the coming years, which promises to revolutionize our understanding of this large and biologically and medically important class of receptors. PMID:23046381

  13. Connective tissue growth factor (CTGF) and cancer progression.

    PubMed

    Chu, Chia-Yu; Chang, Cheng-Chi; Prakash, Ekambaranellore; Kuo, Min-Liang

    2008-11-01

    Connective tissue growth factor (CTGF) is a member of the CCN family of secreted, matrix-associated proteins encoded by immediate early genes that play various roles in angiogenesis and tumor growth. CCN family proteins share uniform modular structure which mediates various cellular functions such as regulation of cell division, chemotaxis, apoptosis, adhesion, motility, angiogenesis, neoplastic transformation, and ion transport. Recently, CTGF expression has been shown to be associated with tumor development and progression. There is growing body of evidence that CTGF may regulate cancer cell migration, invasion, angiogenesis, and anoikis. In this review, we will highlight the influence of CTGF expression on the biological behavior and progression of various cancer cells, as well as its regulation on various types of protein signals and their mechanisms.

  14. Mobile camera-space manipulation

    NASA Technical Reports Server (NTRS)

    Seelinger, Michael J. (Inventor); Yoder, John-David S. (Inventor); Skaar, Steven B. (Inventor)

    2001-01-01

    The invention is a method of using computer vision to control systems consisting of a combination of holonomic and nonholonomic degrees of freedom such as a wheeled rover equipped with a robotic arm, a forklift, and earth-moving equipment such as a backhoe or a front-loader. Using vision sensors mounted on the mobile system and the manipulator, the system establishes a relationship between the internal joint configuration of the holonomic degrees of freedom of the manipulator and the appearance of features on the manipulator in the reference frames of the vision sensors. Then, the system, perhaps with the assistance of an operator, identifies the locations of the target object in the reference frames of the vision sensors. Using this target information, along with the relationship described above, the system determines a suitable trajectory for the nonholonomic degrees of freedom of the base to follow towards the target object. The system also determines a suitable pose or series of poses for the holonomic degrees of freedom of the manipulator. With additional visual samples, the system automatically updates the trajectory and final pose of the manipulator so as to allow for greater precision in the overall final position of the system.

  15. Internalization Mechanisms of the Epidermal Growth Factor Receptor after Activation with Different Ligands

    PubMed Central

    Henriksen, Lasse; Grandal, Michael Vibo; Knudsen, Stine Louise Jeppe; van Deurs, Bo; Grøvdal, Lene Melsæther

    2013-01-01

    The epidermal growth factor receptor (EGFR) regulates normal growth and differentiation, but dysregulation of the receptor or one of the EGFR ligands is involved in the pathogenesis of many cancers. There are eight ligands for EGFR, however most of the research into trafficking of the receptor after ligand activation focuses on the effect of epidermal growth factor (EGF) and transforming growth factor-α (TGF-α). For a long time it was believed that clathrin-mediated endocytosis was the major pathway for internalization of the receptor, but recent work suggests that different pathways exist. Here we show that clathrin ablation completely inhibits internalization of EGF- and TGF-α-stimulated receptor, however the inhibition of receptor internalization in cells treated with heparin-binding EGF-like growth factor (HB-EGF) or betacellulin (BTC) was only partial. In contrast, clathrin knockdown fully inhibits EGFR degradation after all ligands tested. Furthermore, inhibition of dynamin function blocked EGFR internalization after stimulation with all ligands. Knocking out a number of clathrin-independent dynamin-dependent pathways of internalization had no effect on the ligand-induced endocytosis of the EGFR. We suggest that EGF and TGF-α lead to EGFR endocytosis mainly via the clathrin-mediated pathway. Furthermore, we suggest that HB-EGF and BTC also lead to EGFR endocytosis via a clathrin-mediated pathway, but can additionally use an unidentified internalization pathway or better recruit the small amount of clathrin remaining after clathrin knockdown. PMID:23472148

  16. IMU-based online kinematic calibration of robot manipulator.

    PubMed

    Du, Guanglong; Zhang, Ping

    2013-01-01

    Robot calibration is a useful diagnostic method for improving the positioning accuracy in robot production and maintenance. An online robot self-calibration method based on inertial measurement unit (IMU) is presented in this paper. The method requires that the IMU is rigidly attached to the robot manipulator, which makes it possible to obtain the orientation of the manipulator with the orientation of the IMU in real time. This paper proposed an efficient approach which incorporates Factored Quaternion Algorithm (FQA) and Kalman Filter (KF) to estimate the orientation of the IMU. Then, an Extended Kalman Filter (EKF) is used to estimate kinematic parameter errors. Using this proposed orientation estimation method will result in improved reliability and accuracy in determining the orientation of the manipulator. Compared with the existing vision-based self-calibration methods, the great advantage of this method is that it does not need the complex steps, such as camera calibration, images capture, and corner detection, which make the robot calibration procedure more autonomous in a dynamic manufacturing environment. Experimental studies on a GOOGOL GRB3016 robot show that this method has better accuracy, convenience, and effectiveness than vision-based methods.

