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Sample records for growth factor independence

  1. A Growth Initiation Factor for Host-Independent Derivatives of Bdellovibrio bacteriovorus

    PubMed Central

    Ishiguro, Edward E.

    1973-01-01

    Host-independent (H-I) derivatives of Bdellovibrio bacteriovorus 109 Davis could not be isolated when concentrated suspensions of host-dependent (H-D) cultures, washed free of spent medium, were plated on host-free media. However, H-I colonies did appear when spent broth was incorporated into the isolation medium, indicating the presence of a factor in the spent medium essential for the growth of H-I cells. This growth factor (GIF) was also present in cell-free extracts of Escherichia coli and a variety of other microorganisms including H-D and H-I derivatives of strain 109 Davis. GIF was heat stable, non-dialyzable, and present in both soluble and particulate fractions of extracts. Heating of extracts at 70 C for 10 min resulted in 10- to 40-fold stimulation in GIF activity, and evidence for a heat-labile inhibitor was obtained. Colonies appearing on host-free medium in these experiments were shown to be those of typical H-I derivatives by isolation and subsequent host-independent cultivation of these organisms. GIF was a conditional requirement dependent on age and size of inoculum for all H-I derivatives characterized. Although GIF stimulated the growth of washed exponential phase cells transferred to fresh medium, it was not essential for growth. However, it was essential for the initiation of growth of washed stationary phase cells from small inocula transferred to fresh medium. It is proposed that GIF is required to initiate growth of metabolically quiescent cells. Images PMID:4197902

  2. Enhanced dimerization drives ligand-independent activity of mutant epidermal growth factor receptor in lung cancer

    PubMed Central

    Valley, Christopher C.; Arndt-Jovin, Donna J.; Karedla, Narain; Steinkamp, Mara P.; Chizhik, Alexey I.; Hlavacek, William S.; Wilson, Bridget S.; Lidke, Keith A.; Lidke, Diane S.

    2015-01-01

    Mutations within the epidermal growth factor receptor (EGFR/erbB1/Her1) are often associated with tumorigenesis. In particular, a number of EGFR mutants that demonstrate ligand-independent signaling are common in non–small cell lung cancer (NSCLC), including kinase domain mutations L858R (also called L834R) and exon 19 deletions (e.g., ΔL747-P753insS), which collectively make up nearly 90% of mutations in NSCLC. The molecular mechanisms by which these mutations confer constitutive activity remain unresolved. Using multiple subdiffraction-limit imaging modalities, we reveal the altered receptor structure and interaction kinetics of NSCLC-associated EGFR mutants. We applied two-color single quantum dot tracking to quantify receptor dimerization kinetics on living cells and show that, in contrast to wild-type EGFR, mutants are capable of forming stable, ligand-independent dimers. Two-color superresolution localization microscopy confirmed ligand-independent aggregation of EGFR mutants. Live-cell Förster resonance energy transfer measurements revealed that the L858R kinase mutation alters ectodomain structure such that unliganded mutant EGFR adopts an extended, dimerization-competent conformation. Finally, mutation of the putative dimerization arm confirmed a critical role for ectodomain engagement in ligand-independent signaling. These data support a model in which dysregulated activity of NSCLC-associated kinase mutants is driven by coordinated interactions involving both the kinase and extracellular domains that lead to enhanced dimerization. PMID:26337388

  3. Growth factor independence-1 antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia

    PubMed Central

    Khandanpour, Cyrus; Phelan, James D.; Vassen, Lothar; Schütte, Judith; Chen, Riyan; Horman, Shane R.; Gaudreau, Marie-Claude; Krongold, Joseph; Zhu, Jinfang; Paul, William E.; Dührsen, Ulrich; Göttgens, Bertie; Grimes, H. Leighton; Möröy, Tarik

    2013-01-01

    Summary Most patients with acute lymphoblastic leukemia (ALL) fail current treatments highlighting the need for better therapies. Since oncogenic signaling activates a p53-dependent DNA-damage response and apoptosis, leukemic cells must devise appropriate countermeasures. We show here that growth factor independence 1 (Gfi1) can serve such a function, since Gfi1 ablation exacerbates p53 responses, and lowers the threshold for p53-induced cell death. Specifically, Gfi1 restricts p53 activity and expression of pro-apoptotic p53 targets such as Bax, Noxa (Pmaip1) and Puma (Bbc3). Subsequently, Gfi1 ablation cures mice from leukemia and limits the expansion of primary human T-ALL xenografts in mice. This suggests that targeting Gfi1 could improve the prognosis of patients with T-ALL or other lymphoid leukemias. PMID:23410974

  4. Gene profiling of growth factor independence 1B gene (Gfi-1B) in leukemic cells.

    PubMed

    Koldehoff, Michael; Zakrzewski, Johannes L; Klein-Hitpass, Ludger; Beelen, Dietrich W; Elmaagacli, Ahmet H

    2008-01-01

    To investigate the molecular effects of growth factor independence 1B (Gfi-1B), a transcription factor essential for the development of hematopoietic cells and differentiation of erythroid and megakaryocytic lineages, the naturally Gfi-1B overexpressing cell line K562 was cultured in the presence of Gfi-1B target-specific small interfering RNA (siRNA). SiRNA treatment significantly knocked down Gfi-1B expression with an efficiency of nearly 90%. Analysis of the siRNA silencing protocol by colony-forming units ensured that it was not cytotoxic. Samples from Gfi-1B overexpressing cells and cells with knocked-down Gfi-1B were analyzed by oligonucleotide microarray technology and based upon rigorous statistical analysis of the data; relevant genes were chosen for confirmation by reserve transcriptase-polymerase chain reaction, including MYC/MYCBP and CDKN1A. Interestingly, transcripts within components of the signalling cascade of immune cells (PLD1, LAMP1, HSP90, IL6ST), of the tyrosine kinase pathway (TPR, RAC3) and of the transcription factors (RAC3, CEP290, JEM-1, ATR, MYC, SMC3, RARA, RBBP6) were found to be differentially expressed in Gfi-1B overexpressing cells compared to controls. Individual genes such as ZDHHC17, DMXL1, ZNF292 were found to be upregulated in Gfi-1B overexpressing cells. In addition, down-regulated transcripts showed cell signaling transcripts for several chemokine gene members including GNAL, CXCL5, GNL3L, GPR65, TMEM30, BCL11B and transcription factors (GTF2H3, ATXN3). In conclusion, several essential cell signalling factors, as well as transcriptional and post-translational regulation genes were differentially expressed in cells that overexpressed Gfi-1B compared to control cells with knocked-down Gfi-1B. Our data indicate that Gfi-1B signalling is important for commitment and maturation of hematopoietic cell populations. PMID:18224412

  5. Serum Level of Fibroblast Growth Factor 21 Is Independently Associated with Acute Myocardial Infarction

    PubMed Central

    Ding, Wenhui; Wang, Fang

    2015-01-01

    Background Fibroblast growth factor 21 (FGF21) has been described as a metabolic hormone critical for glucose and lipid metabolism. Previously, high levels of FGF21 were observed in patients with coronary heart disease and non-acute myocardial infarction (non-AMI). In this study, we investigated the changes in FGF21 levels in Chinese patients with AMI. Methodology/Principal Findings We used ELISA to measure circulating FGF21 levels in 55 AMI patients and 45 non-AMI control patients on the 1st day after syndrome onset. All patients were followed-up within 30 days. FGF21 levels in AMI patients were significantly higher than those in non-AMI controls (0.25 (0.16–0.34) vs. 0.14 (0.11–0.20) ng/mL, P < 0.001). FGF21 levels reached the maximum within approximately 24 h after the onset of AMI and remained at high for 7 days, and the FGF21 level (OR: 16.93; 95% confidence interval (CI): 2.65–108.05; P = 0.003) was identified as an independent factor associated with the presence of AMI. On the 7th day, FGF21 levels were significantly higher in the patients who subsequently developed re-infarction within 30 days than in the patients who did not develop re-infarction (with vs. without re-infarction: 0.45 (0.22–0.64) vs. 0.21 (0.15–0.29) ng/mL, P = 0.014). Conclusions/Significance The level of serum FGF21 is independently associated with the presence of AMI in Chinese patients. High FGF21 levels might be related to the incidence of re-infarction within 30 days after onset. PMID:26091256

  6. SUMOylation Regulates Growth Factor Independence 1 in Transcriptional Control and Hematopoiesis.

    PubMed

    Andrade, Daniel; Velinder, Matthew; Singer, Jason; Maese, Luke; Bareyan, Diana; Nguyen, Hong; Chandrasekharan, Mahesh B; Lucente, Helena; McClellan, David; Jones, David; Sharma, Sunil; Liu, Fang; Engel, Michael E

    2016-05-15

    Cell fate specification requires precise coordination of transcription factors and their regulators to achieve fidelity and flexibility in lineage allocation. The transcriptional repressor growth factor independence 1 (GFI1) is comprised of conserved Snail/Slug/Gfi1 (SNAG) and zinc finger motifs separated by a linker region poorly conserved with GFI1B, its closest homolog. Moreover, GFI1 and GFI1B coordinate distinct developmental fates in hematopoiesis, suggesting that their functional differences may derive from structures within their linkers. We show a binding interface between the GFI1 linker and the SP-RING domain of PIAS3, an E3-SUMO (small ubiquitin-related modifier) ligase. The PIAS3 binding region in GFI1 contains a conserved type I SUMOylation consensus element, centered on lysine-239 (K239). In silico prediction algorithms identify K239 as the only high-probability site for SUMO modification. We show that GFI1 is modified by SUMO at K239. SUMOylation-resistant derivatives of GFI1 fail to complement Gfi1 depletion phenotypes in zebrafish primitive erythropoiesis and granulocytic differentiation in cultured human cells. LSD1/CoREST recruitment and MYC repression by GFI1 are profoundly impaired for SUMOylation-resistant GFI1 derivatives, while enforced expression of MYC blocks granulocytic differentiation. These findings suggest that SUMOylation within the GFI1 linker favors LSD1/CoREST recruitment and MYC repression to govern hematopoietic differentiation. PMID:26951200

  7. Drosophila Vps4 promotes Epidermal growth factor receptor signaling independently of its role in receptor degradation

    PubMed Central

    Legent, Kevin; Liu, Hui Hua; Treisman, Jessica E.

    2015-01-01

    Endocytic trafficking of signaling receptors is an important mechanism for limiting signal duration. Components of the Endosomal Sorting Complexes Required for Transport (ESCRT), which target ubiquitylated receptors to intra-lumenal vesicles (ILVs) of multivesicular bodies, are thought to terminate signaling by the epidermal growth factor receptor (EGFR) and direct it for lysosomal degradation. In a genetic screen for mutations that affect Drosophila eye development, we identified an allele of Vacuolar protein sorting 4 (Vps4), which encodes an AAA ATPase that interacts with the ESCRT-III complex to drive the final step of ILV formation. Photoreceptors are largely absent from Vps4 mutant clones in the eye disc, and even when cell death is genetically prevented, the mutant R8 photoreceptors that develop fail to recruit surrounding cells to differentiate as R1-R7 photoreceptors. This recruitment requires EGFR signaling, suggesting that loss of Vps4 disrupts the EGFR pathway. In imaginal disc cells mutant for Vps4, EGFR and other receptors accumulate in endosomes and EGFR target genes are not expressed; epistasis experiments place the function of Vps4 at the level of the receptor. Surprisingly, Vps4 is required for EGFR signaling even in the absence of Shibire, the Dynamin that internalizes EGFR from the plasma membrane. In ovarian follicle cells, in contrast, Vps4 does not affect EGFR signaling, although it is still essential for receptor degradation. Taken together, these findings indicate that Vps4 can promote EGFR activity through an endocytosis-independent mechanism. PMID:25790850

  8. Transforming Growth Factor {beta} Can Stimulate Smad1 Phosphorylation Independently of Bone Morphogenic Protein Receptors.

    PubMed

    Wrighton, Katharine H; Lin, Xia; Yu, Paul B; Feng, Xin-Hua

    2009-04-10

    Transforming growth factor-beta (TGFbeta) superfamily ligands control a diverse set of cellular processes by activating type I and type II serine-threonine receptor kinases. Canonical TGFbeta signaling is mediated via the TbetaRI/ALK5 type I receptor that phosphorylates Smad2 and Smad3 in their SXS motif to facilitate their activation and subsequent role in transcriptional regulation. Canonical bone morphogenic protein (BMP) signaling is mediated via the ALK1/2/3/6 type I receptors that phosphorylate Smad1, Smad5, and Smad8 in their SXS motif. However, studies in endothelial cells have shown that TGFbeta can also lead to the phosphorylation of Smad1, dependent on ALK1 receptor activity. Here we present data showing that TGFbeta can significantly induce Smad1 phosphorylation in several non-endothelial cell lineages. Additionally, by using chemical inhibitors specific for the TGFbeta/activin/nodal (ALK4/5/7) and BMP (ALK1/2/3/6) type I receptors, we show that in some cell types TGFbeta induces Smad1 phosphorylation independently of the BMP type I receptors. Thus, TGFbeta-mediated Smad1 phosphorylation appears to occur via different receptor complexes in a cell type-specific manner. PMID:19224917

  9. Fetuin-A promotes primary keratinocyte migration: independent of epidermal growth factor receptor signalling.

    PubMed

    Wang, Xue-Qing; Hung, Betsy S; Kempf, Margit; Liu, Pei-Yun; Dalley, Andrew J; Saunders, Nicholas A; Kimble, Roy M

    2010-08-01

    Previously, we reported that fetuin-A is a major component of ovine foetal skin and significantly enhances 'wound closure' in primary keratinocyte cultures. In this study, we found that in human newborn foreskin, a high level of fetuin-A protein is detected throughout the dermis. However, in adult skin a low level of fetuin-A is observed throughout the epidermal and dermal layers, except at regions surrounding hair follicles and at the epidermal-dermal junction where the level of fetuin-A is relatively high. Fetuin-A significantly induces actin-rich protrusions in human primary keratinocytes. Interestingly, blockade of epidermal growth factor (EGF) receptor signalling has a limited effect on fetuin-A promoted 'wound closure' on primary human keratinocytes, but significantly inhibits fetuin-A's effect on HaCaT cells. These results indicate that high levels of fetuin-A may partially contribute to less scar formation in newborn foreskin and that the effect of fetuin-A on primary keratinocyte migration is independent of EGF receptor signalling. PMID:19758338

  10. Smad-Independent Transforming Growth Factor-β Regulation of Early Growth Response-1 and Sustained Expression in Fibrosis

    PubMed Central

    Bhattacharyya, Swati; Chen, Shu-Jen; Wu, Minghua; Warner-Blankenship, Matthew; Ning, Hongyan; Lakos, Gabriella; Mori, Yasuji; Chang, Eric; Nihijima, Chihiro; Takehara, Kazuhiro; Feghali-Bostwick, Carol; Varga, John

    2008-01-01

    Transforming growth factor-β (TGF-β) plays a key role in scleroderma pathogenesis. The transcription factor early growth response-1 (Egr-1) mediates the stimulation of collagen transcription elicited by TGF-β and is necessary for the development of pulmonary fibrosis in mice. Here, we report that TGF-β causes a time- and dose-dependent increase in Egr-1 protein and mRNA levels and enhanced transcription of the Egr-1 gene via serum response elements in normal fibroblasts. The ability of TGF-β to stimulate Egr-1 was preserved in Smad3-null mice and in explanted Smad3-null fibroblasts. The response was blocked by a specific mitogen-activated protein kinase kinase 1 (MEK1) inhibitor but not by an ALK5 kinase inhibitor. Furthermore, MEK1 was phosphorylated by TGF-β, which was sufficient to drive Egr-1 transactivation. Stimulation by TGF-β enhanced the transcriptional activity of Elk-1 via the MEK-extracellular signal-regulated kinase 1/2 pathway. Bleomycin-induced scleroderma in the mouse was accompanied by increased Egr-1 accumulation in lesional fibroblasts. Furthermore, biopsies of lesional skin and lung from patients with scleroderma showed increased Egr-1 levels, which were highest in early diffuse disease. Moreover, both Egr-1 mRNA and protein were elevated in explanted scleroderma skin fibroblasts in vitro. Together, these findings define a Smad-independent TGF-β signal transduction mechanism that underlies the stimulation of Egr-1, demonstrate for the first time sustained Egr-1 up-regulation in fibrotic lesions and suggests that Egr-1 has a role in the induction and progression of fibrosis. PMID:18772333

  11. Advanced Glycation End-Products Induce Connective Tissue Growth Factor-Mediated Renal Fibrosis Predominantly through Transforming Growth Factor β-Independent Pathway

    PubMed Central

    Zhou, Guihua; Li, Cai; Cai, Lu

    2004-01-01

    Advanced glycation end-products (AGEs) play a critical role in diabetic nephropathy by stimulating extracellular matrix (ECM) synthesis. Connective tissue growth factor (CTGF) is a potent inducer of ECM synthesis and increases in the diabetic kidneys. To determine the critical role of CTGF in AGE-induced ECM accumulation leading to diabetic nephropathy, rats were given AGEs by intravenous injection for 6 weeks. AGE treatment induced a significant renal ECM accumulation, as shown by increases in periodic acid-Schiff-positive materials, fibronectin, and type IV collagen (Col IV) accumulation in glomeruli, and a mild renal dysfunction, as shown by increases in urinary volume and protein content. AGE treatment also caused significant increases in renal CTGF and transforming growth factor (TGF)-β1 mRNA and protein expression. Direct exposure of rat mesangial cells to AGEs in vitro significantly induced increases in fibronectin and Col IV production, which could be completely prevented by pretreatment with anti-CTGF antibody. AGE treatment also significantly increased both TGF-β1 and CTGF mRNA expression; however, inhibition of TGF-β1 mRNA expression by shRNA or neutralization of TGF-β1 protein by anti-TGF-β1 antibody did not significantly prevent AGE-increased expression of CTGF mRNA and protein. These results suggest that AGE-induced CTGF expression, predominantly through a TGF-β1-independent pathway, plays a critical role in renal ECM accumulation leading to diabetic nephropathy. PMID:15579446

  12. Ras-induced reactive oxygen species promote growth factor-independent proliferation in human CD34+ hematopoietic progenitor cells.

    PubMed

    Hole, Paul S; Pearn, Lorna; Tonks, Amanda J; James, Philip E; Burnett, Alan K; Darley, Richard L; Tonks, Alex

    2010-02-11

    Excessive production of reactive oxygen species (ROS) is a feature of human malignancy and is often triggered by activation of oncogenes such as activated Ras. ROS act as second messengers and can influence a variety of cellular process including growth factor responses and cell survival. We have examined the contribution of ROS production to the effects of N-Ras(G12D) and H-Ras(G12V) on normal human CD34(+) progenitor cells. Activated Ras strongly up-regulated the production of both superoxide and hydrogen peroxide through the stimulation of NADPH oxidase (NOX) activity, without affecting the expression of endogenous antioxidants or the production of mitochondrially derived ROS. Activated Ras also promoted both the survival and the growth factor-independent proliferation of CD34(+) cells. Using oxidase inhibitors and antioxidants, we found that excessive ROS production by these cells did not contribute to their enhanced survival; rather, ROS promoted their growth factor-independent proliferation. Although Ras-induced ROS production specifically activated the p38(MAPK) oxidative stress response, this failed to induce expression of the cell-cycle inhibitor, p16(INK4A); instead, ROS promoted the expression of D cyclins. These data are the first to show that excessive ROS production in the context of oncogene activation can promote proliferative responses in normal human hematopoietic progenitor cells. PMID:20007804

  13. MiR-378 is an independent prognostic factor and inhibits cell growth and invasion in colorectal cancer

    PubMed Central

    2014-01-01

    Background MicroRNAs(miRNAs) are small non-coding RNAs that participate in a variety of biologic processes, and dysregulation of miRNA is always associated with cancer development and progression. Aberrant expression of miR-378 has been found in some types of cancer. However, effects and potential mechanisms of miR-378 in colorectal cancer (CRC) have not been explored. Methods Quantitative RT-PCR was performed to evaluate miR-378 levels in CRC cell lines and 84 pairs of CRC cancer and normal adjacent mucosa. Kaplan–Meier and Cox proportional regression analyses were utilized to determine the association of miR-378 expression with survival of patients. MTT and invasion assays were used to determine the role of miR-378 in regulation of CRC cancer cell growth and invasion, respectively. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice. Luciferase assay was performed to assess miR-378 binding to vimentin gene. Results In this study, we confirmed that miR-378 significantly down-regulated in CRC cancer tissues and cell lines. Moreover, patients with low miR-378 expression had significantly poorer overall survival, and miR-378 expression was an independent prognostic factor in CRC. Over-expression of miR-378 inhibited SW620 cell growth and invasion, and resulted in down-regulation of vimentin expression. However, miR-378 knock-down promoted these processes and enhanced the expression of vimentin. In addition, we further identified vimentin as the functional downstream target of miR-378 by directly targeting the 3′-UTR of vimentin. Conclusions In conclusion, miR-378 may function as a tumor suppressor and plays an important role in inhibiting tumor growth and invasion. Our present results implicate the potential effects of miR-378 on prognosis and treatment of CRC cancer. PMID:24555885

  14. Serum Levels of Growth Differentiation Factor 11 Are Independently Associated with Low Hemoglobin Values in Hemodialysis Patients.

    PubMed

    Yamagishi, Sho-Ichi; Matsui, Takanori; Kurokawa, Yuka; Fukami, Kei

    2016-01-01

    Circulating levels of growth differentiation factor 11 (GDF11) have been shown to decrease with age in several mammalian species, and supplementation of GDF11 by heterochronic parabiosis or systemic administration reverses age-related organ damage. However, there is some controversy about the pathophysiological role of GDF11 in aging-associated organ damage. Since aging process is accelerated in uremia, we compared serum levels of GDF11 in hemodialysis (HD) patients with those in age-matched healthy controls, and then determined the independent clinical correlates of GDF11 in HD subjects. Sixty-two maintenance HD patients (34 male and 28 female; mean age, 52.6 years; mean duration of HD, 7.7 months) were enrolled in the present study. Twenty-nine age-matched subjects were used as a control. GDF11 was measured by a commercially available enzyme-linked immunosorbent assay kit. Serum GDF11 levels in HD patients were significantly higher than those in controls (9.4 ± 5.1 pg/mL vs. 7.3 ± 5.9 pg/mL). A statistical significance was demonstrated between GDF11 and hemoglobin (inversely). Multiple stepwise regression analysis revealed that hemoglobin (p < 0.001) was a sole independent correlate of GDF11 levels in HD patients (R (2) = 0.168). Our present study suggests that kinetics and regulation of circulating GDF11 may differ between normal physiological aging process and accelerated pathological aging conditions, such as uremia. Given that GDF11 has been shown to inhibit erythroid maturation in mice, elevation of GDF11 levels may be involved in erythropoietin-resistant anemia in HD patients. PMID:27298756

  15. Evidence for RNA synthesis-dependent and -independent pathways in stimulation of neurite outgrowth by nerve growth factor

    PubMed Central

    Burstein, David E.; Greene, Lloyd A.

    1978-01-01

    Studies on the mechanism of action of nerve growth factor (NGF) were carried out with PC12 rat pheochromocytoma cells. PC12 cells are uniquely useful for such studies because they respond to, but (unlike normal neurons) do not require, NGF and may undergo either generation or regeneration of neurites in response to NGF. Regeneration is defined here as NGF-dependent regrowth of neurites within 24 hr after subculture of NGF-treated PC12 cells. As in cultures of normal NGF-responsive neurons, neurite regeneration by PC12 cells occurs even in the presence of high concentrations of RNA synthesis inhibitors. Generation of neurites is defined as the de novo initiation of outgrowth when PC12 cells are exposed to NGF for the first time. In contrast to regeneration, neurite generation takes place with a lag of at least 24 hr and is blocked by low concentrations of RNA synthesis inhibitors. Such findings suggest that there are both RNA synthesis-dependent and -independent pathways in the mechanism whereby NGF stimulates neurite outgrowth. In addition, NGF-treated PC12 cells undergo a time-dependent loss of the capacity for neurite regeneration after pretreatment with RNA synthesis inhibitors or withdrawal of NGF. Such findings suggest that (i) initiation of neurite outgrowth requires NGF-stimulated, RNA synthesis-dependent accumulation of intracellular material(s), (ii) once such accumulation occurs, RNA synthesis-independent regeneration can occur (but only in the presence of NGF), and (iii) the turnover of such material(s) in the absence of their replacement leads to loss of the capacity for regeneration. A tentative sequence is presented for the events whereby NGF may stimulate neurite outgrowth. PMID:310552

  16. Serum Levels of Growth Differentiation Factor 11 Are Independently Associated with Low Hemoglobin Values in Hemodialysis Patients

    PubMed Central

    Yamagishi, Sho-ichi; Matsui, Takanori; Kurokawa, Yuka; Fukami, Kei

    2016-01-01

    Abstract Circulating levels of growth differentiation factor 11 (GDF11) have been shown to decrease with age in several mammalian species, and supplementation of GDF11 by heterochronic parabiosis or systemic administration reverses age-related organ damage. However, there is some controversy about the pathophysiological role of GDF11 in aging-associated organ damage. Since aging process is accelerated in uremia, we compared serum levels of GDF11 in hemodialysis (HD) patients with those in age-matched healthy controls, and then determined the independent clinical correlates of GDF11 in HD subjects. Sixty-two maintenance HD patients (34 male and 28 female; mean age, 52.6 years; mean duration of HD, 7.7 months) were enrolled in the present study. Twenty-nine age-matched subjects were used as a control. GDF11 was measured by a commercially available enzyme-linked immunosorbent assay kit. Serum GDF11 levels in HD patients were significantly higher than those in controls (9.4 ± 5.1 pg/mL vs. 7.3 ± 5.9 pg/mL). A statistical significance was demonstrated between GDF11 and hemoglobin (inversely). Multiple stepwise regression analysis revealed that hemoglobin (p < 0.001) was a sole independent correlate of GDF11 levels in HD patients (R2 = 0.168). Our present study suggests that kinetics and regulation of circulating GDF11 may differ between normal physiological aging process and accelerated pathological aging conditions, such as uremia. Given that GDF11 has been shown to inhibit erythroid maturation in mice, elevation of GDF11 levels may be involved in erythropoietin-resistant anemia in HD patients. PMID:27298756

  17. Gefitinib and Erlotinib Lead to Phosphorylation of Eukaryotic Initiation Factor 2 Alpha Independent of Epidermal Growth Factor Receptor in A549 Cells

    PubMed Central

    Koyama, Satoshi; Omura, Tomohiro; Yonezawa, Atsushi; Imai, Satoshi; Nakagawa, Shunsaku; Nakagawa, Takayuki; Yano, Ikuko; Matsubara, Kazuo

    2015-01-01

    Gefitinib and erlotinib are anticancer agents, which inhibit epidermal growth factor receptor (EGFR) tyrosine kinase. Interstitial lung disease (ILD) occurs in patients with non-small cell lung cancer receiving EGFR inhibitors. In the present study, we examined whether gefitinib- and erlotinib-induced lung injury related to ILD through endoplasmic reticulum (ER) stress, which is a causative intracellular mechanism in cytotoxicity caused by various chemicals in adenocarcinomic human alveolar basal epithelial cells. These two EGFR inhibitors increased Parkinson juvenile disease protein 2 and C/EBP homologous protein mRNA expressions, and activated the eukaryotic initiation factor (eIF) 2α/activating transcription factor 4 pathway without protein kinase R-like ER kinase activation in A549 cells. Gefitinib and erlotinib caused neither ER stress nor cell death; however, these agents inhibited cell growth via the reduction of cyclin-D1 expression. Tauroursodeoxycholic acid, which is known to suppress eIF2α phosphorylation, cancelled the effects of EGFR inhibitors on cyclin-D1 expression and cell proliferation in a concentration-dependent manner. The results of an EGFR-silencing study using siRNA showed that gefitinib and erlotinib affected eIF2α phosphorylation and cyclin-D1 expression independent of EGFR inhibition. Therefore, the inhibition of cell growth by these EGFR inhibitors might equate to impairment of the alveolar epithelial cell repair system via eIF2α phosphorylation and reduced cyclin-D1 expression. PMID:26288223

  18. Gefitinib and Erlotinib Lead to Phosphorylation of Eukaryotic Initiation Factor 2 Alpha Independent of Epidermal Growth Factor Receptor in A549 Cells.

    PubMed

    Koyama, Satoshi; Omura, Tomohiro; Yonezawa, Atsushi; Imai, Satoshi; Nakagawa, Shunsaku; Nakagawa, Takayuki; Yano, Ikuko; Matsubara, Kazuo

    2015-01-01

    Gefitinib and erlotinib are anticancer agents, which inhibit epidermal growth factor receptor (EGFR) tyrosine kinase. Interstitial lung disease (ILD) occurs in patients with non-small cell lung cancer receiving EGFR inhibitors. In the present study, we examined whether gefitinib- and erlotinib-induced lung injury related to ILD through endoplasmic reticulum (ER) stress, which is a causative intracellular mechanism in cytotoxicity caused by various chemicals in adenocarcinomic human alveolar basal epithelial cells. These two EGFR inhibitors increased Parkinson juvenile disease protein 2 and C/EBP homologous protein mRNA expressions, and activated the eukaryotic initiation factor (eIF) 2α/activating transcription factor 4 pathway without protein kinase R-like ER kinase activation in A549 cells. Gefitinib and erlotinib caused neither ER stress nor cell death; however, these agents inhibited cell growth via the reduction of cyclin-D1 expression. Tauroursodeoxycholic acid, which is known to suppress eIF2α phosphorylation, cancelled the effects of EGFR inhibitors on cyclin-D1 expression and cell proliferation in a concentration-dependent manner. The results of an EGFR-silencing study using siRNA showed that gefitinib and erlotinib affected eIF2α phosphorylation and cyclin-D1 expression independent of EGFR inhibition. Therefore, the inhibition of cell growth by these EGFR inhibitors might equate to impairment of the alveolar epithelial cell repair system via eIF2α phosphorylation and reduced cyclin-D1 expression. PMID:26288223

  19. Sargaquinoic acid supports the survival of neuronal PC12D cells in a nerve growth factor-independent manner.

    PubMed

    Tsang, Chi Kwan; Kamei, Yuto

    2004-03-19

    Sargaquinoic acid (designated previously as MC14) was isolated from a marine brown alga Sargassum macrocarpum, and has been found to possess a novel nerve growth factor (NGF)-dependent neurite outgrowth promoting activity in PC12D cells. In this study, we explored the neuroprotective effects of MC14 in terms of its survival supporting, antioxidant and neurite-regenerating activities under NGF deficient or deprived conditions. Intriguingly, MC14 did not only promote the NGF-induced survival support on neuronal PC12D cells, but also significantly abated neuronal PC12D cell death even in the absence of NGF. The pharmacological inhibition of phosphatidylinositol-3 kinase (PI3K) by wortmannin significantly suppressed the survival supporting activity of MC14, whereas the NGF receptor (tyrosine kinase A or TrkA) inhibitor K252a showed no detectable effect on MC14 activity. These results demonstrate that MC14 supports survival of neuronal PC12D cells in an NGF-independent manner, and that PI3K may be required for the neuroprotective activity of MC14. In addition, we have shown that MC14 markedly enhanced neurite-regeneration and protected PC12D cells from hydrogen peroxide (H(2)O(2))-induced oxidative stress. These pharmacological features suggest that MC14 may be a potentially important neuroprotective agent. PMID:15044030

  20. Cellular Internalization of Fibroblast Growth Factor-12 Exerts Radioprotective Effects on Intestinal Radiation Damage Independently of FGFR Signaling

    SciTech Connect

    Nakayama, Fumiaki; Umeda, Sachiko; Yasuda, Takeshi; Fujita, Mayumi; Asada, Masahiro; Meineke, Viktor; Imamura, Toru; Imai, Takashi

    2014-02-01

    Purpose: Several fibroblast growth factors (FGFs) were shown to inhibit radiation-induced tissue damage through FGF receptor (FGFR) signaling; however, this signaling was also found to be involved in the pathogenesis of several malignant tumors. In contrast, FGF12 cannot activate any FGFRs. Instead, FGF12 can be internalized readily into cells using 2 cell-penetrating peptide domains (CPP-M, CPP-C). Therefore, this study focused on clarifying the role of FGF12 internalization in protection against radiation-induced intestinal injury. Methods and Materials: Each FGF or peptide was administered intraperitoneally to BALB/c mice in the absence of heparin 24 hours before or after total body irradiation with γ rays at 9 to 12 Gy. Several radioprotective effects were examined in the jejunum. Results: Administration of FGF12 after radiation exposure was as effective as pretreatment in significantly promoting intestinal regeneration, proliferation of crypt cells, and epithelial differentiation. Two domains, comprising amino acid residues 80 to 109 and 140 to 169 of FGF12B, were identified as being responsible for the radioprotective activity, so that deletion of both domains from FGF12B resulted in a reduction in activity. Interestingly, these regions included the CPP-M and CPP-C domains, respectively; however, CPP-C by itself did not show an antiapoptotic effect. In addition, FGF1, prototypic FGF, possesses a domain corresponding to CPP-M, whereas it lacks CPP-C, so the fusion of FGF1 with CPP-C (FGF1/CPP-C) enhanced cellular internalization and increased radioprotective activity. However, FGF1/CPP-C reduced in vitro mitogenic activity through FGFRs compared with FGF1, implying that FGFR signaling might not be essential for promoting the radioprotective effect of FGF1/CPP-C. In addition, internalized FGF12 suppressed the activation of p38α after irradiation, resulting in reduced radiation-induced apoptosis. Conclusions: These findings indicate that FGF12 can protect the

  1. Regulation of histamine synthesis and tryptase expression through transcription factors, growth factor independent 1 (Gfi1) and Gfi1b, in murine cultured mast cells.

    PubMed

    Taura, Azusa; Furuta, Kazuyuki; Yamaguchi, Tomoko; Kawabata, Kenji; Tanaka, Satoshi

    2014-01-01

    Mast cells are involved in various immunological responses, although it remains unknown how their terminal differentiation is regulated. We previously established a culture model that mimics the process of mast cell maturation in the cutaneous tissue and found that growth factor independent 1 (Gfi1) was up-regulated whereas its paralogue Gfi1b down-regulated. Here we investigated the roles of Gfi1 and Gfi1b in the process of mast cell maturation using a murine mast cell line, MC9. Gfi1 and Gfi1b cDNAs were stably expressed in MC9 cells using the recombinant lentivirus. Histamine synthesis was significantly induced by stem cell factor (SCF) alone, whereas tryptase expression was significantly augmented in the presence of both SCF and Swiss 3T3 cells. Since exogenously expressed Gfi1 and Gfi1b might affect their expression levels in MC9 cells, we investigated the relationship between the expression profiles of Gfi1/Gfi1b proteins and maturation indices, such as histamine synthesis and tryptase expression. The comparison suggested that histamine synthesis during the co-culture period was positively regulated by Gfi1b while augmented expression of tryptase was abolished by one-sided expression of Gfi1/Gfi1b. Our findings indicated the involvement of Gfi1 and Gfi1b in the process of murine mast cell maturation. PMID:24389484

  2. Biographical factors of occupational independence.

    PubMed

    Müller, G F

    2001-10-01

    The present study examined biographical factors of occupational independence including any kind of nonemployed profession. Participants were 59 occupationally independent and 58 employed persons of different age (M = 36.3 yr.), sex, and profession. They were interviewed on variables like family influence, educational background, occupational role models, and critical events for choosing a particular type of occupational career. The obtained results show that occupationally independent people reported stronger family ties, experienced fewer restrictions of formal education, and remembered fewer negative role models than the employed people. Implications of these results are discussed. PMID:11783553

  3. Stromal platelet-derived growth factor receptor α (PDGFRα) provides a therapeutic target independent of tumor cell PDGFRα expression in lung cancer xenografts

    PubMed Central

    Gerber, David E.; Gupta, Puja; Dellinger, Michael T.; Toombs, Jason E.; Peyton, Michael; Duignan, Inga; Malaby, Jennifer; Bailey, Timothy; Burns, Colleen; Brekken, Rolf A.; Loizos, Nick

    2012-01-01

    In lung cancer, platelet-derived growth factor receptor α (PDGFRα) is expressed frequently by tumor-associated stromal cells and by cancer cells in a subset of tumors. We sought to determine the effect of targeting stromal PDGFRα in preclinical lung tumor xenograft models (human tumor, mouse stroma). Effects of anti-human (IMC-3G3) and anti-mouse (1E10) PDGFRα mAbs on proliferation and PDGFRα signaling were evaluated in lung cancer cell lines and mouse fibroblasts. Therapy studies were performed using established PDGFRα-positive H1703 cells and PDGFRα-negative Calu-6, H1993, and A549 subcutaneous tumors in immunocompromised mice treated with vehicle, anti-PDGFRα mAbs, chemotherapy, or combination therapy. Tumors were analyzed for growth and levels of growth factors. IMC-3G3 inhibited PDGFRα activation and the growth of H1703 cells in vitro and tumor growth in vivo, but had no effect on PDGFRα-negative cell lines or mouse fibroblasts. 1E10 inhibited growth and PDGFRα activation of mouse fibroblasts, but had no effect on human cancer cell lines in vitro. In vivo, 1E10-targeted inhibition of murine PDGFRα reduced tumor growth as single-agent therapy in Calu-6 cells and enhanced the effect of chemotherapy in xenografts derived from A549 cells. We also identified that low expression cancer cell expression of VEGF-A and elevated expression of PDGF-AA were associated with response to stromal PDGFRα targeting. We conclude that stromal PDGFRα inhibition represents a means for enhancing control of lung cancer growth in some cases, independent of tumor cell PDGFRα expression. PMID:22933705

  4. Naringenin prevents obesity, hepatic steatosis, and glucose intolerance in male mice independent of fibroblast growth factor 21.

    PubMed

    Assini, Julia M; Mulvihill, Erin E; Burke, Amy C; Sutherland, Brian G; Telford, Dawn E; Chhoker, Sanjiv S; Sawyez, Cynthia G; Drangova, Maria; Adams, Andrew C; Kharitonenkov, Alexei; Pin, Christopher L; Huff, Murray W

    2015-06-01

    The molecular mechanisms and metabolic pathways whereby the citrus flavonoid, naringenin, reduces dyslipidemia and improves glucose tolerance were investigated in C57BL6/J wild-type mice and fibroblast growth factor 21 (FGF21) null (Fgf21(-/-)) mice. FGF21 regulates energy homeostasis and the metabolic adaptation to fasting. One avenue of this regulation is through induction of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc1a), a regulator of hepatic fatty acid oxidation and ketogenesis. Because naringenin is a potent activator of hepatic FA oxidation, we hypothesized that induction of FGF21 might be an integral part of naringenin's mechanism of action. Furthermore, we predicted that FGF21 deficiency would potentiate high-fat diet (HFD)-induced metabolic dysregulation and compromise metabolic protection by naringenin. The absence of FGF21 exacerbated the response to a HFD. Interestingly, naringenin supplementation to the HFD robustly prevented obesity in both genotypes. Gene expression analysis suggested that naringenin was not primarily targeting fatty acid metabolism in white adipose tissue. Naringenin corrected hepatic triglyceride concentrations and normalized hepatic expression of Pgc1a, Cpt1a, and Srebf1c in both wild-type and Fgf21(-/-) mice. HFD-fed Fgf21(-/-) mice displayed greater muscle triglyceride deposition, hyperinsulinemia, and impaired glucose tolerance as compared with wild-type mice, confirming the role of FGF21 in insulin sensitivity; however, naringenin supplementation improved these metabolic parameters in both genotypes. We conclude that FGF21 deficiency exacerbates HFD-induced obesity, hepatic steatosis, and insulin resistance. Furthermore, FGF21 is not required for naringenin to protect mice from HFD-induced metabolic dysregulation. Collectively these studies support the concept that naringenin has potent lipid-lowering effects and may act as an insulin sensitizer in vivo. PMID:25774553

  5. Thrombospondin-1 Affects Bovine Luteal Function via Transforming Growth Factor-Beta1-Dependent and Independent Actions.

    PubMed

    Farberov, Svetlana; Meidan, Rina

    2016-01-01

    Thrombospondin-1 (THBS1) and transforming growth factor-beta1 (TGFB1) are specifically up-regulated by prostaglandin F2alpha in mature corpus luteum (CL). This study examined the relationship between the expression of THBS1 and TGFB1 and the underlying mechanisms of their actions in luteal endothelial cells (ECs). TGFB1 stimulated SMAD2 phosphorylation and SERPINE1 levels in dose- and time-dependent manners in luteal EC. THBS1 also elevated SERPINE1; this effect was abolished by TGFB1 receptor-1 kinase inhibitor (SB431542). The findings here further imply that THBS1 activates TGFB1 in luteal ECs: THBS1 increased the effects of latent TGFB1 on phosphorylated SMAD (phospho-SMAD) 2 and SERPINE1. THBS1 silencing significantly decreased SERPINE1 and levels of phospho-SMAD2. Lastly, THBS1 actions on SERPINE1 were inhibited by LSKL peptide (TGFB1 activation inhibitor); LSKL also counteracted latent TGFB1-induced phospho-SMAD2. We found that TGFB1 up-regulated its own mRNA levels and those of THBS1. Both compounds generated apoptosis, but THBS1 was significantly more effective (2.5-fold). Notably, this effect of THBS1 was not mediated by TGFB1. THBS1 and TGFB1 also differed in their activation of p38 mitogen-activated protein kinase. Whereas TGFB1 rapidly induced phospho-p38, THBS1 had a delayed effect. Inhibition of p38 pathway by SB203580 did not modulate TGFB1 effect on cell viability, but it amplified THBS1 actions. THBS1-stimulated caspase-3 activation coincided with p38 phosphorylation, suggesting that caspase-induced DNA damage initiated p38 phosphorylation. The in vitro data suggest that a feed-forward loop exists between THBS1, TGFB1, and SERPINE1. Indeed all these three genes were similarly induced in the regressing CL. Their gene products can promote vascular instability, apoptosis, and matrix remodeling during luteolysis. PMID:26658711

  6. Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via Insulin-like growth factor-1 receptor-independent mechanism

    PubMed Central

    Waraky, Ahmed; Akopyan, Karen; Parrow, Vendela; Strömberg, Thomas; Axelson, Magnus; Abrahmsén, Lars; Lindqvist, Arne; Larsson, Olle; Aleem, Eiman

    2014-01-01

    Picropodophyllin (PPP) is an anticancer drug undergoing clinical development in NSCLC. PPP has been shown to suppress IGF-1R signaling and to induce a G2/M cell cycle phase arrest but the exact mechanisms remain to be elucidated. The present study identified an IGF-1-independent mechanism of PPP leading to pro-metaphase arrest. The mitotic block was induced in human cancer cell lines and in an A549 xenograft mouse but did not occur in normal hepatocytes/mouse tissues. Cell cycle arrest by PPP occurred in vitro and in vivo accompanied by prominent CDK1 activation, and was IGF-1R-independent since it occurred also in IGF-1R-depleted and null cells. The tumor cells were not arrested in G2/M but in mitosis. Centrosome separation was prevented during mitotic entry, resulting in a monopolar mitotic spindle with subsequent prometaphase-arrest, independent of Plk1/Aurora A or Eg5, and leading to cell features of mitotic catastrophe. PPP also increased soluble tubulin and decreased spindle-associated tubulin within minutes, indicating that it interfered with microtubule dynamics. These results provide a novel IGF-1R-independent mechanism of antitumor effects of PPP. PMID:25268741

  7. Transforming growth factor-beta activities in 'in vivo' lines of hormone-dependent and independent mammary adenocarcinomas induced by medroxyprogesterone acetate in BALB/c mice.