  17. IMU-Based Online Kinematic Calibration of Robot Manipulator

    PubMed Central

    2013-01-01

    Robot calibration is a useful diagnostic method for improving the positioning accuracy in robot production and maintenance. An online robot self-calibration method based on inertial measurement unit (IMU) is presented in this paper. The method requires that the IMU is rigidly attached to the robot manipulator, which makes it possible to obtain the orientation of the manipulator with the orientation of the IMU in real time. This paper proposed an efficient approach which incorporates Factored Quaternion Algorithm (FQA) and Kalman Filter (KF) to estimate the orientation of the IMU. Then, an Extended Kalman Filter (EKF) is used to estimate kinematic parameter errors. Using this proposed orientation estimation method will result in improved reliability and accuracy in determining the orientation of the manipulator. Compared with the existing vision-based self-calibration methods, the great advantage of this method is that it does not need the complex steps, such as camera calibration, images capture, and corner detection, which make the robot calibration procedure more autonomous in a dynamic manufacturing environment. Experimental studies on a GOOGOL GRB3016 robot show that this method has better accuracy, convenience, and effectiveness than vision-based methods. PMID:24302854

  18. Growth Factors and Stem Cells for the Management of Anterior Cruciate Ligament Tears

    PubMed Central

    Rizzello, Giacomo; Longo, Umile Giuseppe; Petrillo, Stefano; Lamberti, Alfredo; Khan, Wasim Sardar; Maffulli, Nicola; Denaro, Vincenzo

    2012-01-01

    The anterior cruciate ligament (ACL) is fundamental for the knee joint stability. ACL tears are frequent, especially during sport activities, occurring mainly in young and active patients. Nowadays, the gold standard for the management of ACL tears remains the surgical reconstruction with autografts or allografts. New strategies are being developed to resolve the problems of ligament grafting and promote a physiological healing process of ligamentous tissue without requiring surgical reconstruction. Moreover, these strategies can be applicable in association surgical reconstruction and may be useful to promote and accelerate the healing process. The use of growth factors and stem cells seems to offer a new and fascinating solution for the management of ACL tears. The injection of stem cell and/or growth factors in the site of ligamentous injury can potentially enhance the repair process of the physiological tissue. These procedures are still at their infancy, and more in vivo and in vitro studies are required to clarify the molecular pathways and effectiveness of growth factors and stem cells therapy for the management of ACL tears. This review aims to summarize the current knowledge in the field of growth factors and stem cells for the management of ACL tears. PMID:23248722

  19. Insulin-like growth factor-I treatment of children with Laron syndrome (primary growth hormone insensitivity).

    PubMed

    Laron, Zvi

    2008-03-01

    Laron syndrome (LS, congenital primary GH insensitivity) is caused by deletions or mutations in the GH receptor gene, resulting in an inability to generate insulin-like growth factor-I (IGF-I). If untreated, the deficiency of IGF-I results in severe dwarfism, as well as skeletal and muscular underdevelopment. The only treatment is the daily administration of recombinant IGF-I. This review summarizes the present experience by several groups worldwide. The main conclusions are: A. The one or two injections regimen result in the same growth velocity; B. The growth velocity obtained with IGF-I administration is smaller than that observed with hGH in children with congenital isolated GH deficiency; C. Overdosage of IGF-I causes a series of adverse effects which can be avoided by carefully monitoring the serum IGF-I and GH levels.

  20. The DNA replication licensing factor miniature chromosome maintenance 7 is essential for RNA splicing of epidermal growth factor receptor, c-Met, and platelet-derived growth factor receptor.

    PubMed

    Chen, Zhang-Hui; Yu, Yan P; Michalopoulos, George; Nelson, Joel; Luo, Jian-Hua

    2015-01-16

    Miniature chromosome maintenance 7 (MCM7) is an essential component of DNA replication licensing complex. Recent studies indicate that MCM7 is amplified and overexpressed in a variety of human malignancies. In this report, we show that MCM7 binds SF3B3. The binding motif is located in the N terminus (amino acids 221-248) of MCM7. Knockdown of MCM7 or SF3B3 significantly increased unspliced RNA of epidermal growth factor receptor, platelet-derived growth factor receptor, and c-Met. A dramatic drop of reporter gene expression of the oxytocin exon 1-intron-exon 2-EGFP construct was also identified in SF3B3 and MCM7 knockdown PC3 and DU145 cells. The MCM7 or SF3B3 depleted cell extract failed to splice reporter RNA in in vitro RNA splicing analyses. Knockdown of SF3B3 and MCM7 leads to an increase of cell death of both PC3 and DU145 cells. Such cell death induction is partially rescued by expressing spliced c-Met. To our knowledge, this is the first report suggesting that MCM7 is a critical RNA splicing factor, thus giving significant new insight into the oncogenic activity of this protein. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Vascular Endothelial Growth Factor (VEGF) and Platelet (PF-4) Factor 4 Inputs Modulate Human Microvascular Endothelial Signaling in a Three-Dimensional Matrix Migration Context*

    PubMed Central

    Hang, Ta-Chun; Tedford, Nathan C.; Reddy, Raven J.; Rimchala, Tharathorn; Wells, Alan; White, Forest M.; Kamm, Roger D.; Lauffenburger, Douglas A.

    2013-01-01

    The process of angiogenesis is under complex regulation in adult organisms, particularly as it often occurs in an inflammatory post-wound environment. As such, there are many impacting factors that will regulate the generation of new blood vessels which include not only pro-angiogenic growth factors such as vascular endothelial growth factor, but also angiostatic factors. During initial postwound hemostasis, a large initial bolus of platelet factor 4 is released into localized areas of damage before progression of wound healing toward tissue homeostasis. Because of its early presence and high concentration, the angiostatic chemokine platelet factor 4, which can induce endothelial anoikis, can strongly affect angiogenesis. In our work, we explored signaling crosstalk interactions between vascular endothelial growth factor and platelet factor 4 using phosphotyrosine-enriched mass spectrometry methods on human dermal microvascular endothelial cells cultured under conditions facilitating migratory sprouting into collagen gel matrices. We developed new methods to enable mass spectrometry-based phosphorylation analysis of primary cells cultured on collagen gels, and quantified signaling pathways over the first 48 h of treatment with vascular endothelial growth factor in the presence or absence of platelet factor 4. By observing early and late signaling dynamics in tandem with correlation network modeling, we found that platelet factor 4 has significant crosstalk with vascular endothelial growth factor by modulating cell migration and polarization pathways, centered around P38α MAPK, Src family kinases Fyn and Lyn, along with FAK. Interestingly, we found EphA2 correlational topology to strongly involve key migration-related signaling nodes after introduction of platelet factor 4, indicating an influence of the angiostatic factor on this ambiguous but generally angiogenic signal in this complex environment. PMID:24023389

  2. The Fibroblast Growth Factor signaling pathway

    PubMed Central

    Ornitz, David M; Itoh, Nobuyuki

    2015-01-01

    The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs). Interaction of FGF ligands with their signaling receptors is regulated by protein or proteoglycan cofactors and by extracellular binding proteins. Activated FGFRs phosphorylate specific tyrosine residues that mediate interaction with cytosolic adaptor proteins and the RAS-MAPK, PI3K-AKT, PLCγ, and STAT intracellular signaling pathways. Four structurally related intracellular non-signaling FGFs interact with and regulate the family of voltage gated sodium channels. Members of the FGF family function in the earliest stages of embryonic development and during organogenesis to maintain progenitor cells and mediate their growth, differentiation, survival, and patterning. FGFs also have roles in adult tissues where they mediate metabolic functions, tissue repair, and regeneration, often by reactivating developmental signaling pathways. Consistent with the presence of FGFs in almost all tissues and organs, aberrant activity of the pathway is associated with developmental defects that disrupt organogenesis, impair the response to injury, and result in metabolic disorders, and cancer. © 2015 Wiley Periodicals, Inc. PMID:25772309

  3. Effect of Irrigation Time of Antiseptic Solutions on Bone Cell Viability and Growth Factor Release.

    PubMed

    Sawada, Kosaku; Nakahara, Ken; Haga-Tsujimura, Maiko; Fujioka-Kobayashi, Masako; Iizuka, Tateyuki; Miron, Richard J

    2018-03-01

    Antiseptic solutions are commonly utilized to treat local infection in the oral and maxillofacial region. However, surrounding vital bone is also exposed to antiseptic agents during irrigation and may have a potential negative impact on bone survival. The aim of the present study was therefore to investigate the effect of rinsing time with various antiseptic solutions on bone cell viability, as well as their subsequent release of growth factors important for bone regeneration. The bone samples collected from porcine mandible were rinsed in the following commonly utilized antiseptic solutions; povidone-iodine (0.5%), chlorhexidine digluconate (CHX, 0.2%), hydrogen peroxide (1%), and sodium hypochlorite (0.25%) for 1, 5, 10, 20, 30, or 60 minutes and assessed for cell viability and release of growth factors including vascular endothelial growth factor, transforming growth factor beta 1, bone morphogenetic protein 2, receptor activator of nuclear factor kappa-B ligand, and interleukin-1 beta by enzyme-linked immunosorbent assay. It was found in all the tested groups that the long exposure of any of the tested antiseptic solutions drastically promoted higher cell death. Sodium hypochlorite demonstrated the significantly highest cell death and at all time points. Interestingly, bone cell viability was highest in the CHX group post short-term rinsing of 1, 5, or 10 minutes when compared with the other 4 tested groups. A similar trend was also observed in subsequent growth factor release. The present study demonstrated that of the 4 tested antiseptic solutions, short-term CHX rinsing (ideally within 1 minute) favored bone cell viability and growth factor release. Clinical protocols should be adapted accordingly.