    PubMed

    Elizalde, P V; Lanari, C; Kordon, E; Tezón, J; Charreau, E H

    1990-07-01

    We have determined the presence of transforming growth factor-beta (TGF-beta)-like polypeptides in mammary adenocarcinomas induced by medroxyprogesterone acetate (MPA) in BALB/c mice. In hormone-dependent tumors (HD) from nontreated and MPA-treated mice a high molecular weight (43 kDa) transforming activity was purified by Bio-Gel P-60 chromatography. This TGF was able to confer the neoplastic phenotype on NRK-49F cells without the addition of epidermal growth factor (EGF), though its activity was potentiated by EGF. It did not compete for binding to the EGF receptor, had no mitogenic activity on monolayer cultures of NRK fibroblasts, and was a potent inhibitor of DNA synthesis induced in these cells by EGF and insulin. In HD and hormone-independent tumors (HI) another TGF with a Mr of 13 kDa was isolated. This transforming activity showed the same biological properties as 43 kDa TGF, with the exception that in the absence of EGF it did not stimulate soft agar growth of NRK-49F cells. The synthesis of both factors in 'in vivo' HD tumors seems to be under MPA control, since it is much lower in HD tumors from MPA-treated mice. Further purification of the 13 and 43 kDa TGFs by hydrophobic interaction HPLC demonstrated that each one eluted in a different position, and that their elution profile differed from the TGF-beta from human platelets. The biological activity of the 13 and 43 kDa TGFs was not neutralized by a specific anti-TGF-beta antibody. PMID:2145045

  8. BAG-1 enhances cell-cell adhesion, reduces proliferation and induces chaperone-independent suppression of hepatocyte growth factor-induced epidermal keratinocyte migration

    SciTech Connect

    Hinitt, C.A.M.; Wood, J.; Lee, S.S.; Williams, A.C.; Howarth, J.L.; Glover, C.P.; Uney, J.B.; Hague, A.

    2010-08-01

    Cell motility is important in maintaining tissue homeostasis, facilitating epithelial wound repair and in tumour formation and progression. The aim of this study was to determine whether BAG-1 isoforms regulate epidermal cell migration in in vitro models of wound healing. In the human epidermal cell line HaCaT, endogenous BAG-1 is primarily nuclear and increases with confluence. Both transient and stable p36-Bag-1 overexpression resulted in increased cellular cohesion. Stable transfection of either of the three human BAG-1 isoforms p36-Bag-1 (BAG-1S), p46-Bag-1 (BAG-1M) and p50-Bag-1 (BAG-1L) inhibited growth and wound closure in serum-containing medium. However, in response to hepatocyte growth factor (HGF) in serum-free medium, BAG-1S/M reduced communal motility and colony scattering, but BAG-1L did not. In the presence of HGF, p36-Bag-1 transfectants retained proliferative response to HGF with no change in ERK1/2 activation. However, the cells retained E-cadherin localisation at cell-cell junctions and exhibited pronounced cortical actin. Point mutations in the BAG domain showed that BAG-1 inhibition of motility is independent of its function as a chaperone regulator. These findings are the first to suggest that BAG-1 plays a role in regulating cell-cell adhesion and suggest an important function in epidermal cohesion.

  9. Promoter-dependent and -independent activation of insulin-like growth factor binding protein-5 gene expression by prostaglandin E2 in primary rat osteoblasts

    NASA Technical Reports Server (NTRS)

    McCarthy, T. L.; Casinghino, S.; Mittanck, D. W.; Ji, C. H.; Centrella, M.; Rotwein, P.

    1996-01-01

    Insulin-like growth factor (IGF) action is mediated by high affinity cell surface IGF receptors and modulated by a family of secreted IGF binding proteins (IGFBPs). IGFBP-5, the most conserved of six IGFBPs characterized to date, uniquely potentiates the anabolic actions of IGF-I for skeletal cells. In osteoblasts, IGFBP-5 production is stimulated by prostaglandin E2 (PGE2), a local factor that mediates certain effects induced by parathyroid hormone, cytokines such as interleukin-1 and transforming growth factor-beta, and mechanical strain. In this study, we show that transcriptional and post-transcriptional events initiated by PGE2 collaborate to enhance IGFBP-5 gene expression in primary fetal rat osteoblast cultures. PGE2 treatment stimulated up to a 7-fold rise in steady-state levels of IGFBP-5 mRNA throughout 32 h of incubation. Analysis of nascent IGFBP-5 mRNA suggested that PGE2 had only a modest stimulatory effect on IGFBP-5 gene transcription, and transient transfection studies with IGFBP-5 promoter-reporter genes confirmed that PGE2 enhanced promoter activity by approximately 2-fold. Similar stimulatory effects were seen with forskolin. A DNA fragment with only 51 base pairs of the 5'-flanking sequence retained hormonal responsiveness, which may be mediated by a binding site for transcription factor AP-2 located at positions -44 to -36 in the proximal IGFBP-5 promoter. Incubation of osteoblasts with the mRNA transcriptional inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole demonstrated that PGE2 enhanced IGFBP-5 mRNA stability by 2-fold, increasing the t1/2 from 9 to 18 h. The effects of PGE2 on steady-state IGFBP-5 transcripts were abrogated by preincubating cells with cycloheximide, indicating that the effects of PGE2 on both gene transcription and mRNA stability required ongoing protein synthesis. Therefore, both promoter-dependent and -independent pathways converge to enhance IGFBP-5 gene expression in response to PGE2 in osteoblasts.

  10. Insulin-like growth factor-independent insulin-like growth factor binding protein 3 promotes cell migration and lymph node metastasis of oral squamous cell carcinoma cells by requirement of integrin β1.

    PubMed

    Yen, Yi-Chen; Hsiao, Jenn-Ren; Jiang, Shih Sheng; Chang, Jeffrey S; Wang, Ssu-Han; Shen, Ying-Ying; Chen, Chung-Hsing; Chang, I-Shou; Chang, Jang-Yang; Chen, Ya-Wen

    2015-12-01

    Frequent metastasis to the cervical lymph nodes leads to poor survival of patients with oral squamous cell carcinoma (OSCC). To understand the underlying mechanisms of lymph node metastasis, two sublines were successfully isolated from cervical lymph nodes of nude mice through in vivo selection, and identified as originating from poorly metastatic parental cells. These two sublines specifically metastasized to cervical lymph nodes in 83% of mice, whereas OEC-M1 cells did not metastasize after injection into the oral cavity. After gene expression analysis, we identified insulin-like growth factor binding protein 3 (IGFBP3) as one of the significantly up-regulated genes in the sublines in comparison with their parental cells. Consistently, meta-analysis of the public microarray datasets and IGFBP3 immunohistochemical analysis revealed increased both levels of IGFBP3 mRNA and protein in human OSCC tissues when compared to normal oral or adjacent nontumorous tissues. Interestingly, the up-regulated IGFBP3 mRNA expression was significantly associated with OSCC patients with lymph node metastasis. IGFBP3 knockdown in the sublines impaired and ectopic IGFBP3 expression in the parental cells promoted migration, transendothelial migration and lymph node metastasis of orthotopic transplantation. Additionally, ectopic expression of IGFBP3 with an IGF-binding defect sustained the IGFBP3-enhanced biological functions. Results indicated that IGFBP3 regulates metastasis-related functions of OSCC cells through an IGF-independent mechanism. Furthermore, exogenous IGFBP3 was sufficient to induce cell motility and extracellular signal-regulated kinase (ERK) activation. The silencing of integrin β1 was able to impair exogenous IGFBP3-mediated migration and ERK phosphorylation, suggesting a critical role of integrin β1 in IGFBP3-enchanced functions. PMID:26540630

  11. Insulin-like growth factor-independent insulin-like growth factor binding protein 3 promotes cell migration and lymph node metastasis of oral squamous cell carcinoma cells by requirement of integrin β1

    PubMed Central

    Jiang, Shih Sheng; Chang, Jeffrey S.; Wang, Ssu-Han; Shen, Ying-Ying; Chen, Chung-Hsing; Chang, I-Shou; Chang, Jang-Yang; Chen, Ya-Wen

    2015-01-01

    Frequent metastasis to the cervical lymph nodes leads to poor survival of patients with oral squamous cell carcinoma (OSCC). To understand the underlying mechanisms of lymph node metastasis, two sublines were successfully isolated from cervical lymph nodes of nude mice through in vivo selection, and identified as originating from poorly metastatic parental cells. These two sublines specifically metastasized to cervical lymph nodes in 83% of mice, whereas OEC-M1 cells did not metastasize after injection into the oral cavity. After gene expression analysis, we identified insulin-like growth factor binding protein 3 (IGFBP3) as one of the significantly up-regulated genes in the sublines in comparison with their parental cells. Consistently, meta-analysis of the public microarray datasets and IGFBP3 immunohistochemical analysis revealed increased both levels of IGFBP3 mRNA and protein in human OSCC tissues when compared to normal oral or adjacent nontumorous tissues. Interestingly, the up-regulated IGFBP3 mRNA expression was significantly associated with OSCC patients with lymph node metastasis. IGFBP3 knockdown in the sublines impaired and ectopic IGFBP3 expression in the parental cells promoted migration, transendothelial migration and lymph node metastasis of orthotopic transplantation. Additionally, ectopic expression of IGFBP3 with an IGF-binding defect sustained the IGFBP3-enhanced biological functions. Results indicated that IGFBP3 regulates metastasis-related functions of OSCC cells through an IGF-independent mechanism. Furthermore, exogenous IGFBP3 was sufficient to induce cell motility and extracellular signal-regulated kinase (ERK) activation. The silencing of integrin β1 was able to impair exogenous IGFBP3-mediated migration and ERK phosphorylation, suggesting a critical role of integrin β1 in IGFBP3-enchanced functions. PMID:26540630

  12. Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2 (FGFR2)

    PubMed Central

    O’Donovan, M.C.; Norton, N.; Williams, H.; Peirce, T.; Moskvina, V.; Nikolov, I.; Hamshere, M.; Carroll, L.; Georgieva, L.; Dwyer, S; Holmans, P.; Marchini, J. L.; Spencer, C.C.A.; Howie, B.; Leung, H-T.; Giegling, I.; Hartmann, A.M.; Möller, H.-J.; Morris, D.W.; Shi, Y.; Feng, G.; Hoffmann, P.; Propping, P.; Vasilescu, C.; Maier, W.; Rietschel, M.; Zammit, S.; Schumacher, J.; Quinn, E.M.; Schulze, T.G.; Iwata, N.; Ikeda, M.; Darvasi, A.; Shifman, S.; He, L.; Duan, J.; Sanders, A.R.; Levinson, D.F.; Adolfsson, R.; Ösby, U.; Terenius, Lars; Jönsson, Erik G; Cichon, S.; Nöthen, M. M.; Gill, M.; Corvin, A.P.; Rujescu, D.; Gejman, P.V.; Kirov, G.; Craddock, N.; Williams, N.M.; Owen, M.J.

    2010-01-01

    We and others have previously reported linkage to schizophrenia on chromosome 10q25-q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 SNPs mapping to 10q25-q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with p<0.01 (n=40) were genotyped in an additional 163 UK cases and those markers that remained nominally significant at p<0.01 (n=22) were genotyped in replication samples from Ireland, Germany and Bulgaria consisting of a total of 1664 cases with schizophrenia and 3541 controls. Only one SNP, rs17101921, was nominally significant after meta-analyses across the replication samples and this was genotyped in an additional six samples from the US/Australia, Germany, China, Japan, Israel and Sweden (n= 5142 cases/ 6561 controls). Across all replication samples, the allele at rs17101921 that was associated in the GWAS showed evidence for association independent of the original data (OR 1.17 (95% CI 1.06-1.29), p=0.0009). The SNP maps 85kb from the nearest gene encoding fibroblast growth factor receptor 2 (FGFR2) making this a potential susceptibility gene for schizophrenia. PMID:18813210

  13. Interleukin-10- and Transforming Growth Factor β-Independent Regulation of CD8+ T Cells Expressing Type 1 and Type 2 Cytokines in Human Lymphatic Filariasis

    PubMed Central

    Anuradha, Rajamanickam; George, Parakkal Jovvian; Kumaran, Paul; Nutman, Thomas B.

    2014-01-01

    Lymphatic filariasis is known to be associated with diminished CD4+ Th1 and elevated CD4+ Th2 responses to parasite-specific antigens. The roles of cytokine-expressing CD8+ T cells in immune responses to filarial infections are not well defined. To study the roles of CD8+ T cells expressing type 1, type 2, and type 17 cytokines in filarial infections, we examined the frequencies of these cells in clinically asymptomatic, patently infected (INF) individuals, directly ex vivo and in response to parasite or nonparasite antigens; these frequencies were compared with the results for individuals with filarial lymphedema (i.e., clinical pathology [CP]) and those without active infection or pathology (i.e., endemic normal [EN]). INF individuals exhibited significant decreases in the frequencies of CD8+ T cells expressing tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), and interleukin-22 (IL-22) at baseline and/or in response to filarial antigens, compared with CP and EN individuals. In contrast, the same individuals exhibited significant increases in the frequencies of CD8+ T cells expressing IL-4, IL-5, IL-9, IL-13, and IL-21, compared with CP and/or EN individuals. Curative treatment resulted in significantly increased frequencies of CD8+ T cells expressing IL-2 and significantly decreased frequencies of CD8+ T cells expressing type 2 cytokines. Finally, the regulation of these responses appears to be independent of IL-10 and transforming growth factor β (TGF-β), since blockade of IL-10 or TGF-β signaling did not significantly alter the frequencies of type 1 or type 2 cytokine-expressing CD8+ T cells. Our findings suggest that alterations in the frequencies of cytokine-expressing CD8+ T cells are characteristic features of lymphatic filarial infections. PMID:25253667

  14. A Cationic-Independent Mannose 6-Phosphate Receptor Inhibitor (PXS64) Ameliorates Kidney Fibrosis by Inhibiting Activation of Transforming Growth Factor-β1

    PubMed Central

    Zhang, Jie; Wong, Muh Geot; Wong, May; Gross, Simon; Chen, Jason; Pollock, Carol; Saad, Sonia

    2015-01-01

    The activity of transforming growth factor-β1 (TGF-β1) is regulated by its conversion from the latent to the active form. We have previously shown that the conversion is at least in part mediated by the cationic-independent mannose 6-phosphate receptor (CI-M6PR), as the CI-M6PR inhibitor, PXS-25 has anti-fibrotic properties in human kidney tubular (HK-2) cells under high glucose conditions. However, its clinical use is limited by low bioavailability. Our aim was to determine the effects of PXS64, a pro-drug of PXS25, in in vitro and in vivo models of renal fibrosis. HK-2 cells were exposed to latent TGFβ1+/- PXS64 for 48 hours. The mRNA and protein levels of pro-fibrotic and pro-inflammatory markers were determined. A 7 day unilateral ureteric obstruction (UUO) model was used and the following experimental groups were studied: (i) Sham operated, (ii) UUO, (iii) UUO + telmisartan (iv) UUO + PSX64. HK-2 cells exposed to PXS64 reduced TGFβ mediated effects on collagen IV, fibronectin, macrophage chemotactic protein-1 (MCP-1) and phospho-smad2 protein expression, consistent with inhibition of the conversion of latent to active TGF-β1. PXS 64 treated UUO mice had a lower tubulointerstitial fibrosis index, collagen IV and fibronectin protein and mRNA expression when compared to untreated UUO mice. In addition, these animals had lower MCP-1 mRNA expression, reduced inflammarory cell infiltrate, as indicated by fewer CD45, F4/80 positive cells, and reduced phospho-Smad2 protein expression when compared to untreated UUO animals. Our data demonstrates that PSX64 is an effective anti-fibrotic agent by inhibiting the activation of latent TGF-β1. PMID:25658916

  15. Vascular endothelial growth factor A (VEGF-A) decreases expression and secretion of pleiotrophin in a VEGF receptor-independent manner.

    PubMed

    Poimenidi, Evangelia; Theodoropoulou, Christina; Koutsioumpa, Marina; Skondra, Lamprini; Droggiti, Eirini; van den Broek, Marloes; Koolwijk, Pieter; Papadimitriou, Evangelia

    2016-05-01

    Vascular endothelial growth factor A (VEGF-A) is a key molecule in angiogenesis acting through VEGF receptors (VEGFRs), ανβ3 integrin, receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and cell surface nucleolin (NCL). Pleiotrophin (PTN) stimulates endothelial cell migration and limits the angiogenic effects of VEGF-A165 to the levels of its own effect, possibly acting as a VEGF-A165 modifier. Since PTN and VEGF-A165 share receptors and actions on endothelial cells, in the present work we studied whether and how VEGF-A165 affects PTN expression or secretion. VEGF-A165 decreased PTN mRNA and protein levels acting at the transcriptional level. Bevacizumab, a selective VEGFR2 tyrosine kinase inhibitor and down-regulation of VEGFR2 expression by siRNA did not affect this decrease, suggesting that it is VEGFR-independent. VEGF-A121 also decreased PTN mRNA and protein levels, suggesting that heparin binding of VEGF-A165 is not involved. Blockage of cell surface NCL, lack of expression or mutation of β3 integrin and down-regulation of RPTPβ/ζ abolished the inhibitory effect of VEGF-A165 on PTN expression and secretion. Down-regulation of endogenous PTN in endothelial cells enhanced VEGF-A165-induced increase in migration and tube formation on matrigel. Collectively, these data suggest that VEGF-A down-regulates PTN expression and secretion through the RPTPβ/ζ-ανβ3-NCL axis to enhance its own effect on cell migration and further highlight the role of RPTPβ/ζ in VEGF-A actions. PMID:26924457

  16. Klotho/fibroblast growth factor 23- and PTH-independent estrogen receptor-α-mediated direct downregulation of NaPi-IIa by estrogen in the mouse kidney.

    PubMed

    Webster, Rose; Sheriff, Sulaiman; Faroqui, Rashma; Siddiqui, Faraaz; Hawse, John R; Amlal, Hassane

    2016-08-01

    Estrogen treatment causes renal phosphate (Pi) wasting and hypophosphatemia in rats and humans; however, the signaling mechanisms mediating this effect are still poorly understood. To determine the specific roles of estrogen receptor isoforms (ERα and ERβ) and the Klotho pathway in mediating these effects, we studied the effects of estrogen on renal Pi handling in female mice with null mutations of ERα or ERβ or Klotho and their wild type (WT) using balance studies in metabolic cages. Estrogen treatment of WT and ERβ knockout (KO) mice caused a significant reduction in food intake along with increased renal phosphate wasting. The latter resulted from a significant downregulation of NaPi-IIa and NaPi-IIc protein abundance. The mRNA expression levels of both transporters were unchanged in estrogen-treated mice. These effects on both food intake and renal Pi handling were absent in ERα KO mice. Estrogen treatment of Klotho KO mice or parathyroid hormone (PTH)-depleted thyroparathyroidectomized mice exhibited a significant downregulation of NaPi-IIa with no change in the abundance of NaPi-IIc. Estrogen treatment of a cell line (U20S) stably coexpressing both ERα and ERβ caused a significant downregulation of NaPi-IIa protein when transiently transfected with a plasmid containing full-length or open-reading frame (ORF) 3'-untranslated region (UTR) but not 5'-UTR ORF of mouse NaPi-IIa transcript. In conclusion, estrogen causes phosphaturia and hypophosphatemia in mice. These effects result from downregulation of NaPi-IIa and NaPi-IIc proteins in the proximal tubule through the activation of ERα. The downregulation of NaPi-IIa by estrogen involves 3'-UTR of its mRNA and is independent of Klotho/fibroblast growth factor 23 and PTH signaling pathways. PMID:27194721

  17. Extracellular Nm23H1 stimulates neurite outgrowth from dorsal root ganglia neurons in vitro independently of nerve growth factor supplementation or its nucleoside diphosphate kinase activity

    SciTech Connect

    Wright, K.T.; Seabright, R.; Logan, A.; Lilly, A.J.; Khanim, F.; Bunce, C.M.; Johnson, W.E.B.

    2010-07-16

    Research highlights: {yields} Extracellular Nm23H1 stimulates nerve growth. {yields} Extracellular Nm23H1 provides pathfinding cues to growth cones. {yields} The neurotrophic activity of Nm23H1 is independent of NDP kinase activity. {yields} The neurotrophic activity of Nm23H1 is independent of NGF. -- Abstract: The nucleoside diphosphate (NDP) kinase, Nm23H1, is a highly expressed during neuronal development, whilst induced over-expression in neuronal cells results in increased neurite outgrowth. Extracellular Nm23H1 affects the survival, proliferation and differentiation of non-neuronal cells. Therefore, this study has examined whether extracellular Nm23H1 regulates nerve growth. We have immobilised recombinant Nm23H1 proteins to defined locations of culture plates, which were then seeded with explants of embryonic chick dorsal root ganglia (DRG) or dissociated adult rat DRG neurons. The substratum-bound extracellular Nm23H1 was stimulatory for neurite outgrowth from chick DRG explants in a concentration-dependent manner. On high concentrations of Nm23H1, chick DRG neurite outgrowth was extensive and effectively limited to the location of the Nm23H1, i.e. neuronal growth cones turned away from adjacent collagen-coated substrata. Nm23H1-coated substrata also significantly enhanced rat DRG neuronal cell adhesion and neurite outgrowth in comparison to collagen-coated substrata. These effects were independent of NGF supplementation. Recombinant Nm23H1 (H118F), which does not possess NDP kinase activity, exhibited the same activity as the wild-type protein. Hence, a novel neuro-stimulatory activity for extracellular Nm23H1 has been identified in vitro, which may function in developing neuronal systems.

  18. FGF growth factor analogs

    DOEpatents

    Zamora, Paul O.; Pena, Louis A.; Lin, Xinhua; Takahashi, Kazuyuki

    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.

  19. 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.

  20. 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.

  1. Growth factors in haemopoiesis.

    PubMed

    Jones, A L; Millar, J L

    1989-01-01

    Haemopoietic growth factors have for over two decades allowed experimentalists to grow haemopoietic bone marrow cells in vitro. With refinements in technique and the discovery of novel growth factors, all of the known haemopoietic lineages can now be grown in vitro. This has allowed a much greater understanding of the complex process of haemopoiesis from the haemopoietic stem cell to the mature, functioning end-cell. The in vivo action of these growth factors has been harder to investigate. Although recombinant technology has afforded us the much greater quantities necessary for in vivo work, problems remain with administration because of effects on other tissues. Interpretation of results is difficult because of the complex inter-relationships which exist between factors. Some of these have been defined in vitro and it appears likely that they also operate in vivo. Erythropoietin is a physiological regulator of erythropoiesis. It has been detected in vivo with levels responding appropriately to stress (i.e. elevated in anaemia) and, when administered in pharmacological doses, has been shown to correct anaemia. Granulocyte/macrophage colony-stimulating factor (GM-CSF) has been detected in vivo and may influence the production and function of granulocytes and macrophages, although how it is regulated is unknown. Granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor are ore lineage-specific. Interleukin 3 (IL-3), although it has not been detected in vivo, may act on a primitive marrow precursor by expanding the population and making these cells more susceptible to other growth factors, such as GM-CSF. Interleukin 1 (IL-1) has been detected in vivo, does not appear to have any isolated action on bone marrow (except possibly radioprotection) but probably acts synergistically with other growth factors, such as G-CSF. Interleukins 2, 4, 5 and 6 have not been detected in vivo. All have effects on B-cells. In addition IL-2 is an essential

  2. Peptide growth factors, part B

    SciTech Connect

    Barnes, D.; Sirbasku, D.A.

    1987-01-01

    This book discusses the following topics: Platelet-Derived Growth Factor;Nerve and Glial Growth Factors;PC12 Pheochromocytoma Cells;Techniques for the Study of Growth Factor Activity;Genetic Approaches and Biological Effects.

  3. Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field Development.

    PubMed

    Lewandowski, Sara L; Janardhan, Harish P; Trivedi, Chinmay M

    2015-11-01

    About two-thirds of human congenital heart disease involves second heart field-derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the epigenome; however, their functions within the second heart field remain elusive. Here we demonstrate that histone deacetylase 3 (HDAC3) orchestrates epigenetic silencing of Tgf-β1, a causative factor in congenital heart disease pathogenesis, in a deacetylase-independent manner to regulate development of second heart field-derived structures. In murine embryos lacking HDAC3 in the second heart field, increased TGF-β1 bioavailability is associated with ascending aortic dilatation, outflow tract malrotation, overriding aorta, double outlet right ventricle, aberrant semilunar valve development, bicuspid aortic valve, ventricular septal defects, and embryonic lethality. Activation of TGF-β signaling causes aberrant endothelial-to-mesenchymal transition and altered extracellular matrix homeostasis in HDAC3-null outflow tracts and semilunar valves, and pharmacological inhibition of TGF-β rescues these defects. HDAC3 recruits components of the PRC2 complex, methyltransferase EZH2, EED, and SUZ12, to the NCOR complex to enrich trimethylation of Lys-27 on histone H3 at the Tgf-β1 regulatory region and thereby maintains epigenetic silencing of Tgf-β1 specifically within the second heart field-derived mesenchyme. Wild-type HDAC3 or catalytically inactive HDAC3 expression rescues aberrant endothelial-to-mesenchymal transition and epigenetic silencing of Tgf-β1 in HDAC3-null outflow tracts and semilunar valves. These findings reveal that epigenetic dysregulation within the second heart field is a predisposing factor for congenital heart disease. PMID:26420484

  4. Change in Growth Differentiation Factor 15, but Not C-Reactive Protein, Independently Predicts Major Cardiac Events in Patients with Non-ST Elevation Acute Coronary Syndrome

    PubMed Central

    Hernandez-Baldomero, Idaira F.; Bosa-Ojeda, Francisco

    2014-01-01

    Among the numerous emerging biomarkers, high-sensitivity C-reactive protein (hsCRP) and growth-differentiation factor-15 (GDF-15) have received widespread interest, with their potential role as predictors of cardiovascular risk. The concentrations of inflammatory biomarkers, however, are influenced, among others, by physiological variations, which are the natural, within-individual variation occurring over time. The aims of our study are: (a) to describe the changes in hsCRP and GDF-15 levels over a period of time and after an episode of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and (b) to examine whether the rate of change in hsCRP and GDF-15 after the acute event is associated with long-term major cardiovascular adverse events (MACE). Two hundred and Fifty five NSTE-ACS patients were included in the study. We measured hsCRP and GDF-15 concentrations, at admission and again 36 months after admission (end of the follow-up period). The present study shows that the change of hsCRP levels, measured after 36 months, does not predict MACE in NSTEACS-patients. However, the level of GDF-15 measured, after 36 months, was a stronger predictor of MACE, in comparison to the acute unstable phase. PMID:24839357

  5. Regulation of epidermal-growth-factor-receptor signal transduction by cis-unsaturated fatty acids. Evidence for a protein kinase C-independent mechanism.

    PubMed Central

    Casabiell, X; Pandiella, A; Casanueva, F F

    1991-01-01

    The effect of acute treatment with non-esterified fatty acids (NEFA) on transmembrane signalling has been investigated in three different cell lines. In EGFR T17 cells, pretreatment with cis-unsaturated (oleic and palmitoleic acids) NEFA, but not with saturated or trans-unsaturated NEFA, inhibited the epidermal-growth-factor (EGF)-induced increases in cytosolic [Ca2+], membrane potential and Ins(1,4,5)P3 generation. The blocking effect was found to be time- and dose-dependent and rapidly reversible after washout. However, oleic acid treatment did not block either binding of 125I-EGF to its receptor or EGF-induced autophosphorylation of the EGF receptor. The mechanism of action of NEFA could not be attributed to protein kinase C activation, since (i) down-regulation of the enzyme by long-term treatment with phorbol esters did not prevent blockade by oleic acid, and (ii) the effects of acutely administered phorbol ester and oleic acid were additive. In this cell line, signalling at bradykinin and bombesin receptors was also impaired by oleic acid. In A431 cells, oleic acid also blocked signal transduction at the EGF and B2 bradykinin receptors. Finally, in PC12 cells, oleic acid blocked the Ca2+ influx mediated by the activation of B2 bradykinin receptors. In conclusion: (1) NEFA block signal transduction by interfering with receptor-phospholipase C or phospholipase C-substrate interaction without preventing ligand binding; (2) NEFA do not act by a protein kinase C-mediated mechanism; (3) the effect of NEFA is dependent on their configuration rather than hydrophobicity or chain length; (4) this effect is evident in several different cell lines and receptor systems. Images Fig. 4. PMID:1898356

  6. The Interaction of Protein-tyrosine Phosphatase α (PTPα) and RACK1 Protein Enables Insulin-like Growth Factor 1 (IGF-1)-stimulated Abl-dependent and -independent Tyrosine Phosphorylation of PTPα*

    PubMed Central

    Khanna, Ranvikram S.; Le, Hoa T.; Wang, Jing; Fung, Thomas C. H.; Pallen, Catherine J.

    2015-01-01

    Protein tyrosine phosphatase α (PTPα) promotes integrin-stimulated cell migration in part through the role of Src-phosphorylated PTPα-Tyr(P)-789 in recruiting and localizing p130Cas to focal adhesions. The growth factor IGF-1 also stimulates PTPα-Tyr-789 phosphorylation to positively regulate cell movement. This is in contrast to integrin-induced PTPα phosphorylation, that induced by IGF-1 can occur in cells lacking Src family kinases (SFKs), indicating that an unknown kinase distinct from SFKs can target PTPα. We show that this IGF-1-stimulated tyrosine kinase is Abl. We found that PTPα binds to the scaffold protein RACK1 and that RACK1 coordinates the IGF-1 receptor, PTPα, and Abl in a complex to enable IGF-1-stimulated and Abl-dependent PTPα-Tyr-789 phosphorylation. In cells expressing SFKs, IGF-1-stimulated phosphorylation of PTPα is mediated by RACK1 but is Abl-independent. Furthermore, expressing the SFKs Src and Fyn in SFK-deficient cells switches IGF-1-induced PTPα phosphorylation to occur in an Abl-independent manner, suggesting that SFK activity dominantly regulates IGF-1/IGF-1 receptor signaling to PTPα. RACK1 is a molecular scaffold that integrates growth factor and integrin signaling, and our identification of PTPα as a RACK1 binding protein suggests that RACK1 may coordinate PTPα-Tyr-789 phosphorylation in these signaling networks to promote cell migration. PMID:25694432

  7. The interaction of protein-tyrosine phosphatase α (PTPα) and RACK1 protein enables insulin-like growth factor 1 (IGF-1)-stimulated Abl-dependent and -independent tyrosine phosphorylation of PTPα.

    PubMed

    Khanna, Ranvikram S; Le, Hoa T; Wang, Jing; Fung, Thomas C H; Pallen, Catherine J

    2015-04-10

    Protein tyrosine phosphatase α (PTPα) promotes integrin-stimulated cell migration in part through the role of Src-phosphorylated PTPα-Tyr(P)-789 in recruiting and localizing p130Cas to focal adhesions. The growth factor IGF-1 also stimulates PTPα-Tyr-789 phosphorylation to positively regulate cell movement. This is in contrast to integrin-induced PTPα phosphorylation, that induced by IGF-1 can occur in cells lacking Src family kinases (SFKs), indicating that an unknown kinase distinct from SFKs can target PTPα. We show that this IGF-1-stimulated tyrosine kinase is Abl. We found that PTPα binds to the scaffold protein RACK1 and that RACK1 coordinates the IGF-1 receptor, PTPα, and Abl in a complex to enable IGF-1-stimulated and Abl-dependent PTPα-Tyr-789 phosphorylation. In cells expressing SFKs, IGF-1-stimulated phosphorylation of PTPα is mediated by RACK1 but is Abl-independent. Furthermore, expressing the SFKs Src and Fyn in SFK-deficient cells switches IGF-1-induced PTPα phosphorylation to occur in an Abl-independent manner, suggesting that SFK activity dominantly regulates IGF-1/IGF-1 receptor signaling to PTPα. RACK1 is a molecular scaffold that integrates growth factor and integrin signaling, and our identification of PTPα as a RACK1 binding protein suggests that RACK1 may coordinate PTPα-Tyr-789 phosphorylation in these signaling networks to promote cell migration. PMID:25694432

  8. Overexpression of Cyclooxygenase-2 and Transforming Growth Factor-Beta 1 is an Independent Predictor of Poor Virological Response to Interferon Therapy in Chronic HCV Genotype 4 Patients

    PubMed Central

    Gomaa, Wafaey M.; Ibrahim, Mohammed A.; Shatat, Mohamed E.

    2014-01-01

    Background/Aims: COX-2 and TGF-β1 are overexpressed in hepatitis C virus (HCV) infection and are related to hepatitis pathogenesis and hepatic fibrosis. The current study investigated the relationship between pretreatment COX-2 and TGF-β1 hepatic expression in HCV genotype 4 and the virological response to interferon therapy. Patients and Methods: Liver biopsies of 55 patients with HCV infection genotype 4 were selected together with 10 liver biopsies as control. The patients’ clinicopathological data were collected. Immunohistochemistry was done using anti-COX-2 and anti-TGF-β1 antibodies. Statistical tests were used to determine the association between both COX-2 and TGF-β1 expression in relation to clinicopathological parameters and response to interferon therapy. Results: COX-2 was upregulated especially in nonresponders and was an independent predictor of poor virological response. However, COX-2 showed no association with other clinicopathological features. TGF-β1 was upregulated and associated with nonresponders, histological activity, and fibrosis stage. There was no association between TGF-β1 and other clinicopathological features. There was an association between COX-2 and TGF-β1 immunoexpression. Conclusion: Overexpression of COX-2 and TGF-β1 is an independent predictor for poor outcome of interferon and ribavirin therapy and these might be useful markers for the response to treatment. Both molecules are associated together; however, their role during hepatitis treatment has to be clarified. PMID:24496160

  9. Aortic Carboxypeptidase-like Protein (ACLP) Enhances Lung Myofibroblast Differentiation through Transforming Growth Factor β Receptor-dependent and -independent Pathways*

    PubMed Central

    Tumelty, Kathleen E.; Smith, Barbara D.; Nugent, Matthew A.; Layne, Matthew D.

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal lung disease characterized by the overgrowth, hardening, and scarring of lung tissue. The exact mechanisms of how IPF develops and progresses are unknown. IPF is characterized by extracellular matrix remodeling and accumulation of active TGFβ, which promotes collagen expression and the differentiation of smooth muscle α-actin (SMA)-positive myofibroblasts. Aortic carboxypeptidase-like protein (ACLP) is an extracellular matrix protein secreted by fibroblasts and myofibroblasts and is expressed in fibrotic human lung tissue and in mice with bleomycin-induced fibrosis. Importantly, ACLP knockout mice are significantly protected from bleomycin-induced fibrosis. The goal of this study was to identify the mechanisms of ACLP action on fibroblast differentiation. As primary lung fibroblasts differentiated into myofibroblasts, ACLP expression preceded SMA and collagen expression. Recombinant ACLP induced SMA and collagen expression in mouse and human lung fibroblasts. Knockdown of ACLP slowed the fibroblast-to-myofibroblast transition and partially reverted differentiated myofibroblasts by reducing SMA expression. We hypothesized that ACLP stimulates myofibroblast formation partly through activating TGFβ signaling. Treatment of fibroblasts with recombinant ACLP induced phosphorylation and nuclear translocation of Smad3. This phosphorylation and induction of SMA was dependent on TGFβ receptor binding and kinase activity. ACLP-induced collagen expression was independent of interaction with the TGFβ receptor. These findings indicate that ACLP stimulates the fibroblast-to-myofibroblast transition by promoting SMA expression via TGFβ signaling and promoting collagen expression through a TGFβ receptor-independent pathway. PMID:24344132

  10. Growth hormone, growth factors, and acromegaly

    SciTech Connect

    Ludecke, D.K.; Tolis, G.T.

    1987-01-01

    This book contains five sections, each consisting of several papers. The section headings are: Biochemistry and Physiology of GH and Growth Factors, Pathology of Acromegaly, Clinical Endocrinology of Acromegaly, Nonsurgical Therapy of Acromegaly, and Surgical Therapy of Acromegaly.

  11. Insulin-Like Growth Factor I Produces an Antidepressant-Like Effect and Elicits N-Methyl-D-Aspartate Receptor Independent Long-Term Potentiation of Synaptic Transmission in Medial Prefrontal Cortex and Hippocampus

    PubMed Central

    Zhang, Xiao-lei; Colechio, Elizabeth M.; Ghoreishi-Haack, Nayereh; Gross, Amanda; Kroes, Roger A.; Stanton, Patric K.; Moskal, Joseph R.

    2016-01-01

    Background: Growth factors play an important role in regulating neurogenesis and synapse formation and may be involved in regulating the antidepressant response to conventional antidepressants. To date, Insulin-like growth factor I (IGFI) is the only growth factor that has shown antidepressant properties in human clinical trials. However, its mechanism of action remains unclear. Methods: The antidepressant-like effect of a single IV dose of IGFI was determined using a chronic unpredictable stress paradigm in the rat Porsolt, sucrose preference, novelty-induced hypophagia, and ultrasonic vocalization models. The dependence of the medial prefrontal cortex for these effects was determined by direct medial prefrontal cortex injection followed by Porsolt testing as well as IGFI receptor activation in the medial prefrontal cortex following an optimal IV antidepressant-like dose of IGFI. The effect of IGFI on synaptic transmission and long-term potentiation (LTP) of synaptic strength was assessed in the hippocampus and medial prefrontal cortex. The dependence of these effects on IGFI and AMPA receptor activation and protein synthesis were also determined. Results: IGFI produced a rapid-acting and long-lasting antidepressant-like effect in each of the depression models. These effects were blocked by IGFI and AMPA receptor antagonists, and medial prefrontal cortex was localized. IGFI robustly increased synaptic strength in the hippocampus and medial prefrontal cortex and these effects were IGFI receptor and protein synthesis-dependent but N-methyl-d-aspartate receptor independent. IGFI also robustly facilitated hippocampal metaplasticity 24 hours postdosing. Conclusions: These data support the conclusion that the antidepressant-like effects of IGFI are mediated by a persistent, LTP-like enhancement of synaptic strength requiring both IGFIR activation and ongoing protein synthesis. PMID:26374350

  12. Partially transformed, anchorage-independent human diploid fibroblasts result from overexpression of the c-sis oncogene: mitogenic activity of an apparent monomeric platelet-derived growth factor 2 species.

    PubMed Central

    Stevens, C W; Brondyk, W H; Burgess, J A; Manoharan, T H; Häne, B G; Fahl, W E

    1988-01-01

    A human c-sis cDNA in an expression vector was introduced into human diploid fibroblasts by transfection or electroporation. Fibroblast clones showing an aberrant, densely packed colony morphology were isolated and found to overexpress a 3.6-kilobase sis mRNA species and associated immunoprecipitable platelet-derived growth factor (PDGF) 2 proteins. Parallel analyses in cell clones of sis mRNA expression and colony formation in agar indicated that, above a threshold, a linear, positive correlation existed between sis overexpression and acquired anchorage independence. The sis-overexpressing cells formed transient, regressing tumor nodules when injected into nude mice, consistent with the finite life span which they retained. Protein products generated from the transfected c-sis construct in two overexpressing clones were immunoprecipitated with anti-human PDGF antibodies. One clone contained an apparent PDGF dimer of 21 kilodaltons; the second clone contained only an apparent PDGF monomer of 12 kilodaltons, which was shown to account for all of the mitogenic activity present in the cells, essentially all of which was concentrated in the membrane fraction. The results demonstrate a clear link between sis overexpression and acquisition of a partially transformed, anchorage-independent phenotype, and when combined with previous observations of sis overexpression in human tumors, clearly implicate sis overexpression as a genetic mechanism which contributes to human cell transformation. Images PMID:3290648

  13. Fibroblast Growth Factor 21 Levels in Young Healthy Females Display Day and Night Variations and Are Increased in Response to Short-Term Energy Deprivation Through a Leptin-Independent Pathway

    PubMed Central

    Foo, Joo-Pin; Aronis, Konstantinos N.; Chamberland, John P.; Paruthi, Jason; Moon, Hyun-Seuk; Mantzoros, Christos S.

    2013-01-01

    OBJECTIVE Fibroblast growth factor (FGF)-21 is an endocrine factor with potent metabolic effects. Its day–night patterns of secretion and/or its physiological response to energy deprivation and relationship to free fatty acids (FFAs) and/or leptin remain to be fully elucidated. We aim to elucidate day–night pattern of FGF-21 levels and its relationship to FFA, to assess whether energy deprivation alters its circulating patterns, and to examine whether leptin may mediate these changes. RESEARCH DESIGN AND METHODS Six healthy lean females were studied for 72 h in a cross-over interventional study under three different conditions: on isocaloric diet and in a fasting state with administration of either placebo or metreleptin in physiological replacement doses. Blood samples were obtained hourly from 8:00 a.m. on day 4 until 8:00 a.m. on day 5. RESULTS FGF-21 exhibited day–night variation pattern during the isocaloric fed state. Fasting significantly increased FGF-21 levels (P < 0.01) via a leptin-independent pathway. Day–night variation pattern in the fed state was lost on fasting. Leptin replacement in the hypoleptinemic state restored approximate entropy of FGF-21 time series but did not alter circulating levels. FGF-21 levels were closely cross-correlated with FFA levels in all three states. CONCLUSIONS A day–night variation in the levels of FGF-21 exists in young lean females in the fed state. Energy deprivation increases FGF-21 levels via a leptin-independent pathway. The interaction between FGF-21 and starvation-induced lipolysis, as indicated by its close cross-correlations with FFA in both fed state and energy deprivation, needs to be studied further. PMID:23193213

  14. Interstitial fibrosis and growth factors.

    PubMed Central

    Lasky, J A; Brody, A R

    2000-01-01

    Interstitial pulmonary fibrosis (IPF) is scarring of the lung caused by a variety of inhaled agents including mineral particles, organic dusts, and oxidant gases. The disease afflicts millions of individuals worldwide, and there are no effective therapeutic approaches. A major reason for this lack of useful treatments is that few of the molecular mechanisms of disease have been defined sufficiently to design appropriate targets for therapy. Our laboratory has focused on the molecular mechanisms through which three selected peptide growth factors could play a role in the development of IPF. Hundreds of growth factors and cytokines could be involved in the complex disease process. We are studying platelet-derived growth factor because it is the most potent mesenchymal cell mitogen yet described, transforming growth factor beta because it is a powerful inducer of extracellular matrix (scar tissue) components by mesenchymal cells, and tumor necrosis factor alpha because it is a pleiotropic cytokine that we and others have shown is essential for the development of IPF in animal models. This review describes some of the evidence from studies in humans, in animal models, and in vitro, that supports the growth factor hypothesis. The use of modern molecular and transgenic technologies could elucidate those targets that will allow effective therapeutic approaches. Images Figure 1 Figure 2 PMID:10931794

  15. Knockdown of hepatoma-derived growth factor-related protein-3 induces apoptosis of H1299 cells via ROS-dependent and p53-independent NF-κB activation

    SciTech Connect

    Yun, Hong Shik; Baek, Jeong-Hwa; Yim, Ji-Hye; Lee, Su-Jae; Lee, Chang-Woo; Song, Jie-Young; Um, Hong-Duck; Park, Jong Kuk; Park, In-Chul; Hwang, Sang-Gu

    2014-07-11

    Highlights: • HRP-3 is a radiation- and anticancer drug-responsive protein in H1299 cells. • Depletion of HRP-3 induces apoptosis of radio- and chemoresistant H1299 cells. • Depletion of HRP-3 promotes ROS generation via inhibition of the Nrf2/HO-1 pathway. • ROS generation enhances NF-κB activity, which acts as an upstream signal in the c-Myc/Noxa apoptotic pathway. - Abstract: We previously identified hepatoma-derived growth factor-related protein-3 (HRP-3) as a radioresistant biomarker in p53 wild-type A549 cells and found that p53-dependent induction of the PUMA pathway was a critical event in regulating the radioresistant phenotype. Here, we found that HRP-3 knockdown regulates the radioresistance of p53-null H1299 cells through a distinctly different molecular mechanism. HRP-3 depletion was sufficient to cause apoptosis of H1299 cells by generating substantial levels of reactive oxygen species (ROS) through inhibition of the Nrf2/HO-1 antioxidant pathway. Subsequent, ROS-dependent and p53-independent NF-κB activation stimulated expression of c-Myc and Noxa proteins, thereby inducing the apoptotic machinery. Our results thus extend the range of targets for the development of new drugs to treat both p53 wild-type or p53-null radioresistant lung cancer cells.

  16. Stimulation of low-density lipoprotein uptake in HepG2 cells by epidermal growth factor via a tyrosine kinase-dependent, but protein kinase C-independent, mechanism.

    PubMed Central

    Graham, A; Russell, L J

    1994-01-01

    Epidermal growth factor (EGF), a potent mitogenic polypeptide, stimulated the uptake and degradation of [3H]sucrose-labelled low-density lipoprotein (LDL) by HepG2 cells. The increase in LDL uptake was prevented by the presence of the tyrosine kinase inhibitor genistein. Activation of protein kinase C with phorbol 12-myristate 13-acetate (PMA) also stimulated the uptake of [3H]LDL by HepG2 cells. When EGF and PMA were added together, PMA increased the response to EGF in an additive manner. The protein kinase C inhibitor Ro-31-8220 prevented the increase in LDL uptake caused by PMA, but did not affect EGF stimulation of LDL uptake. Similarly, down-regulation of protein kinase C activity by chronic treatment with PMA also did not affect the EGF stimulation of LDL uptake. These results suggest that the EGF stimulation of LDL uptake and degradation by HepG2 cells is mediated by a tyrosine kinase-dependent, but protein kinase C-independent, mechanism. PMID:8141769

  17. Growth factors in ischemic stroke

    PubMed Central

    Lanfranconi, S; Locatelli, F; Corti, S; Candelise, L; Comi, G P; Baron, P L; Strazzer, S; Bresolin, N; Bersano, A

    2011-01-01

    Abstract Data from pre-clinical and clinical studies provide evidence that colony-stimulating factors (CSFs) and other growth factors (GFs) can improve stroke outcome by reducing stroke damage through their anti-apoptotic and anti-inflammatory effects, and by promoting angiogenesis and neurogenesis. This review provides a critical and up-to-date literature review on CSF use in stroke. We searched for experimental and clinical studies on haemopoietic GFs such as granulocyte CSF, erythropoietin, granulocyte-macrophage colony-stimulating factor, stem cell factor (SCF), vascular endothelial GF, stromal cell-derived factor-1α and SCF in ischemic stroke. We also considered studies on insulin-like growth factor-1 and neurotrophins. Despite promising results from animal models, the lack of data in human beings hampers efficacy assessments of GFs on stroke outcome. We provide a comprehensive and critical view of the present knowledge about GFs and stroke, and an overview of ongoing and future prospects. PMID:20015202

  18. Reductive carboxylation supports redox homeostasis during anchorage-independent growth.

    PubMed

    Jiang, Lei; Shestov, Alexander A; Swain, Pamela; Yang, Chendong; Parker, Seth J; Wang, Qiong A; Terada, Lance S; Adams, Nicholas D; McCabe, Michael T; Pietrak, Beth; Schmidt, Stan; Metallo, Christian M; Dranka, Brian P; Schwartz, Benjamin; DeBerardinis, Ralph J

    2016-04-14

    Cells receive growth and survival stimuli through their attachment to an extracellular matrix (ECM). Overcoming the addiction to ECM-induced signals is required for anchorage-independent growth, a property of most malignant cells. Detachment from ECM is associated with enhanced production of reactive oxygen species (ROS) owing to altered glucose metabolism. Here we identify an unconventional pathway that supports redox homeostasis and growth during adaptation to anchorage independence. We observed that detachment from monolayer culture and growth as anchorage-independent tumour spheroids was accompanied by changes in both glucose and glutamine metabolism. Specifically, oxidation of both nutrients was suppressed in spheroids, whereas reductive formation of citrate from glutamine was enhanced. Reductive glutamine metabolism was highly dependent on cytosolic isocitrate dehydrogenase-1 (IDH1), because the activity was suppressed in cells homozygous null for IDH1 or treated with an IDH1 inhibitor. This activity occurred in absence of hypoxia, a well-known inducer of reductive metabolism. Rather, IDH1 mitigated mitochondrial ROS in spheroids, and suppressing IDH1 reduced spheroid growth through a mechanism requiring mitochondrial ROS. Isotope tracing revealed that in spheroids, isocitrate/citrate produced reductively in the cytosol could enter the mitochondria and participate in oxidative metabolism, including oxidation by IDH2. This generates NADPH in the mitochondria, enabling cells to mitigate mitochondrial ROS and maximize growth. Neither IDH1 nor IDH2 was necessary for monolayer growth, but deleting either one enhanced mitochondrial ROS and reduced spheroid size, as did deletion of the mitochondrial citrate transporter protein. Together, the data indicate that adaptation to anchorage independence requires a fundamental change in citrate metabolism, initiated by IDH1-dependent reductive carboxylation and culminating in suppression of mitochondrial ROS. PMID:27049945

  19. Reductive carboxylation supports redox homeostasis during anchorage-independent growth

    PubMed Central

    Jiang, Lei; Shestov, Alexander A.; Swain, Pamela; Yang, Chendong; Parker, Seth J.; Wang, Qiong A.; Terada, Lance S.; Adams, Nicholas D.; McCabe, Michael T.; Pietrak, Beth; Schmidt, Stan; Metallo, Christian M.; Dranka, Brian P.; Schwartz, Benjamin; DeBerardinis, Ralph J.

    2016-01-01

    Epithelial cells receive growth and survival stimuli through their attachment to an extracellular matrix (ECM)1. Overcoming the addiction to ECM-induced signals is required for anchorage-independent growth, a property of most malignant cells2. Detachment from ECM is associated with enhanced reactive oxygen species (ROS) due to altered glucose metabolism2. Here we identify an unconventional pathway that supports redox homeostasis and growth during adaptation to anchorage independence. We observed that detachment from monolayer culture and growth as anchorage-independent tumor spheroids was accompanied by changes in both glucose and glutamine metabolism. Specifically, oxidation of both nutrients was suppressed in spheroids, whereas reductive formation of citrate from glutamine was enhanced. Reductive glutamine metabolism was highly dependent on cytosolic isocitrate dehydrogenase-1 (IDH1), because the activity was suppressed in cells homozygous null for IDH1 or treated with an IDH1 inhibitor. This activity occurred in absence of hypoxia, a well-known inducer of reductive metabolism. Rather, IDH1 mitigated mitochondrial ROS in spheroids, and suppressing IDH1 reduced spheroid growth through a mechanism requiring mitochondrial ROS. Isotope tracing revealed that in spheroids, isocitrate/citrate produced reductively in the cytosol could enter the mitochondria and participate in oxidative metabolism, including oxidation by IDH2. This generates NADPH in the mitochondria, enabling cells to mitigate mitochondrial ROS and maximize growth. Neither IDH1 nor IDH2 was necessary for monolayer growth, but deleting either one enhanced mitochondrial ROS and reduced spheroid size, as did deletion of the mitochondrial citrate transporter protein. Together, the data indicate that adaptation to anchorage independence requires a fundamental change in citrate metabolism, initiated by IDH1-dependent reductive carboxylation and culminating in suppression of mitochondrial ROS. PMID:27049945

  20. Fibroblast Growth Factor 8 Expression in GT1-7 GnRH-Secreting Neurons Is Androgen-Independent, but Can Be Upregulated by the Inhibition of DNA Methyltransferases

    PubMed Central

    Linscott, Megan L.; Chung, Wilson C. J.

    2016-01-01

    Fibroblast growth factor 8 (FGF8) is a potent morphogen that regulates the embryonic development of hypothalamic neuroendocrine cells. Indeed, using Fgf8 hypomorphic mice, we showed that reduced Fgf8 mRNA expression completely eliminated the presence of gonadotropin-releasing hormone (GnRH) neurons. These findings suggest that FGF8 signaling is required during the embryonic development of mouse GnRH neurons. Additionally, in situ hybridization studies showed that the embryonic primordial birth place of GnRH neurons, the olfactory placode, is highly enriched for Fgf8 mRNA expression. Taken together these data underscore the importance of FGF8 signaling for GnRH emergence. However, an important question remains unanswered: How is Fgf8 gene expression regulated in the developing embryonic mouse brain? One major candidate is the androgen receptor (AR), which has been shown to upregulate Fgf8 mRNA in 60–70% of newly diagnosed prostate cancers. Therefore, we hypothesized that ARs may be involved in the regulation of Fgf8 transcription in the developing mouse brain. To test this hypothesis, we used chromatin-immunoprecipitation (ChIP) assays to elucidate whether ARs interact with the 5′UTR region upstream of the translational start site of the Fgf8 gene in immortalized mouse GnRH neurons (GT1-7) and nasal explants. Our data showed that while AR interacts with the Fgf8 promoter region, this interaction was androgen-independent, and that androgen treatment did not affect Fgf8 mRNA levels, indicating that androgen signaling does not induce Fgf8 transcription. In contrast, inhibition of DNA methyltransferases (DNMT) significantly upregulated Fgf8 mRNA levels indicating that Fgf8 transcriptional activity may be dependent on DNA methylation status. PMID:27200347

  1. Changes in epidermal growth factor receptor expression and response to ligand associated with acquired tamoxifen resistance or oestrogen independence in the ZR-75-1 human breast cancer cell line.

    PubMed Central

    Long, B.; McKibben, B. M.; Lynch, M.; van den Berg, H. W.

    1992-01-01

    We have examined the expression of receptors for epidermal growth factor (EGFR) by the ZR-75-1 human breast cancer cell line and tamoxifen resistant (ZR-75-9al 8 microM) and oestrogen independent/tamoxifen sensitive (ZR-PR-LT) variants. The parent line expressed a single class of high affinity binding sites (4,340 +/- 460 receptors/cell; Kd 0.23 +/- 0.04 nM). ZR-75-9al 8 microM cells, routinely maintained in medium containing 8 microM tamoxifen, were negative for oestrogen receptor (ER) and progesterone receptor (PGR) and expressed a markedly increased number of EGFR (14,723 +/- 2116 receptors/cell). Receptor affinity was unchanged. Time dependent reversal of the tamoxifen resistant phenotype was accompanied by a return to ER and PGR positivity and a fall in EGFR numbers to parent cell levels. In contrast ZR-PR-LT cells had a greatly reduced EGFR content (803 +/- 161 receptors/cell) accompanying elevated PGR numbers. Pre-treatment of these cells with suramin or mild acid stripping failed to expose receptors which may have been occupied by endogenously produced ligand. Increased proliferation of ZR-75-1 cells treated with EGFR (0.01-10 ng ml-1) was only observed in serum-free medium lacking insulin and oestradiol. Under these conditions untreated cells failed to proliferate. Both variant lines continued to proliferate in serum free medium in the absence or presence of insulin and oestradiol but failed to respond to exogenous EGF. PMID:1616857

  2. Constrained growth of complex scale-independent systems

    NASA Astrophysics Data System (ADS)

    Hébert-Dufresne, Laurent; Allard, Antoine; Young, Jean-Gabriel; Dubé, Louis J.

    2016-03-01

    Scale independence is a ubiquitous feature of complex systems that implies a highly skewed distribution of resources with no characteristic scale. Research has long focused on why systems as varied as protein networks, evolution, and stock actions all feature scale independence. Assuming that they simply do, we focus here on describing how this behavior emerges, in contrast to more idealized models usually considered. We arrive at the conjecture that a minimal model to explain the growth toward scale independence involves only two coupled dynamical features: the first is the well-known preferential attachment principle, and the second is a general form of delayed temporal scaling. While the first is sufficient, the second is present in all studied data and appears to maximize the speed of convergence to true scale independence. The delay in this temporal scaling acts as a coupling between population growth and individual activity. Together, these two dynamical properties appear to pave a precise evolution path, such that even an instantaneous snapshot of a distribution is enough to reconstruct the past of the system and predict its future. We validate our approach and confirm its usefulness in diverse spheres of human activities, ranging from scientific and artistic productivity to sexual relations and online traffic.

  3. Constrained growth of complex scale-independent systems.

    PubMed

    Hébert-Dufresne, Laurent; Allard, Antoine; Young, Jean-Gabriel; Dubé, Louis J

    2016-03-01

    Scale independence is a ubiquitous feature of complex systems that implies a highly skewed distribution of resources with no characteristic scale. Research has long focused on why systems as varied as protein networks, evolution, and stock actions all feature scale independence. Assuming that they simply do, we focus here on describing how this behavior emerges, in contrast to more idealized models usually considered. We arrive at the conjecture that a minimal model to explain the growth toward scale independence involves only two coupled dynamical features: the first is the well-known preferential attachment principle, and the second is a general form of delayed temporal scaling. While the first is sufficient, the second is present in all studied data and appears to maximize the speed of convergence to true scale independence. The delay in this temporal scaling acts as a coupling between population growth and individual activity. Together, these two dynamical properties appear to pave a precise evolution path, such that even an instantaneous snapshot of a distribution is enough to reconstruct the past of the system and predict its future. We validate our approach and confirm its usefulness in diverse spheres of human activities, ranging from scientific and artistic productivity to sexual relations and online traffic. PMID:27078363

  4. Interleukin-10- and transforming growth factor β-independent regulation of CD8⁺ T cells expressing type 1 and type 2 cytokines in human lymphatic filariasis.

    PubMed

    Anuradha, Rajamanickam; George, Parakkal Jovvian; Kumaran, Paul; Nutman, Thomas B; Babu, Subash

    2014-12-01

    Lymphatic filariasis is known to be associated with diminished CD4⁺ Th1 and elevated CD4⁺ Th2 responses to parasite-specific antigens. The roles of cytokine-expressing CD8⁺ T cells in immune responses to filarial infections are not well defined. To study the roles of CD8⁺ T cells expressing type 1, type 2, and type 17 cytokines in filarial infections, we examined the frequencies of these cells in clinically asymptomatic, patently infected (INF) individuals, directly ex vivo and in response to parasite or nonparasite antigens; these frequencies were compared with the results for individuals with filarial lymphedema (i.e., clinical pathology [CP]) and those without active infection or pathology (i.e., endemic normal [EN]). INF individuals exhibited significant decreases in the frequencies of CD8⁺ T cells expressing tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), and interleukin-22 (IL-22) at baseline and/or in response to filarial antigens, compared with CP and EN individuals. In contrast, the same individuals exhibited significant increases in the frequencies of CD8⁺ T cells expressing IL-4, IL-5, IL-9, IL-13, and IL-21, compared with CP and/or EN individuals. Curative treatment resulted in significantly increased frequencies of CD8⁺ T cells expressing IL-2 and significantly decreased frequencies of CD8⁺ T cells expressing type 2 cytokines. Finally, the regulation of these responses appears to be independent of IL-10 and transforming growth factor β (TGF-β), since blockade of IL-10 or TGF-β signaling did not significantly alter the frequencies of type 1 or type 2 cytokine-expressing CD8⁺ T cells. Our findings suggest that alterations in the frequencies of cytokine-expressing CD8⁺ T cells are characteristic features of lymphatic filarial infections. PMID:25253667

  5. Growth factors in orthopedic surgery

    PubMed Central

    Zaharia, C; Despa, N; Simionescu, M; Jinga, V; Fleseriu, I

    2010-01-01

    Growth factors have represented an essential issue of interest for the researchers and clinicians in orthopedics and trauma over the last 40 years. In the last 10 to 15 years, the advances registered in this field have permitted the identification of the most active cellular and humoral factors as well as the improvement of their use in the orthopedic and trauma surgery. Their domain of application has been continuously enlarged and the results have been visible from the beginning. The authors present their appreciation on the actual state of this subject as well as their experience with results and related conclusions. PMID:20302195

  6. Growth hormone-insulinlike growth factor I and immune function.

    PubMed

    Gelato, M C

    1993-04-01

    Growth hormone (GH) and insulinlike growth factor I (IGF-I) may be part of a neuroendocrine immune axis that stimulates cellular proliferation of primary lymphoid organs (bone marrow, thymus) as well as stimulates activation of peripheral lymphocytes and macrophages to enhance specific immune responses. GH can also stimulate production of thymic hormones and cytokines, and in this way impact on immune function. It is not clear whether GH and IGF-I act independently or whether the action of GH is mediated by local production of IGF-I by lymphocytes. Both GH and IGF-I and their receptors are present in lymphocytes. Thus, cells of the immune system may be important targets of the GH-IGF-I axis. PMID:18407143

  7. Benefit to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2)-targeted therapies in HER2-positive primary breast cancer is independent of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) status

    PubMed Central

    Nuciforo, P. G.; Aura, C.; Holmes, E.; Prudkin, L.; Jimenez, J.; Martinez, P.; Ameels, H.; de la Peña, L.; Ellis, C.; Eidtmann, H.; Piccart-Gebhart, M. J.; Scaltriti, M.; Baselga, J.

    2015-01-01

    Background Assessment of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) might be an important tool in identifying human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients unlikely to derive benefit from anti-HER2 therapies. However, studies to date have failed to demonstrate its predictive role in any treatment setting. Patients and methods Prospectively collected baseline core biopsies from 429 early-stage HER2-positive breast cancer patients treated with trastuzumab, lapatinib, or their combination in the Neo-ALTTO study were stained using two anti-PTEN monoclonal antibodies (CST and DAKO). The association of PTEN status and PI3K pathway activation (defined as either PTEN loss and/or PIK3CA mutation) with total pathological complete response (tpCR) at surgery, event-free survival (EFS), and overall survival (OS) was evaluated. Results PTEN loss was observed in 27% and 29% of patients (all arms, n = 361 and n = 363) for CST and DAKO, respectively. PTEN loss was more frequently observed in hormone receptor (HR)-negative (33% and 36% with CST and DAKO, respectively) compared with HR-positive tumours (20% and 22% with CST and DAKO, respectively). No significant differences in tpCR rates were observed according to PTEN status. PI3K pathway activation was found in 47% and 48% of patients (all arms, n = 302 and n = 301) for CST and DAKO, respectively. Similarly, tpCR rates were not significantly different for those with or without PI3K pathway activation. Neither PTEN status nor PI3K pathway activation were predictive of tpCR, EFS, or OS, independently of treatment arm or HR status. High inter-antibody and inter-observer agreements were found (>90%). Modification of scoring variables significantly affected the correlation between PTEN and HR status but not with tpCR. Conclusion These data show that PTEN status determination is not a useful biomarker to predict resistance to trastuzumab and lapatinib-based therapies. The lack of

  8. Nerve Growth Factor and Diabetic Neuropathy

    PubMed Central

    Vinik, Aaron

    2003-01-01

    Neuropathy is one of the most debilitating complications of both type 1 and type 2 diabetes, with estimates of prevalence between 50–90% depending on the means of detection. Diabetic neuropathies are heterogeneous and there is variable involvement of large myelinated fibers and small, thinly myelinated fibers. Many of the neuronal abnormalities in diabetes can be duplicated by experimental depletion of specific neurotrophic factors, their receptors or their binding proteins. In experimental models of diabetes there is a reduction in the availability of these growth factors, which may be a consequence of metabolic abnormalities, or may be independent of glycemic control. These neurotrophic factors are required for the maintenance of the neurons, the ability to resist apoptosis and regenerative capacity. The best studied of the neurotrophic factors is nerve growth factor (NGF) and the related members of the neurotrophin family of peptides. There is increasing evidence that there is a deficiency of NGF in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) that may also contribute to the clinical symptoms resulting from small fiber dysfunction. Similarly, NT3 appears to be important for large fiber and IGFs for autonomic neuropathy. Whether the observed growth factor deficiencies are due to decreased synthesis, or functional, e.g. an inability to bind to their receptor, and/or abnormalities in nerve transport and processing, remains to be established. Although early studies in humans on the role of neurotrophic factors as a therapy for diabetic neuropathy have been unsuccessful, newer agents and the possibilities uncovered by further studies should fuel clinical trials for several generations. It seems reasonable to anticipate that neurotrophic factor therapy, specifically targeted at different nerve fiber populations, might enter the therapeutic armamentarium. PMID:14668049

  9. Transforming growth factor-beta 1 and fibroblast growth factors in rat growth plate.

    PubMed

    Jingushi, S; Scully, S P; Joyce, M E; Sugioka, Y; Bolander, M E

    1995-09-01

    Chondrocytes in the growth plate progress in an orderly fashion from resting through proliferating to hypertrophic cells. In the region of hypertrophic chondrocytes, the cartilage is invaded by capillary loops and endochondral ossification is initiated. It is currently believed that growth factors may regulate the proliferation and maturation of chondrocytes and the synthesis of extracellular matrix in the growth plate. The ordered sequence of proliferation and differentiation observed in the growth plate provides a unique opportunity to study the role of acidic fibroblast growth factor, basic fibroblast growth factor, and transforming growth factor-beta 1 in the regulation of these processes. In this study, expression of the mRNA of these growth factors was examined using total RNA extracted from the physis and epiphysis of rat tibias. Transforming growth factor-beta 1 mRNA was detected by Northern hybridization. Expression of the genes encoding acidic and basic fibroblast growth factors was demonstrated by polymerase chain reaction amplification. In addition, using polyclonal antibodies against these growth factors, we localized them by immunohistochemical analysis. Strong intracellular staining with a predominantly nuclear pattern was observed in chondrocytes from the proliferating and upper hypertrophic zones. In contrast, chondrocytes in the resting zone stained only faintly for the presence of these growth factors. Some chondrocytes in the resting zone adjacent to the proliferating zone stained with these antibodies, and the antibodies also stained cells in the zone of Ranvier, which regulates latitudinal bone growth. Lastly, the location of transforming growth factor-beta 1 was examined further with use of a polyclonal antipeptide antibody specific for its extracellular epitope.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7472755

  10. Epidermal growth factor and growth in vivo

    SciTech Connect

    Rhodes, J.A.

    1986-01-01

    Epidermal growth factor (EGF) causes a dose-dependent thickening of the epidermis in suckling mice. The cellular mechanisms underlying this thickening were analyzed by measuring the effect of EGF on the cell-cycle. Neonatal mice were given daily injections of either 2ug EGF/g body weight/day or an equivalent volume of saline, and on the seventh day received a single injection of /sup 3/H-thymidine. At various times the mice were perfused with fixative; 1um sections of skin were stained with a modification of Harris' hematoxylin and were autoradiographed. The sections were analyzed using three methods based on the dependence on time after injection of /sup 3/H-thymidine of: frequency of labelled mitoses, labelling index, and reciprocal grains/nucleus. It was found that EGF caused a two-fold increase in the cell production rate. The effect of exogenous EGF on the morphology of gastric mucosa and incisors of suckling mice was also studied. The gastric mucosa appeared thicker in EGF-treated animals, but the effect was not statistically significant. In contrast to its effect on epidermis and gastric mucosa, EGF caused a significant, dose-dependent decrease in the size of the incisors. Because the mouse submandibular salivary gland is the major source of EGF the effect of sialoadenectomy on female reproductive functions was examined. Ablation of the submandibular gland had no effect on: length of estrus cycle, ability of the female to produce litters, length of the gestation period, litter size, and weight of the litter at birth. There was also no effect on survival of the offspring or on age at which the eyelids separated.

  11. Growth Factor Mediated Signaling in Pancreatic Pathogenesis

    PubMed Central

    Nandy, Debashis; Mukhopadhyay, Debabrata

    2011-01-01

    Functionally, the pancreas consists of two types of tissues: exocrine and endocrine. Exocrine pancreatic disorders mainly involve acute and chronic pancreatitis. Acute pancreatitis typically is benign, while chronic pancreatitis is considered a risk factor for developing pancreatic cancer. Pancreatic carcinoma is the fourth leading cause of cancer related deaths worldwide. Most pancreatic cancers develop in the exocrine tissues. Endocrine pancreatic tumors are more uncommon, and typically are less aggressive than exocrine tumors. However, the endocrine pancreatic disorder, diabetes, is a dominant cause of morbidity and mortality. Importantly, different growth factors and their receptors play critical roles in pancreatic pathogenesis. Hence, an improved understanding of how various growth factors affect pancreatitis and pancreatic carcinoma is necessary to determine appropriate treatment. This chapter describes the role of different growth factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and transforming growth factor (TGF) in various pancreatic pathophysiologies. Finally, the crosstalk between different growth factor axes and their respective signaling mechanisms, which are involved in pancreatitis and pancreatic carcinoma, are also discussed. PMID:24212642

  12. Waste management - cytokines, growth factors and cachexia.

    PubMed

    Saini, Amarjit; Al-Shanti, Nasser; Nasser, Al-Shanti; Stewart, Claire E H

    2006-12-01

    Muscle damage with a lack of regeneration, manifests itself in several life-threatening diseases, including cancer cachexia, congestive heart failure, AIDS and sepsis. Often misdiagnosed as a condition simply of weight loss, cachexia is actually a highly complex metabolic disorder involving features of anorexia, anaemia, lipolysis and insulin resistance. A significant loss of lean body mass arises from such conditions, resulting in wasting of skeletal muscle. Unlike starvation, the weight loss seen in chronic illnesses arises equally from loss of muscle and of fat. The cachectic state is particularly problematic in cancer, typifying poor prognosis and often lowering responses to chemotherapy and radiation treatment. More than half of cancer patients suffer from cachexia, and strikingly, nearly one-third of cancer deaths are related to cachexia rather than the tumour burden. In considering this disorder, we are faced with a conundrum; how is it possible for uncontrolled growth to prevail in the tumour, in the face of unrestrained tissue loss in our muscles? Consistently, the catabolic state has been associated with a shift in the homeostatic balance between muscle synthesis and degradation mediated by the actions of growth factors and cytokines. Indeed, tumour necrosis factor-alpha (TNF-alpha) levels are raised in several animal models of cachectic muscle wasting, whereas the insulin-like growth factor (IGF) system acts potently to regulate muscle development, hypertrophy and maintenance. This concept of skeletal muscle homeostasis, often viewed as the net balance between two separate processes of protein synthesis and degradation has however changed. More recently, the view is that these two biochemical processes are not occurring independently of each other but in fact are finely co-ordinated by a web of intricate signalling networks. This review, therefore, aims to discuss data currently available regarding the mechanisms of degeneration and regeneration with

  13. Fibroblast growth factor 23 and bone mineralisation

    PubMed Central

    Guo, Yu-Chen; Yuan, Quan

    2015-01-01

    Fibroblast growth factor 23 (FGF23) is a hormone that is mainly secreted by osteocytes and osteoblasts in bone. The critical role of FGF23 in mineral ion homeostasis was first identified in human genetic and acquired rachitic diseases and has been further characterised in animal models. Recent studies have revealed that the levels of FGF23 increase significantly at the very early stages of chronic kidney disease (CKD) and may play a critical role in mineral ion disorders and bone metabolism in these patients. Our recent publications have also shown that FGF23 and its cofactor, Klotho, may play an independent role in directly regulating bone mineralisation instead of producing a systematic effect. In this review, we will discuss the new role of FGF23 in bone mineralisation and the pathophysiology of CKD-related bone disorders. PMID:25655009

  14. Speeding up Growth: Selection for Mass-Independent Maximal Metabolic Rate Alters Growth Rates.

    PubMed

    Downs, Cynthia J; Brown, Jessi L; Wone, Bernard W M; Donovan, Edward R; Hayes, Jack P

    2016-03-01

    Investigations into relationships between life-history traits, such as growth rate and energy metabolism, typically focus on basal metabolic rate (BMR). In contrast, investigators rarely examine maximal metabolic rate (MMR) as a relevant metric of energy metabolism, even though it indicates the maximal capacity to metabolize energy aerobically, and hence it might also be important in trade-offs. We studied the relationship between energy metabolism and growth in mice (Mus musculus domesticus Linnaeus) selected for high mass-independent metabolic rates. Selection for high mass-independent MMR increased maximal growth rate, increased body mass at 20 weeks of age, and generally altered growth patterns in both male and female mice. In contrast, there was little evidence that the correlated response in mass-adjusted BMR altered growth patterns. The relationship between mass-adjusted MMR and growth rate indicates that MMR is an important mediator of life histories. Studies investigating associations between energy metabolism and life histories should consider MMR because it is potentially as important in understanding life history as BMR. PMID:26913943

  15. Nerve growth factor and asthma.

    PubMed

    Bonini, S; Lambiase, A; Lapucci, G; Properzi, F; Bresciani, M; Bracci Laudiero, M L; Mancini, M J; Procoli, A; Micera, A; Sacerdoti, G; Bonini, S; Levi-Schaffer, F; Rasi, G; Aloe, L

    2002-01-01

    An increasing body of evidence shows that nerve growth factor (NGF) exerts biological activity not only on the central and peripheral nervous system, but also on the immune system thereby influencing allergic diseases and asthma. (1) NGF circulating levels are increased in patients with allergic diseases and asthma, and are related to the severity of the inflammatory process and disease. In vernal keratoconjunctivitis, NGF plasma levels correlate with the number of mast cells infiltrating the conjunctiva, and NGF mRNA is increased in nasal mucosal scrapings of patients with allergic rhinitis who have high levels of NGF in serum and nasal fluids; NGF is further increased in nasal fluids after specific allergen challenge. (2) NGF is produced and released by several modulatory and effector cells of allergic inflammation and asthma, for example T-helper 2 lymphocytes, mast cells and eosinophils. (3) NGF receptors are expressed on the conjunctival epithelium of patients with allergic conjunctivitis and the number of NGF-receptor positive cells is increased in the conjunctiva of these patients. Indeed, local administration of NGF induces fibroblast activation and healing processes of human corneal ulcers, which suggests that NGF plays a role in tissue remodelling processes occurring in asthma. (4) NGF increases airway hyperreactivity to histamine in an animal model of asthma, while anti-NGF treatment reduces airway hyperreactivity induced by ovalbumin topical challenge in the sensitized mouse. PMID:12144547

  16. 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.

  17. Autocrine growth factors and solid tumor malignancy.

    PubMed Central

    Walsh, J. H.; Karnes, W. E.; Cuttitta, F.; Walker, A.

    1991-01-01

    The ability of malignant cells to escape the constraint that normally regulate cell growth and differentiation has been a primary focus of attention for investigators of cancer cell biology. An outcome of this attention has been the discovery that the protein products of oncogenes play a role in the activation of growth signal pathways. A second outcome, possibly related to abnormal oncogene expression, has been the discovery that malignant cells frequently show an ability to regulate their own growth by the release of autocrine growth modulatory substances. Most important, the growth of certain malignant cell types has been shown to depend on autocrine growth circuits. A malignant tumor whose continued growth depends on the release of an autocrine growth factor may be vulnerable to treatment with specific receptor antagonists or immunoneutralizing antibodies designed to break the autocrine circuit. Information is rapidly emerging concerning autocrine growth factors in selected human solid tissue malignancy. Images PMID:1926844

  18. Direct binding of hepatocyte growth factor and vascular endothelial growth factor to CD44v6

    PubMed Central

    Volz, Yvonne; Koschut, David; Matzke-Ogi, Alexandra; Dietz, Marina S.; Karathanasis, Christos; Richert, Ludovic; Wagner, Moritz G.; Mély, Yves; Heilemann, Mike; Niemann, Hartmut H.; Orian-Rousseau, Véronique

    2015-01-01

    CD44v6, a member of the CD44 family of transmembrane glycoproteins is a co-receptor for two receptor tyrosine kinases (RTKs), Met and VEGFR-2 (vascular endothelial growth factor receptor 2). CD44v6 is not only required for the activation of these RTKs but also for signalling. In order to understand the role of CD44v6 in Met and VEGFR-2 activation and signalling we tested whether CD44v6 binds to their ligands, HGF (hepatocyte growth factor) and VEGF (vascular endothelial growth factor), respectively. FACS analysis and cellular ELISA showed binding of HGF and VEGF only to cells expressing CD44v6. Direct binding of CD44v6 to HGF and VEGF was demonstrated in pull-down assays and the binding affinities were determined using MicroScale Thermophoresis, fluorescence correlation spectroscopy and fluorescence anisotropy. The binding affinity of CD44v6 to HGF is in the micromolar range in contrast with the high-affinity binding measured in the case of VEGF and CD44v6, which is in the nanomolar range. These data reveal a heparan sulfate-independent direct binding of CD44v6 to the ligands of Met and VEGFR-2 and suggest different roles of CD44v6 for these RTKs. PMID:26181364

  19. Roles for Growth Factors in Cancer Progression

    PubMed Central

    Witsch, Esther; Sela, Michael; Yarden, Yosef

    2011-01-01

    Under physiological conditions, cells receive fate-determining signals from their tissue surroundings, primarily in the form of polypeptide growth factors. Integration of these extracellular signals underlies tissue homeostasis. Although departure from homeostasis and tumor initiation are instigated by oncogenic mutations rather than by growth factors, the latter are the major regulators of all subsequent steps of tumor progression, namely clonal expansion, invasion across tissue barriers, angiogenesis, and colonization of distant niches. Here, we discuss the relevant growth factor families, their roles in tumor biology, as well as the respective downstream signaling pathways. Importantly, cancer-associated activating mutations that impinge on these pathways often relieve, in part, the reliance of tumors on growth factors. On the other hand, growth factors are frequently involved in evolvement of resistance to therapeutic regimens, which extends the roles for polypeptide factors to very late phases of tumor progression and offers opportunities for cancer therapy. PMID:20430953

  20. 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.

  1. Ral-Arf6 crosstalk regulates Ral dependent exocyst trafficking and anchorage independent growth signalling.

    PubMed

    Pawar, Archana; Meier, Jeremy A; Dasgupta, Anwesha; Diwanji, Neha; Deshpande, Neha; Saxena, Kritika; Buwa, Natasha; Inchanalkar, Siddhi; Schwartz, Martin Alexander; Balasubramanian, Nagaraj

    2016-09-01

    Integrin dependent regulation of growth factor signalling confers anchorage dependence that is deregulated in cancers. Downstream of integrins and oncogenic Ras the small GTPase Ral is a vital mediator of adhesion dependent trafficking and signalling. This study identifies a novel regulatory crosstalk between Ral and Arf6 that controls Ral function in cells. In re-adherent mouse fibroblasts (MEFs) integrin dependent activation of RalA drives Arf6 activation. Independent of adhesion constitutively active RalA and RalB could both however activate Arf6. This is further conserved in oncogenic H-Ras containing bladder cancer T24 cells, which express anchorage independent active Ral that supports Arf6 activation. Arf6 mediates active Ral-exocyst dependent delivery of raft microdomains to the plasma membrane that supports anchorage independent growth signalling. Accordingly in T24 cells the RalB-Arf6 crosstalk is seen to preferentially regulate anchorage independent Erk signalling. Active Ral we further find uses a Ral-RalBP1-ARNO-Arf6 pathway to mediate Arf6 activation. This study hence identifies Arf6, through this regulatory crosstalk, to be a key downstream mediator of Ral isoform function along adhesion dependent pathways in normal and cancer cells. PMID:27269287

  2. Growth factors from genes to clinical application

    SciTech Connect

    Sara, V.R. ); Hall, K.; Low, H. )

    1990-01-01

    The last decade has witnessed an explosion in the identification of growth factors and their receptors. This has been greatly facilitated by recombinant DNA technology, which has provided the tools not only to identify these proteins at the gene level but also to produce recombinant proteins for evaluating their biological activities. With the help of such techniques, we are moving toward an understanding of the biosynthesis of growth factors and their receptors, structure-function relationships, as well as mechanisms for intracellular signal transmission. The possibility of modifying these factors has opened new fields of clinical application. In this paper, four major areas of growth factor research are presented: the characterization of growth factor genes and their protein products, growth factor receptors and signal transduction by the receptors to mediate biological action, the biological actions of the various growth factors, and the role of growth factors in health and disease and their possible clinical application. Some of the topics covered include: structure of the IGFs and their variants; isoforms of PDGF receptor types; tyrosine kinase activation; structure of G-proteins in biological membranes; possible therapeutic application of NGF in the treatment of Parkinson's and Alzheimer's diseases; PDGF's possible role in the development of several fibroproliferative diseases and its therapeutic application in wound healing; and the possible use of angiogenic inhibitors in tumor treatment.

  3. The role of psychological factors in the career of the independent dancer.

    PubMed

    Aujla, Imogen; Farrer, Rachel

    2015-01-01

    Previous research indicates that psychological factors such as motivation and mental skills play an important role in relation to performance and to negotiating talent development stages. However, little is known about these factors in dance, particularly with regard to the independent dancer whose career may involve multiple roles, varied work patterns, and periods of instability. The aim of this study was to explore dancers' motivation to work in an independent capacity, and the extent to which dancers' psychological characteristics and skills enabled them to navigate a career in this demanding sector. In-depth semi-structured interviews were conducted with 14 dancers at different stages of their careers. Interviews were transcribed verbatim and content analyzed. Analysis revealed that the dancers were intrinsically motivated and highly committed to the profession. Working in the independent sector offered dancers opportunities for growth and fulfillment; they appreciated the autonomy, flexibility and freedom that the independent career afforded, as well as working with new people across roles and disciplines. In order to overcome the various challenges associated with the independent role, optimism, self-belief, social support, and career management skills were crucial. The mental skills reported by the participants had developed gradually in response to the demands that they faced. Therefore, mental skills training could be invaluable for dancers to help them successfully negotiate the independent sector. PMID:26579059

  4. The role of psychological factors in the career of the independent dancer

    PubMed Central

    Aujla, Imogen; Farrer, Rachel

    2015-01-01

    Previous research indicates that psychological factors such as motivation and mental skills play an important role in relation to performance and to negotiating talent development stages. However, little is known about these factors in dance, particularly with regard to the independent dancer whose career may involve multiple roles, varied work patterns, and periods of instability. The aim of this study was to explore dancers’ motivation to work in an independent capacity, and the extent to which dancers’ psychological characteristics and skills enabled them to navigate a career in this demanding sector. In-depth semi-structured interviews were conducted with 14 dancers at different stages of their careers. Interviews were transcribed verbatim and content analyzed. Analysis revealed that the dancers were intrinsically motivated and highly committed to the profession. Working in the independent sector offered dancers opportunities for growth and fulfillment; they appreciated the autonomy, flexibility and freedom that the independent career afforded, as well as working with new people across roles and disciplines. In order to overcome the various challenges associated with the independent role, optimism, self-belief, social support, and career management skills were crucial. The mental skills reported by the participants had developed gradually in response to the demands that they faced. Therefore, mental skills training could be invaluable for dancers to help them successfully negotiate the independent sector. PMID:26579059

  5. Growth factors for the treatment of ischemic brain injury (growth factor treatment).

    PubMed

    Larpthaveesarp, Amara; Ferriero, Donna M; Gonzalez, Fernando F

    2015-01-01

    In recent years, growth factor therapy has emerged as a potential treatment for ischemic brain injury. The efficacy of therapies that either directly introduce or stimulate local production of growth factors and their receptors in damaged brain tissue has been tested in a multitude of models for different Central Nervous System (CNS) diseases. These growth factors include erythropoietin (EPO), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor (IGF-1), among others. Despite the promise shown in animal models, the particular growth factors that should be used to maximize both brain protection and repair, and the therapeutic critical period, are not well defined. We will review current pre-clinical and clinical evidence for growth factor therapies in treating different causes of brain injury, as well as issues to be addressed prior to application in humans. PMID:25942688

  6. 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.

  7. Environmental factors influencing growth and pubertal development.

    PubMed Central

    Delemarre-van de Waal, H A

    1993-01-01

    Postnatal growth is based on hereditary signals and environmental factors in a complex regulatory network. Each factor must be in an optimal state for normal growth of the child. Fetal conditions may also have consequences on postnatal height. Intrauterine growth retardation can be recovered postnatally, although postnatal growth remains depressed in about one-third of cases. After birth, the environment may exert either a positive or negative effect on growth. In underdeveloped countries, malnutrition plays a major role in inhibiting the growth process. Children from families of higher socioeconomic classes are taller than their coevals in the lower socioeconomic groups. Urbanization also has a positive effect on growth. Better child care is supported by sufficient food supply, appropriate health and sanitation services, and a higher level of education. Over the last century, these factors have induced a taller stature and a more rapid maturity in Europe, North America, and Australia; a phenomenon which has been referred to as "the secular trend" in growth. Recently, a secular trend has also been reported in some developing countries. Although urbanization in general appears to be associated with better conditions of living, this is not the case in the slums of South America or in Africa where rural children are better off than children living in the poor cities. This paper describes in more detail the different hereditary and environmental factors that act during the fetal period and postnatally, and which play a role in human growth and pubertal development. PMID:8243404

  8. Vascular growth factors in neuropsychiatry

    PubMed Central

    Newton, Samuel S.; Fournier, Neil M.; Duman, Ronald S.

    2014-01-01

    Recent advances in understanding the cellular and molecular basis of psychiatric illnesses have shed light on the important role played by trophic factors in modulating functional parameters associated with disease causality and drug action. Disease mechanisms are now thought to involve multiple cell types, including neurons and endothelial cells. These functionally distinct but interactively coupled cell types engage in cellular cross talk via shared and common signaling molecules. Dysregulation in their cellular signaling pathways influences brain function and alters behavioral performance. Multifunctional trophic factors such as VEGF and EPO that possess both neurotrophic and angiogenic actions are of particular interest due to their ability to rescue structural and plasticity deficits in neurons and vasculature. Obtaining insight into the behavioral, cellular and molecular actions of multi-functional trophic factors has the potential to open new and transformative therapeutic approaches. PMID:23475069

  9. Paan without tobacco: an independent risk factor for oral cancer.

    PubMed

    Merchant, A; Husain, S S; Hosain, M; Fikree, F F; Pitiphat, W; Siddiqui, A R; Hayder, S J; Haider, S M; Ikram, M; Chuang, S K; Saeed, S A

    2000-04-01

    Oral cancer is the second most common cancer in women and the third most common in men in Pakistan. Tobacco is smoked and chewed extensively in Pakistan. Paan is a quid of piper betel leaf that contains areca nut, lime, condiment, sweeteners, and sometimes tobacco, which is also used extensively. We did this study to clarify the independent association of paan and oral cancer. Between July 1996 and March 1998, we recruited biopsy-proven, primary cases of oral squamous-cell carcinoma, from 3 tertiary teaching centers in Karachi, Pakistan, and controls pair-matched for age, gender, hospital and time of occurrence, excluding persons with a past or present history of any malignancy. There were 79 cases and 149 controls. Approximately 68% of the cases were men, 49 years old on average, the youngest being 22 years old and the eldest 80. People with oral submucous fibrosis were 19.1 times more likely to develop oral cancer than those without it, after adjusting for other risk factors. People using paan without tobacco were 9.9 times, those using paan with tobacco 8.4 times, more likely to develop oral cancer as compared with non-users, after adjustment for other covariates. This study identifies an independent effect of paan without tobacco in the causation of oral cancer. Its findings may be of significance in South Asian communities where paan is used, and among health-care providers who treat persons from South Asia. PMID:10728606

  10. New Clue Found to Growth Factor Action.

    ERIC Educational Resources Information Center

    Hoffman, Michelle

    1991-01-01

    Discussed is the discovery which may help to explain epidermal growth factor effects on the cell skeleton. The role of a protein called profilin in the regulation of the microfilament system is described. (CW)

  11. Expression of growth factors in Dictyostelium discoideum.

    PubMed

    Asgari, S; Arun, S; Slade, M B; Marshall, J; Williams, K L; Wheldrake, J F

    2001-07-01

    Growth factors and their binding proteins are important proteins regulating mammalian cell proliferation and differentiation so there is considerable interest in producing them as recombinant proteins, especially in hosts that do not already produce a complex mixture of growth factors. Many growth factors require post-translational modifications making them unsuitable for production in Escherichia coli or other prokaryotes. Since several expression vector systems have been recently developed for foreign protein production in the cellular slime mould, Dictyostelium discoideum, we attempted to use two of these systems to express human insulin-like growth factor binding protein 6 (hIGFBP6) and bovine beta-cellulin (bBTC) as secreted proteins. Although both proteins were successfully produced in stably transformed amoebae, no secretion was detected in spite of several attempts to facilitate this occurring. PMID:11361083

  12. [T-LYMPHOCYTES AND TISSUE GROWTH FACTORS].