  4. Basic Fibroblast Growth Factor Activates Serum Response Factor Gene Expression by Multiple Distinct Signaling Mechanisms

    PubMed Central

    Spencer, Jeffrey A.; Major, Michael L.; Misra, Ravi P.

    1999-01-01

    Serum response factor (SRF) plays a central role in the transcriptional response of mammalian cells to a variety of extracellular signals. It is a key regulator of many cellular early response genes which are believed to be involved in cell growth and differentiation. The mechanism by which SRF activates transcription in response to mitogenic agents has been extensively studied; however, significantly less is known about regulation of the SRF gene itself. Previously, we identified distinct regulatory elements in the SRF promoter that play a role in activation, including a consensus ETS domain binding site, a consensus overlapping Sp/Egr-1 binding site, and two SRF binding sites. We further showed that serum induces SRF by a mechanism that requires an intact SRF binding site, also termed a CArG box. In the present study we demonstrate that in response to stimulation of cells by a purified growth factor, basic fibroblast growth factor (bFGF), the SRF promoter is upregulated by a complex pathway that involves at least two independent mechanisms: a CArG box-independent mechanism that is mediated by an ETS binding site, and a novel CArG box-dependent mechanism that requires both an Sp factor binding site and the CArG motifs for maximal stimulation. Our analysis indicates that the CArG/Sp element activation mechanism is mediated by distinct signaling pathways. The CArG box-dependent component is targeted by a Rho-mediated pathway, and the Sp binding site-dependent component is targeted by a Ras-mediated pathway. Both SRF and bFGF have been implicated in playing an important role in mediating cardiogenesis during development. The implications of our findings for SRF expression during development are discussed. PMID:10330138

  5. Loxoprofen sodium suppresses mouse tumor growth by inhibiting vascular endothelial growth factor.

    PubMed

    Kanda, Akio; Ebihara, Satoru; Takahashi, Hidenori; Sasaki, Hidetada

    2003-01-01

    There is increasing evidence to suggest the anti-tumor effects of non-steroidal anti-inflammatory drugs (NSAIDs). In this study it was shown that the most popular NSAID in Japan, loxoprofen sodium (LOX), inhibited in vivo growth of implanted Lewis lung carcinoma (LLC), whereas LOX did not affect the proliferation and viability of LLC cells in vitro. Intratumoral vessel density in LOX-treated mice was significantly lower than that of mice without treatment. Intratumoral expressions of vascular endothelial growth factor (VEGF) mRNA were attenuated by the LOX treatment. LOX suppressed both intratumoral and systemic VEGF protein in LLC-implanted mice. LOX also inhibited tubular formation of primary cultured human umbilical vein endothelial cells, presumably due to the inhibition of VEGF. In patients with advanced non-small cell lung cancer, LOX medication (120 mg/day) for a week significantly decreased the plasma VEGF level. These results suggest that LOX may have potent anti-cancer effects in patients with advanced NSCLC.

  6. Effect of experimental manipulation on survival and recruitment of feral pigs

    USGS Publications Warehouse

    Hanson, L.B.; Mitchell, M.S.; Grand, J.B.; Jolley, D.B.; Sparklin, B.D.; Ditchkoff, S.S.

    2009-01-01

    Lethal removal is commonly used to reduce the density of invasive-species populations, presuming it reduces population growth rate; the actual effect of lethal removal on the vital rates contributing to population growth, however, is rarely tested. We implemented a manipulative experiment of feral pig (Sus scrofa) populations at Fort Benning, Georgia, USA, to assess the demographic effects of harvest intensity. Using markrecapture data, we estimated annual survival, recruitment, and population growth rates of populations in a moderately harvested area and a heavily harvested area for 200406. Population growth rates did not differ between the populations. The top-ranked model for survival included a harvest intensity effect; model-averaged survival was lower for the heavily harvested population than for the moderately harvested population. Increased immigration and reproduction likely compensated for the increased mortality in the heavily harvested population. We conclude that compensatory responses in feral pig recruitment can limit the success of lethal control efforts. ?? 2009 CSIRO.

  7. Combination Growth Factor Therapy via Electrostatically Assembled Wound Dressings Improves Diabetic Ulcer Healing In Vivo.

    PubMed

    Almquist, Benjamin D; Castleberry, Steven A; Sun, Julia B; Lu, Alice Y; Hammond, Paula T

    2015-10-01

    Chronic skin ulcerations are a common complication of diabetes mellitus, affecting up to one in four diabetic individuals. Despite the prevalence of these wounds, current pharmacologic options for treating them remain limited. Growth factor-based therapies have displayed a mixed ability to drive successful healing, which may be due to nonoptimal delivery strategies. Here, a method for coating commercially available nylon dressings using the layer-by-layer process is described to enable both sustained release and independent control over the release kinetics of vascular endothelial growth factor 165 and platelet-derived growth factor BB. It is shown that the use of strategically spaced diffusion barriers formed spontaneously by disulfide bonds enables independent control over the release rates of incorporated growth factors, and that in vivo these dressings improve several aspects of wound healing in db/db mice. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. The Personal Mobility and Manipulation Appliance (PerMMA): a robotic wheelchair with advanced mobility and manipulation.

    PubMed

    Wang, Hongwu; Grindle, Garrett G; Candiotti, Jorge; Chung, Chengshiu; Shino, Motoki; Houston, Elaine; Cooper, Rory A

    2012-01-01

    The Personal Mobility and Manipulation Appliance (PerMMA) is a recently developed personal assistance robot developed to provide people with disabilities and older adults enhanced assistance in both mobility and manipulation, which are two fundamental components for independently activities of daily life performing, community participation, and quality of life. Technologies to assist with mobility and manipulation are among the most important tools for clinicians, end users and caregivers; however, there are currently few systems that provide practical and coordinated assistance with mobility and manipulation tasks. The PerMMA was not only developed and evaluated to provide users and caregivers enhanced mobility and manipulation options, but also as a clinical tool as well as research platform. The development and evaluation of PerMMA are presented in the paper.

  9. Klotho and the Growth Hormone/Insulin-Like Growth Factor 1 Axis: Novel Insights into Complex Interactions.

    PubMed

    Rubinek, T; Modan-Moses, D

    2016-01-01

    The growth hormone (GH)/insulin-like growth factor (IGF)-1 axis is pivotal for many metabolic functions, including proper development and growth of bones, skeletal muscles, and adipose tissue. Defects in the axis' activity during childhood result in growth abnormalities, while increased secretion of GH from the pituitary results in acromegaly. In order to keep narrow physiologic concentration, GH and IGF-1 secretion and activity are tightly regulated by hypothalamic, pituitary, endocrine, paracrine, and autocrine factors. Klotho was first discovered as an aging-suppressor gene. Mice that do not express klotho die prematurely with multiple symptoms of aging, several of them are also characteristic of decreased GH/IGF-1 axis activity. Klotho is highly expressed in the brain, the kidney, and parathyroid and pituitary glands, but can also serve as a circulating hormone by its shedding, forming soluble klotho that can be detected in blood, cerebrospinal fluid, and urine. Several lines of evidence suggest an association between klotho levels and activity of the GH/IGF-1 axis: the GH-secreting cells in the anterior pituitary of klotho-deficient mice are hypotrophic; klotho levels are altered in subjects with pathologies of the GH/IGF-1 axis; and accumulating data indicate that klotho is a direct regulator of GH secretion. Thus, klotho seems to be a new player in the intricate regulation of the GH/IGF-1 axis. © 2016 Elsevier Inc. All rights reserved.

  10. Aloe vera oral administration accelerates acute radiation-delayed wound healing by stimulating transforming growth factor-β and fibroblast growth factor production.

    PubMed

    Atiba, Ayman; Nishimura, Mayumi; Kakinuma, Shizuko; Hiraoka, Takeshi; Goryo, Masanobu; Shimada, Yoshiya; Ueno, Hiroshi; Uzuka, Yuji

    2011-06-01

    Delayed wound healing is a significant clinical problem in patients who have had previous irradiation. This study investigated the effectiveness of Aloe vera (Av) on acute radiation-delayed wound healing. The effect of Av was studied in radiation-exposed rats compared with radiation-only and control rats. Skin wounds were excised on the back of rats after 3 days of local radiation. Wound size was measured on days 0, 3, 6, 9, and 12 after wounding. Wound tissues were examined histologically and the expressions of transforming growth factor β-1 (TGF-β-1) and basic fibroblast growth factor (bFGF) were examined by immunohistochemistry and reverse-transcription polymerase chain reaction. Wound contraction was accelerated significantly by Av on days 6 and 12 after wounding. Furthermore, the inflammatory cell infiltration, fibroblast proliferation, collagen deposition, angiogenesis, and the expression levels of TGF-β-1 and bFGF were significantly higher in the radiation plus Av group compared with the radiation-only group. These data showed the potential application of Av to improve the acute radiation-delayed wound healing by increasing TGF-β-1 and bFGF production. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Role of Vascular Endothelial Growth Factor and Transforming Growth Factor-β2 in Rat Bone Tissue after Bone Fracture and Placement of Titanium Implants with Bioactive Bioresorbable Coatings.