    PubMed

    Tishevskaya, N V; Gevorkyan, N M; Kozlova, N I

    2015-08-01

    Lympnoici regulation, in aciaition to ensuring tne protection of tne antigen, is aimecl at maintaining a qualitative, quantitative, structural and functional integrity of the body. T-lymphocytes and growth factors are involved in cell proliferation, differentiation, and tissue and organ regeneration. Lymphocyte's, sensitivity to homeostasis changes and their morphogenetic function are connected with a large number of receptors to bioactive substances and with their ability to syn- thesize and secrete hormones and tissue growth factors. At the same time tissue growth factors are involved in the development of thymocytes, in the differentiation of T helper and cytotoxic lymphocytes. Growth factors modulate the functions of Thl, Th2, Treg, Thl7, Th9. The important aspects of the interaction of T cells and EGF, TGF-P, FGF, VEGF, PlGF, HGF/SF in normal and pathological conditions are shown in this review. PMID:26591583

  13. Cellular Actions of Insulin-Like Growth Factor Binding Proteins

    PubMed Central

    Ferry, R. J.; Katz, L. E. L.; Grimberg, Adda; Cohen, P.; Weinzimer, S. A.

    2014-01-01

    The insulin-like growth factors (IGFs), insulin-like growth factor binding proteins (IGFBPs), and the IGFBP proteases are involved in the regulation of somatic growth and cellular proliferation both in vivo and in vitro. IGFs are potent mitogenic agents whose actions are determined by the availability of free IGFs to interact with the IGF receptors. IGFBPs comprise a family of proteins that bind IGFs with high affinity and specificity and thereby regulate IGF-dependent actions. IGFBPs have recently emerged as IGF-independent regulators of cell growth. Various IGFBP association proteins as well as cleavage of IGFBPs by specific proteases modulate levels of free IGFs and IGFBPs. The ubiquity and complexity of the IGF axis promise exciting discoveries and applications for the future. PMID:10226802

  14. Activation of cap-independent translation by variant eukaryotic initiation factor 4G in vivo

    PubMed Central

    Kaiser, Constanze; Dobrikova, Elena Y.; Bradrick, Shelton S.; Shveygert, Mayya; Herbert, James T.; Gromeier, Matthias

    2008-01-01

    Protein synthesis is tightly controlled by assembly of an intricate ribonucleoprotein complex at the m7GTP-cap on eukaryotic mRNAs. Ensuing linear scanning of the 5′ untranslated region (UTR) is believed to transfer the preinitiation complex to the initiation codon. Eukaryotic mRNAs are characterized by significant 5′ UTR heterogeneity, raising the possibility of differential control of translation initiation rate at individual mRNAs. Curiously, many mRNAs with unconventional, highly structured 5′ UTRs encode proteins with central biological roles in growth control, metabolism, or stress response. The 5′ UTRs of such mRNAs may influence protein synthesis rate in multiple ways, but most significantly they have been implicated in mediating alternative means of translation initiation. Cap-independent initiation bypasses strict control over the formation of initiation intermediates at the m7GTP cap. However, the molecular mechanisms that favor alternative means of ribosome recruitment are not understood. Here we provide evidence that eukaryotic initiation factor (eIF) 4G controls cap-independent translation initiation at the c-myc and vascular endothelial growth factor (VEGF) 5′ UTRs in vivo. Cap-independent translation was investigated in tetracycline-inducible cell lines expressing either full-length eIF4G or a C-terminal fragment (Ct) lacking interaction with eIF4E and poly(A) binding protein. Expression of Ct, but not intact eIF4G, potently stimulated cap-independent initiation at the c-myc/VEGF 5′ UTRs. In vitro RNA-binding assays suggest that stimulation of cap-independent translation initiation by Ct is due to direct association with the c-myc/VEGF 5′ UTR, enabling 43S preinitiation complex recruitment. Our work demonstrates that variant translation initiation factors enable unconventional translation initiation at mRNA subsets with distinct structural features. PMID:18755839

  15. Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer cells.

    PubMed

    Wise, Randi; Duhachek-Muggy, Sara; Qi, Yue; Zolkiewski, Michal; Zolkiewska, Anna

    2016-06-01

    Metastatic breast cancer cells are exposed to stress of detachment from the extracellular matrix (ECM). Cultured breast cancer cells that survive this stress and are capable of anchorage-independent proliferation form mammospheres. The purpose of this study was to explore a link between mammosphere growth, ECM gene expression, and the protein quality control system in the endoplasmic reticulum (ER). We compared the mRNA and protein levels of ER folding factors in SUM159PT and MCF10DCIS.com breast cancer cells grown as mammospheres versus adherent conditions. Publicly available gene expression data for mammospheres formed by primary breast cancer cells and for circulating tumor cells (CTCs) were analyzed to assess the status of ECM/ER folding factor genes in clinically relevant samples. Knock-down of selected protein disulfide isomerase (PDI) family members was performed to examine their roles in SUM159PT mammosphere growth. We found that cells grown as mammospheres had elevated expression of ECM genes and ER folding quality control genes. CTC gene expression data for an index patient indicated that upregulation of ECM and ER folding factor genes occurred at the time of acquired therapy resistance and disease progression. Knock-down of PDI, ERp44, or ERp57, three members of the PDI family with elevated protein levels in mammospheres, in SUM159PT cells partially inhibited the mammosphere growth. Thus, breast cancer cell survival and growth under detachment conditions require enhanced assistance of the ER protein folding machinery. Targeting ER folding factors, in particular members of the PDI family, may improve the therapeutic outcomes in metastatic breast cancer. PMID:27161215

  16. 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

  17. Organic growth factor requirements of some yeasts.

    PubMed

    Madan, M; Gulati, N

    1980-01-01

    Some sporogenous yeasts (Brettanomyces bruxellensis, Debaryomyces hansenii, Hansenula ciferrii, Hansenula polymorpha, Pichia polymorpha, Saccharomycopsis guttulata, and Saccharomyces chevalieri), isolated from various fruits have been examined for their organic growth factor requisites. H. ciferrii was completely deficient in thiamine, biotin, inositol, riboflavin, niacin, and partially deficient in pantothenic acid. It required an external supply of 0.1-1.0 ppm thiamine, 0.01-0.1 ppm biotin, 10.0 ppm inositol, 0.10 ppm niacin and riboflavin for its optimum growth. H. polymorpha showed partial deficiency only in xanthine. P. polymorpha gave indications of partial deficiencies in thiamine and biotin. S. guttulata was completely deficient in biotin, and partially deficient in adenine sulphate. It required 0.01 ppm biotin for optimum growth. S chevalieri was completely deficient in pyridoxine and partially deficient in thiamine. It required 0.1 ppm pyridoxine for maximum growth. D. hansenii and B bruxellensis were auxoautotrophic for the various growth factors studied. PMID:7242379

  18. Gastric reflux is an independent risk factor for laryngopharyngeal carcinoma

    PubMed Central

    Langevin, Scott M.; Michaud, Dominique S.; Marsit, Carmen J.; Nelson, Heather H.; Birnbaum, Ariel E.; Eliot, Melissa; Christensen, Brock C.; McClean, Michael D.; Kelsey, Karl T.

    2013-01-01

    Background Gastric reflux can reach into the upper airway, inducing cellular damage in the epithelial lining. This condition is believed to be a risk factor for development of laryngopharyngeal squamous cell carcinoma (LPSCC), although the literature is conflicting. Methods To better clarify this relationship, we assessed the association of self-reported heartburn history and medication use among 631 LPSCC patients and 1234 control subjects (frequency-matched on age, gender and town of residence) enrolled as part of a population-based case-control study of head and neck squamous cell carcinoma in the greater Boston area. Results After adjusting for age, gender, race, smoking, alcohol consumption, HPV16 seropositivity, education and body mass index, subjects reporting a history of frequent heartburn and who were neither a heavy smoker nor heavy drinker had a significantly elevated risk of LPSCC (OR = 1.78, 95% CI: 1.00–3.16). Among those with a history of heartburn, there was an inverse association between antacid use and LPSCC relative to those never taking heartburn medication (OR = 0.59, 95% CI: 0.38–0.93) that remained consistent when analyzed by smoking/drinking status, HPV16 status, or by primary tumor site. Conclusions Our data show that gastric reflux is an independent risk factor for squamous cancers of the pharynx and larynx. Further studies are needed to clarify the possible chemopreventive role of antacid use for patients with gastric reflux. Impact Elucidation of additional risk factors for head and neck cancer can allow for risk stratification and inform surveillance of high-risk patients. PMID:23703970

  19. High salt intake: independent risk factor for obesity?

    PubMed

    Ma, Yuan; He, Feng J; MacGregor, Graham A

    2015-10-01

    High salt intake is the major cause of raised blood pressure and accordingly leads to cardiovascular diseases. Recently, it has been shown that high salt intake is associated with an increased risk of obesity through sugar-sweetened beverage consumption. Increasing evidence also suggests a direct link. Our study aimed to determine whether there was a direct association between salt intake and obesity independent of energy intake. We analyzed the data from the rolling cross-sectional study-the UK National Diet and Nutrition Survey 2008/2009 to 2011/2012. We included 458 children (52% boys; age, 10±4 years) and 785 adults (47% men; age, 49±17 years) who had complete 24-hour urine collections. Energy intake was calculated from 4-day diary and misreporting was assessed by Goldberg method. The results showed that salt intake as measured by 24-hour urinary sodium was higher in overweight and obese individuals. A 1-g/d increase in salt intake was associated with an increase in the risk of obesity by 28% (odds ratio, 1.28; 95% confidence interval, 1.12-1.45; P=0.0002) in children and 26% (odds ratio, 1.26; 95% confidence interval, 1.16-1.37; P<0.0001) in adults, after adjusting for age, sex, ethnic group, household income, physical activity, energy intake, and diet misreporting, and in adults with additional adjustment for education, smoking, and alcohol consumption. Higher salt intake was also significantly related to higher body fat mass in both children (P=0.001) and adults (P=0.001) after adjusting for age, sex, ethnic group, and energy intake. These results suggest that salt intake is a potential risk factor for obesity independent of energy intake. PMID:26238447

  20. Source separation in astrophysical maps using independent factor analysis.

    PubMed

    Kuruoğlu, Ercan E; Bedini, Luigi; Paratore, Maria T; Salerno, Emanuele; Tonazzini, Anna

    2003-01-01

    A microwave sky map results from a combination of signals from various astrophysical sources, such as cosmic microwave background radiation, synchrotron radiation and galactic dust radiation. To derive information about these sources, one needs to separate them from the measured maps on different frequency channels. Our insufficient knowledge of the weights to be given to the individual signals at different frequencies makes this a difficult task. Recent work on the problem led to only limited success due to ignoring the noise and to the lack of a suitable statistical model for the sources. In this paper, we derive the statistical distribution of some source realizations, and check the appropriateness of a Gaussian mixture model for them. A source separation technique, namely, independent factor analysis, has been suggested recently in the literature for Gaussian mixture sources in the presence of noise. This technique employs a three layered neural network architecture which allows a simple, hierarchical treatment of the problem. We modify the algorithm proposed in the literature to accommodate for space-varying noise and test its performance on simulated astrophysical maps. We also compare the performances of an expectation-maximization and a simulated annealing learning algorithm in estimating the mixture matrix and the source model parameters. The problem with expectation-maximization is that it does not ensure global optimization, and thus the choice of the starting point is a critical task. Indeed, we did not succeed to reach good solutions for random initializations of the algorithm. Conversely, our experiments with simulated annealing yielded initialization-independent results. The mixing matrix and the means and coefficients in the source model were estimated with a good accuracy while some of the variances of the components in the mixture model were not estimated satisfactorily. PMID:12672442

  1. Retention of prolyl hydroxylase PHD2 in the cytoplasm prevents PHD2-induced anchorage-independent carcinoma cell growth

    SciTech Connect

    Jokilehto, Terhi; Hoegel, Heidi; Heikkinen, Pekka; Rantanen, Krista; Elenius, Klaus; Sundstroem, Jari; Jaakkola, Panu M.

    2010-04-15

    Cellular oxygen tension is sensed by a family of prolyl hydroxylases (PHD1-3) that regulate the degradation of hypoxia-inducible factors (HIF-1{alpha} and -2{alpha}). The PHD2 isoform is considered as the main downregulator of HIF in normoxia. Our previous results have shown that nuclear translocation of PHD2 associates with poorly differentiated tumor phenotype implying that nuclear PHD2 expression is advantageous for tumor growth. Here we show that a pool of PHD2 is shuttled between the nucleus and the cytoplasm. In line with this, accumulation of wild type PHD2 in the nucleus was detected in human colon adenocarcinomas and in cultured carcinoma cells. The PHD2 isoforms showing high nuclear expression increased anchorage-independent carcinoma cell growth. However, retention of PHD2 in the cytoplasm inhibited the anchorage-independent cell growth. A region that inhibits the nuclear localization of PHD2 was identified and the deletion of the region promoted anchorage-independent growth of carcinoma cells. Finally, the cytoplasmic PHD2, as compared with the nuclear PHD2, less efficiently downregulated HIF expression. Forced HIF-1{alpha} or -2{alpha} expression decreased and attenuation of HIF expression increased the anchorage-independent cell growth. However, hydroxylase-inactivating mutations in PHD2 had no effect on cell growth. The data imply that nuclear PHD2 localization promotes malignant cancer phenotype.

  2. Is Maternal Parity an Independent Risk Factor for Birth Defects?

    PubMed Central

    Duong, Hao T.; Hoyt, Adrienne T.; Carmichael, Suzan L.; Gilboa, Suzanne M.; Canfield, Mark A.; Case, Amy; McNeese, Melanie L.; Waller, Dorothy Kim

    2015-01-01

    BACKGROUND Although associations between maternal parity and birth defects have been observed previously, few studies have focused on the possibility that parity is an independent risk factor for birth defects. We investigated the relation between levels of parity and a range of birth defects, adjusting each defect group for the same covariates. METHODS We included infants who had an estimated delivery date between 1997 and 2007 and participated in the National Birth Defects Prevention Study, a multisite case-control study. Cases included infants or fetuses belonging to 38 phenotypes of birth defects (n = 17,908), and controls included infants who were unaffected by a major birth defect (n = 7173). Odds ratios (ORs) were adjusted for 12 covariates using logistic regression. RESULTS Compared with primiparous mothers, nulliparous mothers were more likely to have infants with amniotic band sequence, hydrocephaly, esophageal atresia, hypospadias, limb reduction deficiencies, diaphragmatic hernia, omphalocele, gastroschisis, tetralogy of Fallot, and septal cardiac defects, with significant ORs (1.2 to 2.3). Compared with primiparous mothers, multiparous mothers had a significantly increased risk of omphalocele, with an OR of 1.5, but had significantly decreased risk of hypospadias and limb reduction deficiencies, with ORs of 0.77 and 0.77. CONCLUSIONS Nulliparity was associated with an increased risk of specific phenotypes of birth defects. Most of the phenotypes associated with nulliparity in this study were consistent with those identified by previous studies. Research into biologic or environmental factors that are associated with nulliparity may be helpful in explaining some or all of these associations. PMID:22371332

  3. [Hyperhomocyst(e)inemia--an independent risk factor of stroke].

    PubMed

    Lalouschek, W; Aull, S; Deecke, L; Schnider, P; Uhl, F; Zeiler, K

    1996-07-01

    The total of free and protein-bound homocysteine including its derivatives is usually summarised as "homocyst(e)ine [H(e)]". Several congenital enzyme deficiencies may cause markedly elevated H(e) plasma levels, leading to the well-known clinical syndromes of homocystinuria. Recently, mild hyperhomocyst(e)inemia has been recognised as an independent risk factor for ischaemic cerebrovascular disease, coronary heart disease, and peripheral artery disease. H(e) levels are also related to the extent of atherosclerotic vessel wall alterations. The role of mild hyperhomocyst(e)inemia in venous thromboembolic disease, however, is not yet clear. A considerable proportion of patients with mild hyperhomocyst(e)inemia suffers from a deficiency of folate, vitamin B12, and/or vitamin B6. Supplementation of these agents--alone or combined with betain--leads to a decrease or even to a normalisation of elevated H(e) levels in the majority of such patients. Hitherto, no prospective randomised studies dealing with the clinical efficacy of such a--probably innocuous--supplementation have been performed. In the meantime, adequate alimentary intake of folate should be ensured. PMID:8765893

  4. 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

  5. Overexpressed EDIL3 predicts poor prognosis and promotes anchorage-independent tumor growth in human pancreatic cancer

    PubMed Central

    Feng, Ming-Xuan; Wang, Ya-Hui; Yang, Xiao-Mei; He, Ping; Tian, Guang-Ang; Zhang, Xiao-Xin; Li, Qing; Cao, Xiao-Yan; Huo, Yan-Miao; Yang, Min-Wei; Fu, Xue-Liang; Li, Jiao; Liu, De-Jun; Dai, Miao; Wen, Shan-Yun; Gu, Jian-Ren; Hong, Jie; Hua, Rong; Zhang, Zhi-Gang; Sun, Yong-Wei

    2016-01-01

    Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein associated with vascular morphogenesis and remodeling, is commonly upregulated in multiple types of human cancers and correlates with tumor progression. However, its expression pattern and underlying cellular functions in pancreatic ductal adenocarcinoma (PDAC) remain largely unexplored. In current study, we observed that expression of EDIL3 was significantly up-regulated in PDAC compared with normal controls in both cell lines and clinical specimens. In addition, elevated EDIL3 expression was positively correlated with patients’ TNM stage and T classification. Kaplan-Meier analysis indicated that high EDIL3 expression was significantly associated with shorter overall survival times in PDAC patients. Multivariate Cox regression analysis confirmed EDIL3 expression, age, lymph node metastasis and histological differentiation as independent prognostic factors in PDAC. Knockdown of EDIL3 showed no significant influence on cell viability, migration, invasion and starvation-induced apoptosis, but compromised anoikis resistance and anchorage independent tumor growth of PDAC cells. Meanwhile, treatment with recombinant EDIL3 protein markedly promoted anoikis resistance and anchorage independent tumor growth. Mechanistically, we demonstrated that altered protein expression of Bcl-2 family might contribute to the oncogenic activities of EDIL3. In conclusion, this study provides evidences that EDIL3 is a potential predictor and plays an important role in anchorage independent tumor growth of PDAC and EDIL3-related pathways might represent a novel therapeutic strategy for treatment of pancreatic cancer. PMID:26735172

  6. Hypoxia Inducible Factor-1 (HIF-1) Independent Microvascular Angiogenesis in the Aged Rat Brain

    PubMed Central

    Ndubuizu, Obinna I.; Tsipis, Constantinos P.; Li, Ang; LaManna, Joseph C.

    2010-01-01

    Angiogenesis is a critical component of mammalian brain adaptation to prolonged hypoxia. Hypoxia-induced angiogenesis is mediated by hypoxia inducible factor-1 (HIF-1) dependent transcriptional activation of growth factors, such as vascular endothelial growth factor (VEGF). Microvascular angiogenesis occurs over a three week period in the rodent brain. We have recently reported that HIF-1α accumulation and transcriptional activation of HIF target genes in the aged cortex of 24 month F344 rats is significantly attenuated during acute hypoxic exposure. In the present study, we show that cortical HIF-1α accumulation and HIF-1 activation remains absent during chronic hypoxic exposure in the aged rat brain (24 month F344). Despite this lack of HIF-1 activation, there is no significant difference in baseline or post-hypoxic brain capillary density counts between the young (3 month F344) and old age groups. VEGF mRNA and protein levels are significantly elevated in the aged cortex despite the lack of HIF-1 activation. Other HIF-independent mediators of hypoxia inducible genes could be involved during chronic hypoxia in the aged brain. PPAR-γ coactivator (PGC)-1α, a known regulator of VEGF gene transcription, is elevated in the young and aged cortex during the chronic hypoxic exposure. Overall, our results suggest a compensatory HIF-1 independent preservation of hypoxic-induced microvascular angiogenesis in the aged rat brain. PMID:20875806

  7. Heparin Binding Epidermal Growth Factor Like Growth Factor Heals Chronic Tympanic Membrane Perforations With Advantage Over Fibroblast Growth Factor 2 and Epidermal Growth Factor in an Animal Model

    PubMed Central

    Santa Maria, Peter Luke; Weierich, Kendall; Kim, Sungwoo; Yang, Yunzhi Peter

    2016-01-01

    Hypothesis That heparin binding epidermal growth factor like growth factor (HB-EGF) heals chronic tympanic membrane (TM) perforations at higher rates than fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF) in an animal model. Background A non-surgical treatment for chronic TM perforation would benefit those unable to access surgery or those unable to have surgery, as well as reducing the cost of tympanoplasty. Growth factor (GF) treatments have been reported in the literature with variable success with the lack of a suitable animal providing a major obstacle. Methods The GFs were tested in a validated mouse model of chronic TM perforation. A bio absorbable hydrogel polymer was used to deliver the GF at a steady concentration as it dissolved over four weeks. A control (polymer only, n=18) was compared to polymer loaded with HB-EGF (5ug/ml, n=18), FGF2 (100ug/ml, n=19) and EGF (250ug/ml, n=19). Perforations were inspected at four weeks. Results The healing rates, as defined as one hundred percent perforation closure, were control (5/18, 27.8%), HB-EGF (15/18, 83.3%), FGF2 (6/19, 31.6%) and EGF (3/19, 15.8%). There were no differences between FGF2 (p=0.80) and EGF (p=0.31) with control healing rates. HB-EGF (p= 0.000001) showed a significant difference for healing. The HB-EGF healed TMs showed layers similar to a normal TM, whilst the other groups showed a lack of epithelial migration. Conclusion This study confirms the advantage of HB-EGF over two other commonly used growth factors and is a promising non-surgical treatment of chronic TM perforations. PMID:26075672

  8. Epidermal Growth Factor and Intestinal Barrier Function.

    PubMed

    Tang, Xiaopeng; Liu, Hu; Yang, Shufen; Li, Zuohua; Zhong, Jinfeng; Fang, Rejun

    2016-01-01

    Epidermal growth factor (EGF) is a 53-amino acid peptide that plays an important role in regulating cell growth, survival, migration, apoptosis, proliferation, and differentiation. In addition, EGF has been established to be an effective intestinal regulator helping to protect intestinal barrier integrity, which was essential for the absorption of nutrients and health in humans and animals. Several researches have demonstrated that EGF via binding to the EGF receptor and subsequent activation of Ras/MAPK, PI3K/AKT, PLC-γ/PKC, and STATS signal pathways regulates intestinal barrier function. In this review, the relationship between epidermal growth factor and intestinal development and intestinal barrier is described, to provide a better understanding of the effects of EGF on intestine development and health. PMID:27524860

  9. Epidermal Growth Factor and Intestinal Barrier Function

    PubMed Central

    Liu, Hu; Yang, Shufen; Li, Zuohua; Zhong, Jinfeng

    2016-01-01

    Epidermal growth factor (EGF) is a 53-amino acid peptide that plays an important role in regulating cell growth, survival, migration, apoptosis, proliferation, and differentiation. In addition, EGF has been established to be an effective intestinal regulator helping to protect intestinal barrier integrity, which was essential for the absorption of nutrients and health in humans and animals. Several researches have demonstrated that EGF via binding to the EGF receptor and subsequent activation of Ras/MAPK, PI3K/AKT, PLC-γ/PKC, and STATS signal pathways regulates intestinal barrier function. In this review, the relationship between epidermal growth factor and intestinal development and intestinal barrier is described, to provide a better understanding of the effects of EGF on intestine development and health. PMID:27524860

  10. Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells.

    PubMed

    Hsieh, Chen-Lin; Cai, Changmeng; Giwa, Ahmed; Bivins, Aaronica; Chen, Shao-Yong; Sabry, Dina; Govardhan, Kumara; Shemshedini, Lirim

    2008-07-01

    Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-alpha1 (sGCalpha1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA(I)-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells. PMID:18469090

  11. Determining the Independent Risk Factors and Mortality Rate of Nosocomial Infections in Pediatric Patients.

    PubMed

    Aktar, Fesih; Tekin, Recep; Güneş, Ali; Ülgen, Cevat; Tan, İlhan; Ertuğrul, Sabahattin; Köşker, Muhammet; Balık, Hasan; Karabel, Duran; Yolbaş, Ilyas

    2016-01-01

    The objective of this study was to determine the rate, independent risk factors, and outcomes of healthcare-associated infections in pediatric patients. This study was performed between 2011 and 2014 in pediatric clinic and intensive care unit. 86 patients and 86 control subjects were included in the study. Of 86 patients with nosocomial infections (NIs), there were 100 NIs episodes and 90 culture growths. The median age was 32.0 months. The median duration of hospital stay of the patients was 30.0 days. The most frequent pathogens were Coagulase-negative Staphylococcus, Acinetobacter spp., Klebsiella spp., and Candida spp. Unconsciousness, prolonged hospitalization, transfusion, mechanical ventilation, use of central venous catheter, enteral feeding via a nasogastric tube, urinary catheter, and receiving carbapenems and glycopeptides were found to be significantly higher in NIs patients. Multivariate logistic regression analysis showed prolonged hospitalization, neutropenia, and use of central venous catheter and carbapenems as the independent risk factors for NIs. In the univariate analysis, unconsciousness, mechanical ventilation, enteral feeding, use of enteral feeding via a nasogastric tube, H2 receptor blockers, and port and urinary catheter were significantly associated with mortality. In the multiple logistic regression analysis, only mechanical ventilation was found as an independent predictor of mortality in patients with NIs. PMID:26981536

  12. Determining the Independent Risk Factors and Mortality Rate of Nosocomial Infections in Pediatric Patients

    PubMed Central

    Aktar, Fesih; Tekin, Recep; Güneş, Ali; Ülgen, Cevat; Tan, İlhan; Ertuğrul, Sabahattin; Köşker, Muhammet; Balık, Hasan; Karabel, Duran; Yolbaş, Ilyas

    2016-01-01

    The objective of this study was to determine the rate, independent risk factors, and outcomes of healthcare-associated infections in pediatric patients. This study was performed between 2011 and 2014 in pediatric clinic and intensive care unit. 86 patients and 86 control subjects were included in the study. Of 86 patients with nosocomial infections (NIs), there were 100 NIs episodes and 90 culture growths. The median age was 32.0 months. The median duration of hospital stay of the patients was 30.0 days. The most frequent pathogens were Coagulase-negative Staphylococcus, Acinetobacter spp., Klebsiella spp., and Candida spp. Unconsciousness, prolonged hospitalization, transfusion, mechanical ventilation, use of central venous catheter, enteral feeding via a nasogastric tube, urinary catheter, and receiving carbapenems and glycopeptides were found to be significantly higher in NIs patients. Multivariate logistic regression analysis showed prolonged hospitalization, neutropenia, and use of central venous catheter and carbapenems as the independent risk factors for NIs. In the univariate analysis, unconsciousness, mechanical ventilation, enteral feeding, use of enteral feeding via a nasogastric tube, H2 receptor blockers, and port and urinary catheter were significantly associated with mortality. In the multiple logistic regression analysis, only mechanical ventilation was found as an independent predictor of mortality in patients with NIs. PMID:26981536

  13. Mapping growth-factor-modulated Akt signaling dynamics.

    PubMed

    Gross, Sean M; Rotwein, Peter

    2016-05-15

    Growth factors alter cellular behavior through shared signaling cascades, raising the question of how specificity is achieved. Here, we have determined how growth factor actions are encoded into Akt signaling dynamics by real-time tracking of a fluorescent sensor. In individual cells, Akt activity was encoded in an analog pattern, with similar latencies (∼2 min) and half-maximal peak response times (range of 5-8 min). Yet, different growth factors promoted dose-dependent and heterogeneous changes in signaling dynamics. Insulin treatment caused sustained Akt activity, whereas EGF or PDGF-AA promoted transient signaling; PDGF-BB produced sustained responses at higher concentrations, but short-term effects at low doses, actions that were independent of the PDGF-α receptor. Transient responses to EGF were caused by negative feedback at the receptor level, as a second treatment yielded minimal responses, whereas parallel exposure to IGF-I caused full Akt activation. Small-molecule inhibitors reduced PDGF-BB signaling to transient responses, but only decreased the magnitude of IGF-I actions. Our observations reveal distinctions among growth factors that use shared components, and allow us to capture the consequences of receptor-specific regulatory mechanisms on Akt signaling. PMID:27044757

  14. Transforming growth factor alpha and epidermal growth factor levels in bladder cancer and their relationship to epidermal growth factor receptor.

    PubMed Central

    Mellon, J. K.; Cook, S.; Chambers, P.; Neal, D. E.

    1996-01-01

    We have examined levels of epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) in neoplastic and non-neoplastic bladder tissue using a standard radioimmunoassay technique. Tumour samples had much higher TGF-alpha levels compared with EGF and TGF-alpha levels in malignant tissue were significantly higher than in benign bladder samples. There was, in addition, a difference in mean EGF levels from 'normal' bladder samples from non-tumour bearing areas of bladder in patients with bladder cancer compared with 'normal' bladder tissue obtained at the time of organ retrieval surgery. Levels of EGF and TGF-alpha did not correlate with levels of EGF receptor (EGFR) as determined by a radioligand binding method but levels of TGF-alpha > 10 ng gm-1 of tumour tissue did correlate with EGFR positivity defined using immunohistochemistry. These data suggest that TGF-alpha is the likely ligand for EGFR in bladder tumours. PMID:8605103

  15. Lifetime growth in wild meerkats: incorporating life history and environmental factors into a standard growth model.

    PubMed

    English, Sinéad; Bateman, Andrew W; Clutton-Brock, Tim H

    2012-05-01

    Lifetime records of changes in individual size or mass in wild animals are scarce and, as such, few studies have attempted to model variation in these traits across the lifespan or to assess the factors that affect them. However, quantifying lifetime growth is essential for understanding trade-offs between growth and other life history parameters, such as reproductive performance or survival. Here, we used model selection based on information theory to measure changes in body mass over the lifespan of wild meerkats, and compared the relative fits of several standard growth models (monomolecular, von Bertalanffy, Gompertz, logistic and Richards). We found that meerkats exhibit monomolecular growth, with the best model incorporating separate growth rates before and after nutritional independence, as well as effects of season and total rainfall in the previous nine months. Our study demonstrates how simple growth curves may be improved by considering life history and environmental factors, which may be particularly relevant when quantifying growth patterns in wild populations. PMID:22108854

  16. Regulation of the Low Dose Radiation Paracrine-Specific Anchorage-Independent Growth Response by Annexin A2

    SciTech Connect

    Weber, Thomas J.; Opresko, Lee K.; Waisman, David M.; Newton, Gregory J.; Quesenberry, Ryan D.; Bollinger, Nikki; Moore, Ronald J.; Smith, Richard D.

    2009-07-13

    ABSTRACT-Here we identify release of annexin A2 into the culture medium in response to low dose X-ray radiation exposure and establish functional linkages to an established paracrine factor-mediated anchorage-independent growth response. Using a standard bicameral coculture model, we observe that annexin A2 levels associated with non-irradiated neighboring cells seeded in the lower chamber (annexin A2 silenced [shRNA] JB6 cells) are increased upon coculture with irradiated (10-50 cGy) JB6 cells seeded in the upper chamber, relative to coculture with sham exposed JB6 cells seeded in the upper chamber, suggesting that annexin A2 released into the medium is capable of communicating in a paracrine fashion. Using a previously established coculture model, we observed that the paracrine factor-mediated anchorage-independent growth response to low dose X-ray radiation is markedly reduced when irradiated annexin A2 silenced (shRNA) JB6 cells are used, relative to coculture with irradiated annexin A2 competent vector control counterparts. These observations suggest that annexin A2 is functionally linked to the radiation paracrine factor-specific anchorage-independent growth response in JB6 cells.

  17. ELF3-PIF4 interaction regulates plant growth independently of the Evening Complex.

    PubMed

    Nieto, Cristina; López-Salmerón, Vadir; Davière, Jean-Michel; Prat, Salomé

    2015-01-19

    The circadian clock plays a pivotal role in the control of Arabidopsis hypocotyl elongation by regulating rhythmic expression of the bHLH factors PHYTOCHROME INTERACTING FACTOR 4 and 5 (PIF4 and 5). Coincidence of increased PIF4/PIF5 transcript levels with the dark period allows nuclear accumulation of these factors, and in short days it phases maximal hypocotyl growth at dawn. During early night, PIF4 and PIF5 transcription is repressed by the Evening Complex (EC) proteins EARLY FLOWERING3 (ELF3), EARLY FLOWERING4 (ELF4), and LUX ARRHYTHMO (LUX). While ELF3 has an essential role in EC complex assembly, several lines of evidence indicate that this protein controls plant growth via other mechanisms that are presently unknown. Here, we show that the ELF3 and PIF4 proteins interact in an EC-independent manner, and that this interaction prevents PIF4 from activating its transcriptional targets. We also show that PIF4 overexpression leads to ELF3 protein destabilization, and that this effect is mediated indirectly by negative feedback regulation of photoactive PHYTOCHROME B (phyB). Physical interaction of the phyB photoreceptor with ELF3 has been reported, but its functional relevance remains poorly understood. Our findings establish that phyB is needed for ELF3 accumulation in the light, most likely by competing for CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1)-mediated ubiquitination and the proteasomal degradation of ELF3. Our results explain the short hypocotyl phenotype of ELF3 overexpressors, despite their normal clock function, and provide a molecular framework for understanding how warm temperatures promote hypocotyl elongation and affect the endogenous clock. PMID:25557667

  18. 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

  19. Growth hormone, insulin-like growth factor system and carcinogenesis.

    PubMed

    Boguszewski, Cesar Luiz; Boguszewski, Margaret Cristina da Silva; Kopchick, John J

    2016-01-01

    The growth hormone (GH) and insulin-like growth factor (IGF) system plays an important role in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. In terms of cell cycle regulation, the GH-IGF system induces signalling pathways for cell growth that compete with other signalling systems that result in cell death; thus the final effect of these opposed forces is critical for normal and abnormal cell growth. The association of the GH-IGF system with carcinogenesis has long been hypothesised, mainly based on in vitro studies and the use of a variety of animal models of human cancer, and also on epidemiological and clinical evidence in humans. While ample experimental evidence supports a role of the GH-IGF system in tumour promotion and progression, with several of its components being currently tested as central targets for cancer therapy, the strength of evidence from patients with acromegaly, GH deficiency, or treated with GH is much weaker. In this review, we will attempt to consolidate this data. (Endokrynol Pol 2016; 67 (4): 414-426). PMID:27387246

  20. Tonicity-independent regulation of the osmosensitive transcription factor TonEBP (NFAT5).

    PubMed

    Halterman, Julia A; Kwon, H Moo; Wamhoff, Brian R

    2012-01-01

    Tonicity-responsive enhancer binding protein (TonEBP/nuclear factor of activated T-cells 5 [NFAT5]) is a Rel homology transcription factor classically known for its osmosensitive role in regulating cellular homeostasis during states of hypo- and hypertonic stress. A recently growing body of research indicates that TonEBP is not solely regulated by tonicity, but that it can be stimulated by various tonicity-independent mechanisms in both hypertonic and isotonic tissues. Physiological and pathophysiological stimuli such as cytokines, growth factors, receptor and integrin activation, contractile agonists, ions, and reactive oxygen species have been implicated in the positive regulation of TonEBP expression and activity in diverse cell types. These new data demonstrate that tonicity-independent stimulation of TonEBP is critical for tissue-specific functions like enhanced cell survival, migration, proliferation, vascular remodeling, carcinoma invasion, and angiogenesis. Continuing research will provide a better understanding as to how these and other alternative TonEBP stimuli regulate gene expression in both health and disease. PMID:21998140

  1. Growth Factors and Astrocytes Metabolism: Possible Roles for Platelet Derived Growth Factor.

    PubMed

    Cabezas, Ricardo; Avila-Rodriguez, Marco; Vega-Vela, Nelson E; Echeverria, Valentina; González, Janneth; Hidalgo, Oscar A; Santos, Altair B; Aliev, Gjumrakch; Barreto, George E

    2016-01-01

    Astrocytes exert multiple functions in the brain such as the development of blood-brain barrier characteristics, the promotion of neurovascular coupling, attraction of cells through the release of chemokines, clearance of toxic substances and generation of antioxidant molecules and growth factors. In this aspect, astrocytes secrete several growth factors (BDNF, GDNF, NGF, and others) that are fundamental for cell viability, oxidant protection, genetic expression and modulation of metabolic functions. The platelet derived growth factor (PDGF), which is expressed by many SNC cells, including astrocytes, is an important molecule that has shown neuroprotective potential, improvement of wound healing, regulation of calcium metabolism and mitochondrial function. Here we explore some of these astrocyte-driven functions of growth factors and their possible therapeutic uses in the context of neurodegeneration. PMID:26477707

  2. The suppression of fibroblast growth factor 2/fibroblast growth factor 4-dependent tumour angiogenesis and growth by the anti-growth factor activity of dextran derivative (CMDB7).

    PubMed Central

    Bagheri-Yarmand, R.; Kourbali, Y.; Mabilat, C.; Morère, J. F.; Martin, A.; Lu, H.; Soria, C.; Jozefonvicz, J.; Crépin, M.