    PubMed

    Kalinichenko, S G; Matveeva, N Yu; Kostiv, R E; Puz', A V

    2017-03-01

    The study established enhanced expression of vascular endothelial growth factor (VEGF) in the subpopulation of osteoblasts located in the regeneration region of femoral bone fracture near the titanium implants with bioactive calcium phosphate and hydroxyapatite coatings and suppressed activity of transforming growth factor-β2 (TGF-β2) in chondroblasts during the two weeks after surgery. In the delayed posttraumatic period, the distribution of TGF-β2 inversely related to its maximal activity. The data revealed the up-regulating effect of bioresorbable coatings on expression of VEGF and TGF-β2 and their implication in the control over various stages of reparative osteogenesis.

  12. Neurocognitive development of the ability to manipulate information in working memory.

    PubMed

    Crone, Eveline A; Wendelken, Carter; Donohue, Sarah; van Leijenhorst, Linda; Bunge, Silvia A

    2006-06-13

    The ability to manipulate information in working memory is a key factor in cognitive development. Here, we used event-related functional MRI to test the hypothesis that developmental improvements in manipulation, relative to pure maintenance, are associated with increased recruitment of dorsolateral (DL) prefrontal cortex (PFC) and superior parietal cortex. Three age groups (8-12 years old, 13-17 years old, and 18-25 years old) performed an object-working memory task with separate maintenance and manipulation conditions. We found that 8- to 12-year-olds did not perform the task as well as adolescents or adults, particularly on trials requiring manipulation in addition to maintenance. In this study, no age differences were observed in the activation profile of ventrolateral PFC, a region associated with online maintenance. In contrast, unlike the older participants, 8- to 12-year-olds failed to recruit right DL PFC and bilateral superior parietal cortex during the delay period for manipulation relative to maintenance. This group difference was observed specifically during the delay period, while participants reordered items in working memory, and could not be accounted for by group differences in performance. Across participants, activation levels in right DL PFC and superior parietal cortex, but not ventrolateral PFC, were positively correlated with performance on manipulation trials. These results indicate that increased recruitment of right DL PFC and bilateral parietal cortex during adolescence is associated with improvements in the ability to work with object representations.

  13. Predictors of outcome after manipulation under anaesthesia in patients with a stiff total knee arthroplasty.

    PubMed

    Vanlommel, L; Luyckx, T; Vercruysse, G; Bellemans, J; Vandenneucker, H

    2017-11-01

    Flexion in a stiff total knee arthroplasty (TKA) can be improved by manipulation under anaesthesia (MUA). Although this intervention usually results in an improvement in range of motion, the expected result is not always achieved. The purpose of this study is to determine which factors affect range of motion after manipulation in patients with a stiff total knee. After exclusion (n = 22), the data of 158 patients (138 knees) with a stiff knee after TKA who received a manipulation under anaesthesia between 2004 and 2014 were retrospectively analysed. Pre-, peri- and post-operative variables were identified and examined for their influence on flexion after the manipulation using Kruskal-Wallis and Mann-Whitney U tests and Spearman correlations. After MUA, a mean improvement in flexion of 30.3° was observed at the final follow-up. Preoperative TKA flexion, design of TKA and interval between TKA procedure and MUA were positive associated with an increase in flexion after MUA. MUA performed 12 weeks or more after TKA procedure deteriorated the outcome. Three factors, pre-TKA flexion type of prosthesis and interval between TKA procedure and manipulation under anaesthesia, were found to have impact on flexion after TKA and MUA were identified. Results are expected to be inferior in patients with low flexion before TKA procedure or with a long interval (>12 weeks) between the TKA procedure and the manipulation under anaesthesia. IV.

  14. Improved vascularization of planar membrane diffusion devices following continuous infusion of vascular endothelial growth factor.

    PubMed

    Trivedi, N; Steil, G M; Colton, C K; Bonner-Weir, S; Weir, G C

    2000-01-01

    Improving blood vessel formation around an immunobarrier device should improve the survival of the encapsulated tissue. In the present study we investigated the formation of new blood vessels around a planar membrane diffusion device (the Baxter Theracyte System) undergoing a continuous infusion of vascular endothelial growth factor through the membranes and into the surrounding tissue. Each device (20 microl) had both an inner immunoisolation membrane and an outer vascularizing membrane. Human recombinant vascular endothelial growth factor-165 was infused at 100 ng/day (low dose: n = 6) and 500 ng/day (high dose: n = 7) for 10 days into devices implanted s.c. in Sprague-Dawley rats; noninfused devices transplanted for an identical period were used as controls (n = 5). Two days following the termination of VEGF infusion, devices were loaded with 20 microl of Lispro insulin (1 U/kg) and the kinetics of insulin release from the lumen of the device was assessed. Devices were then explanted and the number of blood vessels (capillary and noncapillary) was quantified using morphometry. High-dose vascular endothelial growth factor infusion resulted in two- to threefold more blood vessels around the device than that obtained with the noninfused devices and devices infused with low-dose vascular endothelial growth factor. This increase in the number of blood vessels was accompanied by a modest increase in insulin diffusion from the device in the high-dose vascular endothelial growth factor infusion group. We conclude that vascular endothelial growth factor can be used to improve blood vessel formation adjacent to planar membrane diffusion devices.

  15. Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction

    PubMed Central

    Shah, Nisarg J.; Hyder, Md. Nasim; Quadir, Mohiuddin A.; Dorval Courchesne, Noémie-Manuelle; Seeherman, Howard J.; Nevins, Myron; Spector, Myron; Hammond, Paula T.

    2014-01-01

    Traumatic wounds and congenital defects that require large-scale bone tissue repair have few successful clinical therapies, particularly for craniomaxillofacial defects. Although bioactive materials have demonstrated alternative approaches to tissue repair, an optimized materials system for reproducible, safe, and targeted repair remains elusive. We hypothesized that controlled, rapid bone formation in large, critical-size defects could be induced by simultaneously delivering multiple biological growth factors to the site of the wound. Here, we report an approach for bone repair using a polyelectrolye multilayer coating carrying as little as 200 ng of bone morphogenetic protein-2 and platelet-derived growth factor-BB that were eluted over readily adapted time scales to induce rapid bone repair. Based on electrostatic interactions between the polymer multilayers and growth factors alone, we sustained mitogenic and osteogenic signals with these growth factors in an easily tunable and controlled manner to direct endogenous cell function. To prove the role of this adaptive release system, we applied the polyelectrolyte coating on a well-studied biodegradable poly(lactic-co-glycolic acid) support membrane. The released growth factors directed cellular processes to induce bone repair in a critical-size rat calvaria model. The released growth factors promoted local bone formation that bridged a critical-size defect in the calvaria as early as 2 wk after implantation. Mature, mechanically competent bone regenerated the native calvaria form. Such an approach could be clinically useful and has significant benefits as a synthetic, off-the-shelf, cell-free option for bone tissue repair and restoration. PMID:25136093

  16. Flow Line, Durafill VS, and Dycal toxicity to dental pulp cells: effects of growth factors

    PubMed Central

    Furey, Alyssa; Hjelmhaug, Julie; Lobner, Doug

    2010-01-01

    Introduction The objective was to determine the effects of growth factor treatment on dental pulp cell sensitivity to toxicity of two composite restoration materials, Flow Line and Durafill VS, and a calcium hydroxide pulp capping material, Dycal. Methods Toxicity of the dental materials to cultures of primary dental pulp cells was determined by the MTT metabolism assay. The ability of six different growth factors to influence the toxicity was tested. Results A 24 hour exposure to either Flow Line or Durafill VS caused approximately 40% cell death, while Dycal exposure caused approximately 80% cell death. The toxicity of Flow Line and Durafill VS was mediated by oxidative stress. Four of the growth factors tested (BMP-2, BMP-7, EGF, and TGF-β) decreased the basal MTT values while making the cells resistant to Flow Line and Durafill VS toxicity, except BMP-2 which made the cells more sensitive to Flow Line. Treatment with FGF-2 caused no change in basal MTT metabolism, prevented the toxicity of Durafill VS, but increased the toxicity of Flow Line. Treatment with IGF-I increased basal MTT metabolism and made the cells resistant to Flow Line and Durafill VS toxicity. None of the growth factors made the cells resistant to Dycal toxicity. Conclusions The results indicate that growth factors can be used to alter the sensitivity of dental pulp cells to commonly used restoration materials. The growth factors BMP-7, EGF, TGF-β, and IGF-I provided the best profile of effects, making the cells resistant to both Flow Line and Durafill VS toxicity. PMID:20630288

  17. Platelets promote osteosarcoma cell growth through activation of the platelet-derived growth factor receptor-Akt signaling axis.