    1998-01-01

    Our previous studies showed that carboxymethyl benzylamide dextran (CMDB7) blocks basic fibroblast growth factor (FGF-2)-dependent cell proliferation of a human breast epithelial line (HBL100), suggesting its potential role as a potent antiangiogenic substance. The derived cell line (HH9), which was transformed with the hst/FGF4 gene, has been shown to be highly proliferative in vitro and to induce angiogenic tumours in nude mice. We show here that CMDB7 inhibits the mitogenic activities of the conditioned media from HBL 100 and HH9 cells in a dose-dependent manner. When HH9 cells were injected s.c. into nude mice, CMDB7 treatment (300 mg kg(-1) week(-1)) suppressed the tumour take and the tumour growth by about 50% and 80% respectively. Immunohistochemical analysis showed a highly significant decrease, by more than threefold, in the endothelial density of viable tumour regions, together with a significant increase in the necrosis area. This antiangiogenic activity of CMDB7 was further demonstrated by direct inhibition of calf pulmonary artery (CPAE) and human umbilical vein (HUVEC) endothelial cell proliferation and migration in vitro. In addition, we showed that CMDB7 inhibits specifically the mitogenic effects of the growth factors that bind to heparin such as FGF-2, FGF-4, platelet-derived growth factor (PDGF-BB) and transforming growth factor (TGF-beta1), but not those of epidermal growth factor (EGF) and insulin-like growth factor (IGF-1). These results demonstrate that CMDB7 inhibits FGF-2/FGF-4-dependent tumour growth and angiogenesis, most likely by disrupting the autocrine and paracrine effects of growth factors released from the tumour cells. Images Figure 4 PMID:9662260

  3. Key roles of necroptotic factors in promoting tumor growth.

    PubMed

    Liu, Xinjian; Zhou, Min; Mei, Ling; Ruan, Jiaying; Hu, Qian; Peng, Jing; Su, Hang; Liao, Hong; Liu, Shanling; Liu, WeiPing; Wang, He; Huang, Qian; Li, Fang; Li, Chuan-Yuan

    2016-04-19

    Necroptotic factors are generally assumed to play a positive role in tumor therapy by eliminating damaged tumor cells. Here we show that, contrary to expectation, necroptotic factors RIPK1, RIPK3, and MLKL promote tumor growth. We demonstrate that genetic knockout of necroptotic genes RIPK1, RIPK3, or MLKL in cancer cells significantly attenuated their abilities to grow in an anchorage-independent manner. In addition, they exhibited significantly enhanced radiosensitivity. The knockout cells also showed greatly reduced ability to form tumors in mice. Moreover, necrosulfonamide (NSA), a previously identified chemical inhibitor of necroptosis, could significantly delay tumor growth in a xenograft model. Mechanistically, we show that necroptoic factors play a significant role in maintaining the activity of NF-κB. Finally, we found that high levels of phosphorylated MLKL in human esophageal and colon cancers are associated with poor overall survival. Taken together, we conclude that pro-necroptic factors such as RIPK1, RIPK3, and MLKL may play a role in supporting tumor growth, and MLKL may be a promising target for cancer treatment. PMID:26959742

  4. Key roles of necroptotic factors in promoting tumor growth

    PubMed Central

    Liu, Xinjian; Zhou, Min; Mei, Ling; Ruan, Jiaying; Hu, Qian; Peng, Jing; Su, Hang; Liao, Hong; Liu, Shanling; Liu, WeiPing; Wang, He; Huang, Qian; Li, Fang; Li, Chuan-Yuan

    2016-01-01

    Necroptotic factors are generally assumed to play a positive role in tumor therapy by eliminating damaged tumor cells. Here we show that, contrary to expectation, necroptotic factors RIPK1, RIPK3, and MLKL promote tumor growth. We demonstrate that genetic knockout of necroptotic genes RIPK1, RIPK3, or MLKL in cancer cells significantly attenuated their abilities to grow in an anchorage-independent manner. In addition, they exhibited significantly enhanced radiosensitivity. The knockout cells also showed greatly reduced ability to form tumors in mice. Moreover, necrosulfonamide (NSA), a previously identified chemical inhibitor of necroptosis, could significantly delay tumor growth in a xenograft model. Mechanistically, we show that necroptoic factors play a significant role in maintaining the activity of NF-κB. Finally, we found that high levels of phosphorylated MLKL in human esophageal and colon cancers are associated with poor overall survival. Taken together, we conclude that pro-necroptic factors such as RIPK1, RIPK3, and MLKL may play a role in supporting tumor growth, and MLKL may be a promising target for cancer treatment. PMID:26959742

  5. 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. PMID:27347885

  6. Blocking Fibroblast Growth Factor Receptor Signaling Inhibits Tumor Growth, Lymphangiogenesis, and Metastasis

    PubMed Central

    Larrieu-Lahargue, Frédéric; Welm, Alana L.; Bouchecareilh, Marion; Alitalo, Kari; Li, Dean Y.; Bikfalvi, Andreas; Auguste, Patrick

    2012-01-01

    Fibroblast Growth Factor receptor (FGFR) activity plays crucial roles in tumor growth and patient survival. However, FGF (Fibroblast Growth Factor) signaling as a target for cancer therapy has been under-investigated compared to other receptor tyrosine kinases. Here, we studied the effect of FGFR signaling inhibition on tumor growth, metastasis and lymphangiogenesis by expressing a dominant negative FGFR (FGFR-2DN) in an orthotopic mouse mammary 66c14 carcinoma model. We show that FGFR-2DN-expressing 66c14 cells proliferate in vitro slower than controls. 66c14 tumor outgrowth and lung metastatic foci are reduced in mice implanted with FGFR-2DN-expressing cells, which also exhibited better overall survival. We found 66c14 cells in the lumen of tumor lymphatic vessels and in lymph nodes. FGFR-2DN-expressing tumors exhibited a decrease in VEGFR-3 (Vascular Endothelial Growth Factor Receptor-3) or podoplanin-positive lymphatic vessels, an increase in isolated intratumoral lymphatic endothelial cells and a reduction in VEGF-C (Vascular Endothelial Growth Factor-C) mRNA expression. FGFs may act in an autocrine manner as the inhibition of FGFR signaling in tumor cells suppresses VEGF-C expression in a COX-2 (cyclooxygenase-2) or HIF1-α (hypoxia-inducible factor-1 α) independent manner. FGFs may also act in a paracrine manner on tumor lymphatics by inducing expression of pro-lymphangiogenic molecules such as VEGFR-3, integrin α9, prox1 and netrin-1. Finally, in vitro lymphangiogenesis is impeded in the presence of FGFR-2DN 66c14 cells. These data confirm that both FGF and VEGF signaling are necessary for the maintenance of vascular morphogenesis and provide evidence that targeting FGFR signaling may be an interesting approach to inhibit tumor lymphangiogenesis and metastatic spread. PMID:22761819

  7. Elevated Fibroblast Growth Factor 23 is a Risk Factor for Kidney Transplant Loss and Mortality

    PubMed Central

    Molnar, Miklos Z.; Amaral, Ansel P.; Czira, Maria E.; Rudas, Anna; Ujszaszi, Akos; Kiss, Istvan; Rosivall, Laszlo; Kosa, Janos; Lakatos, Peter; Kovesdy, Csaba P.; Mucsi, Istvan

    2011-01-01

    An increased circulating level of fibroblast growth factor 23 (FGF23) is an independent risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease (CKD), but its role in transplant allograft and patient survival is unknown. We tested the hypothesis that increased FGF23 is an independent risk factor for all-cause mortality and allograft loss in a prospective cohort of 984 stable kidney transplant recipients. At enrollment, estimated GFR (eGFR) was 51 ± 21 ml/min per 1.73 m2 and median C-terminal FGF23 was 28 RU/ml (interquartile range, 20 to 43 RU/ml). Higher FGF23 levels independently associated with increased risk of the composite outcome of all-cause mortality and allograft loss (full model hazard ratio: 1.46 per SD increase in logFGF23, 95% confidence interval: 1.28 to 1.68, P < 0.001). The results were similar for each component of the composite outcome and in all sensitivity analyses, including prespecified analyses of patients with baseline eGFR of 30 to 90 ml/min per 1.73 m2. In contrast, other measures of phosphorus metabolism, including serum phosphate and parathyroid hormone (PTH) levels, did not consistently associate with outcomes. We conclude that a high (or elevated) FGF23 is an independent risk factor for death and allograft loss in kidney transplant recipients. PMID:21436289

  8. Mouse nerve growth factor gene: structure and expression.

    PubMed Central

    Selby, M J; Edwards, R; Sharp, F; Rutter, W J

    1987-01-01

    The organization and biologically significant sequences of the entire mouse nerve growth factor (NGF) gene have been determined. The gene spans 45 kilobases and contains several small 5' exons. Transcription of the gene results in four different mRNA species, which can be accounted for by alternative splicing and independent initiation from two promoters. These transcripts encode proteins which have divergent N termini and the NGF moiety at their C termini. The levels of the various NGF transcripts have been determined in different tissues and throughout postnatal development. We have also examined the expression of these transcripts in the brain in response to specific early sensory deprivation. The results suggest that the expression of NGF mRNA during postnatal development is regulated independently of the formation of complex neural networks. Images PMID:3670305

  9. Pitch Discrimination: An Independent Factor in Cochlear Implant Performance Outcomes

    PubMed Central

    Kenway, Bruno; Tam, Yu Chuen; Vanat, Zebunnisa; Harris, Frances; Gray, Roger; Birchall, John; Carlyon, Robert; Axon, Patrick

    2015-01-01

    Objective: To assess differences in pitch-ranking ability across a range of speech understanding performance levels and as a function of electrode position. Study Design: An observational study of a cross-section of cochlear implantees. Setting: Tertiary referral center for cochlear implantation. Patients: A total of 22 patients were recruited. All three manufacturers’ devices were included (MED-EL, Innsbruck, Austria, n = 10; Advanced Bionics, California, USA, n = 8; and Cochlear, Sydney, Australia, n = 4) and all patients were long-term users (more than 18 months). Twelve of these were poor performers (scores on BKB sentence lists <60%) and 10 were excellent performers (BKB >90%). Intervention: After measurement of threshold and comfort levels, and loudness balancing across the array, all patients underwent thorough pitch-ranking assessments at 80% of comfort levels. Main Outcome Measure: Ability to discriminate pitch across the electrode array, measured by consistency in discrimination of adjacent pairs of electrodes, as well as an assessment of the pitch order across the array using the midpoint comparison task. Results: Within the poor performing group there was wide variability in ability to pitch rank, from no errors, to a complete inability to reliably and consistently differentiate pitch change across the electrode array. Good performers were overall significantly more accurate at pitch ranking (p = 0.026). Consistent pitch ranking was found to be a significant independent predictor of BKB score, even after adjusting for age. Users of the MED-EL implant experienced significantly more pitch confusions at the apex than at more basal parts of the electrode array. Conclusions: Many cochlear implant users struggle to discriminate pitch effectively. Accurate pitch ranking appears to be an independent predictor of overall outcome. Future work will concentrate on manipulating maps based upon pitch discrimination findings in an attempt to improve

  10. Growth hormone-releasing hormone (GHRH) antagonists inhibit the proliferation of androgen-dependent and -independent prostate cancers.

    PubMed

    Letsch, Markus; Schally, Andrew V; Busto, Rebeca; Bajo, Ana M; Varga, Jozsef L

    2003-02-01

    The antiproliferative effects of an antagonist of growth hormone-releasing hormone (GHRH) JV-1-38 were evaluated in nude mice bearing s.c. xenografts of LNCaP and MDA-PCa-2b human androgen-sensitive and DU-145 androgen-independent prostate cancers. In the androgen-sensitive models, JV-1-38 greatly potentiated the antitumor effect of androgen deprivation induced by surgical castration, but was ineffective when given alone. Thus, in castrated animals bearing MDA-PCa-2b cancers, the administration of JV-1-38 for 35 days virtually arrested tumor growth (94% inhibition vs. intact control, P < 0.01; and 75% vs. castrated control, P < 0.05). The growth of LNCaP tumors was also powerfully suppressed by JV-1-38 combined with castration (83% inhibition vs. intact control, P < 0.01; and 68% vs. castrated control, P < 0.05). However, in androgen-independent DU-145 cancers, JV-1-38 alone could inhibit tumor growth by 57% (P < 0.05) after 45 days. In animals bearing MDA-PCa-2b and LNCaP tumors, the reduction in serum prostate-specific antigen levels, after therapy with JV-1-38, paralleled the decrease in tumor volume. Inhibition of MDA-PCa-2b and DU-145 cancers was associated with the reduction in the expression of mRNA and protein levels of vascular endothelial growth factor. The mRNA expression for GHRH receptor splice variants was found in all these models of prostate cancer. Our results demonstrate that GHRH antagonists inhibit androgen-independent prostate cancers and, after combination with androgen deprivation, also androgen-sensitive tumors. Thus, the therapy with GHRH antagonist could be considered for the management of both androgen-dependent or -independent prostate cancers. PMID:12538852

  11. Growth hormone-releasing hormone (GHRH) antagonists inhibit the proliferation of androgen-dependent and -independent prostate cancers

    PubMed Central

    Letsch, Markus; Schally, Andrew V.; Busto, Rebeca; Bajo, Ana M.; Varga, Jozsef L.

    2003-01-01

    The antiproliferative effects of an antagonist of growth hormone-releasing hormone (GHRH) JV-1-38 were evaluated in nude mice bearing s.c. xenografts of LNCaP and MDA-PCa-2b human androgen-sensitive and DU-145 androgen-independent prostate cancers. In the androgen-sensitive models, JV-1-38 greatly potentiated the antitumor effect of androgen deprivation induced by surgical castration, but was ineffective when given alone. Thus, in castrated animals bearing MDA-PCa-2b cancers, the administration of JV-1-38 for 35 days virtually arrested tumor growth (94% inhibition vs. intact control, P < 0.01; and 75% vs. castrated control, P < 0.05). The growth of LNCaP tumors was also powerfully suppressed by JV-1-38 combined with castration (83% inhibition vs. intact control, P < 0.01; and 68% vs. castrated control, P < 0.05). However, in androgen-independent DU-145 cancers, JV-1-38 alone could inhibit tumor growth by 57% (P < 0.05) after 45 days. In animals bearing MDA-PCa-2b and LNCaP tumors, the reduction in serum prostate-specific antigen levels, after therapy with JV-1-38, paralleled the decrease in tumor volume. Inhibition of MDA-PCa-2b and DU-145 cancers was associated with the reduction in the expression of mRNA and protein levels of vascular endothelial growth factor. The mRNA expression for GHRH receptor splice variants was found in all these models of prostate cancer. Our results demonstrate that GHRH antagonists inhibit androgen-independent prostate cancers and, after combination with androgen deprivation, also androgen-sensitive tumors. Thus, the therapy with GHRH antagonist could be considered for the management of both androgen-dependent or -independent prostate cancers. PMID:12538852

  12. THIAMINE AND NICOTINIC ACID: ANAEROBIC GROWTH FACTORS FOR MUCOR ROUXII

    PubMed Central

    Bartnicki-Garcia, S.; Nickerson, Walter J.

    1961-01-01

    Bartnicki-Garcia, S. (Rutgers, the State University, New Brunswick, N. J.), and Walter J. Nickerson. Thiamine and nicotinic acid: Anaerobic growth factors for Mucor rouxii. J. Bacteriol. 82:142–148. 1961.—Mucor rouxii requires preformed thiamine and nicotinic acid for anaerobic growth. Such requirements are not manifested during aerobic incubation. Aerobically, the fungus was shown to be able to synthesize both vitamins. The yeastlike form and the filamentous form of anaerobically grown M. rouxii exhibit the same vitamin requirements. Thiamine can be substituted by its thiazole moiety. Under certain conditions, nicotinic acid was partly substituted by tryptophan, kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid. Anaerobically. the fungus (thiamine requiring) was about ten times more susceptible to pyrithiamine antagonism than the same organism grown aerobically (thiamine independent). PMID:16561911

  13. Insulin-like factor regulates neural induction through an IGF1 receptor-independent mechanism

    PubMed Central

    Haramoto, Yoshikazu; Takahashi, Shuji; Oshima, Tomomi; Onuma, Yasuko; Ito, Yuzuru; Asashima, Makoto

    2015-01-01

    Insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) signalling is required for normal embryonic growth and development. Previous reports indicated that the IGF/IGF1R/MAPK pathway contributes to neural induction and the IGF/IGF1R/PI3K/Akt pathway to eye development. Here, we report the isolation of insulin3 encoding a novel insulin-like ligand involved in neural induction. Insulin3 has a similar structure to pro-insulin and mature IGF ligands, but cannot activate the IGF1 receptor. However, similar to IGFs, Insulin3 induced the gene expression of an anterior neural marker, otx2, and enlarged anterior head structures by inhibiting Wnt signalling. Insulin3 are predominantly localised to the endoplasmic reticulum when otx2 is induced by insulin3. Insulin3 reduced extracellular Wnts and cell surface localised Lrp6. These results suggest that Insulin3 is a novel cell-autonomous inhibitor of Wnt signalling. This study provides the first evidence that an insulin-like factor regulates neural induction through an IGF1R-independent mechanism. PMID:26112133

  14. Drosha as an interferon-independent antiviral factor.

    PubMed

    Shapiro, Jillian S; Schmid, Sonja; Aguado, Lauren C; Sabin, Leah R; Yasunaga, Ari; Shim, Jaehee V; Sachs, David; Cherry, Sara; tenOever, Benjamin R

    2014-05-13

    Utilization of antiviral small interfering RNAs is thought to be largely restricted to plants, nematodes, and arthropods. In an effort to determine whether a physiological interplay exists between the host small RNA machinery and the cellular response to virus infection in mammals, we evaluated antiviral activity in the presence and absence of Dicer or Drosha, the RNase III nucleases responsible for generating small RNAs. Although loss of Dicer did not compromise the cellular response to virus infection, Drosha deletion resulted in a significant increase in virus levels. Here, we demonstrate that diverse RNA viruses trigger exportin 1 (XPO1/CRM1)-dependent Drosha translocation into the cytoplasm in a manner independent of de novo protein synthesis or the canonical type I IFN system. Additionally, increased virus infection in the absence of Drosha was not due to a loss of viral small RNAs but, instead, correlated with cleavage of viral genomic RNA and modulation of the host transcriptome. Taken together, we propose that Drosha represents a unique and conserved arm of the cellular defenses used to combat virus infection. PMID:24778219

  15. Polyamines regulate cell growth and cellular methylglyoxal in high-glucose medium independently of intracellular glutathione.

    PubMed

    Kwak, Min-Kyu; Lee, Mun-Hyoung; Park, Seong-Jun; Shin, Sang-Min; Liu, Rui; Kang, Sa-Ouk

    2016-03-01

    Polyamines can presumably inhibit protein glycation, when associated with the methylglyoxal inevitably produced during glycolysis. Herein, we hypothesized a nonenzymatic interaction between putrescine and methylglyoxal in putrescine-deficient or -overexpressing Dictyostelium cells in high-glucose medium, which can control methylglyoxal production. Putrescine was essentially required for growth rescue accompanying methylglyoxal detoxification when cells underwent growth defect and cell cycle G1-arrest when supplemented with high glucose. Furthermore, methylglyoxal regulation by putrescine seemed to be a parallel pathway independent of the changes in cellular glutathione content in high-glucose medium. Consequently, we suggest that Dictyostelium cells need polyamines for normal growth and cellular methylglyoxal regulation. PMID:26898161

  16. Diameter-Independent Kinetics in the Vapor-Liquid-Solid Growth of Si Nanowires

    NASA Astrophysics Data System (ADS)

    Kodambaka, S.; Tersoff, J.; Reuter, M. C.; Ross, F. M.

    2006-03-01

    We examine individual Si nanowires grown by the vapor-liquid-solid mechanism, using real-time in situ ultra high vacuum transmission electron microscopy. By directly observing Au-catalyzed growth of Si wires from disilane, we show that the growth rate is independent of wire diameter, contrary to the expected behavior. Our measurements show that the unique rate-limiting step here is the irreversible, kinetically limited, dissociative adsorption of disilane directly on the catalyst surface. We also identify a novel dependence of growth rate on wire taper.

  17. Diameter-independent kinetics in the vapor-liquid-solid growth of Si nanowires.

    PubMed

    Kodambaka, S; Tersoff, J; Reuter, M C; Ross, F M

    2006-03-10

    We examine individual Si nanowires grown by the vapor-liquid-solid mechanism, using real-time in situ ultra high vacuum transmission electron microscopy. By directly observing Au-catalyzed growth of Si wires from disilane, we show that the growth rate is independent of wire diameter, contrary to the expected behavior. Our measurements show that the unique rate-limiting step here is the irreversible, kinetically limited, dissociative adsorption of disilane directly on the catalyst surface. We also identify a novel dependence of growth rate on wire taper. PMID:16606284

  18. Decorin: A Growth Factor Antagonist for Tumor Growth Inhibition

    PubMed Central

    Järvinen, Tero A. H.; Prince, Stuart

    2015-01-01

    Decorin (DCN) is the best characterized member of the extracellular small leucine-rich proteoglycan family present in connective tissues, typically in association with or “decorating” collagen fibrils. It has substantial interest to clinical medicine owing to its antifibrotic, anti-inflammatory, and anticancer effects. Studies on DCN knockout mice have established that a lack of DCN is permissive for tumor development and it is regarded as a tumor suppressor gene. A reduced expression or a total disappearance of DCN has been reported to take place in various forms of human cancers during tumor progression. Furthermore, when used as a therapeutic molecule, DCN has been shown to inhibit tumor progression and metastases in experimental cancer models. DCN affects the biology of various types of cancer by targeting a number of crucial signaling molecules involved in cell growth, survival, metastasis, and angiogenesis. The active sites for the neutralization of different growth factors all reside in different parts of the DCN molecule. An emerging concept that multiple proteases, especially those produced by inflammatory cells, are capable of cleaving DCN suggests that native DCN could be inactivated in a number of pathological inflammatory conditions. In this paper, we review the role of DCN in cancer. PMID:26697491

  19. Induction of p53-independent growth inhibition in lung carcinoma cell A549 by gypenosides.

    PubMed

    Liu, Jung-Sen; Chiang, Tzu-Hsuan; Wang, Jinn-Shyan; Lin, Li-Ju; Chao, Wei-Chih; Inbaraj, Baskaran Stephen; Lu, Jyh-Feng; Chen, Bing-Huei

    2015-07-01

    The objectives of this study are to investigate antiproliferative effect and mechanisms of bioactive compounds from Gynostemma pentaphyllum (G. pentaphyllum) on lung carcinoma cell A549. Saponins, carotenoids and chlorophylls were extracted and fractionated by column chromatography, and were subjected to high-performance liquid chromatography-mass spectrometry analyses. The saponin fraction, which consisted mainly of gypenoside (Gyp) XXII and XXIII, rather than the carotenoid and chlorophyll ones, was effective in inhibiting A549 cell growth in a concentration- and a time-dependent manner as evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The estimated half maximal inhibitory concentration (IC50 ) of Gyp on A549 cells was 30.6 μg/ml. Gyp was further demonstrated to induce an apparent arrest of the A549 cell cycle at both the S phase and the G2/M phase, accompanied by a concentration- and a time-dependent increase in the proportions of both the early and late apoptotic cells. Furthermore, Gyp down-regulated cellular expression of cyclin A and B as well as BCL-2, while up-regulated the expression of BAX, DNA degradation factor 35 KD, poly [ADP-ribose] polymerase 1, p53, p21 and caspase-3. Nevertheless, both the treatment of a p53 inhibitor, pifithrin-α, and the small hairpin RNA-mediated p53 knockdown in the A549 cells did not alter the growth inhibition effect induced by Gyp. As a result, the cell cycle arrest and apoptosis of A549 cells induced by Gyp would most likely proceed through p53-independent pathway(s). PMID:25781909

  20. Induction of p53-independent growth inhibition in lung carcinoma cell A549 by gypenosides

    PubMed Central

    Liu, Jung-Sen; Chiang, Tzu-Hsuan; Wang, Jinn-Shyan; Lin, Li-Ju; Chao, Wei-Chih; Inbaraj, Baskaran Stephen; Lu, Jyh-Feng; Chen, Bing-Huei

    2015-01-01

    The objectives of this study are to investigate antiproliferative effect and mechanisms of bioactive compounds from Gynostemma pentaphyllum (G. pentaphyllum) on lung carcinoma cell A549. Saponins, carotenoids and chlorophylls were extracted and fractionated by column chromatography, and were subjected to high-performance liquid chromatography-mass spectrometry analyses. The saponin fraction, which consisted mainly of gypenoside (Gyp) XXII and XXIII, rather than the carotenoid and chlorophyll ones, was effective in inhibiting A549 cell growth in a concentration- and a time-dependent manner as evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The estimated half maximal inhibitory concentration (IC50) of Gyp on A549 cells was 30.6 μg/ml. Gyp was further demonstrated to induce an apparent arrest of the A549 cell cycle at both the S phase and the G2/M phase, accompanied by a concentration- and a time-dependent increase in the proportions of both the early and late apoptotic cells. Furthermore, Gyp down-regulated cellular expression of cyclin A and B as well as BCL-2, while up-regulated the expression of BAX, DNA degradation factor 35 KD, poly [ADP-ribose] polymerase 1, p53, p21 and caspase-3. Nevertheless, both the treatment of a p53 inhibitor, pifithrin-α, and the small hairpin RNA-mediated p53 knockdown in the A549 cells did not alter the growth inhibition effect induced by Gyp. As a result, the cell cycle arrest and apoptosis of A549 cells induced by Gyp would most likely proceed through p53-independent pathway(s). PMID:25781909

  1. Keratinocyte growth factor and hepatocyte growth factor/scatter factor are heparin-binding growth factors for alveolar type II cells in fibroblast-conditioned medium.

    PubMed Central

    Panos, R J; Rubin, J S; Csaky, K G; Aaronson, S A; Mason, R J

    1993-01-01

    Epithelial-mesenchymal interactions mediate aspects of normal lung growth and development and are important in the restoration of normal alveolar architecture after lung injury. To determine if fibroblasts are a source of soluble growth factors for alveolar type II cells, we investigated the effect of fibroblast-conditioned medium (CM) on alveolar type II cell DNA synthesis. Serum-free CM from confluent adult human lung fibroblasts was concentrated fivefold by lyophilization. Type II cells were isolated from adult rats by elastase dissociation and incubated with [3H]thymidine and varying dilutions of concentrated CM and serum from day 1 to 3 of culture. Stimulation of type II cell DNA synthesis by fibroblast-CM was maximal after 48 h of conditioning and required the presence of serum. The activity of the CM was eliminated by boiling and by treatment with trypsin, pepsin, or dithiothreitol and was additive with saturating concentrations of acidic fibroblast growth factor, epidermal growth factor, and insulin. The growth factor activity bound to heparin-Sepharose and was eluted with 0.6 and 1.0 M NaCl. Neutralizing antibody studies demonstrated that the primary mitogens isolated in the 0.6 and 1.0 M NaCl fractions were keratinocyte growth factor (KGF, fibroblast growth factor 7) and hepatocyte growth factor/scatter factor (HGF/SF), respectively. HGF/SF was demonstrated in the crude CM and KGF was detected in the 0.6 M NaCl eluent by immunoblotting. Northern blot analysis confirmed that the lung fibroblasts expressed both KGF and HGF/SF transcripts. Human recombinant KGF and HGF/SF induced a concentration- and serum-dependent increase in rat alveolar type II cell DNA synthesis. We conclude that adult human lung fibroblasts produce at least two soluble heparin-binding growth factors, KGF and HGF/SF, which promote DNA synthesis and proliferation of rat alveolar type II cells in primary culture. KGF and HGF/SF may be important stimuli for alveolar type II cell

  2. Identification of genes essential for prey-independent growth of Bdellovibrio bacteriovorus HD100.

    PubMed

    Roschanski, Nicole; Klages, Sven; Reinhardt, Richard; Linscheid, Michael; Strauch, Eckhard

    2011-04-01

    Bdellovibrio bacteriovorus HD100 is an obligate predatory bacterium that attacks and invades Gram-negative bacteria. The predator requires living bacteria to survive as growth and replication take place inside the bacterial prey. It is possible to isolate mutants that grow and replicate outside prey bacteria. Such mutants are designated host or prey independent, and their nutritional requirements vary. Some mutants are saprophytic and require prey extracts for extracellular growth, whereas other mutants grow axenically, which denotes the formation of colonies on complete medium in the absence of any prey components. The initial events leading to prey-independent growth are still under debate, and several genes may be involved. We selected new mutants by three different methods: spontaneous mutation, transposon mutagenesis, and targeted gene knockout. By all approaches we isolated mutants of the hit (host interaction) locus. As the relevance of this locus for the development of prey independence has been questioned, we performed whole-genome sequencing of five prey-independent mutants. Three mutants were saprophytic, and two mutants could grow axenically. Whole-genome analysis revealed that the mutation of a small open reading frame of the hit locus is sufficient for the conversion from predatory to saprophytic growth. Complementation experiments were performed by introduction of a plasmid carrying the wild-type hit gene into saprophytic mutants, and predatory growth could be restored. Whole-genome sequencing of two axenic mutants demonstrated that in addition to the hit mutation the colony formation on complete medium was shown to be influenced by the mutations of two genes involved in RNA processing. Complementation experiments with a wild-type gene encoding an RNA helicase, RhlB, abolished the ability to form colonies on complete medium, indicating that stability of RNA influences axenic growth. PMID:21278289

  3. Characterization of insulin-like growth factor I and epidermal growth factor receptors in meningioma

    SciTech Connect

    Kurihara, M.; Tokunaga, Y.; Tsutsumi, K.; Kawaguchi, T.; Shigematsu, K.; Niwa, M.; Mori, K. )

    1989-10-01

    Receptors for insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) were localized and characterized in eight samples of human meningioma (four fibrous, two meningothelial, and two angioblastic types), using quantitative autoradiographic techniques. Effects of both growth factors on deoxyribonucleic acid (DNA) synthesis in the cultured meningioma cells were examined. High numbers of specific binding sites for both IGF-I and EGF were homogeneously present in tissue sections derived from fibrous and meningothelial types of meningiomas, whereas binding sites for these growth factors were not detectable in adjacent leptomeninges. While relatively large numbers of IGF-I binding sites were located in the wall of the intratumoral vasculature, the number of binding sites in the stromal component was lower in angioblastic-type meningiomas, including a low number of EGF binding sites detected only in the stromal portion. Scatchard analysis revealed the presence of a single class of high-affinity binding sites for both IGF-I and EGF in the meningiomas examined (dissociation constant (Kd) = 0.6 to 2.9 nM, and the maximum number of binding sites (Bmax) = 16 to 80 fmol/mg for IGF-I; and Kd = 0.6 to 4.0 nM, Bmax = 3 to 39 fmol/mg for EGF). Both growth factors increased the synthesis of DNA, in a dose-dependent manner, as measured by 3H-thymidine incorporation. The combination of IGF-I and EGF synergistically stimulated the synthesis of DNA, and the effects seen with 10% fetal bovine serum could be reproduced at a concentration of 10(-10) M. These observations can be interpreted to mean that both IGF-I and EGF may be involved in the growth modulation of meningiomas, possibly through paracrine or autocrine mechanisms.

  4. The Roles of Growth Factors in Keratinocyte Migration

    PubMed Central

    Seeger, Mark A.; Paller, Amy S.

    2015-01-01

    Significance: The re-epithelialization of wounded skin requires the rapid and coordinated migration of keratinocytes (KC) into the wound bed. Almost immediately after wounding, cells present at or attracted to the wound site begin to secrete a complex milieu of growth factors. These growth factors exert mitogenic and motogenic effects on KCs, inducing the rapid proliferation and migration of KCs at the wound edge. Recent Advances: New roles for growth factors in KC biology are currently being discovered and investigated. This review will highlight the growth factors, particularly transforming growth factor-α (TGF-α), heparin-binding epidermal growth factor (HB-EGF), insulin-like growth factor 1 (IGF-1), fibroblast growth factor 7 (FGF-7), FGF-10, and hepatocyte growth factor (HGF), which have conclusively been shown to be the most motogenic for KCs. Critical Issues: The cellular and molecular heterogeneity of wounded tissue makes establishing direct relationships between specific growth factors and KC migration difficult in situ. The absence of this complexity in simplified in vitro experimental models of migration makes the clinical relevance of the results obtained from these in vitro studies ambiguous. Future Directions: Deciphering the relationship between growth factors and KC migration is critical for understanding the process of wound healing in normal and disease states. Insights into the basic science of the effects of growth factors on KC migration will hopefully lead to the development of new therapies to treat acute and chronic wounds. PMID:25945284

  5. Transcription factor LSF (TFCP2) inhibits melanoma growth

    PubMed Central

    Goto, Yuji; Yajima, Ichiro; Kumasaka, Mayuko; Ohgami, Nobutaka; Tanaka, Asami; Tsuzuki, Toyonori; Inoue, Yuji; Fukushima, Satoshi; Ihn, Hironobu; Kyoya, Mikiko; Ohashi, Hiroyuki; Kawakami, Tamihiro; Bennett, Dorothy C.; Kato, Masashi

    2016-01-01

    Late SV40 factor 3 (LSF), a transcription factor, contributes to human hepatocellular carcinoma (HCC). However, decreased expression level of LSF in skin melanoma compared to that in benign melanocytic tumors and nevi in mice and humans was found in this study. Anchorage-dependent and -independent growth of melanoma cells was suppressed by LSF overexpression through an increased percentage of G1 phase cells and an increased p21CIP1 expression level in vitro and in vivo. Anchorage-dependent growth in LSF-overexpressed melanoma cells was promoted by depletion of LSF in the LSF-overexpressed cells. Integrated results of our EMSA and chromatin immunoprecipitation assays showed binding of LSF within a 150-bp upstream region of the transcription start site of p21CIP1 in melanoma cells. Taken together, our results suggest potential roles of LSF as a growth regulator through control of the transcription of p21CIP1 in melanocytes and melanoma cells as well as a biomarker for nevus. PMID:26506241

  6. Transcription factor LSF (TFCP2) inhibits melanoma growth.

    PubMed

    Goto, Yuji; Yajima, Ichiro; Kumasaka, Mayuko; Ohgami, Nobutaka; Tanaka, Asami; Tsuzuki, Toyonori; Inoue, Yuji; Fukushima, Satoshi; Ihn, Hironobu; Kyoya, Mikiko; Ohashi, Hiroyuki; Kawakami, Tamihiro; Bennett, Dorothy C; Kato, Masashi

    2016-01-19

    Late SV40 factor 3 (LSF), a transcription factor, contributes to human hepatocellular carcinoma (HCC). However, decreased expression level of LSF in skin melanoma compared to that in benign melanocytic tumors and nevi in mice and humans was found in this study. Anchorage-dependent and -independent growth of melanoma cells was suppressed by LSF overexpression through an increased percentage of G1 phase cells and an increased p21CIP1 expression level in vitro and in vivo. Anchorage-dependent growth in LSF-overexpressed melanoma cells was promoted by depletion of LSF in the LSF-overexpressed cells. Integrated results of our EMSA and chromatin immunoprecipitation assays showed binding of LSF within a 150-bp upstream region of the transcription start site of p21CIP1 in melanoma cells. Taken together, our results suggest potential roles of LSF as a growth regulator through control of the transcription of p21CIP1 in melanocytes and melanoma cells as well as a biomarker for nevus. PMID:26506241

  7. Diabetes, growth hormone-insulin-like growth factor pathways and association to benign prostatic hyperplasia.

    PubMed

    Wang, Zongwei; Olumi, Aria F

    2011-01-01

    Diabetes significantly increases the risk of benign prostatic hyperplasia (BPH) and low urinary tract symptoms (LUTS). The major endocrine aberration in connection with the metabolic syndrome is hyperinsulinemia. Insulin is an independent risk factor and a promoter of BPH. Insulin resistance may change the risk of BPH through several biological pathways. Hyperinsulinemia stimulates the liver to produce more insulin-like growth factor (IGF), another mitogen and an anti-apoptotic agent which binds insulin receptor/IGF receptor and stimulates prostate growth. The levels of IGFs and IGF binding proteins (IGFBPs) in prostate tissue and in blood are associated with BPH risk, with the regulation of circulating androgen and growth hormone. Stromal-epithelial interactions play a critical role in the development and growth of the prostate gland and BPH. Previously, we have shown that the expression of c-Jun in the fibroblastic stroma can promote secretion of IGF-I, which stimulates prostate epithelial cell proliferation through activating specific target genes. Here, we will review the epidemiologic, clinical, and molecular findings which have evaluated the relation between diabetes and development of BPH. PMID:21536370

  8. Neuropeptides as lung cancer growth factors.

    PubMed

    Moody, Terry W; Moreno, Paola; Jensen, Robert T

    2015-10-01

    This manuscript is written in honor of the Festschrift for Abba Kastin. I met Abba at a Society for Neuroscience meeting and learned that he was Editor-in-Chief of the Journal Peptides. I submitted manuscripts to the journal on "Neuropeptides as Growth Factors in Cancer" and subsequently was named to the Editorial Advisory Board. Over the past 30 years I have published dozens of manuscripts in Peptides and reviewed hundreds of submitted manuscripts. It was always rewarding to interact with Abba, a consummate professional. When I attended meetings in New Orleans I would sometimes go out to dinner with him at the restaurant "Commanders Palace". When I chaired the Summer Neuropeptide Conference we were honored to have him receive the Fleur Strand Award one year in Israel. I think that his biggest editorial contribution has been the "Handbook of Biologically Active Peptides." I served as a Section Editor on "Cancer/Anticancer Peptides" and again found that it was a pleasure working with him. This review focuses on the mechanisms by which bombesin-like peptides, neurotensin and vasoactive intestinal peptide regulate the growth of lung cancer. PMID:25836991

  9. 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

  10. Epidermal growth factor signaling in transformed cells

    PubMed Central

    Lindsey, Stephan; Langhans, Sigrid A.

    2016-01-01

    Members of the epidermal growth factor receptor (EGFR/ErbB) family play a critical role in normal cell growth and development. However, many ErbB family members, especially EGFR, are aberrantly expressed or deregulated in tumors and are thought to play crucial roles in cancer development and metastatic progression. In this chapter, we provide an overview of key mechanisms contributing to aberrant EGFR/ErbB signaling in transformed cells which results in many phenotypic changes associated with the earliest stages of tumor formation, including several hallmarks of epithelial-to-mesenchymal transition (EMT). These changes often occur through interaction with other major signaling pathways important to tumor progression resulting in a multitude of transcriptional changes that ultimately impact cell morphology, proliferation and adhesion, all of which are crucial for tumor progression. The resulting mesh of signaling networks will need to be taken into account as new regimens are designed for targeting EGFR for therapeutic intervention. As new insights into the molecular mechanisms of the cross-talk of EGFR signaling with other signaling pathways and their role in therapeutic resistance to anti-EGFR therapies are gained a continual reassessment of clinical therapeutic regimes and strategies will be required. Understanding the consequences and complexity of EGF signaling and how it relates to tumor progression is critical for the development of clinical compounds and establishing clinical protocols for the treatment of cancer. PMID:25619714

  11. Effects of growth hormone and insulin-like growth factor I on muscle in mouse models of human growth disorders.

    PubMed

    Clark, Ryan P; Schuenke, Mark; Keeton, Stephanie M; Staron, Robert S; Kopchick, John J

    2006-01-01

    The precise effects of growth hormone (GH) and insulin-like growth factor I (IGF-I) on muscle development and physiology are relatively unknown. Furthermore, there have been conflicting reports on the effects of GH/IGF-I on muscle. Distinguishing the direct effects of GH versus those of IGF-I is problematic, but animal models with altered GH/IGF-I action could help to alleviate some of the conflicting results and help to determine the independent actions of GH and IGF-I. The phenotypes of several mouse models, namely the GH receptor-gene-disrupted (GHR -/-) mouse and a variety of IGF-I -/- mice, are summarized, which ultimately will aid our understanding of this complex area. PMID:17259718

  12. Polyelectrolyte Complex for Heparin Binding Domain Osteogenic Growth Factor Delivery.

    PubMed

    Wing Moon Lam, Raymond; Abbah, Sunny Akogwu; Ming, Wang; Naidu, Mathanapriya; Ng, Felly; Tao, Hu; Goh Cho Hong, James; Ting, Kang; Hee Kit, Wong

    2016-01-01

    During reconstructive bone surgeries, supraphysiological amounts of growth factors are empirically loaded onto scaffolds to promote successful bone fusion. Large doses of highly potent biological agents are required due to growth factor instability as a result of rapid enzymatic degradation as well as carrier inefficiencies in localizing sufficient amounts of growth factor at implant sites. Hence, strategies that prolong the stability of growth factors such as BMP-2/NELL-1, and control their release could actually lower their efficacious dose and thus reduce the need for larger doses during future bone regeneration surgeries. This in turn will reduce side effects and growth factor costs. Self-assembled PECs have been fabricated to provide better control of BMP-2/NELL-1 delivery via heparin binding and further potentiate growth factor bioactivity by enhancing in vivo stability. Here we illustrate the simplicity of PEC fabrication which aids in the delivery of a variety of growth factors during reconstructive bone surgeries. PMID:27585207

  13. Design of Growth Factor Sequestering Biomaterials

    PubMed Central

    Belair, David G.; Le, Ngoc Nhi; Murphy, William L.

    2014-01-01

    Growth factors (GFs) are major regulatory proteins that can govern cell fate, migration, and organization. Numerous aspects of the cell milieu can modulate cell responses to GFs, and GF regulation is often achieved by the native extracellular matrix (ECM). For example, the ECM can sequester GFs and thereby control GF bioavailability. In addition, GFs can exert distinct effects depending on whether they are sequestered in solution, at two-dimensional interfaces, or within three-dimensional matrices. Understanding how the context of GF sequestering impacts cell function in the native ECM can instruct the design of soluble or insoluble GF sequestering moieties, which can then be used in a variety of bioengineering applications. This Feature Article provides an overview of the natural mechanisms of GF sequestering in the cell milieu, and reviews the recent bioengineering approaches that have sequestered GFs to modulate cell function. Results to date demonstrate that the cell response to GF sequestering depends on the affinity of the sequestering interaction, the spatial proximity of sequestering in relation to cells, the source of the GF (supplemented or endogenous), and the phase of the sequestering moiety (soluble or insoluble). We highlight the importance of context for the future design of biomaterials that can leverage endogenous molecules in the cell milieu and mitigate the need for supplemented factors. PMID:25182455

  14. MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

    PubMed Central

    Mohseni, Morassa; Cidado, Justin; Croessmann, Sarah; Cravero, Karen; Cimino-Mathews, Ashley; Wong, Hong Yuen; Scharpf, Rob; Zabransky, Daniel J.; Abukhdeir, Abde M.; Garay, Joseph P.; Wang, Grace M.; Beaver, Julia A.; Cochran, Rory L.; Blair, Brian G.; Rosen, D. Marc; Erlanger, Bracha; Argani, Pedram; Hurley, Paula J.; Lauring, Josh; Park, Ben Ho

    2014-01-01

    Tamoxifen is effective for treating estrogen receptor-alpha (ER) positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. Here we describe a previously unidentified gene, MACROD2 that confers tamoxifen resistance and estrogen independent growth. We found MACROD2 is amplified and overexpressed in metastatic tamoxifen-resistant tumors. Transgene overexpression of MACROD2 in breast cancer cell lines results in tamoxifen resistance, whereas RNAi-mediated gene knock down reverses this phenotype. MACROD2 overexpression also leads to estrogen independent growth in xenograft assays. Mechanistically, MACROD2 increases p300 binding to estrogen response elements in a subset of ER regulated genes. Primary breast cancers and matched metastases demonstrate MACROD2 expression can change with disease evolution, and increased expression and amplification of MACROD2 in primary tumors is associated with worse overall survival. These studies establish MACROD2 as a key mediator of estrogen independent growth and tamoxifen resistance, as well as a potential novel target for diagnostics and therapy. PMID:25422431

  15. [Risk factors for preterm birth in a group of unemployed women. II. Analysis of independent variables].

    PubMed

    Siedlecka, J; Makowiec-Dabrowska, T

    2000-01-01

    The incidence of preterm birth is conditioned by a number of factors. The identification of these factors in individual groups of women helps to adopt well-oriented preventive measures. The analysis of logistic regression allows to identify significant and independent factors responsible for preterm birth. This paper describes the results of the analysis carried out in the group of non-employed women. The results revealed two following independent factors of risk for preterm birth in the study group of women: the state of health and the burden of considerable physical strain resulting from difficult economic situation of women. PMID:11288689

  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. Gene Expression of Growth Factors and Growth Factor Receptors for Potential Targeted Therapy of Canine Hepatocellular Carcinoma

    PubMed Central

    IIDA, Gentoku; ASANO, Kazushi; SEKI, Mamiko; SAKAI, Manabu; KUTARA, Kenji; ISHIGAKI, Kumiko; KAGAWA, Yumiko; YOSHIDA, Orie; TESHIMA, Kenji; EDAMURA, Kazuya; WATARI, Toshihiro

    2013-01-01

    ABSTRACT The purpose of this study was to evaluate the gene expression of growth factors and growth factor receptors of primary hepatic masses, including hepatocellular carcinoma (HCC) and nodular hyperplasia (NH), in dogs. Quantitative real-time reverse transcriptase-polymerase chain reaction was performed to measure the expression of 18 genes in 18 HCCs, 10 NHs, 11 surrounding non-cancerous liver tissues and 4 healthy control liver tissues. Platelet-derived growth factor-B (PDGF-B), transforming growth factor-α, epidermal growth factor receptor, epidermal growth factor and hepatocyte growth factor were found to be differentially expressed in HCC compared with NH and the surrounding non-cancerous and healthy control liver tissues. PDGF-B is suggested to have the potential to become a valuable ancillary target for the treatment of canine HCC. PMID:24189579

  18. Role of growth factors in the human endometrium during aging.

    PubMed

    Leone, M; Costantini, C; Gallo, G; Voci, A; Massajoli, M; Messeni Leone, M; de Cecco, L

    1993-01-01

    The aim of this study was to investigate the possible role of epidermal growth factor (EGF) and of insulin-like growth factor-I (IGF-I) in physiological and pathological changes of the endometrial tissue during aging. Thirty-four patients undergoing hysterectomy were divided into three groups: (A) premenopausal women with regular menses, (B) pre-menopausal women with irregular bleeding and (C) post-menopausal women. Endometrial samples were collected after the removal of uterus and were used for immunohistochemical evaluation of EGF, EGF receptor (EGFr) and IGF-I and also for Northern blot analysis of IGF-I gene expression. Plasma levels of 17 beta-oestradiol (E2), D4-androstenedione (D4-A) and oestrone (E1) were also assayed. The immunohistochemical scores (HSCORES) for EGF, EGFr and IGF-I were significantly higher in groups A and B than in group C. Independently from the menstrual history, significantly higher HSCORES of EGF, EGFr and IGF-I were present in hyperplastic endometrium than in those which were proliferative and atrophic. Moreover, IGF-I mRNA expression was observed in all pre-menopausal women, whereas only 1 post-menopausal women with hyperplastic endometrium showed detectable RNA encoding for IGF-I. Higher levels of D4-A were also significantly correlated (P < 0.05) with higher HSCORES of EGF, EGFr and IGF-I. Our results suggest that the above mentioned growth factors could act as mediators of oestrogens on the endometrial functional activity. PMID:7679182

  19. Transforming growth factor-β, insulin-like growth factor I/insulin-like growth factor I receptor and vascular endothelial growth factor-A: Prognostic and predictive markers in triple-negative and non-triple-negative breast cancer

    PubMed Central

    BAHHNASSY, ABEER; MOHANAD, MARWA; SHAARAWY, SABRY; ISMAIL, MANAL F.; EL-BASTAWISY, AHMED; ASHMAWY, ABEER M.; ZEKRI, ABDEL-RAHMAN

    2015-01-01

    In the current study, the prognostic and predictive values of serum transforming growth factor-β1 (TGF-β1), insulin-like growth factor I (IGF-I)/IGF-I receptor (IGF-IR) and vascular endothelial growth factor-A (VEGF-A) were evaluated in triple-negative and non-triple-negative breast cancer (TNBC and non-TNBC). The aim was to identify a group of serological biomarkers and to identify possible candidates for targeted therapy in patients with TNBC and non-TNBC. Protein levels of TGF-β1, IGF-I/IGF-IR and VEGF-A in the serum were measured in 43 TNBC, 53 non-TNBC and 20 normal control participants using quantitative ELISA assays. Results were correlated against standard prognostic factors, response to treatment and survival. TNBC was identified to be associated with poor prognosis and serum levels of VEGF-A and IGF/IGF-IR were significantly higher in the TNBC group compared with the non-TNBC group. IGF-IR and VEGF-A overexpression was observed to be correlated with TGF-β1 expression and all of the markers investigated were associated with metastasis and disease progression. In the multivariate analysis, VEGF-A, IGF-I and IGF-IR were observed to be independent predictors for overall survival, whereas TGF-β1 and lymph node status were identified as independent predictors for disease-free survival. The overall response rate was significantly lower in patients with TNBC and those with high levels of TGF-β1, IGF-I/IGF-IR and VEGF-A. In view of the present results, it was concluded that TGF-β1, IGF-I/IGF-IR and VEGF-A overexpression is associated with the presence of aggressive tumors, which exhibit an increased probability of metastasis, a poor response to treatment and reduced survival rate. This indicates that VEGF-A, IGF-IR and IGF-I have the potential to be used as surrogate biomarkers and are promising candidates for targeted therapy, particularly in patients with TNBC. PMID:25824321

  20. Transgenic Soybean Production of Bioactive Human Epidermal Growth Factor (EGF)

    PubMed Central

    He, Yonghua; Schmidt, Monica A.; Erwin, Christopher; Guo, Jun; Sun, Raphael; Pendarvis, Ken; Warner, Brad W.; Herman, Eliot M.