    PubMed

    Takagi, Satoshi; Takemoto, Ai; Takami, Miho; Oh-Hara, Tomoko; Fujita, Naoya

    2014-08-01

    The interactions of tumor cells with platelets contribute to the progression of tumor malignancy, and the expression levels of platelet aggregation-inducing factors positively correlate with the metastatic potential of osteosarcoma cells. However, it is unclear how tumor-platelet interaction contributes to the proliferation of osteosarcomas. We report here that osteosarcoma-platelet interactions induce the release of platelet-derived growth factor (PDGF) from platelets, which promotes the proliferation of osteosarcomas. Co-culture of platelets with MG63 or HOS osteosarcoma cells, which could induce platelet aggregation, enhanced the proliferation of each cell line in vitro. Analysis of phospho-antibody arrays revealed that co-culture of MG63 cells with platelets induced the phosphorylation of platelet derived growth factor receptor (PDGFR) and Akt. The addition of supernatants of osteosarcoma-platelet reactants also increased the growth of MG63 and HOS cells as well as the level of phosphorylated-PDGFR and -Akt. Sunitinib or LY294002, but not erlotinib, significantly inhibited the platelet-induced proliferation of osteosarcoma cells, indicating that PDGF released from platelets plays an important role in the proliferation of osteosarcomas by activating the PDGFR and then Akt. Our results suggest that inhibitors that specifically target osteosarcoma-platelet interactions may eradicate osteosarcomas. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  18. Revisiting Mathematics Manipulative Materials

    ERIC Educational Resources Information Center

    Swan, Paul; Marshall, Linda

    2010-01-01

    It is over 12 years since "APMC" published Bob Perry and Peter Howard's research on the use of mathematics manipulative materials in primary mathematics classrooms. Since then the availability of virtual manipulatives and associated access to computers and interactive whiteboards have caused educators to rethink the use of mathematics…

  19. Hepatocyte growth factor/scatter factor-MET signaling in neural crest-derived melanocyte development.

    PubMed

    Kos, L; Aronzon, A; Takayama, H; Maina, F; Ponzetto, C; Merlino, G; Pavan, W

    1999-02-01

    The mechanisms governing development of neural crest-derived melanocytes, and how alterations in these pathways lead to hypopigmentation disorders, are not completely understood. Hepatocyte growth factor/scatter factor (HGF/SF) signaling through the tyrosine-kinase receptor, MET, is capable of promoting the proliferation, increasing the motility, and maintaining high tyrosinase activity and melanin synthesis of melanocytes in vitro. In addition, transgenic mice that ubiquitously overexpress HGF/SF demonstrate hyperpigmentation in the skin and leptomenigenes and develop melanomas. To investigate whether HGF/ SF-MET signaling is involved in the development of neural crest-derived melanocytes, transgenic embryos, ubiquitously overexpressing HGF/SF, were analyzed. In HGF/SF transgenic embryos, the distribution of melanoblasts along the characteristic migratory pathway was not affected. However, additional ectopically localized melanoblasts were also observed in the dorsal root ganglia and neural tube, as early as 11.5 days post coitus (p.c.). We utilized an in vitro neural crest culture assay to further explore the role of HGF/SF-MET signaling in neural crest development. HGF/SF added to neural crest cultures increased melanoblast number, permitted differentiation into pigmented melanocytes, promoted melanoblast survival, and could replace mast-cell growth factor/Steel factor (MGF) in explant cultures. To examine whether HGF/SF-MET signaling is required for the proper development of melanocytes, embryos with a targeted Met null mutation (Met-/-) were analysed. In Met-/- embryos, melanoblast number and location were not overtly affected up to 14 days p.c. These results demonstrate that HGF/SF-MET signaling influences, but is not required for, the initial development of neural crest-derived melanocytes in vivo and in vitro.

  20. Regulation of adhesion and growth of fibrosarcoma cells by NF-kappa B RelA involves transforming growth factor beta.

    PubMed Central

    Perez, J R; Higgins-Sochaski, K A; Maltese, J Y; Narayanan, R

    1994-01-01

    The NF-kappa B transcription factor is a pleiotropic activator that participates in the induction of a wide variety of cellular genes. Antisense oligomer inhibition of the RelA subunit of NF-kappa B results in a block of cellular adhesion and inhibition of tumor cell growth. Investigation of the molecular basis for these effects showed that in vitro inhibition of the growth of transformed fibroblasts by relA antisense oligonucleotides can be reversed by the parental-cell-conditioned medium. Cytokine profile analysis of these cells treated with relA antisense oligonucleotides revealed inhibition of transforming growth factor beta 1 (TGF-beta 1 to the transformed fibroblasts reversed the inhibitory effects of relA antisense oligomers on soft agar colony formation and cell adhesion to the substratum. Direct inhibition of TGF-beta 1 expression by antisense phosphorothioates to TGF-beta 1 mimicked the in vitro effects of blocking cell adhesion that are elicited by antisense relA oligomers. These results may explain the in vitro effects of relA antisense oligomers on fibrosarcoma cell growth and adhesion. Images PMID:8035811