    2016-01-01

    Necrotizing enterocolitis (NEC) is a devastating condition of premature infants that results from the gut microbiome invading immature intestinal tissues. This results in a life-threatening disease that is frequently treated with the surgical removal of diseased and dead tissues. Epidermal growth factor (EGF), typically found in bodily fluids, such as amniotic fluid, salvia and mother’s breast milk, is an intestinotrophic growth factor and may reduce the onset of NEC in premature infants. We have produced human EGF in soybean seeds to levels biologically relevant and demonstrated its comparable activity to commercially available EGF. Transgenic soybean seeds expressing a seed-specific codon optimized gene encoding of the human EGF protein with an added ER signal tag at the N’ terminal were produced. Seven independent lines were grown to homozygous and found to accumulate a range of 6.7 +/- 3.1 to 129.0 +/- 36.7 μg EGF/g of dry soybean seed. Proteomic and immunoblot analysis indicates that the inserted EGF is the same as the human EGF protein. Phosphorylation and immunohistochemical assays on the EGF receptor in HeLa cells indicate the EGF protein produced in soybean seed is bioactive and comparable to commercially available human EGF. This work demonstrates the feasibility of using soybean seeds as a biofactory to produce therapeutic agents in a soymilk delivery platform. PMID:27314851

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

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman W.

    1987-01-01

    New muscle tissue culture techniques were developed to grow embryonic skeletal myofibers which are able to differentiate into more adultlike myofibers. Studies on mechanical simulation of cultured muscle cell growth will now be more directly applicable to mechanically-induced growth in adult muscle, and lead to better models for understanding muscle tissue atrophy caused by disuse in the microgravity of space.

  2. Anchorage Independent Growth of Breast Carcinoma Cells is Mediated by Serum Exosomes

    PubMed Central

    Ochieng, Josiah; Pratap, Siddharth; Khatua, Atanu K.; Sakwe., Amos M.

    2009-01-01

    We hereby report studies that suggest a role for serum exosomes in the anchorage independent growth (AIG) of tumor cells. In AIG assays, fetal bovine serum is one of the critical ingredients. We therefore purified exosomes from fetal bovine serum and examined their potential to promote growth of breast carcinoma cells in soft agar and Matrigel after reconstituting them into growth medium (EEM). In all the assays, viable colonies were formed only in the presence of exosomes. Some of the exosomal proteins we identified, have been documented by others and could be considered exosomal markers. Labeled purified exosomes were up-taken by the tumor cells, a process that could be competed out with excess unlabeled vesicles. Our data also suggested that once endocytosed by a cell, the exosomes could be recycled back to the conditioned medium from where they can be up-taken by other cells. We also demonstrated that low concentrations of exosomes activate MAP kinases, suggesting a mechanism by which they maintain the growth of the tumor cells in soft agar. Taken together, our data demonstrate that serum exosomes form a growth promoting platform for AIG of tumor cells and may open a new vista into cancer cell growth in vivo. PMID:19327352

  3. Fruit growth in Arabidopsis occurs via DELLA-dependent and DELLA-independent gibberellin responses.

    PubMed

    Fuentes, Sara; Ljung, Karin; Sorefan, Karim; Alvey, Elizabeth; Harberd, Nicholas P; Østergaard, Lars

    2012-10-01

    Fruit growth and development depend on highly coordinated hormonal activities. The phytohormone gibberellin (GA) promotes growth by inducing degradation of the growth-repressing DELLA proteins; however, the extent to which DELLA proteins contribute to GA-mediated gynoecium and fruit development remains to be clarified. Here, we provide an in-depth characterization of the role of DELLA proteins in Arabidopsis thaliana fruit growth. We show that DELLA proteins are key regulators of reproductive organ size and important for ensuring optimal fertilization. We demonstrate that the seedless fruit growth (parthenocarpy) observed in della mutants can be directly attributed to the constitutive activation of GA signaling. It has been known for >75 years that another hormone, auxin, can induce formation of seedless fruits. Using mutants with complete lack of DELLA activity, we show here that auxin-induced parthenocarpy occurs entirely through GA signaling in Arabidopsis. Finally, we uncover the existence of a DELLA-independent GA response that promotes fruit growth. This response requires GIBBERELLIN-INSENSITIVE DWARF1-mediated GA perception and a functional 26S proteasome and involves the basic helix-loop-helix protein SPATULA as a key component. Taken together, our results describe additional complexities in GA signaling during fruit development, which may be particularly important to optimize the conditions for successful reproduction. PMID:23064323

  4. Isolated placental vessel response to vascular endothelial growth factor and placenta growth factor in normal and growth-restricted pregnancy.

    PubMed

    Szukiewicz, Dariusz; Szewczyk, Grzegorz; Watroba, Mateusz; Kurowska, Ewa; Maslinski, Slawomir

    2005-01-01

    Vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) cause vasodilation. We examined the vasomotor response of isolated placental vessels to VEGF and PlGF in normal (group I) and intrauterine growth retardation (IUGR)-complicated pregnancy (group II). Rings of vessels were prepared in vitro and mounted on the vessel myograph plunged in tissue bath. The magnitude of dilation to increased doses of VEGF and PlGF has been studied. VEGF is a more potent vasodilator than PlGF. Both, VEGF- and PlGF-induced vasorelaxation was diminished in the IUGR (group II) nearly by half, compared to control (group I). Relative placental nitric oxide deficiency, or decreased sensitivity to VEGF and PlGF may contribute to the development of high impedance fetoplacental circulation. PMID:15591804

  5. The Role of Vascular Endothelial Growth Factors and Fibroblast Growth Factors in Angiogenesis during Otitis Media

    PubMed Central

    Husseman, Jacob; Palacios, Sean D.; Rivkin, Alexander Z.; Oehl, Heinz; Ryan, Allen F.

    2012-01-01

    The middle ear response to otitis media includes transformation and hyperplasia of the mucosal epithelium and subepithelial connective tissue. Significant neovascularization is also noted, which occurs both to support the hypertrophied mucosa and to mediate the increased trafficking of leukocytes. We investigated the role of two known potent angiogenic growth factor families, the fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs), in middle ear mucosal angiogenesis. DNA microarrays were used to evaluate the expression of FGFs and VEGFs, as well as their receptors and unique signaling proteins, in the middle ears of mice undergoing a complete course of acute bacterial otitis media. In addition, a member of each family was introduced to the middle ear submucosal compartment of the normal middle ears of guinea pigs, by a continuous-release osmotic minipump system over 1 week. During the course of bacterial otitis media, a significant regulation of a number of genes important for angiogenesis was identified. Histologic evaluation of middle ear mucosa following micropump infusion of both FGF1 and VEGF-A showed significant angiogenesis at the site of infusion in comparison to control saline infusion. These results support a role for FGFs and VEGFs in the neovascularization of the middle ear mucosa during otitis media, and offer a potential avenue for therapeutic intervention. PMID:22104377

  6. Vascular Endothelial Growth Factor in Eye Disease

    PubMed Central

    Penn, J.S.; Madan, A.; Caldwell, R.B.; Bartoli, M.; Caldwell, R.W.; Hartnett, M.E.

    2012-01-01

    Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis. PMID:18653375

  7. [Epidermal growth factor, innovation and safety].

    PubMed

    Esquirol Caussa, Jordi; Herrero Vila, Elisabeth

    2015-10-01

    Bioidentical recombinant human epidermal growth factor (rhEGF) is available in concentrations and purity suitable for therapeutic use in long time stable formulations. Beneficial effects in several skin pathologies and lesions have been reported (traumatic and surgical wound healing, laser induced wounds, abnormal scars, keloids, radiation or chemotherapy induced dermatitis, post inflammatory hyperpigmentation or for skin aging damage repairing) and also may be considered for the treatment of several oropharingeal and high gastroesophageal tract mucosa diseases (mouth sores, pharyngeal fistulas, ulcers), and several corneal or conjunctive mucosa lesions. rhEGF has not shown any important side or collateral effects in humans or in laboratory experimentation animals, showing optimal tolerability and safety with continuous use for months. Compounding gives advantages of versatility, individualization, personalization, molecular stability, safety and effectiveness in ideal conditions, showing good tissue penetration, both on intact skin and skin lesions that expose the lower planes to the surface. rhEGF compounds can be considered for prevention or as a treatment of diverse skin and mucosa diseases and conditions through compounding preparations. PMID:25433777

  8. Connective tissue growth factor in tumor pathogenesis

    PubMed Central

    2012-01-01

    Key roles for connective tissue growth factor (CTGF/CCN2) are demonstrated in the wound repair process where it promotes myofibroblast differentiation and angiogenesis. Similar mechanisms are active in tumor-reactive stroma where CTGF is expressed. Other potential roles include prevention of hypoxia-induced apoptosis and promoting epithelial-mesenchymal transistion (EMT). CTGF expression in tumors has been associated to both tumor suppression and progression. For example, CTGF expression in acute lymphoblastic leukemia, breast, pancreas and gastric cancer correlates to worse prognosis whereas the opposite is true for colorectal, lung and ovarian cancer. This discrepancy is not yet understood. High expression of CTGF is a hallmark of ileal carcinoids, which are well-differentiated endocrine carcinomas with serotonin production originating from the small intestine and proximal colon. These tumors maintain a high grade of differentiation and low proliferation. Despite this, they are malignant and most patients have metastatic disease at diagnosis. These tumors demonstrate several phenotypes potentially related to CTGF function namely: cell migration, absent tumor cell apoptosis, as well as, reactive and well vascularised myofibroblast rich stroma and fibrosis development locally and in distal organs. The presence of CTGF in other endocrine tumors indicates a role in the progression of well-differentiated tumors. PMID:23259759

  9. Insulin-like growth factor-binding protein-3 inhibition of prostate cancer growth involves suppression of angiogenesis.

    PubMed

    Liu, B; Lee, K-W; Anzo, M; Zhang, B; Zi, X; Tao, Y; Shiry, L; Pollak, M; Lin, S; Cohen, P

    2007-03-15

    Insulin-like growth factor-binding protein-3 (IGFBP-3) is a multifunctional protein that induces apoptosis utilizing both insulin-like growth factor receptor (IGF)-dependent and -independent mechanisms. We investigated the effects of IGFBP-3 on tumor growth and angiogenesis utilizing a human CaP xenograft model in severe-combined immunodeficiency mice. A 16-day course of IGFBP-3 injections reduced tumor size and increased apoptosis and also led to a reduction in the number of vessels stained with CD31. In vitro, IGFBP-3 inhibited both vascular endothelial growth factor- and IGF-stimulated human umbilical vein endothelial cells vascular network formation in a matrigel assay. This action is primarily IGF independent as shown by studies utilizing the non-IGFBP-binding IGF-1 analog Long-R3. Additionally, we used a fibroblast growth factor-enriched matrigel-plug assay and chick allantoic membrane assays to show that IGFBP-3 has potent antiangiogenic actions in vivo. Finally, overexpression of IGFBP-3 or the non-IGF-binding GGG-IGFBP-3 mutant in Zebrafish embryos confirmed that both IGFBP-3 and the non-IGF-binding mutant inhibited vessel formation in vivo, indicating that the antiangiogenic effect of IGFBP-3 is an IGF-independent phenomenon. Together, these studies provide the first evidence that IGFBP-3 has direct, IGF-independent inhibitory effects on angiogenesis providing an additional mechanism by which it exerts its tumor suppressive effects and further supporting its development for clinical use in the therapy of patients with prostate cancer. PMID:16983336

  10. Growth differentiation factor 15 stimulates rapamycin-sensitive ovarian cancer cell growth and invasion.

    PubMed

    Griner, Samantha E; Joshi, Jayashree P; Nahta, Rita

    2013-01-01

    Identification of novel molecular markers and therapeutic targets may improve survival rates for patients with ovarian cancer. In the current study, immunohistochemical (IHC) analysis of two human ovarian tumor tissue arrays showed high staining for GDF15 in a majority of tissues. Exogenous stimulation of ovarian cancer cell lines with recombinant human GDF15 (rhGDF15) or stable over-expression of a GDF15 expression plasmid promoted anchorage-independent growth, increased invasion, and up-regulation of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). MMP inhibition suppressed GDF15-mediated invasion. In addition, IHC analysis of human ovarian tumor tissue arrays indicated that GDF15 expression correlated significantly with high MMP2 and MMP9 expression. Exogenous and endogenous GDF15 over-expression stimulated phosphorylation of p38, Erk1/2, and Akt. Pharmacologic inhibition of p38, MEK, or PI3K suppressed GDF15-stimulated growth. Further, proliferation, growth, and invasion of GDF15 stable clones were blocked by rapamycin. IHC analysis demonstrated significant correlation between GDF15 expression and phosphorylation of mTOR. Finally, knockdown of endogenous GDF15 or neutralization of secreted GDF15 suppressed invasion and growth of a GDF15-over-expressing ovarian cancer cell line. These data indicate that GDF15 over-expression, which occurred in a majority of human ovarian cancers, promoted rapamycin-sensitive invasion and growth of ovarian cancer cells. Inhibition of mTOR may be an effective therapeutic strategy for ovarian cancers that over-express GDF15. Future studies should examine GDF15 as a novel molecular target for blocking ovarian cancer progression. PMID:23085437

  11. Fishing directly selects on growth rate via behaviour: implications of growth-selection that is independent of size

    PubMed Central

    Biro, Peter A.; Sampson, Portia

    2015-01-01

    Size-selective harvest of fish and crustacean populations has reduced stock numbers, and led to reduced growth rates and earlier maturation. In contrast to the focus on size-selective effects of harvest, here, we test the hypothesis that fishing may select on life-history traits (here, growth rate) via behaviour, even in the absence of size selection. If true, then traditional size-limits used to protect segments of a population cannot fully protect fast growers, because at any given size, fast-growers will be more vulnerable owing to bolder behaviour. We repeatedly measured individual behaviour and growth of 86 crayfish and found that fast-growing individuals were consistently bold and voracious over time, and were subsequently more likely to be harvested in single- and group-trapping trials. In addition, there was some indication that sex had independent effects on behaviour and trappability, whereby females tended to be less active, shyer, slower-growing and less likely to be harvested, but not all these effects were significant. This study represents, to our knowledge, the first across-individual support for this hypothesis, and suggests that behaviour is an important mechanism for fishing selectivity that could potentially lead to evolution of reduced intrinsic growth rates. PMID:25608882

  12. 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

  13. Independence and Interplay between Maternal and Child Risk Factors for Preschool Problem Behaviors?

    ERIC Educational Resources Information Center

    Hughes, Claire; Ensor, Rosie

    2009-01-01

    This study examined the independence and interplay between cognitive risk factors (poor executive function/emotion understanding) and maternal risk factors (low education/high depression) for preschool problem behaviors, indexed by multi-measure, multi-informant (mother/teacher/ researcher) ratings. A socio-economically diverse sample of 235…

  14. Mullerian inhibiting substance inhibits ovarian cell growth through an Rb-independent mechanism.

    PubMed

    Ha, T U; Segev, D L; Barbie, D; Masiakos, P T; Tran, T T; Dombkowski, D; Glander, M; Clarke, T R; Lorenzo, H K; Donahoe, P K; Maheswaran, S

    2000-11-24

    Müllerian inhibiting substance (MIS), a transforming growth factor-beta family member, causes regression of the Müllerian duct in male embryos. MIS overexpression in transgenic mice ablates the ovary, and MIS inhibits the growth of ovarian cancer cell lines in vitro, suggesting a key role for this hormone in postnatal development of the ovary. This report describes a mechanism for MIS-mediated growth inhibition in both a human epithelial ovarian cancer cell line and a cell line derived from normal ovarian surface epithelium, which is the origin of human epithelial ovarian cancers. MIS-treated cells accumulated in the G(1) phase of the cell cycle and subsequently underwent apoptosis. MIS up-regulated the cyclin-dependent kinase inhibitor p16 through an MIS type II receptor-mediated mechanism and inhibited growth in the absence of detectable or inactive Rb protein. Prolonged treatment with MIS down-regulated the Rb-related protein p130 and increased the Rb family-regulated transcription factor E2F1, overexpression of which inhibited growth. These findings demonstrate that p16 is required for MIS-mediated growth inhibition in ovarian epithelial cells and tumor cells and suggest that up-regulation of E2F1 also plays a role in this process. PMID:10958795

  15. N-(3-oxo-acyl) homoserine lactone inhibits tumor growth independent of Bcl-2 proteins

    PubMed Central

    Zhao, Guoping; Neely, Aaron M.; Schwarzer, Christian; Lu, Huayi; Whitt, Aaron G.; Stivers, Nicole S.; Burlison, Joseph A.; White, Carl; Machen, Terry E.; Li, Chi

    2016-01-01

    Pseudomonas aeruginosa produces N-(3-oxododecanoyl)-homoserine lactone (C12) as a quorum-sensing molecule for bacterial communication. C12 has also been reported to induce apoptosis in various types of tumor cells. However, the detailed molecular mechanism of C12-triggerred tumor cell apoptosis is still unclear. In addition, it is completely unknown whether C12 possesses any potential therapeutic effects in vivo. Our data indicate that, unlike most apoptotic inducers, C12 evokes a novel form of apoptosis in tumor cells through inducing mitochondrial membrane permeabilization independent of both pro- and anti-apoptotic Bcl-2 proteins. Importantly, C12 inhibits tumor growth in animals regardless of either pro- or anti-apoptotic Bcl-2 proteins. Furthermore, opposite to conventional chemotherapeutics, C12 requires paraoxonase 2 (PON2) to exert its cytotoxicity on tumor cells in vitro and its inhibitory effects on tumor growth in vivo. Overall, our results demonstrate that C12 inhibits tumor growth independent of both pro- and anti-apoptotic Bcl-2 proteins, and through inducing unique apoptotic signaling mediated by PON2 in tumor cells. PMID:26758417

  16. N-(3-oxo-acyl) homoserine lactone inhibits tumor growth independent of Bcl-2 proteins.

    PubMed

    Zhao, Guoping; Neely, Aaron M; Schwarzer, Christian; Lu, Huayi; Whitt, Aaron G; Stivers, Nicole S; Burlison, Joseph A; White, Carl; Machen, Terry E; Li, Chi

    2016-02-01

    Pseudomonas aeruginosa produces N-(3-oxododecanoyl)-homoserine lactone (C12) as a quorum-sensing molecule for bacterial communication. C12 has also been reported to induce apoptosis in various types of tumor cells. However, the detailed molecular mechanism of C12-triggerred tumor cell apoptosis is still unclear. In addition, it is completely unknown whether C12 possesses any potential therapeutic effects in vivo. Our data indicate that, unlike most apoptotic inducers, C12 evokes a novel form of apoptosis in tumor cells through inducing mitochondrial membrane permeabilization independent of both pro- and anti-apoptotic Bcl-2 proteins. Importantly, C12 inhibits tumor growth in animals regardless of either pro- or anti-apoptotic Bcl-2 proteins. Furthermore, opposite to conventional chemotherapeutics, C12 requires paraoxonase 2 (PON2) to exert its cytotoxicity on tumor cells in vitro and its inhibitory effects on tumor growth in vivo. Overall, our results demonstrate that C12 inhibits tumor growth independent of both pro- and anti-apoptotic Bcl-2 proteins, and through inducing unique apoptotic signaling mediated by PON2 in tumor cells. PMID:26758417

  17. Fibroblast Growth Factor Signaling in Metabolic Regulation

    PubMed Central

    Nies, Vera J. M.; Sancar, Gencer; Liu, Weilin; van Zutphen, Tim; Struik, Dicky; Yu, Ruth T.; Atkins, Annette R.; Evans, Ronald M.; Jonker, Johan W.; Downes, Michael Robert

    2016-01-01

    The prevalence of obesity is a growing health problem. Obesity is strongly associated with several comorbidities, such as non-alcoholic fatty liver disease, certain cancers, insulin resistance, and type 2 diabetes, which all reduce life expectancy and life quality. Several drugs have been put forward in order to treat these diseases, but many of them have detrimental side effects. The unexpected role of the family of fibroblast growth factors in the regulation of energy metabolism provides new approaches to the treatment of metabolic diseases and offers a valuable tool to gain more insight into metabolic regulation. The known beneficial effects of FGF19 and FGF21 on metabolism, together with recently discovered similar effects of FGF1 suggest that FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic conditions. To facilitate the development of new therapies with improved targeting and minimal side effects, a better understanding of the molecular mechanism of action of FGFs is needed. In this review, we will discuss what is currently known about the physiological roles of FGF signaling in tissues important for metabolic homeostasis. In addition, we will discuss current concepts regarding their pharmacological properties and effector tissues in the context of metabolic disease. Also, the recent progress in the development of FGF variants will be reviewed. Our goal is to provide a comprehensive overview of the current concepts and consensuses regarding FGF signaling in metabolic health and disease and to provide starting points for the development of FGF-based therapies against metabolic conditions. PMID:26834701

  18. Novel Drosophila receptor that binds multiple growth factors

    SciTech Connect

    Rosner, M.R.; Thompson, K.L.; Garcia, V.; Decker, S.J.

    1986-05-01

    The authors have recently reported the identification of a novel growth factor receptor from Drosophila cell cultures that has dual binding specificity for both insulin and epidermal growth factor (EGF). This 100 kDa protein is also antigenically related to the cytoplasmic region of the mammalian EGF receptor-tyrosine kinase. They now report that this protein binds to mammalian nerve growth factor and human transforming growth factor alpha as well as insulin and EGF with apparent dissociation constants ranging from 10/sup -6/ to 10/sup -8/ M. The 100 kDa protein can be affinity-labeled with these /sup 125/I-labeled growth factors after immunoprecipitation with anti-EGF receptor antiserum. These four growth factors appear to share a common binding site, as evidenced by their ability to block affinity labelling by /sup 125/I-insulin. No significant binding to the 100 kDa protein was observed with platelet-derived growth factor, transforming growth factor beta, or glucagon. The 100 kDa Drosophila protein has a unique ligand-binding spectrum with no direct counterpart in mammalian cells and may represent an evolutionary precursor of the mammalian receptors for these growth factors.

  19. Growth factor array fabrication using a color ink jet printer.

    PubMed

    Watanabe, Kohei; Miyazaki, Takeshi; Matsuda, Ryoichi

    2003-04-01

    We have developed a novel method for growth factor analysis using a commercial color ink jet printer to fabricate substrata patterned with growth factors. We prepared substrata with insulin printed in a simple pattern or containing multiple areas of varying quantities of printed insulin. When we cultured the mouse myoblast cell line, C2C12, on the insulin-patterned substrata, the cells were grown in the same pattern with the insulin-printed pattern. Cell culture with the latter substrata demonstrated that quantity control of insulin deposition by a color ink jet printer is possible. For further applications, we developed substrata with insulin-like growth factor-I (IGF-I) and basic fibroblast growth factor (bFGF) spotted in 16 different areas in varying combinations and concentrations (growth factor array). With this growth factor array, C2C12 cells were cultured, and the onset of muscle cell differentiation was monitored for the expression of the myogenic regulator myogenin. The ratio of cells expressing myogenin varied with the doses of IGF-I and bFGF in the sections, demonstrating a feasibility of growth factor array fabrication by a color ink jet printer. Since a printer manipulates several colors, this method can be easily applied to multivariate analyses of growth factors and attachment factors affecting cell growth and differentiation. This method may provide a powerful tool for cell biology and tissue engineering, especially for stem cell research in investigating unknown conditions for differentiation. PMID:12719645

  20. Dual Control of Muscle Cell Survival by Distinct Growth Factor-Regulated Signaling Pathways

    PubMed Central

    Lawlor, Margaret A.; Feng, Xiuhong; Everding, Daniel R.; Sieger, Kerry; Stewart, Claire E. H.; Rotwein, Peter

    2000-01-01

    In addition to their ability to stimulate cell proliferation, polypeptide growth factors are able to maintain cell survival under conditions that otherwise lead to apoptotic death. Growth factors control cell viability through regulation of critical intracellular signal transduction pathways. We previously characterized C2 muscle cell lines that lacked endogenous expression of insulin-like growth factor II (IGF-II). These cells did not differentiate but underwent apoptotic death in low-serum differentiation medium. Death could be prevented by IGF analogues that activated the IGF-I receptor or by unrelated growth factors such as platelet-derived growth factor BB (PDGF-BB). Here we analyze the signaling pathways involved in growth factor-mediated myoblast survival. PDGF treatment caused sustained activation of extracellular-regulated kinases 1 and 2 (ERK1 and -2), while IGF-I only transiently induced these enzymes. Transient transfection of a constitutively active Mek1, a specific upstream activator of ERKs, maintained myoblast viability in the absence of growth factors, while inhibition of Mek1 by the drug UO126 blocked PDGF-mediated but not IGF-stimulated survival. Although both growth factors activated phosphatidylinositol 3-kinase (PI3-kinase) to similar extents, only IGF-I treatment led to sustained stimulation of its downstream kinase, Akt. Transient transfection of a constitutively active PI3-kinase or an inducible Akt promoted myoblast viability in the absence of growth factors, while inhibition of PI3-kinase activity by the drug LY294002 selectively blocked IGF- but not PDGF-mediated muscle cell survival. In aggregate, these observations demonstrate that distinct growth factor-regulated signaling pathways independently control myoblast survival. Since IGF action also stimulates muscle differentiation, these results suggest a means to regulate myogenesis through selective manipulation of different signal transduction pathways. PMID:10757809

  1. Antisense oligonucleotides targeting the progesterone receptor inhibit hormone-independent breast cancer growth in mice

    PubMed Central

    Lamb, Caroline A; Helguero, Luisa A; Giulianelli, Sebastián; Soldati, Rocío; Vanzulli, Silvia I; Molinolo, Alfredo; Lanari, Claudia

    2005-01-01

    Introduction Previous data from our laboratory suggested that progesterone receptors (PRs) are involved in progestin-independent growth of mammary carcinomas. To investigate this possibility further, we studied the effects of PR antisense oligodeoxynucleotides (asPR) on in vivo tumor growth. Method BALB/c mice with subcutaneous 25 mm2 mammary carcinomas expressing estrogen receptor-α and PR were either injected intraperitoneally with 1 mg asPR every 24 or 12 hours for 5–10 days, or subcutaneously with RU 486 (6.5 mg/kg body weight) every 24 hours. Control mice received vehicle or scPR. Results Significant inhibition of tumor growth as well as a significant decrease in bromodeoxyuridine uptake was observed in asPR-treated mice, which correlated with histological signs of regression and increased apoptosis. Mice treated with RU 486 experienced almost complete tumor regression. No differences were detected between vehicle-treated and scPR-treated mice. Anti-progestin-treated and asPR-treated mice were in a continuous estrous/meta-estrous state. Decreased phosphorylated extracellular signal-regulated kinase (ERK)1 and ERK2 levels and estrogen receptor-α expression were observed as late events in RU 486-treated and asPR-treated mice with regressing tumors. Conclusion We demonstrate, for the first time, inhibition of tumor growth in vivo using asPR. Our results provide further evidence for a critical and hierarchical role of the PR pathway in mammary carcinomas. PMID:16457691

  2. Bile duct invasion can be an independent prognostic factor in early stage hepatocellular carcinoma

    PubMed Central

    Jang, Ye-Rang; Kim, Hyeyoung; Lee, Jeong-Moo; Yi, Nam-Joon; Suh, Kyung-Suk

    2015-01-01

    Backgrounds/Aims In hepatocellular carcinoma (HCC), bile duct invasion occurs far more rarely than vascular invasion and is not well characterized. In addition, the pathologic finding of bile duct invasion is not considered an independent prognostic factor for HCC following surgery. In this study, we determined the characteristics of HCC with bile duct invasion, and assessed the clinical significance of bile duct invasion. Methods We retrospectively reviewed the medical records of 363 patients who underwent hepatic resection for HCC at Seoul National University Hospital (SNUH) from January 2009 to December 2011. Preoperative, operative, and pathological data were collected. The risk factors for recurrence and survival were analyzed. Subsequently, the patients were divided into 2 groups according to disease stage (American Joint Committee on Cancer/International Union Against Cancer 7th edition): early stage (T1 and 2) and advanced stage (T3 and 4) group; and risk factors in the sub-groups were analyzed. Results Among 363 patients, 13 showed bile duct invasion on pathology. Patients with bile duct invasion had higher preoperative total bilirubin levels, greater microvascular invasion, and a higher death rate than those without bile duct invasion. In multivariate analysis, bile duct invasion was not an independent prognostic factor for survival for the entire cohort, but, was an independent prognostic factor for early stage. Conclusions Bile duct invasion accompanied microvascular invasion in most cases, and could be used as an independent prognostic factor for survival especially in early stage HCC (T1 and T2). PMID:26693236

  3. An Exploratory Study of Factors Differentiating Freshmen Educational Growth.

    ERIC Educational Resources Information Center

    Lenning, Oscar T.

    The present study was an exploratory investigation of factors that differentiate students who exhibit "negative educational growth" from a group of equally able students who exhibit marked "positive educational growth." Educational growth was operationally defined as estimated true test-retest change on American College Tests (ACT) composite…

  4. Fibroblast Growth Factor 23 in Patients Undergoing Peritoneal Dialysis

    PubMed Central

    Isakova, Tamara; Xie, Huiliang; Barchi-Chung, Allison; Vargas, Gabriela; Sowden, Nicole; Houston, Jessica; Wahl, Patricia; Lundquist, Andrew; Epstein, Michael; Smith, Kelsey; Contreras, Gabriel; Ortega, Luis; Lenz, Oliver; Briones, Patricia; Egbert, Phyllis; Ikizler, T. Alp; Jueppner, Harald

    2011-01-01

    Summary Background and objectives Fibroblast growth factor 23 (FGF23) is an independent risk factor for mortality in patients with ESRD. Before FGF23 testing can be integrated into clinical practice of ESRD, further understanding of its determinants is needed. Design, setting, participants, & measurements In a study of 67 adults undergoing peritoneal dialysis, we tested the hypothesis that longer dialysis vintage and lower residual renal function and renal phosphate clearance are associated with higher FGF23. We also compared the monthly variability of FGF23 versus parathyroid hormone (PTH) and serum phosphate. Results In unadjusted analyses, FGF23 correlated with serum phosphate (r = 0.66, P < 0.001), residual renal function (r = −0.37, P = 0.002), dialysis vintage (r = 0.31, P = 0.01), and renal phosphate clearance (r = −0.38, P = 0.008). In adjusted analyses, absence of residual renal function and greater dialysis vintage associated with higher FGF23, independent of demographics, laboratory values, peritoneal dialysis modality and adequacy, and treatment with vitamin D analogs and phosphate binders. Urinary and dialysate FGF23 clearances were minimal. In three serial monthly measurements, within-subject variability accounted for only 10% of total FGF23 variability compared with 50% for PTH and 60% for serum phosphate. Conclusions Increased serum phosphate, loss of residual renal function, longer dialysis vintage, and lower renal phosphate clearance are associated with elevated FGF23 levels in ESRD patients undergoing peritoneal dialysis. FGF23 may be a more stable marker of phosphate metabolism in ESRD than PTH or serum phosphate. PMID:21903990

  5. Imperatorin sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells.

    PubMed

    Choochuay, Kanuengnit; Chunhacha, Preedakorn; Pongrakhananon, Varisa; Luechapudiporn, Rataya; Chanvorachote, Pithi

    2013-07-01

    The anoikis-sensitization activity of imperatorin, an active furanocoumarin component of Angelica dahurica root, is reported herein for the first time. The present study demonstrated that the imperatorin treatment at sub-toxic concentrations enhanced human lung cancer H23 cell apoptosis after detachment. A Western blot analysis showed that imperatorin significantly enhanced the p53 protein level, which subsequently down-regulated Mcl-1 protein and up-regulated Bax, while it had a minimal effect on Bcl-2 expression. In addition, an anchorage-independent growth assay was performed to support the anti-metastasis potential of imperatorin. Consistent with anoikis assay, imperatorin exhibited a strong inhibitory effect on the anchorage-independent growth of the cells. Further, this study demonstrated that imperatorin sensitizes anoikis in other lung cancer cells, namely, H292 and A549. Because anoikis was shown to be a critical hindrance in preventing cancer cell metastasis, the knowledge regarding such an activity and an underlying mechanism may lead to the development of this compound for a cancer therapy. PMID:23108812

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

    PubMed

    Johns, D E; Athanasiou, K A

    2008-09-01

    Tissue-engineered fibrocartilage could become a feasible option for replacing tissues such as the knee meniscus or temporomandibular joint disc. This study employed five growth factors (insulin-like growth factor-I, transforming growth factor-beta1, 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 had lower biomechanical and biochemical properties than the controls with no growth factors, suggesting a detrimental effect, but the treatment with insulin-like growth factor-I tended to improve the constructs. Additionally, the 6-week time point was consistently better than that at 3 weeks, 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

  7. Oncogenic herpesvirus HHV-8 promotes androgen-independent prostate cancer growth.

    PubMed

    Mygatt, Justin G; Singhal, Adit; Sukumar, Gauthaman; Dalgard, Clifton L; Kaleeba, Johnan A R

    2013-09-15

    Mechanisms underlying progression to androgen-independent prostate cancer following radical ablation therapy remain poorly defined. Although intraprostatic infections have been highlighted as potential cofactors, pathogen influences on pathways that support tumor regrowth are not known. To explore this provocative concept, we derived androgen-sensitive and -insensitive prostate epithelial cells persistently infected with human herpesvirus 8 (HHV-8), an oncogenic herpesvirus that has been detected in normal prostate epithelium, prostate adenocarcinoma, and biologic fluids of patients with prostate cancer, to explore its effects on transition to hormone-refractory disease. Strikingly, we found that HHV-8 infection of androgen-sensitive prostate cancer cells conferred the capacity for androgen-independent growth. This effect was associated with altered expression and transcriptional activity of the androgen receptor (AR). However, HHV-8 infection bypassed AR signaling by promoting enhancer of zeste homolog 2 (EZH2)-mediated epigenetic silencing of tumor-suppressor genes, including MSMB and DAB2IP that are often inactivated in advanced disease. Furthermore, we found that HHV-8 triggered epithelial-to-mesenchymal transition. Although HHV-8 has not been linked etiologically to prostate cancer, virologic outcomes revealed by our study provide mechanistic insight into how intraprostatic infections could constitute risk for progression to androgen-independent metastatic disease where EZH2 has been implicated. Taken together, our findings prompt further evaluations of the relationship between HHV-8 infections and risk of advanced prostate cancer. PMID:24005834

  8. Targeting the opioid growth factor: opioid growth factor receptor axis for treatment of human ovarian cancer.

    PubMed

    Zagon, Ian S; Donahue, Renee; McLaughlin, Patricia J

    2013-05-01

    The opioid growth factor (OGF) - opioid growth factor receptor (OGFr) axis is a biological pathway that is present in human ovarian cancer cells and tissues. OGF, chemically termed [Met(5)]-enkephalin, is an endogenous opioid peptide that interfaces with OGFr to delay cells moving through the cell cycle by upregulation of cyclin-dependent inhibitory kinase pathways. OGF inhibitory activity is dose dependent, receptor mediated, reversible, protein and RNA dependent, but not related to apoptosis or necrosis. The OGF-OGFr axis can be targeted for treatment of human ovarian cancer by (i) administration of exogenous OGF, (ii) genetic manipulation to over-express OGFr and (iii) use of low dosages of naltrexone, an opioid antagonist, which stimulates production of OGF and OGFr for subsequent interaction following blockade of the receptor. The OGF-OGFr axis may be a feasible target for treatment of cancer of the ovary (i) in a prophylactic fashion, (ii) following cytoreduction or (iii) in conjunction with standard chemotherapy for additive effectiveness. In summary, preclinical data support the transition of these novel therapies for treatment of human ovarian cancer from the bench to bedside to provide additional targets for treatment of this devastating disease. PMID:23856908

  9. Neutrino mass, dark energy, and the linear growth factor

    NASA Astrophysics Data System (ADS)

    Kiakotou, Angeliki; Elgarøy, Øystein; Lahav, Ofer

    2008-03-01

    We study the degeneracies between neutrino mass and dark energy as they manifest themselves in cosmological observations. In contradiction to a popular formula in the literature, the suppression of the matter power spectrum caused by massive neutrinos is not just a function of the ratio of neutrino to total mass densities fν=Ων/Ωm, but also each of the densities independently. We also present a fitting formula for the logarithmic growth factor of perturbations in a flat universe, f(z,k;fν,w,ΩDE)≈[1-A(k)ΩDEfν+B(k)fν2-C(k)fν3]Ωmα(z), where α depends on the dark energy equation of state parameter w. We then discuss cosmological probes where the f factor directly appears: peculiar velocities, redshift distortion, and the integrated Sachs-Wolfe effect. We also modify the approximation of Eisenstein and Hu [Astrophys. J.ASJOAB0004-637X 511, 5 (1999)10.1086/306640] for the power spectrum of fluctuations in the presence of massive neutrinos and provide a revised code [http://www.star.ucl.ac.uk/~lahav/nu_matter_power.f].

  10. 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.

  11. Vascular Endothelial Growth Factor is a Secreted Angiogenic Mitogen

    NASA Astrophysics Data System (ADS)

    Leung, David W.; Cachianes, George; Kuang, Wun-Jing; Goeddel, David V.; Ferrara, Napoleone

    1989-12-01

    Vascular endothelial growth factor (VEGF) was purified from media conditioned by bovine pituitary folliculostellate cells (FC). VEGF is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo. Complementary DNA clones for bovine and human VEGF were isolated from cDNA libraries prepared from FC and HL60 leukemia cells, respectively. These cDNAs encode hydrophilic proteins with sequences related to those of the A and B chains of platelet-derived growth factor. DNA sequencing suggests the existence of several molecular species of VEGF. VEGFs are secreted proteins, in contrast to other endothelial cell mitogens such as acidic or basic fibroblast growth factors and platelet-derived endothelial cell growth factor. Human 293 cells transfected with an expression vector containing a bovine or human VEGF cDNA insert secrete an endothelial cell mitogen that behaves like native VEGF.

  12. Growth factor-eluting technologies for bone tissue engineering.

    PubMed

    Nyberg, Ethan; Holmes, Christina; Witham, Timothy; Grayson, Warren L

    2016-04-01

    Growth factors are essential orchestrators of the normal bone fracture healing response. For non-union defects, delivery of exogenous growth factors to the injured site significantly improves healing outcomes. However, current clinical methods for scaffold-based growth factor delivery are fairly rudimentary, and there is a need for greater spatial and temporal regulation to increase their in vivo efficacy. Various approaches used to provide spatiotemporal control of growth factor delivery from bone tissue engineering scaffolds include physical entrapment, chemical binding, surface modifications, biomineralization, micro- and nanoparticle encapsulation, and genetically engineered cells. Here, we provide a brief review of these technologies, describing the fundamental mechanisms used to regulate release kinetics. Examples of their use in pre-clinical studies are discussed, and their capacities to provide tunable, growth factor delivery are compared. These advanced scaffold systems have the potential to provide safer, more effective therapies for bone regeneration than the systems currently employed in the clinic. PMID:25967594

  13. Pumpkin seed extract: Cell growth inhibition of hyperplastic and cancer cells, independent of steroid hormone receptors.

    PubMed

    Medjakovic, Svjetlana; Hobiger, Stefanie; Ardjomand-Woelkart, Karin; Bucar, Franz; Jungbauer, Alois

    2016-04-01

    Pumpkin seeds have been known in folk medicine as remedy for kidney, bladder and prostate disorders since centuries. Nevertheless, pumpkin research provides insufficient data to back up traditional beliefs of ethnomedical practice. The bioactivity of a hydro-ethanolic extract of pumpkin seeds from the Styrian pumpkin, Cucurbita pepo L. subsp. pepo var. styriaca, was investigated. As pumpkin seed extracts are standardized to cucurbitin, this compound was also tested. Transactivational activity was evaluated for human androgen receptor, estrogen receptor and progesterone receptor with in vitro yeast assays. Cell viability tests with prostate cancer cells, breast cancer cells, colorectal adenocarcinoma cells and a hyperplastic cell line from benign prostate hyperplasia tissue were performed. As model for non-hyperplastic cells, effects on cell viability were tested with a human dermal fibroblast cell line (HDF-5). No transactivational activity was found for human androgen receptor, estrogen receptor and progesterone receptor, for both, extract and cucurbitin. A cell growth inhibition of ~40-50% was observed for all cell lines, with the exception of HDF-5, which showed with ~20% much lower cell growth inhibition. Given the receptor status of some cell lines, a steroid-hormone receptor independent growth inhibiting effect can be assumed. The cell growth inhibition for fast growing cells together with the cell growth inhibition of prostate-, breast- and colon cancer cells corroborates the ethnomedical use of pumpkin seeds for a treatment of benign prostate hyperplasia. Moreover, due to the lack of androgenic activity, pumpkin seed applications can be regarded as safe for the prostate. PMID:26976217

  14. Sulfur inhibits the growth of androgen-independent prostate cancer in vivo

    PubMed Central

    DUAN, FEI; LI, YUHUA; CHEN, LIANGKANG; ZHOU, XIAOYU; CHEN, JIANXING; CHEN, HAILIN; LI, RUNSHENG

    2015-01-01

    Sulfur is a bright yellow crystalline solid at room temperature. The aim of the present study was to investigate the inhibitory effect of sulfur on prostate cancer (PCa) in vivo. Prostate tumors were developed by injecting 22Rv1 or DU-145 PCa cells into sulfur-treated or untreated nude mice. The weight and volume of the tumors were measured. The cancer cells were separated from the tumors, and analyzed for their growth rate and clonogenicity in culture. The expression of PCa-targeted genes was also assessed using real-time polymerase chain reaction. The rate of growth of 22Rv1 tumors in sulfur-treated nude mice gradually decreased, and was reduced by 41.99% (P<0.01) after 22 days when compared with that of the control group. In addition, the growth of DU-145 tumors was also suppressed by 75.16% (P<0.05) after 11 weeks. The clonogenicity of the sulfur-treated tumor cells decreased by 36.7% when compared with that of the control cells. However, no significant difference in cell growth was identified. mRNA levels of the androgen-receptor, prostate specific antigen and human Hox (NKX3.1) genes were significantly decreased by 32.8, 48.2 and 42.2% in sulfur-treated tumors, respectively. Additionally, it was found that the hydrogen sulfide concentration in the serum of sulfur-treated mice was increased by 4.73% (P<0.05). Sulfur significantly suppressed the growth of PCa in vivo. Since sulfur is a known ingredient used in traditional Chinese medicine, it may be used clinically for the treatment of PCa, independently or in combination with other medicine. PMID:25436005

  15. Material factors influencing metallic whisker growth

    NASA Astrophysics Data System (ADS)

    Rodekohr, Chad L.

    Whiskering refers to the formation of slender, long, metallic filaments, much thinner than a human hair, that grow on a metallic thin film surface. They are readily observed for pure and alloyed zinc (Zn), silver (Ag), cadmium (Cd), indium (In), and tin (Sn) surfaces. The longest reported whisker length is 4.5 mm long but most high-aspect ratio whiskers range from 1-500 mum. The focus of this research is upon Sn whiskers. Sn whiskers pose serious reliability problems for the electronics industry and are known to be the source of failure in a wide range of electronic devices, such as nuclear power facilities, heart pacemakers, commercial satellites, aviation radar, telecommunication equipment, and desktop computers. The problem with whiskering has been recently exacerbated by the worldwide shift to lead (Pb) free electronics and the continuing reduction in electrical contact pitches. A thorough understanding of the growth mechanism of Sn whiskers is urgently needed. Currently, there is no universally accepted model that explains the broad range of observations on whiskering. The goals of this research are: (1) to develop a more detailed understanding of the physical mechanisms leading to the initiation and growth of Sn whiskers and (2) to outline reasonable mitigation strategies that could be followed to reduce or eliminate the problem of Sn whiskers. The major contributions of this work are: (1) A reliable method for growing Sn whiskers with predictable incubation times has been developed and tested. (2) A surface oxide is not necessary for whisker growth. (3) Intermetallic compounds (IMC) are not necessary for whisker growth. (4) Smoother, not rougher, substrate surfaces promote whisker growth. (5) Whiskers grow under both compressive and tensile thin film stress states. (6) Whisker growth increases with externally applied compression and tension forces. (7) Sn whiskers are composed of pure Sn except for the expected thin, native Sn oxide on their surface. (8) For

  16. Hepatoma-Derived Growth Factor: Its Possible Involvement in the Progression of Hepatocellular Carcinoma

    PubMed Central

    Enomoto, Hirayuki; Nakamura, Hideji; Liu, Weidong; Nishiguchi, Shuhei

    2015-01-01

    The development of hepatocellular carcinoma (HCC) is an important complication of viral infection induced by hepatitis virus C, and our major research theme is to identify a new growth factor related to the progression of HCC. HDGF (hepatoma-derived growth factor) is a novel growth factor that belongs to a new gene family. HDGF was initially purified from the conditioned medium of a hepatoma cell line. HDGF promotes cellular proliferation as a DNA binding nuclear factor and a secreted protein acting via a receptor-mediated pathway. HDGF is a unique multi-functional protein that can function as a growth factor, angiogenic factor and anti-apoptotic factor and it participates in the development and progression of various malignant diseases. The expression level of HDGF may be an independent prognostic factor for predicting the disease-free and overall survival in patients with various malignancies, including HCC. Furthermore, the overexpression of HDGF promotes the proliferation of HCC cells, while a reduction in the HDGF expression inhibits the proliferation of HCC cells. This article provides an overview of the characteristics of HDGF and describes the potential role of HDGF as a growth-promoting factor for HCC. PMID:26101867

  17. Retinol Promotes In Vitro Growth of Proximal Colon Organoids through a Retinoic Acid-Independent Mechanism

    PubMed Central

    Nibe, Yoichi; Akiyama, Shintaro; Matsumoto, Yuka; Nozaki, Kengo; Fukuda, Masayoshi; Hayashi, Ayumi; Mizutani, Tomohiro; Oshima, Shigeru; Watanabe, Mamoru; Nakamura, Tetsuya

    2016-01-01

    Retinol (ROL), the alcohol form of vitamin A, is known to control cell fate decision of various types of stem cells in the form of its active metabolite, retinoic acid (RA). However, little is known about whether ROL has regulatory effects on colonic stem cells. We examined in this study the effect of ROL on the growth of murine normal colonic cells cultured as organoids. As genes involved in RA synthesis from ROL were differentially expressed along the length of the colon, we tested the effect of ROL on proximal and distal colon organoids separately. We found that organoid forming efficiency and the expression level of Lgr5, a marker gene for colonic stem cells were significantly enhanced by ROL in the proximal colon organoids, but not in the distal ones. Interestingly, neither retinaldehyde (RAL), an intermediate product of the ROL-RA pathway, nor RA exhibited growth promoting effects on the proximal colon organoids, suggesting that ROL-dependent growth enhancement in organoids involves an RA-independent mechanism. This was confirmed by the observation that an inhibitor for RA-mediated gene transcription did not abrogate the effect of ROL on organoids. This novel role of ROL in stem cell maintenance in the proximal colon provides insights into the mechanism of region-specific regulation for colonic stem cell maintenance. PMID:27564706

  18. FBXW7 acts as an independent prognostic marker and inhibits tumor growth in human osteosarcoma.

    PubMed

    Li, Zhanchun; Xiao, Jie; Hu, Kongzu; Wang, Gang; Li, Maoqiang; Zhang, Jidong; Cheng, Guangqi

    2015-01-01

    F-box and WD repeat domain-containing 7 (FBXW7) is a potent tumor suppressor in human cancers including breast cancer, colorectal cancer, gastric cancer and hepatocellular carcinoma. In this study, we found that the expressions of FBXW7 protein and mRNA levels in osteosarcoma (OS) cases were significantly lower than those in normal bone tissues. Clinical analysis indicated that FBXW7 was expressed at lower levels in OS patients with advanced clinical stage, high T classification and poor histological differentiation. Furthermore, we demonstrated that high expression of FBXW7 was correlated with a better 5-year survival of OS patients. Multivariate Cox regression analysis indicated that FBXW7 was an independent prognostic marker in OS. Our in vitro studies showed that FBXW7 overexpression inhibited cell cycle transition and cell proliferation, and promoted apoptosis in both U2OS and MG-63 cells. In a nude mouse xenograft model, FBXW7 overexpression slowed down tumor growth by inducing apoptosis and growth arrest. Mechanistically, FBXW7 inversely regulated oncoprotein c-Myc and cyclin E levels in both U2OS and MG-63 cells. Together these findings suggest that FBXW7 may serve as a prognostic biomarker and inhibit tumor progression by inducing apoptosis and growth arrest in OS. PMID:25622249

  19. 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 ...

  20. EDUCATION AS A FACTOR IN ECONOMIC GROWTH.

    ERIC Educational Resources Information Center

    MACKERTICH, ALEX

    THE VALUE OF AN EDUCATION IN THE ECONOMIC GROWTH OF AN UNDERDEVELOPED COUNTRY (INDIA) WAS INVESTIGATED USING THE CASE STUDY APPROACH. DATA WERE GATHERED AT BOTH THE CENTRAL GOVERNMENT AND VILLAGE LEVELS THROUGH INTERVIEWS WITH INDIAN GOVERNMENT OFFICIALS AND FROM OFFICIAL GOVERNMENT PUBLICATIONS CONCERNING THE NATION'S EDUCATIONAL EFFORTS, AS…

  1. Locus of Control, Field Dependence-Independence as Factors in Learning and Memory.

    ERIC Educational Resources Information Center

    Piotrowski, Chris

    The focus of research on cognitive processes has shifted toward an examination of the relationship between memory and interindividual differences of personality. A review of the research on two such personality traits (i.e., locus of control and field dependence-independence) shows that studies of locus of control as a factor in learning and…

  2. Factors Affecting Student Retention at One Independent School in the Southwest

    ERIC Educational Resources Information Center

    Ahlstrom, Dan Roger

    2013-01-01

    This mixed-methods case study determined the factors and examined the issues associated with student retention at a faith-based independent day school in southwestern United States of America. The data included online surveys, personal interviews, collection of archival information, and the researcher's extensive field notes. Surveys (530) were…

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

    SciTech Connect

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

    1988-01-01

    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. Keloid 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.

  4. Factors involved in maintaining prolonged functional independence following supratentorial glioblastoma resection

    PubMed Central

    Chaichana, Kaisorn L.; Halthore, Aditya N.; Parker, Scott L.; Olivi, Alessandro; Weingart, Jon D.; Brem, Henry; Quinones-Hinojosa, Alfredo

    2013-01-01

    Object The median survival duration for patients with glioblastoma is approximately 12 months. Maximizing quality of life (QOL) for patients with glioblastoma is a priority. An important, yet understudied, QOL component is functional independence. The aims of this study were to evaluate functional outcomes over time for patients with glioblastoma, as well as identify factors associated with prolonged functional independence. Methods All patients who underwent first-time resection of either a primary (de novo) or secondary (prior lower grade glioma) glioblastoma at a single institution from 1996 to 2006 were retrospectively reviewed. Patients with a Karnofsky Performance Scale (KPS) score ≥ 80 were included. Kaplan-Meier, log-rank, and multivariate proportional hazards regression analyses were used to identify associations (p < 0.05) with functional independence (KPS score ≥ 60) following glioblastoma resection. Results The median follow-up duration time was 10 months (interquartile range [IQR] 5.6–17.0 months). A patient’s preoperative (p = 0.02) and immediate postoperative (within 2 months) functional status was associated with prolonged survival (p < 0.0001). Of the 544 patients in this series, 302 (56%) lost their functional independence at a median of 10 months (IQR 6–16 months). Factors independently associated with prolonged functional independence were: preoperative KPS score ≥ 90 (p = 0.004), preoperative seizures (p = 0.002), primary glioblastoma (p < 0.0001), gross-total resection (p < 0.0001), and temozolomide chemotherapy (p < 0.0001). Factors independently associated with decreased functional independence were: older age (p < 0.0001), coexistent coronary artery disease (p = 0.009), and incurring a new postoperative motor deficit (p = 0.009). Furthermore, a decline in functional status was independently associated with tumor recurrence (p = 0.01). Conclusions The identification and consideration of these factors associated with prolonged

  5. High-growth-factor implosions (HEP4)

    SciTech Connect

    Landen, O.L.; Keane, C.J.; Hammel, B.A.

    1996-06-01

    In inertial confinement fusion (ICF), the kinetic energy of an ablating, inward-driven, solid spherical shell is used to compressionally heat the low-density fuel inside. For a given drive, the maximum achievable compressed fuel density and temperature - and hence the maximum neutron production rate depend on the degree of shell isentropy and integrity maintained during the compression. Shell integrity will be degraded by hydrodynamic instability growth of areal density imperfections in the capsule. Surface imperfections on the shell grow as a result of the Richtmyer-Meshkov and Rayleigh-Taylor (RT) instabilities when the shell is accelerated by the ablating lower-density plasma. Perturbations at the outer capsule surface are transferred hydrodynamically to the inner surface, where deceleration of the shell by the lower-density fuel gives rise to further RT growth at the pusher-fuel interface.

  6. Growth Factors Regulate Expression of Mineral Associated Genes in Cementoblasts

    PubMed Central

    Saygin, N. Esra; Tokiyasu, Yoshihiko; Giannobile, William V.; Somerman, Martha J.

    2008-01-01

    Background Knowledge of the responsiveness of cells within the periodontal region to specific bioactive agents is important for improving regenerative therapies. The aim of this study was to determine the effect of specific growth factors, insulin-like growth factor-I (IGF-I), platelet-derived growth factor-BB (PDGF-BB), and transforming growth factor-β (TGF-β) on cementoblasts in vitro and ex vivo. Methods Osteocalcin (OC) promoter driven SV40 transgenic mice were used to obtain immortalized cementoblasts. Growth factor effects on DNA synthesis were assayed by [3H]-thymidine incorporation. Northern analysis was used to determine the effects of growth factors on gene expression profile. Effects of growth factors on cementoblast induced biomineralization were determined in vitro (von Kossa stain) and ex vivo (re-implantation of cells in immunodeficient (SCID) mice). Results All growth factors stimulated DNA synthesis compared to control. Twenty-four hour exposure of cells to PDGF-BB or TGF-β resulted in a decrease in bone sialoprotein (BSP) and osteocalcin (OCN) mRNAs while PDGF-BB also increased osteopontin (OPN) mRNA. Cells exposed to IGF-I for 24 hours exhibited decreased transcripts for OCN and OPN with an upregulation of BSP mRNA noted at 72 hours. In vitro mineralization was inhibited by continuous application of PDGF-BB or TGF-β, while cells exposed to these factors prior to implantation into SCID mice still promoted biomineralization. Conclusions These data indicate IGF-I, PDGF-BB, and TGF-β influence mitogenesis, phenotypic gene expression profile, and biomineralization potential of cementoblasts suggesting that such factors alone or in combination with other agents may provide trigger factors required for regenerating periodontal tissues. PMID:11063392

  7. Evaluation of Three Growth Factors for TMJ Disc Tissue Engineering

    PubMed Central

    Detamore, Michael S.; Athanasiou, Kyriacos A.

    2015-01-01

    Arguably one of the most complex joints in the body, the temporomandibular joint (TMJ) presents one of the most difficult problems in modern medicine. Tissue engineering, for the TMJ disc in particular, has been proposed as a potential breakthrough treatment strategy for TMJ disorders. Central to tissue engineering is understanding growth factor effects on TMJ disc cells, and to the best of our knowledge, this is the first 3D growth factor study for these cells. The purpose was to examine the effects of high and low concentrations of basic fibroblast growth factor (bFGF), insulin-like growth factor-I (IGF), and transforming growth factor-β1 (TGF-β) on porcine TMJ disc cells. Cells were seeded onto non-woven PGA scaffolds (95% porosity) in spinner flasks, then cultured with a growth factor for 6 weeks. Constructs were analyzed for mechanical and structural integrity, cell number, and matrix biosynthesis. All growth factors improved mechanical and structural integrity compared to the control. IGF and TGF-β were most effective at promoting collagen synthesis, although there were no significant differences in glycosaminoglycan synthesis or cell number between any groups. After considering the economic advantage of IGF over TGF-β, the conclusion of this study is to use IGF in future TMJ disc tissue engineering experiments. PMID:15868729

  8. Growth factors in critical illness: regulation and therapeutic aspects.

    PubMed

    Frost, R A; Lang, C H

    1998-03-01

    The erosion of lean body mass observed during catabolic illness is still a major cause of morbidity and mortality. The known anabolic actions of growth hormone and insulin-like growth factor-I have stimulated interest in the use of these agents to mitigate the loss of muscle protein after injury. This review summarizes advances in our understanding of how nutrition, hormones and proinflammatory cytokines regulate the somatotropic axis in health and disease, and recent studies involving the use of growth hormone or insulin-like growth factor-I in the treatment of critically ill patients. PMID:10565348

  9. Benzylidene Acylhydrazides Inhibit Chlamydial Growth in a Type III Secretion- and Iron Chelation-Independent Manner

    PubMed Central

    Bao, Xiaofeng; Gylfe, Åsa; Sturdevant, Gail L.; Gong, Zheng; Xu, Shuang; Caldwell, Harlan D.; Elofsson, Mikael

    2014-01-01

    Chlamydiae are widespread Gram-negative pathogens of humans and animals. Salicylidene acylhydrazides, developed as inhibitors of type III secretion system (T3SS) in Yersinia spp., have an inhibitory effect on chlamydial infection. However, these inhibitors also have the capacity to chelate iron, and it is possible that their antichlamydial effects are caused by iron starvation. Therefore, we have explored the modification of salicylidene acylhydrazides with the goal to uncouple the antichlamydial effect from iron starvation. We discovered that benzylidene acylhydrazides, which cannot chelate iron, inhibit chlamydial growth. Biochemical and genetic analyses suggest that the derivative compounds inhibit chlamydiae through a T3SS-independent mechanism. Four single nucleotide polymorphisms were identified in a Chlamydia muridarum variant resistant to benzylidene acylhydrazides, but it may be necessary to segregate the mutations to differentiate their roles in the resistance phenotype. Benzylidene acylhydrazides are well tolerated by host cells and probiotic vaginal Lactobacillus species and are therefore of potential therapeutic value. PMID:24914180

  10. Relationship between early growth and CVD risk factors in adolescents.

    PubMed

    Musa, M G; Kagura, J; Pisa, P T; Norris, S A

    2016-04-01

    Low birth weight and a rapid weight gain in early childhood may lead to an increased risk for developing cardiovascular disease later in life, such as hypertension and dyslipidaemia. In this study, we examined the associations between size at birth, relative weight gain in infancy and childhood with specific cardiovascular disease risk factors in early adulthood. Adolescents (n=1935) from the Birth to Twenty plus (BT20+) cohort were included in the analysis. The following were treated as exposure variables: weight at birth, and relative conditional weight gain (CW), independent of height, between ages 0-24 months and 24-48 months. Outcomes were serum lipids and body composition variables at age 18 years. After adjusting for sex and other confounders, early life exposures were not associated with adolescent lipid profile. Following adjustment for sex and height (body size), birth weight [β=0.704 (0.40, 1.01)], CW 0-24 [β=1.918 (1.56, 2.28)] and CW24-48 [β=1.485 (1.14, 1.82)] accounted for 48% of the variance in fat mass. However, birth weight [β=0.773 (0.54, 1.01)], CW 0-24 [β=1.523 (1.24, 1.80)] and CW24-48 [β=1.226 (0.97, 1.49)] were also positively predicted and accounted for 71% of the variance in fat mass in adolescence (P<0.05). Our data suggests that birth weight and weight gain during infancy and early childhood independent of linear growth are related to adolescent body composition but not blood lipid profiles in an urban African population. PMID:26810380

  11. Probing non-standard gravity with the growth index: a background independent analysis

    SciTech Connect

    Steigerwald, Heinrich; Marinoni, Christian; Bel, Julien E-mail: jbel@cpt.univ-mrs.fr

    2014-05-01

    Measurements of the growth index of linear matter density fluctuations γ(z) provide a clue as to whether Einstein's field equations encompass gravity also on large cosmic scales, those where the expansion of the universe accelerates. We show that the information encoded in this function can be satisfactorily parameterized using a small set of coefficients γ{sub i}, in such a way that the true scaling of the growth index is recovered to better than 1% in most dark energy and dark gravity models. We find that the likelihood of current data, given this formalism and the Λ Cold Dark Matter (ΛCDM) expansion model of Planck, is maximal for γ{sub 0} = 0.74{sup +0.44}{sub −0.41} and γ{sub 1} = 0.01{sup +0.46}{sub −0.46}, a measurement compatible with the ΛCDM predictions (γ{sub 0} = 0.545, γ{sub 1} = −0.007). In addition, data tend to favor models predicting slightly less growth of structures than the Planck ΛCDM scenario. The main aim of the paper is to provide a prescription for routinely calculating, in an analytic way, the amplitude of the growth indices γ{sub i} in relevant cosmological scenarios, and to show that these parameters naturally define a space where predictions of alternative theories of gravity can be compared against growth data in a manner which is independent from the expansion history of the cosmological background. As the standard Ω-plane provides a tool to identify different expansion histories H(t) and their relation to various cosmological models, the γ-plane can thus be used to locate different growth rate histories f(t) and their relation to alternatives model of gravity. As a result, we find that the Dvali-Gabadadze-Porrati gravity model is rejected with a 95% confidence level. By simulating future data sets, such as those that a Euclid-like mission will provide, we also show how to tell apart ΛCDM predictions from those of more extreme possibilities, such as smooth dark energy models, clustering quintessence or

  12. Dual chain synthetic heparin-binding growth factor analogs

    DOEpatents

    Zamora, Paul O.; Pena, Louis A.; Lin, Xinhua

    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.

  13. Dual chain synthetic heparin-binding growth factor analogs

    DOEpatents

    Zamora, Paul O.; Pena, Louis A.; Lin, Xinhua

    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.

  14. 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

  15. Cell-autonomous cytokinin-independent growth of tobacco cells transformed by Agrobacterium tumefaciens strains lacking the cytokinin biosynthesis gene.

    PubMed Central

    Black, R C; Binns, A N; Chang, C F; Lynn, D G

    1994-01-01

    Mutations at the cytokinin biosynthesis locus (tmr) of Agrobacterium tumefaciens usually result in strains that induce tumors exhibiting the rooty phenotype associated with high auxin-to-cytokinin ratios. However, tobacco (Nicotiana tabacum cv Havana 425) leaf disc explants responded to tmr- mutant strain A356 by producing rapidly growing, unorganized tumors, indicating that these lines can grow in a cytokinin-independent fashion despite the absence of a functional tmr gene. Several methods have been used to characterize the physiological and cellular basis of this phenotype. The results indicate that tmr- tumors have a physiologically distinct mechanism for cytokinin-independent growth in comparison to tumors induced by wild-type bacteria. The cytokinin-independent phenotype of the tmr- transformants appears to be cell autonomous in nature: only the transformed cells and their progeny were capable of cytokinin-independent growth. Specifically, the tmr- tumors did not accumulate cytokinin, and clonal analysis indicated the tmr- transformed cells were not capable of stimulating the growth of neighboring nontransformed cells. Finally, the cytokinin-independent phenotype of the tmr- transformants was shown to be cold sensitive, whereas the wild-type tumors exhibited a cold-resistant cytokinin-independent phenotype. Potential mechanisms for this novel form of cytokinin-independent growth, including the role of the dehydrodiconiferyl alcohol glucosides found in both tumor types, are discussed. PMID:8058843

  16. Motogenic substrata and chemokinetic growth factors for human skin cells

    PubMed Central

    Sutherland, Jennifer; Denyer, Morgan; Britland, Stephen

    2005-01-01

    Extracellular matrix remodelling and accurate spatio-temporal coordination of growth factor expression are two factors that are believed to regulate mitoses and cell migration in developing and regenerating tissues. The present quantitative videomicroscopical study examined the influence of some of the principal components of extracellular matrix and several growth factors that are known to be expressed in dermal wounds on three important facets of human skin cell behaviour in culture. Keratinocytes, melanocytes and dermal fibroblasts (and myofibroblast controls) exhibited varying degrees of substrate adhesion, division and migration depending on the composition of the culture substrate. Substrates that are recognized components of transitional matrices generally accentuated cell adhesion and proliferation, and were motogenic, when compared with serum-treated control surfaces, whereas components of more stable structures such as basement membrane had less influence. Platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and α fibroblastic growth factor (αFGF) all promoted cell proliferation and were chemokinetic to dermal fibroblasts, but not keratinocyte growth factor (KGF) or transforming growth factor β (TGFβ). PDGF, EGF and KGF, but not TGFβ or αFGF, all enhanced proliferation of dermal keratinocytes. The same growth factors, and in addition KGF, all stimulated motility in keratinocytes, but TGFβ and αFGF again had no effect. Developing a better understanding of the interdependency of factors that control crucial cell behaviour may assist those who are interested in the regulation of histogenesis and also inform the development of rational therapeutic strategies for the management of chronic and poorly healed wounds. PMID:16011545

  17. Cross talk among tyrosine kinase receptors in PC12 cells: desensitization of mitogenic epidermal growth factor receptors by the neurotrophic factors, nerve growth factor and basic fibroblast growth factor.

    PubMed Central

    Mothe, I; Ballotti, R; Tartare, S; Kowalski-Chauvel, A; Van Obberghen, E

    1993-01-01

    We have studied the effects of nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) on epidermal growth factor (EGF) binding to PC12 cells. We show that NGF and bFGF rapidly induce a reduction in 125I-EGF binding to PC12 cells in a dose-dependent manner. This decrease amounts to 50% for NGF and 35% for bFGF. Both factors appear to act through a protein kinase C(PKC)-independent pathway, because their effect persists in PKC-downregulated PC12 cells. Scatchard analysis indicates that NGF and bFGF decrease the number of high affinity EGF binding sites. In addition to their effect on EGF binding, NGF and bFGF activate in intact PC12 cells one or several serine/threonine kinases leading to EGF receptor threonine phosphorylation. Using an in vitro phosphorylation system, we show that NGF- or bFGF-activated extracellular regulated kinase 1 (ERK1) is able to phosphorylate a kinase-deficient EGF receptor. Phosphoamino acid analysis indicates that this phosphorylation occurs mainly on threonine residues. Furthermore, two comparable phosphopeptides are observed in the EGF receptor, phosphorylated either in vivo after NGF treatment or in a cell-free system by NGF-activated ERK1. Finally, a good correlation was found between the time courses of ERK1 activation and 125I-EGF binding inhibition after NGF or bFGF treatment. In conclusion, in PC12 cells the NGF- and bFGF-stimulated ERK1 appears to be involved in the induction of the threonine phosphorylation of the EGF receptor and the decrease in the number of high affinity EGF binding sites. Images PMID:8400459

  18. Targeting insulin-like growth factor pathways

    PubMed Central

    Yee, D

    2006-01-01

    Some cancer cells depend on the function of specific molecules for their growth, survival, and metastatic potential. Targeting of these critical molecules has arguably been the best therapy for cancer as demonstrated by the success of tamoxifen and trastuzumab in breast cancer. This review will evaluate the type I IGF receptor (IGF-IR) as a potential target for cancer therapy. As new drugs come forward targeting this receptor system, several issues will need to be addressed in the early clinical trials using these agents. PMID:16450000

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

    PubMed Central

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

    2015-01-01

    Background 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. Methods 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. Results 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). Conclusions 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. PMID:25606485

  20. Vascular Endothelial Growth Factor/Placental Growth Factor Heterodimer Levels in Preterm Infants with Bronchopulmonary Dysplasia.

    PubMed

    Procianoy, Renato S; Hentges, Cláudia R; Silveira, Rita C

    2016-04-01

    Background Bronchopulmonary dysplasia (BPD) is associated with changes in pulmonary angiogenesis. However, the role of the vascular endothelial growth factor/placental growth factor (VEGF/PlGF) heterodimer, an antiangiogenic factor, remains unknown in this disease. Objective To compare VEGF/PlGF levels in preterm infants with and without BPD. Methods This study was approved by the Institutional Review Board. Preterm neonates with birth weight <2,000 g and gestational age ≤34 weeks were included. Exclusion criteria were: neonates transferred from other institutions after 72 hours of life; death before blood collection; presence of major congenital malformations, inborn errors of metabolism, and early sepsis; and mothers with multiple pregnancies, TORCH infections, HIV infection, or autoimmune diseases. BPD was defined as the need for oxygen therapy for a period equal to or greater than 28 days, accompanied by radiographic changes compatible with the disease. Blood was collected from neonates in the first 72 hours of life. VEGF/PlGF levels were measured using the enzyme-linked immunosorbent assay method. The chi-square test, t-test, Mann-Whitney test, analysis of variance, and Kruskal-Wallis test were used for statistical analysis. Variables found to be significant in the univariate analysis were included in the multivariate analysis. Results Seventy-three patients were included (19 with BPD, 43 without BPD, and 11 neonates who died in the first 28 days of life), with a mean (SD) gestational age of 30.32 (2.88) weeks and birth weight of 1,288 (462) g. Median VEGF/PlGF levels were higher in the groups with BPD and death in the first 28 days of life than in the group without BPD (16.46 [IQR, 12.19-44.57] and 20.64 [IQR, 13.39-50.22], respectively, vs. 9.14 [IQR, 0.02-20.64] pg/mL], p < 0.001). Higher VEGF/P1GF levels remained associated with BPD and death in the first 28 days of life in the multivariate analysis. Conclusion Higher plasma VEGF

  1. Fibroblast growth factors, old kids on the new block.

    PubMed

    Li, Xiaokun; Wang, Cong; Xiao, Jian; McKeehan, Wallace L; Wang, Fen

    2016-05-01

    The fibroblast growth factors (FGFs) are a family of cell intrinsic regulatory peptides that control a broad spectrum of cellular activities. The family includes canonic FGFs that elicit their activities by activating the FGF receptor (FGFR) tyrosine kinase and non-canonic members that elicit their activities intracellularly and via FGFR-independent mechanisms. The FGF signaling axis is highly complex due to the existence of multiple isoforms of both ligands and receptors, as well as cofactors that include the chemically heterogeneous heparan sulfate (HS) cofactors, and in the case of endocrine FGFs, the Klotho coreceptors. Resident FGF signaling controls embryonic development, maintains tissue homeostasis, promotes wound healing and tissue regeneration, and regulates functions of multiple organs. However, ectopic or aberrant FGF signaling is a culprit for various diseases, including congenital birth defects, metabolic disorder, and cancer. The molecular mechanisms by which the specificity of FGF signaling is achieved remain incompletely understood. Since its application as a druggable target has been gradually recognized by pharmaceutical companies and translational researchers, understanding the determinants of FGF signaling specificity has become even more important in order to get into the position to selectively suppress a particular pathway without affecting others to minimize side effects. PMID:26768548

  2. Phorbol ester phorbol-12-myristate-13-acetate promotes anchorage-independent growth and survival of melanomas through MEK-independent activation of ERK1/2

    SciTech Connect

    Jorgensen, Kjersti; Skrede, Martina; Cruciani, Veronique; Mikalsen, Svein-Ole; Slipicevic, Ana; Florenes, Vivi Ann . E-mail: v.a.florenes@labmed.uio.no

    2005-04-01

    The phorbol ester, phorbol-12-myristate-13-acetate (PMA), an activator of PKCs, is known to stimulate the in vitro growth of monolayer cultures of normal human melanocytes whereas it inhibits the growth of most malignant melanoma cell lines. We examined the effect of PMA on proliferation and survival of melanoma cells grown as multicellular aggregates in suspension (spheroids), and aimed to elucidate downstream targets of PKC signaling. In contrast to monolayer cultures, PMA increased cell proliferation as well as protected melanoma cells from suspension-mediated apoptosis (anoikis). Supporting the importance of PKC in anchorage-independent growth, treatment of anoikis-resistant melanoma cell lines with antisense oligonucleotides against PKC-{alpha}, or the PKC inhibitor Goe6976, strongly induced anoikis. PMA induced activation of ERK1/2, but this effect was not prevented by the MEK inhibitors PD98059 or by U0126. Whereas PD98059 treatment alone led to marked activation of the pro-apoptotic Bim and Bad proteins and significantly increased anoikis, these effects were clearly reversed by PMA. In conclusion, our results indicate that the protective effect of PMA on anchorage-independent survival of melanoma cells at least partly is mediated by MEK-independent activation of ERK1/2 and inactivation of downstream pro-apoptotic effector proteins.

  3. Dysmotility and ppi use are independent risk factors for small intestinal bacterial and/or fungal overgrowth

    PubMed Central

    Jacobs, C; Coss Adame, E; Attaluri, A; Valestin, J; Rao, SSC

    2013-01-01

    Introduction Whether intestinal dysmotility and proton pump inhibitor (PPI) use either independently or together contributes to small intestinal bacterial overgrowth (SIBO), and/or small intestinal fungal overgrowth (SIFO) is not known. Aim Investigate the role of dysmotility and PPI use in patients with persistent gastrointestinal complaints. Methods Patients with unexplained gastrointestinal symptoms and negative endoscopy/radiology tests completed a validated symptom questionnaire and underwent 24-hour ambulatory antro-duodeno-jejunal manometry (ADJM). Simultaneously, duodenal aspirate was obtained for aerobic, anaerobic and fungal culture. Dysmotility was diagnosed by (> 2): absent phase III MMC, absent/diminished postprandial response, diminished amplitude of antral/intestinal phasic activity, impaired antro-duodenal coordination. Bacterial growth ≥103 CFU/mL or fungal growth was considered evidence for SIBO/SIFO. PPI use was documented. Correlation of symptoms with presence of SIBO or SIFO were assessed. Results 150 subjects (M/F=47/103) were evaluated; 94/150 (63%) had overgrowth: 38/94 (40%) had SIBO, 24/94 (26%) had SIFO, and 32/94 (34%) had mixed SIBO/SIFO. SIBO was predominately due to Streptococcus, Enterococcus, Klebsiella, and E. coli. SIFO was due to Candida. 80/150 (53%) patients had dysmotility and 65/150 (43%) used PPI. PPI use (p=.0063) and Dysmotility (p=.0003) were independent significant risk factors (p<0.05) for overgrowth, but together did not pose additional risk. Symptom profiles were similar between those with or without SIBO/SIFO. Conclusions Dysmotility and PPI use were independent risk factors for SIBO or SIFO and were present in over 50% of subjects with unexplained gastrointestinal symptoms. Diagnosis of overgrowth requires testing because symptoms were poor predictors of overgrowth. PMID:23574267

  4. A Novel Mitogen-Activated Protein Kinase Is Responsive to Raf and Mediates Growth Factor Specificity

    PubMed Central

    Janulis, Mark; Trakul, Nicholas; Greene, Geoffrey; Schaefer, Erik M.; Lee, J. D.; Rosner, Marsha Rich

    2001-01-01

    The proto-oncogene Raf is a major regulator of growth and differentiation. Previous studies from a number of laboratories indicate that Raf activates a signaling pathway that is independent of the classic MEK1,2-ERK1,2 cascade. However, no other signaling cascade downstream of Raf has been identified. We describe a new member of the mitogen-activated protein kinase family, p97, an ERK5-related kinase that is activated and Raf associated when cells are stimulated by Raf. Furthermore, p97 is selectively responsive to different growth factors, providing a mechanism for specificity in cellular signaling. Thus, p97 is activated by the neurogenic factor fibroblast growth factor (FGF) but not the mitogenic factor epidermal growth factor (EGF) in neuronal cells. Conversely, the related kinase ERK5 is activated by EGF but not FGF. p97 phosphorylates transcription factors such as Elk-1 and Ets-2 but not MEF2C at transactivating sites, whereas ERK5 phosphorylates MEF2C but not Elk-1 or Ets-2. Finally, p97 is expressed in a number of cell types including primary neural and NIH 3T3 cells. Taken together, these results identify a new signaling pathway that is distinct from the classic Raf-MEK1,2-ERK1,2 kinase cascade and can be selectively stimulated by growth factors that produce discrete biological outcomes. PMID:11238956

  5. Different Protein Kinase C Isoforms Determine Growth Factor Specificity in Neuronal Cells

    PubMed Central

    Corbit, Kevin C.; Soh, Jae-Won; Yoshida, Keiko; Eves, Eva M.; Weinstein, I. Bernard; Rosner, Marsha Rich

    2000-01-01

    Although mitogenic and differentiating factors often activate a number of common signaling pathways, the mechanisms leading to their distinct cellular outcomes have not been elucidated. In a previous report, we demonstrated that mitogen-activated protein (MAP) kinase (ERK) activation by the neurogenic agents fibroblast growth factor (FGF) and nerve growth factor is dependent on protein kinase Cδ (PKCδ), whereas MAP kinase activation in response to the mitogen epidermal growth factor (EGF) is independent of PKCδ in rat hippocampal (H19-7) and pheochromocytoma (PC12) cells. We now show that EGF activates MAP kinase through a PKCζ-dependent pathway involving phosphatidylinositol 3-kinase and PDK1 in H19-7 cells. PKCζ, like PKCδ, acts upstream of MEK, and PKCζ can potentiate Raf-1 activation by EGF. Inhibition of PKCζ also blocks EGF-induced DNA synthesis as monitored by bromodeoxyuridine incorporation in H19-7 cells. Finally, in embryonic rat brain hippocampal cell cultures, inhibitors of PKCζ or PKCδ suppress MAP kinase activation by EGF or FGF, respectively, indicating that these factors activate distinct signaling pathways in primary as well as immortalized neural cells. Taken together, these results implicate different PKC isoforms as determinants of growth factor signaling specificity within the same cell. Furthermore, these data provide a mechanism whereby different growth factors can differentially activate a common signaling intermediate and thereby generate biological diversity. PMID:10891480

  6. Visualization of growth factor receptor sites in rat forebrain

    SciTech Connect

    Quirion, R.; Araujo, D.; Nair, N.P.; Chabot, J.G.

    1988-01-01

    It is now known that various growth factors may also act in the central nervous system. Among them, it has recently been shown that epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) may possess trophic effects in the mammalian brain. We report here on the respective autoradiographic distribution of (/sup 125/I)EGF and (/sup 125/I)IGF-I receptor binding sites in the rat brain, both during ontogeny and in adulthood. It appears that (/sup 125/I)EGF sites are mostly found in the rat forebrain during brain development. On the other hand, (/sup 125/I)IGF-I sites are more widely distributed both during ontogeny and in adulthood. These results reveal the plasticity of the expression of EGF and IGF-I receptor sites in the mammalian brain. This could be relevant for the respective role of these two growth factors in the development and maintenance of neuronal function.

  7. CRITICAL FACTORS CONTROLLING VEGETATION GROWTH ON COMPLETED SANITARY LANDFILLS

    EPA Science Inventory

    This study identifies some of the critical factors that affect tree and shrub growth on reclaimed sanitary landfill sites and determines which woody species are adaptable to the adverse growth conditions of such sites. Trees planted at the Edgeboro Landfill, East Brunswick, New J...

  8. Growth rate of late passage sarcoma cells is independent of epigenetic events but dependent on the amount of chromosomal aberrations

    SciTech Connect

    Becerikli, Mustafa; Jacobsen, Frank; Rittig, Andrea; Köhne, Wiebke; Nambiar, Sandeep; Mirmohammadsadegh, Alireza; Stricker, Ingo; Tannapfel, Andrea; Wieczorek, Stefan; Epplen, Joerg Thomas; Tilkorn, Daniel; Steinstraesser, Lars

    2013-07-15

    Soft tissue sarcomas (STS) are characterized by co-participation of several epigenetic and genetic events during tumorigenesis. Having bypassed cellular senescence barriers during oncogenic transformation, the factors further affecting growth rate of STS cells remain poorly understood. Therefore, we investigated the role of gene silencing (DNA promoter methylation of LINE-1, PTEN), genetic aberrations (karyotype, KRAS and BRAF mutations) as well as their contribution to the proliferation rate and migratory potential that underlies “initial” and “final” passage sarcoma cells. Three different cell lines were used, SW982 (synovial sarcoma), U2197 (malignant fibrous histiocytoma (MFH)) and HT1080 (fibrosarcoma). Increased proliferative potential of final passage STS cells was not associated with significant differences in methylation (LINE-1, PTEN) and mutation status (KRAS, BRAF), but it was dependent on the amount of chromosomal aberrations. Collectively, our data demonstrate that these fairly differentiated/advanced cancer cell lines have still the potential to gain an additional spontaneous growth benefit without external influences and that maintenance of increased proliferative potential towards longevity of STS cells (having crossed senescence barriers) may be independent of overt epigenetic alterations. -- Highlights: Increased proliferative potential of late passage STS cells was: • Not associated with epigenetic changes (methylation changes at LINE-1, PTEN). • Not associated with mutation status of KRAS, BRAF. • Dependent on presence/absence of chromosomal aberrations.

  9. Growth factor signaling to mTORC1 by amino acid–laden macropinosomes

    PubMed Central

    Yoshida, Sei; Pacitto, Regina; Yao, Yao; Inoki, Ken

    2015-01-01

    The rapid activation of the mechanistic target of rapamycin complex-1 (mTORC1) by growth factors is increased by extracellular amino acids through yet-undefined mechanisms of amino acid transfer into endolysosomes. Because the endocytic process of macropinocytosis concentrates extracellular solutes into endolysosomes and is increased in cells stimulated by growth factors or tumor-promoting phorbol esters, we analyzed its role in amino acid–dependent activation of mTORC1. Here, we show that growth factor-dependent activation of mTORC1 by amino acids, but not glucose, requires macropinocytosis. In murine bone marrow–derived macrophages and murine embryonic fibroblasts stimulated with their cognate growth factors or with phorbol myristate acetate, activation of mTORC1 required an Akt-independent vesicular pathway of amino acid delivery into endolysosomes, mediated by the actin cytoskeleton. Macropinocytosis delivered small, fluorescent fluid-phase solutes into endolysosomes sufficiently fast to explain growth factor–mediated signaling by amino acids. Therefore, the amino acid–laden macropinosome is an essential and discrete unit of growth factor receptor signaling to mTORC1. PMID:26438830

  10. Regulation of wound healing by growth factors and cytokines.

    PubMed

    Werner, Sabine; Grose, Richard

    2003-07-01

    Cutaneous wound healing is a complex process involving blood clotting, inflammation, new tissue formation, and finally tissue remodeling. It is well described at the histological level, but the genes that regulate skin repair have only partially been identified. Many experimental and clinical studies have demonstrated varied, but in most cases beneficial, effects of exogenous growth factors on the healing process. However, the roles played by endogenous growth factors have remained largely unclear. Initial approaches at addressing this question focused on the expression analysis of various growth factors, cytokines, and their receptors in different wound models, with first functional data being obtained by applying neutralizing antibodies to wounds. During the past few years, the availability of genetically modified mice has allowed elucidation of the function of various genes in the healing process, and these studies have shed light onto the role of growth factors, cytokines, and their downstream effectors in wound repair. This review summarizes the results of expression studies that have been performed in rodents, pigs, and humans to localize growth factors and their receptors in skin wounds. Most importantly, we also report on genetic studies addressing the functions of endogenous growth factors in the wound repair process. PMID:12843410

  11. The effect of high altitude and other risk factors on birthweight: independent or interactive effects?

    PubMed Central

    Jensen, G M; Moore, L G

    1997-01-01

    OBJECTIVES: This study examined whether the decline in birth-weight with increasing altitude is due to an independent effect of altitude or an exacerbation of other risk factors. METHODS: Maternal, paternal, and infant characteristics were obtained from 3836 Colorado birth certificates from 1989 through 1991. Average altitude of residence for each county was determined. RESULTS: None of the characteristics related to birthweight (gestational age, maternal weight gain, parity, smoking, prenatal care visits, hypertension, previous small-for-gestational-age infant, female newborn) interacted with the effect of altitude. Birthweight declined an average of 102 g per 3300 ft (1000 m) elevation when the other characteristics were taken into account, increasing the percentage of low birthweight by 54% from the lowest to the highest elevations in Colorado. CONCLUSIONS: High altitude acts independently from other factors to reduce birthweight and accounts for Colorado's high rate of low birthweight. PMID:9224184

  12. Effect of sericin on diabetic hippocampal growth hormone/insulin-like growth factor 1 axis

    PubMed Central

    Chen, Zhihong; Yang, Songhe; He, Yaqiang; Song, Chengjun; Liu, Yongping

    2013-01-01

    Previous studies have shown that sericin extracted from silk cocoon significantly reduces blood glucose levels and protects the nervous system against diabetes mellitus. In this study, a rat type 2 diabetes mellitus model was established by intraperitoneal injection of 25 mg/kg streptozotocin for 3 successive days, following which the rats were treated with sericin for 35 days. After treatment, the blood glucose levels of the diabetic rats decreased significantly, the growth hormone level in serum and its expression in the hippocampus decreased significantly, while the insulin-like growth factor-1 level in serum and insulin-like growth factor-1 and growth hormone receptor expression in the hippocampus increased significantly. The experimental findings indicate that sericin improves disorders of the growth hormone/insulin-like growth factor 1 axis to alleviate hippocampal damage in diabetic rats. PMID:25206472

  13. Chronic bronchitis is an independently associated factor for more symptom and high-risk groups

    PubMed Central

    Choi, Joon Young; Yoon, Hyoung Kyu; Park, Seoung Ju; Park, Yong Bum; Shin, Kyeong-Cheol; Na, Ju Ock; Yoo, Kwang Ha; Jung, Ki-Suck; Kim, Young Kyoon; Rhee, Chin Kook

    2016-01-01

    Background The chronic bronchitis (CB) phenotype has been associated with poor quality of life and an increased risk of disease in patients with COPD. However, little information exists regarding the relationship between the CB phenotype and the COPD assessment test (CAT) score. The goal of this study was to reveal the different pattern of CAT scores between CB and non-CB patients. Moreover, we aimed to investigate whether the CB phenotype is an independently associated factor for more symptom and high-risk groups. Methods Data were obtained from the Korea COPD Subgroup Study cohort recruited from 46 centers in South Korea since April 2012. CB patients were defined as having a chronic cough and sputum for 3 months per year, for a period of 2 consecutive years. We investigated the pattern of CAT and subquestionnaire scores between CB and non-CB patients. We also analyzed the proportion of CB phenotypes in each Global initiative for chronic Obstructive Lung Disease (GOLD) stage. Finally, we performed a logistic regression analysis to identify whether the CB phenotype was an independently associated factor for more symptom and high-risk groups. Results Of the 1,106 study patients, 11.5% of patients were found to have a CB phenotype. CB phenotypes were most common in GOLD III (GOLD 2006) and GOLD D (GOLD 2015) stages. CAT scores were significantly higher in CB patients not only in terms of the total score but also for each subquestionnaire. Logistic regression revealed that the CB phenotype is an independently associated factor for more symptom and high-risk groups. Conclusion The present study revealed that CB patients have higher CAT scores and subquestionnaire results compared to non-CB patients. Additionally, we demonstrated that the CB phenotype is an independently associated factor for both more symptom and high-risk groups. PMID:27382269

  14. The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth

    PubMed Central

    Sferruzzi-Perri, A N; Owens, J A; Pringle, K G; Roberts, C T

    2011-01-01

    Maternal insulin-like growth factors (IGFs) play a pivotal role in modulating fetal growth via their actions on both the mother and the placenta. Circulating IGFs influence maternal tissue growth and metabolism, thereby regulating nutrient availability for the growth of the conceptus. Maternal IGFs also regulate placental morphogenesis, substrate transport and hormone secretion, all of which influence fetal growth either via indirect effects on maternal substrate availability, or through direct effects on the placenta and its capacity to supply nutrients to the fetus. The extent to which IGFs influence the mother and/or placenta are dependent on the species and maternal factors, including age and nutrition. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing degenerative diseases in adult life, understanding the role of maternal IGFs during pregnancy is essential in order to identify mechanisms underlying altered fetal growth and offspring programming. PMID:20921199

  15. A monoclonal antibody to the human c-erbB3 protein stimulates the anchorage-independent growth of breast cancer cell lines.

    PubMed Central

    Rajkumar, T.; Gullick, W. J.

    1994-01-01

    The c-erbB3 protein is a member of the type I growth factor receptor family. It has a widespread pattern of expression in normal tissues and is overexpressed in about 20% of breast cancers. We have raised a specific monoclonal antibody, called SGP1, against the extracellular domain of c-erbB3 which recognises the native form of the protein. The monoclonal antibody was found to modestly but significantly stimulate the anchorage-independent cloning efficiency of the breast tumour cell lines BT483 and T47D, both of which express the c-erbB3 protein. No effect was observed on 293 cells lacking expression, nor did a control isotype-matched antibody promote the growth of any of the cells tested. These results suggest that the c-erbB3 protein may normally act as a growth factor receptor. Images Figure 1 Figure 2 Figure 3 Figure 6 PMID:8080731

  16. Growth-promoting action and growth factor release by different platelet derivatives.

    PubMed

    Passaretti, F; Tia, M; D'Esposito, V; De Pascale, M; Del Corso, M; Sepulveres, R; Liguoro, D; Valentino, R; Beguinot, F; Formisano, P; Sammartino, G

    2014-01-01

    Abstract Platelet derivatives are commonly used in wound healing and tissue regeneration. Different procedures of platelet preparation may differentially affect growth factor release and cell growth. Preparation of platelet-rich fibrin (PRF) is accompanied by release of growth factors, including platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and transforming growth factor β1 (TGFβ1), and several cytokines. When compared with the standard procedure for platelet-rich plasma (PRP), PRF released 2-fold less PDGF, but >15-fold and >2-fold VEGF and TGFβ1, respectively. Also, the release of several cytokines (IL-4, IL-6, IL-8, IL-10, IFNγ, MIP-1α, MIP-1β and TNFα) was significantly increased in PRF-conditioned medium (CM), compared to PRP-CM. Incubation of both human skin fibroblasts and human umbilical vein endothelial cells (HUVECs) with PRF-derived membrane (mPRF) or with PRF-CM enhanced cell proliferation by >2-fold (p<0.05). Interestingly, PRP elicited fibroblast growth at a higher extent compared to PRF. At variance, PRF effect on HUVEC growth was significantly greater than that of PRP, consistent with a higher concentration of VEGF in the PRF-CM. Thus, the procedure of PRP preparation leads to a larger release of PDGF, as a possible result of platelet degranulation, while PRF enhances the release of proangiogenic factors. PMID:23855408

  17. Distribution of insulin-like growth factors in condylar hyperplasia.

    PubMed

    Götz, Werner; Lehmann, Tim Sebastian; Appel, Thorsten Robin; Rath-Deschner, Birgit; Dettmeyer, Reinhard; Luder, Hans-Ulrich; Reich, Rudolf H; Jäger, Andreas

    2007-01-01

    Condylar hyperplasia (CH) is a local overgrowth of the condylar process of the temporomandibular joint (TMJ) of unknown etiology. Probably, growth factors like the insulin-like growth factors (IGFs) are involved in its pathogenesis. Specimens from 12 patients were investigated histologically and immunohistochemically to obtain the distribution of the IGFs-I and -II and the IGF1 receptor. The results revealed juvenile and adult subtypes. While generally IGF-II could only be detected weakly, in the juvenile cases strong immunostaining for IGF-I in cartilage and bone supposes an influence on pathological growth processes. PMID:17695990

  18. Nerve growth factor binding domain of the nerve growth factor receptor

    SciTech Connect

    Welcher, A.A.; Bitler, C.M.; Radeke, M.J.; Shooter, E.M. )

    1991-01-01

    A structural analysis of the rat low-affinity nerve growth factor (NGF) receptor was undertaken to define the NGF binding domain. Mutant NGF receptor DNA constructs were expressed in mouse fibroblasts or COS cells, and the ability of the mutant receptors to bind NGF was assayed. In the first mutant, all but 16 amino acid residues of the intracellular domain of the receptor were removed. This receptor bound NGF with a K{sub d} comparable to that of the wild-type receptor. A second mutant contained only the four cysteine-rich sequences from the extracellular portion of the protein. This mutant was expressed in COS cells and the resultant protein was a secreted soluble form of the receptor that was able to bind NGF. Two N-terminal deletions, in which either the first cystein-rich sequence or the first and part of the second cystein-rich sequences were removed, bound NGF. However, a mutant lacking all four cysteine-rich sequences was unable to bind NGF. These results show that the four cysteine-rich sequences of the NGF receptor contain the NGF binding domain.

  19. Regulation of cell surface receptors for different hematopoietic growth factors on myeloid leukemic cells.

    PubMed Central

    Lotem, J; Sachs, L

    1986-01-01

    There are clones of myeloid leukemic cells which are different from normal myeloid cells in that they have become independent of hematopoietic growth factor for cell viability and growth. The ability of these clones to bind three types of hematopoietic growth factors (MGI-1GM = GM-CSF, IL-3 = multi-CSF and MGI-1M = M-CSF = CSF-1) was measured using the method of quantitative absorption at 1 degree C and low pH elution of cell-bound biological activity. Results of binding to normal myeloid and lymphoid cells were similar to those obtained by radioreceptor assays. The results indicate that the number of receptors on different clones of these leukemic cells varied from 0 to 1,300 per cell. The receptors have a high binding affinity. Receptors for different growth factors can be independently expressed in different clones. There was no relationship between expression of receptors for these growth factors and the phenotype of the leukemic cells regarding their ability to be induced to differentiate. The number of receptors on the leukemic cells was lower than on normal mature macrophages. Myeloid leukemic cells induced to differentiate by normal myeloid cell differentiation factor MGI-2 (= DF), or by low doses of actinomycin D or cytosine arabinoside, showed an up-regulation of the number of MGI-1GM and IL-3 receptors. Induction of differentiation of leukemic cells by MGI-2 also induced production and secretion of the growth factor MGI-1GM, and this induced MGI-1GM saturated the up-regulated MGI-1GM receptors. It is suggested that up-regulation of these receptors during differentiation is required for the functioning of differentiated cells. PMID:3023059

  20. [Novel role of growth factors in ovary function].

    PubMed

    Amsterdam, Abraham

    2010-12-01

    The development of the DNA microarray technique facilitated systematic studies of the modulation of gene function. Considerable attention has been focused on members of the growth factor family to elucidate the main regulators of oocyte maturation and ovarian follicle rupture. Among these growth factors, it was found, both in rodents and in humans, that amphiregulin (Ar) and epiregulin (Ep) of the epidermal growth factor (EGF) family were dramatically up-regulated by gonadotrophins in the intact ovary and in primary granulosa cells, respectively. Their role in cumulus expansion and oocyte maturation was established in rodents, and their synthesis under LH stimulation in granulosa cells was demonstrated in humans. To be activated, Ar and Ep must be cleaved by a disintegrin and metalloproteinases (ADAMs) family. However, the precise processing of Ar and Ep by the cumulus cells is still obscure. Future investigations using DNA microarray technique may reveal the repertoire of genes activated in Ar- and Ep-stimulated cumulus cells and may help elucidate the molecular basis of ovulation. EFG-like factors are also involved in triggering ovarian cancer The author hypothesized that the normal ovary maintains cyclicity in the formation of these growth factors preventing the ovary from developing ovarian cancer In ovarian cancer these growth factors are continuously formed in an autocrine manner, leading to transformation and subsequently to ovarian cancer. These growth factors are essential for both normal and neoplastic transformation of the ovary. Taking into consideration these growth factors in the treatment of ovarian malfunction may be one way of curing ovarian cancer. PMID:21916103

  1. Burkholderia BcpA mediates biofilm formation independently of interbacterial contact dependent growth inhibition

    PubMed Central

    Garcia, Erin C.; Anderson, Melissa S.; Hagar, Jon A.; Cotter, Peggy A.

    2013-01-01

    SUMMARY Contact dependent growth inhibition (CDI) is a phenomenon in which Gram-negative bacteria use the toxic C-terminus of a large surface-exposed exoprotein to inhibit the growth of susceptible bacteria upon cell-cell contact. Little is known about when and where bacteria express the genes encoding CDI system proteins and how these systems contribute to the survival of bacteria in their natural niche. Here we establish that, in addition to mediating interbacterial competition, the Burkholderia thailandensis CDI system exoprotein BcpA is required for biofilm development. We also provide evidence that the catalytic activity of BcpA and extracellular DNA are required for the characteristic biofilm pillars to form. We show using a bcpA-gfp fusion that within the biofilm, expression of the CDI system-encoding genes is below the limit of detection for the majority of bacteria and only a subset of cells express the genes strongly at any given time. Analysis of a strain constitutively expressing the genes indicates that native expression is critical for biofilm architecture. Although CDI systems have so far only been demonstrated to be involved in interbacterial competition, constitutive production of the system’s immunity protein in the entire bacterial population did not alter biofilm formation, indicating a CDI-independent role for BcpA in this process. We propose, therefore, that bacteria may use CDI proteins in cooperative behaviors, like building biofilm communities, and in competitive behaviors that prevent non-self bacteria from entering the community. PMID:23879629

  2. Targeting insulin-like growth factor-I and insulin-like growth factor-binding protein-3 signaling pathways. A novel therapeutic approach for asthma.

    PubMed

    Lee, Hyun; Kim, So Ri; Oh, Youngman; Cho, Seong Ho; Schleimer, Robert P; Lee, Yong Chul

    2014-04-01

    Insulin-like growth factor (IGF)-I has been recognized to play critical roles in the pathogenesis of asthma, whereas IGF-binding protein (IGFBP)-3 blocks crucial physiologic manifestations of asthma. IGF-I enhances subepithelial fibrosis, airway inflammation, airway hyperresponsiveness, and airway smooth muscle hyperplasia by interacting with various inflammatory mediators and complex signaling pathways, such as intercellular adhesion molecule-1, and the hypoxia-inducible factor/vascular endothelial growth factor axis. On the other hand, IGFBP-3 decreases airway inflammation and airway hyperresponsiveness through IGFBP-3 receptor-mediated activation of caspases, which subsequently inhibits NF-κB signaling pathway. It also inhibits the IGF-I/hypoxia-inducible factor/vascular endothelial growth factor axis via IGF-I-dependent and/or IGF-I-independent mechanisms. This Translational Review summarizes the role of IGF-I and IGFBP-3 in the context of allergic airway disease, and discusses the therapeutic potential of various strategies targeting the IGF-I and IGFBP-3 signaling pathways for the management of asthma. PMID:24219511

  3. Insulin-like growth factor-II: possible local growth factor in pheochromocytoma.

    PubMed

    Gelato, M C; Vassalotti, J

    1990-11-01

    Pheochromocytomas, neural crest tumors, express an abundance of insulin-like growth factor-II (IGF-II). To assess further the potential for IGF-II to play an autocrine role for these tumors, we measured 1) IGF-II content by RRA in 7 pheochromocytomas and peripheral blood in these patients, 2) IGF-II receptors by Western analysis, and 3) characterized the tumor binding proteins by ligand blot studies. IGF-II levels in the tumors varied from 2.8-41 micrograms/g. Chromatography revealed that 60% of the peptide eluted as a large mol wt form of IGF-II (8.7-10 kDa); the remainder coeluted with mature peptide (7.5 kDa). This was in contrast to IGF-II levels in normal adrenal tissue (0.225 +/- 0.005 micrograms/g) or another neural crest-derived tumor, medullary carcinoma of the thyroid (0.63 +/- 0.02 micrograms/g). Serum IGF-II levels in the 7 patients with pheochromocytoma (720 +/- 71 ng/mL) were similar to those in 35 normal controls (762 +/- 69 ng/mL). Radiolabeled IGF-II (9 +/- 1%) and IGF-I (20 +/- 2%) bound specifically to pheochromocytoma membranes. Western analysis of these membranes using a specific antiserum directed against the type II receptor demonstrated a band at 210 kDa. Affinity cross-linking studies with [125I]IGF-I demonstrated a specific band at 140 kDa. Ligand blot analysis was performed on the void volume pools from the Sephadex G-75 column and demonstrated bands at about 30 and 25 kDa. In conclusion, these data 1) confirm that pheochromocytomas have increased levels of IGF-II; 2) demonstrate that despite high IGF-II concentrations in the tumors, peripheral levels are not elevated, suggesting that very little tumoral IGF-II is released into the circulation, unlike catecholamines; 3) demonstrate the presence of IGF-II and IGF-I receptors; 4) describe binding protein species similar to those present in other tissues. Thus, the presence of high levels of IGF-II and both type I and type II receptors suggests that IGF II may act through both receptors to

  4. An evaluation of density-dependent and density-independent influences on population growth rates in Weddell seals.

    PubMed

    Rotella, Jay J; Link, William A; Nichols, James D; Hadley, Gillian L; Garrott, Robert A; Proffitt, Kelly M

    2009-04-01

    Much of the existing literature that evaluates the roles of density-dependent and density-independent factors on population dynamics has been called into question in recent years because measurement errors were not properly dealt with in analyses. Using state-space models to account for measurement errors, we evaluated a set of competing models for a 22-year time series of mark-resight estimates of abundance for a breeding population of female Weddell seals (Leptonychotes weddellii) studied in Erebus Bay, Antarctica. We tested for evidence of direct density dependence in growth rates and evaluated whether equilibrium population size was related to seasonal sea-ice extent and the Southern Oscillation Index (SOI). We found strong evidence of negative density dependence in annual growth rates for a population whose estimated size ranged from 438 to 623 females during the study. Based on Bayes factors, a density-dependence-only model was favored over models that also included environmental covariates. According to the favored model, the population had a stationary distribution with a mean of 497 females (SD = 60.5), an expected growth rate of 1.10 (95% credible interval = 1.08-1.15) when population size was 441 females, and a rate of 0.90 (95% credible interval = 0.87-.93) for a population of 553 females. A model including effects of SOI did receive some support and indicated a positive relationship between SOI and population size. However, effects of SOI were not large, and including the effect did not greatly reduce our estimate of process variation. We speculate that direct density dependence occurred because rates of adult survival, breeding, and temporary emigration were affected by limitations on per capita food resources and space for parturition and pup-rearing. To improve understanding of the relative roles of various demographic components and their associated vital rates to population growth rate, mark-recapture methods can be applied that incorporate both

  5. An evaluation of density-dependent and density-independent influences on population growth rates in Weddell seals

    USGS Publications Warehouse

    Rotella, J.J.; Link, W.A.; Nichols, J.D.; Hadley, G.L.; Garrott, R.A.; Proffitt, K.M.

    2009-01-01

    Much of the existing literature that evaluates the roles of density-dependent and density-independent factors on population dynamics has been called into question in recent years because measurement errors were not properly dealt with in analyses. Using state-space models to account for measurement errors, we evaluated a set of competing models for a 22-year time series of mark-resight estimates of abundance for a breeding population of female Weddell seals (Leptonychotes weddellii) studied in Erebus Bay, Antarctica. We tested for evidence of direct density dependence in growth rates and evaluated whether equilibrium population size was related to seasonal sea-ice extent and the Southern Oscillation Index (SOI). We found strong evidence of negative density dependence in annual growth rates for a population whose estimated size ranged from 438 to 623 females during the study. Based on Bayes factors, a density-dependence-only model was favored over models that also included en! vironmental covariates. According to the favored model, the population had a stationary distribution with a mean of 497 females (SD = 60.5), an expected growth rate of 1.10 (95% credible interval 1.08-1.15) when population size was 441 females, and a rate of 0.90 (95% credible interval 0.87-0.93) for a population of 553 females. A model including effects of SOI did receive some support and indicated a positive relationship between SOI and population size. However, effects of SOI were not large, and including the effect did not greatly reduce our estimate of process variation. We speculate that direct density dependence occurred because rates of adult survival, breeding, and temporary emigration were affected by limitations on per capita food resources and space for parturition and pup-rearing. To improve understanding of the relative roles of various demographic components and their associated vital rates to population growth rate, mark-recapture methods can be applied that incorporate both

  6. An opioid growth factor regulates the replication of microorganisms.

    PubMed

    Zagon, I S; McLaughlin, P J

    1992-01-01

    An opioid growth factor (OGF), [Met5]-enkephalin, interacts with the zeta (zeta) opioid receptor to modulate development of eukaryotes. We have found that [Met5]-enkephalin, an endogenous opioid peptide serves to inhibit the growth of S. aureus. This effect on growth involves cell proliferative events and is under tonic control, since potent opioid antagonists accelerate cell replication. Both the OGF and zeta opioid receptor were associated with these microorganisms. Other opioid receptors (mu, delta and kappa) were not detected. OGF also controlled the growth of other bacteria: P. aeruginosa and S. marcesans. These results indicate that OGF and its receptor, known to be important in the regulation of mammalian development, also function in the growth of simple unicellular organisms. We suggest that the endogenous opioid system related to growth originated billions of years ago. PMID:1313136

  7. Growth factors in the management of adult acute leukemia.

    PubMed

    Bernstein, S H

    1993-02-01

    This review has explored the various ways that growth factors may be used in the management of adult acute leukemia. Growth factors have the potential to reduce the morbidity and mortality of both induction and postremission therapy by enhancing hematopoietic recovery or, when used as an adjunct to standard antimicrobial therapy, reducing the infectious complications of chemotherapy. In addition, they may have favorable effects on the biology of leukemia either by recruitment of leukemic progenitors into cycle, rendering them more sensitive to the cytotoxic effects of chemotherapy, or by inducing the terminal differentiation of the leukemic clone. Finally, disruption of aberrant growth factor networks, thought to play a role in the pathogenesis of leukemia, may be a therapeutic strategy now that soluble receptors and receptor antagonists to such growth factors as IL-1 are available. Whether growth factors used in such ways will have beneficial, or in fact adverse, effects on the treatment outcome for acute leukemia is not yet known. As such, the use of growth factors in the management of adults with acute leukemia is still experimental and needs to be studied in the context of clinical trials. Perhaps the ultimate benefit to be derived from the study of these growth factors will be a deeper understanding of the genetic perturbations that define the leukemic state. The development of molecular therapeutic techniques, such as gene transfer technology and the use of antisense oligonucleotides, has paralleled our increasing knowledge of cytokines. The hope is that as we come to understand leukemia at the molecular level, we will be able to develop the new therapeutic tools necessary to increase the numbers of patients cured. PMID:8449861

  8. Cell Length Independent PBRB Model for Simulations of HE Reaction Initiation, Growth, and Detonation

    NASA Astrophysics Data System (ADS)

    Dwivedi, Sunil

    2015-06-01

    It has been our focus to use the Physics Based Reaction Burn (PBRB) model to simulate reaction initiation, growth, and detonation of HE composites at the mesoscale. The idealization of hot spots as planar surfaces reduces the 3D model to a 1D hot spot cell (1DHSC) model. The idealization also renders the model dependent on the 1DHSC length and mesh size. New developments are presented making the PBRB model 1DHSC length independent. First, the accurate prediction of the gas-solid interface temperature and thermal gradient are essential, achieved through a finite difference scheme with 500-2000 thermal grid points. Second, keeping the burn mass constant while varying the 1DHSC length is essential, achieved by varying the hot spot specific surface area. 1D and 2D simulation results are presented for shock response of RDX at 1 km/s and 2 km/s impact velocities. The 5, 10, and 50 micro meters 1DHSC lengths yield near identical run-to-detonation, time-to-detonation, and detonation velocity in agreement with experimental data. It is concluded that the new developments make the PBRB model well suited as a generic EOS model for HE composites. - Dr. John Brennan, ARL is acknowledged for his interactions and support. This work is supported in part by ARL Grant W911NF-12-2-0053 and DTRA Grant HDTRA1-12-1-0004.

  9. Cutaneous adverse reactions specific to epidermal growth factor receptor inhibitors

    PubMed Central

    Lupu, I; Voiculescu, VM; Bacalbasa, N; Prie, BE; Cojocaru, I; Giurcaneanu, C

    2015-01-01

    Classical antineoplastic therapy is encumbered by extensively studied adverse reactions, most often of systemic nature. The emergence of new generations of anticancer treatments, including epidermal growth factor receptor inhibitors, besides improving the response to treatment and the survival rate, is accompanied by the occurrence of new specific side effects, incompletely studied. These side effects are most often cutaneous (hand foot syndrome, acneiform reactions), and in some cases are extremely severe, requiring dose reduction or drug discontinuation. The prevention of the cutaneous adverse effects and their treatment require a close collaboration between the oncologist and the dermatologist. The occurrence of some of these skin adverse effects may be a favorable prognostic factor for the response to the cancer treatment and the overall survival. Abbreviations: EGFR = epidermal growth factor receptors; EGFRI = epidermal growth factor receptors inhibitors PMID:26361513

  10. Hepatocyte growth factor, hepatocyte growth factor activator and arginine in a rat fulminant colitis model

    PubMed Central

    Zwintscher, Nathan P.; Shah, Puja M.; Salgar, Shashikumar K.; Newton, Christopher R.; Maykel, Justin A.; Samy, Ahmed; Jabir, Murad; Steele, Scott R.

    2016-01-01

    Introduction Dextran sodium sulfate (DSS) is commonly used to induce a murine fulminant colitis model. Hepatocyte growth factor (HGF) has been shown to decrease the symptoms of inflammatory bowel disease (IBD) but the effect of its activator, HGFA, is not well characterized. Arginine reduces effects of oxidative stress but its effect on IBD is not well known. The primary aim is to determine whether HGF and HGFA, or arginine will decrease IBD symptoms such as pain and diarrhea in a DSS-induced fulminant colitis murine model. Methods A severe colitis was induced in young, male Fischer 344 rats with 4% (w/v) DSS oral solution for seven days; rats were sacrificed on day 10. Rats were divided into five groups of 8 animals: control, HGF (700 mcg/kg/dose), HGF and HGFA (10 mcg/dose), HGF and arginine, and high dose HGF (2800 mcg/kg/dose). Main clinical outcomes were pain, diarrhea and weight loss. Blinded pathologists scored the terminal ileum and distal colon. Results DSS reliably induced severe active colitis in 90% of animals (n = 36/40). There were no differences in injury scores between control and treatment animals. HGF led to 1.38 fewer days in pain (p = 0.036), while arginine led to 1.88 fewer days of diarrhea (P = 0.017) compared to controls. 88% of HGFA-treated rats started regaining weight (P < 0.001). Discussion/Conclusion Although treatment was unable to reverse fulminant disease, HGF and arginine were associated with decreased days of pain and diarrhea. These clinical interventions may reduce associated symptoms for severe IBD patients, even when urgent surgical intervention remains the only viable option. PMID:27144006

  11. Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation

    PubMed Central

    Oscier, David; Wade, Rachel; Davis, Zadie; Morilla, Alison; Best, Giles; Richards, Sue; Else, Monica; Matutes, Estella; Catovsky, Daniel

    2010-01-01

    Background Many prognostic markers have been identified in chronic lymphocytic leukemia, but there have been few opportunities to assess their relative importance in a large randomized trial. The aim of this study was to determine which of the available markers independently predicted outcome in patients requiring treatment and to use these to define new risk groups. Design and Methods A broad panel of clinical and laboratory markers, measured at randomization in patients entering the LRF CLL4 trial, was assessed with respect to treatment response, progression-free and overall survival, at a median follow-up of 68 months. Results Using the factors identified as independent predictors for progression-free survival, patients were subdivided into three risk groups: 6% had poor risk with known TP53 loss of greater than 10%; 72% had an intermediate risk without TP53 loss (≤10%) and with at least one of: unmutated IGHV genes and/or IGHV3-21 usage, 11q deletion, β-2 microglobulin greater than 4 mg/L; 22% had a good risk (with none of the above and mutated IGHV genes). The 5-year progression-free survival rates for these three groups were 0%, 12% and 34%, respectively, and the corresponding 5-year overall survival rates were 9%, 53% and 79% (both P<0.00005 independent of treatment allocation). In the intermediate risk group 250 patients, with data for all three risk factors, were further subdivided into intermediate-low (one risk factor) or intermediate-high (2 or 3 risk factors). The 5-year progression-free survival rates were 18% and 7% (P=0.0001) and the 5-year overall survival rates were 68% and 40% (P<0.00005), respectively. Conclusions This study demonstrates the role of biomarkers in prognosis and shows that, in patients requiring treatment, disease stage may no longer be an independent predictor of outcome. If validated independently, the risk groups defined here may inform the design of future trials in chronic lymphocytic leukemia. (Clinicaltrials

  12. Osteogenic capillaries orchestrate growth plate-independent ossification of the malleus

    PubMed Central

    Matsuo, Koichi; Kuroda, Yukiko; Nango, Nobuhito; Shimoda, Kouji; Kubota, Yoshiaki; Ema, Masatsugu; Bakiri, Latifa; Wagner, Erwin F.; Takeda, Yoshihiro; Yashiro, Wataru; Momose, Atsushi

    2015-01-01

    Endochondral ossification is a developmental process by which cartilage is replaced by bone. Terminally differentiated hypertrophic chondrocytes are calcified, vascularized, and removed by chondroclasts before bone matrix is laid down by osteoblasts. In mammals, the malleus is one of three auditory ossicles that transmit vibrations of the tympanic membrane to the inner ear. The malleus is formed from a cartilaginous precursor without growth plate involvement, but little is known about how bones of this type undergo endochondral ossification. Here, we demonstrate that in the processus brevis of the malleus, clusters of osteoblasts surrounding the capillary loop produce bone matrix, causing the volume of the capillary lumen to decrease rapidly in post-weaning mice. Synchrotron X-ray tomographic microscopy revealed a concentric, cylindrical arrangement of osteocyte lacunae along capillaries, indicative of pericapillary bone formation. Moreover, we report that overexpression of Fosl1, which encodes a component of the AP-1 transcription factor complex, in osteoblasts significantly blocked malleal capillary narrowing. These data suggest that osteoblast/endothelial cell interactions control growth plate-free endochondral ossification through ‘osteogenic capillaries’ in a Fosl1-regulated manner. PMID:26428006

  13. Osteogenic capillaries orchestrate growth plate-independent ossification of the malleus.

    PubMed

    Matsuo, Koichi; Kuroda, Yukiko; Nango, Nobuhito; Shimoda, Kouji; Kubota, Yoshiaki; Ema, Masatsugu; Bakiri, Latifa; Wagner, Erwin F; Takeda, Yoshihiro; Yashiro, Wataru; Momose, Atsushi

    2015-11-15

    Endochondral ossification is a developmental process by which cartilage is replaced by bone. Terminally differentiated hypertrophic chondrocytes are calcified, vascularized, and removed by chondroclasts before bone matrix is laid down by osteoblasts. In mammals, the malleus is one of three auditory ossicles that transmit vibrations of the tympanic membrane to the inner ear. The malleus is formed from a cartilaginous precursor without growth plate involvement, but little is known about how bones of this type undergo endochondral ossification. Here, we demonstrate that in the processus brevis of the malleus, clusters of osteoblasts surrounding the capillary loop produce bone matrix, causing the volume of the capillary lumen to decrease rapidly in post-weaning mice. Synchrotron X-ray tomographic microscopy revealed a concentric, cylindrical arrangement of osteocyte lacunae along capillaries, indicative of pericapillary bone formation. Moreover, we report that overexpression of Fosl1, which encodes a component of the AP-1 transcription factor complex, in osteoblasts significantly blocked malleal capillary narrowing. These data suggest that osteoblast/endothelial cell interactions control growth plate-free endochondral ossification through 'osteogenic capillaries' in a Fosl1-regulated manner. PMID:26428006

  14. Transforming growth factor-betas and vascular disorders.

    PubMed

    Bobik, Alex

    2006-08-01

    Transforming growth factor-beta (TGF-beta) superfamily members, TGF-beta and bone morphogenetic proteins (BMPs), are potent regulatory cytokines with diverse functions on vascular cells. They signal through heteromeric type I and II receptor complexes activating Smad-dependent and Smad-independent signals, which regulate proliferation, differentiation, and survival. They are potent regulators of vascular development and vessel remodeling and play key roles in atherosclerosis and restenosis, regulating endothelial, smooth muscle cell, macrophage, T cell, and probably vascular calcifying cell responses. In atherosclerosis, TGF-beta regulates lesion phenotype by controlling T-cell responses and stimulating smooth muscle cells to produce collagen. It contributes to restenosis by augmenting neointimal cell proliferation and collagen accumulation. Defective TGF-beta signaling in endothelial cells attributable to mutations in endoglin or the type I receptor ALK-1 leads to hereditary hemorrhagic telangiectasia, whereas defective BMP signaling attributable to mutations in the BMP receptor II has been associated with development of primary pulmonary hypertension. The development of mouse models with either cell type-specific or general inactivation of TGF-beta/BMP signaling has started to reveal the importance of the regulatory network of TGF-beta/BMP pathways in vivo and their significance for atherosclerosis, hereditary hemorrhagic telangiectasia, and primary pulmonary hypertension. This review highlights recent findings that have advanced our understanding of the roles of TGF-beta superfamily members in regulating vascular cell responses and provides likely avenues for future research that may lead to novel pharmacological therapies for the treatment or prevention of vascular disorders. PMID:16675726

  15. Beclin 1 regulates growth factor receptor signaling in breast cancer.

    PubMed

    Rohatgi, R A; Janusis, J; Leonard, D; Bellvé, K D; Fogarty, K E; Baehrecke, E H; Corvera, S; Shaw, L M

    2015-10-16

    Beclin 1 is a haploinsufficient tumor suppressor that is decreased in many human tumors. The function of beclin 1 in cancer has been attributed primarily to its role in the degradative process of macroautophagy. However, beclin 1 is a core component of the vacuolar protein sorting 34 (Vps34)/class III phosphatidylinositoI-3 kinase (PI3KC3) and Vps15/p150 complex that regulates multiple membrane-trafficking events. In the current study, we describe an alternative mechanism of action for beclin 1 in breast cancer involving its control of growth factor receptor signaling. We identify a specific stage of early endosome maturation that is regulated by beclin 1, the transition of APPL1-containing phosphatidyIinositol 3-phosphate-negative (PI3P(-)) endosomes to PI3P(+) endosomes. Beclin 1 regulates PI3P production in response to growth factor stimulation to control the residency time of growth factor receptors in the PI3P(-)/APPL(+)-signaling-competent compartment. As a result, suppression of BECN1 sustains growth factor-stimulated AKT and ERK activation resulting in increased breast carcinoma cell invasion. In human breast tumors, beclin 1 expression is inversely correlated with AKT and ERK phosphorylation. Our data identify a novel role for beclin 1 in regulating growth factor signaling and reveal a mechanism by which loss of beclin 1 expression would enhance breast cancer progression. PMID:25639875

  16. Cytokine and Growth Factor Responses After Radiotherapy for Localized Ependymoma

    SciTech Connect

    Merchant, Thomas E. Li Chenghong; Xiong Xiaoping; Gaber, M. Waleed

    2009-05-01

    Purpose: To determine the time course and clinical significance of cytokines and peptide growth factors in pediatric patients with ependymoma treated with postoperative radiotherapy (RT). Methods and Materials: We measured 15 cytokines and growth factors (fibroblast growth factor, epidermal growth factor, vascular endothelial growth factor [VEGF], interleukin [IL]-1{beta}, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, interferon-{gamma}, tumor necrosis factor-{alpha}, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1, and macrophage inflammatory protein-{alpha}) from 30 patients before RT and 2 and 24 h, weekly for 6 weeks, and at 3, 6, 9, and 12 months after the initiation of RT. Two longitudinal models for the trend of log-transformed measurements were fitted, one during treatment and one through 12 months. Results: During RT, log IL-8 declined at a rate of -0.10389/wk (p = 0.0068). The rate of decline was greater (p = 0.028) for patients with an infratentorial tumor location. The decline in IL-8 after RT was significant when stratified by infratentorial tumor location (p = 0.0345) and more than one surgical procedure (p = 0.0272). During RT, the decline in log VEGF was significant when stratified by the presence of a ventriculoperitoneal shunt. After RT, the log VEGF declined significantly at a rate of -0.06207/mo. The decline was significant for males (p = 0.0222), supratentorial tumors (p = 0.0158), one surgical procedure (p = 0.0222), no ventriculoperitoneal shunt (p = 0.0005), and the absence of treatment failure (p = 0.0028). Conclusion: The pro-inflammatory cytokine IL-8 declined significantly during RT and the decline differed according to tumor location. The angiogenesis factor VEGF declined significantly during the 12 months after RT. The decline was greater in males, those without a ventriculoperitoneal shunt, and in those with favorable disease factors, including one surgical procedure, supratentorial tumor location, and

  17. 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

  18. A novel calcium-independent cellular PLA2 acts in insect immunity and larval growth.

    PubMed

    Park, Youngjin; Kumar, Sunil; Kanumuri, Rahul; Stanley, David; Kim, Yonggyun

    2015-11-01

    Phospholipase A2 (PLA2) catalyzes the position-specific hydrolysis of fatty acids linked to the sn-2 position of phospholipids (PLs). PLA2s make up a very large superfamily, with more than known 15 groups, classified into secretory PLA2 (sPLA2), Ca(2+)-dependent cellular PLA2 (sPLA2) and Ca(2+)-independent cellular PLA2 (iPLA2). Only a few insect sPLA2s, expressed in venom glands and immune tissues, have been characterized at the molecular level. This study aimed to test our hypothesis that insects express iPLA2, using the beet armyworm, Spodoptera exigua, our model insect. Substantial PLA2 activities under calcium-free condition were recorded in several larval tissue preparations. The PLA2 activity was significantly reduced in reactions conducted in the presence of a specific iPLA2 inhibitor, bromoenol lactone (BEL). Analysis of a S. exigua hemocyte transcriptome identified a candidate iPLA2 gene (SeiPLA2-A). The open reading frame encoded 816 amino acid residues with a predicted molecular weight of 90.5 kDa and 6.15 pI value. Our phylogenetic analysis clustered SeiPLA2-A with the other vertebrate iPLA2s. SeiPLA2-A was expressed in all tissues we examined, including hemocytes, fat body, midgut, salivary glands, Malpighian tubules and epidermis. Heterologous expression in Sf9 cells indicated that SeiPLA2-A was localized in cytoplasm and exhibited significant PLA2 activity, which was independent of Ca(2+) and inhibited by BEL. RNA interference (RNAi) of SeiPLA2-A using its specific dsRNA in the fifth instar larvae significantly suppressed iPLA2 expression and enzyme activity. dsSeiPLA2-A-treated larvae exhibited significant loss of cellular immune response, measured as nodule formation in response to bacterial challenge, and extended larval-to-pupal developmental time. These results support our hypothesis, showing that SeiPLA2-A predicted from the transcriptome analysis catalyzes hydrolysis of fatty acids from cellular PLs and plays crucial physiological roles in

  19. The biology of human epidermal growth factor receptor 2.

    PubMed

    Sundaresan, S; Penuel, E; Sliwkowski, M X

    1999-09-01

    Our understanding of the normal signaling mechanisms and functions of human epidermal growth factor receptor 2 (HER2) and other members of the HER family, namely epidermal growth factor receptor, HER3, and HER4, is growing rapidly. Activation of these receptors results in a diverse array of signals through the formation of homodimeric and heterodimeric receptor complexes; HER2 is the preferred dimerization partner for the other HERs. These oligomeric receptor complexes activate distinct signaling pathways, such as the Ras-MAPK and PI3-kinase pathways. These, in turn, affect various cellular processes. Recent gene deletion experiments in mice point to an important role for HER2 in cardiac and neural development, and evidence from other studies indicates that HER2 is involved in normal breast growth and development. Thus, HER2 is a key component of a complex signaling network that plays a critical role in the regulation of tissue development, growth, and differentiation. PMID:11122793

  20. Hammerhead Ribozyme-Mediated Knockdown of mRNA for Fibrotic Growth Factors: Transforming Growth Factor-Beta 1 and Connective Tissue Growth Factor

    PubMed Central

    Robinson, Paulette M.; Blalock, Timothy D.; Yuan, Rong; Lewin, Alfred S.; Schultz, Gregory S.

    2013-01-01

    Excessive scarring (fibrosis) is a major cause of pathologies in multiple tissues, including lung, liver, kidney, heart, cornea, and skin. The transforming growth factor- β (TGF- β) system has been shown to play a key role in regulating the formation of scar tissue throughout the body. Furthermore, connective tissue growth factor (CTGF) has been shown to mediate most of the fibrotic actions of TGF- β, including stimulation of synthesis of extracellular matrix and differentiation of fibroblasts into myofibroblasts. Currently, no approved drugs selectively and specifically regulate scar formation. Thus, there is a need for a drug that selectively targets the TGF- β cascade at the molecular level and has minimal off-target side effects. This chapter focuses on the design of hammerhead ribozymes, measurement of kinetic activity, and assessment of knockdown mRNAs of TGF- β and CTGF in cell cultures. PMID:22131029

  1. Cell Cycle-Independent Phospho-Regulation of Fkh2 during Hyphal Growth Regulates Candida albicans Pathogenesis

    PubMed Central

    Greig, Jamie A.; Sudbery, Ian M.; Richardson, Jonathan P.; Naglik, Julian R.; Wang, Yue; Sudbery, Peter E.

    2015-01-01

    The opportunistic human fungal pathogen, Candida albicans, undergoes morphological and transcriptional adaptation in the switch from commensalism to pathogenicity. Although previous gene-knockout studies have identified many factors involved in this transformation, it remains unclear how these factors are regulated to coordinate the switch. Investigating morphogenetic control by post-translational phosphorylation has generated important regulatory insights into this process, especially focusing on coordinated control by the cyclin-dependent kinase Cdc28. Here we have identified the Fkh2 transcription factor as a regulatory target of both Cdc28 and the cell wall biosynthesis kinase Cbk1, in a role distinct from its conserved function in cell cycle progression. In stationary phase yeast cells 2D gel electrophoresis shows that there is a diverse pool of Fkh2 phospho-isoforms. For a short window on hyphal induction, far before START in the cell cycle, the phosphorylation profile is transformed before reverting to the yeast profile. This transformation does not occur when stationary phase cells are reinoculated into fresh medium supporting yeast growth. Mass spectrometry and mutational analyses identified residues phosphorylated by Cdc28 and Cbk1. Substitution of these residues with non-phosphorylatable alanine altered the yeast phosphorylation profile and abrogated the characteristic transformation to the hyphal profile. Transcript profiling of the phosphorylation site mutant revealed that the hyphal phosphorylation profile is required for the expression of genes involved in pathogenesis, host interaction and biofilm formation. We confirmed that these changes in gene expression resulted in corresponding defects in pathogenic processes. Furthermore, we identified that Fkh2 interacts with the chromatin modifier Pob3 in a phosphorylation-dependent manner, thereby providing a possible mechanism by which the phosphorylation of Fkh2 regulates its specificity. Thus, we have

  2. Membrane-association of mRNA decapping factors is independent of stress in budding yeast

    PubMed Central

    Huch, Susanne; Gommlich, Jessie; Muppavarapu, Mridula; Beckham, Carla; Nissan, Tracy

    2016-01-01

    Recent evidence has suggested that the degradation of mRNA occurs on translating ribosomes or alternatively within RNA granules called P bodies, which are aggregates whose core constituents are mRNA decay proteins and RNA. In this study, we examined the mRNA decapping proteins, Dcp1, Dcp2, and Dhh1, using subcellular fractionation. We found that decapping factors co-sediment in the polysome fraction of a sucrose gradient and do not alter their behaviour with stress, inhibition of translation or inhibition of the P body formation. Importantly, their localisation to the polysome fraction is independent of the RNA, suggesting that these factors may be constitutively localised to the polysome. Conversely, polysomal and post-polysomal sedimentation of the decapping proteins was abolished with the addition of a detergent, which shifts the factors to the non-translating RNP fraction and is consistent with membrane association. Using a membrane flotation assay, we observed the mRNA decapping factors in the lower density fractions at the buoyant density of membrane-associated proteins. These observations provide further evidence that mRNA decapping factors interact with subcellular membranes, and we suggest a model in which the mRNA decapping factors interact with membranes to facilitate regulation of mRNA degradation. PMID:27146487

  3. Membrane-association of mRNA decapping factors is independent of stress in budding yeast.

    PubMed

    Huch, Susanne; Gommlich, Jessie; Muppavarapu, Mridula; Beckham, Carla; Nissan, Tracy

    2016-01-01

    Recent evidence has suggested that the degradation of mRNA occurs on translating ribosomes or alternatively within RNA granules called P bodies, which are aggregates whose core constituents are mRNA decay proteins and RNA. In this study, we examined the mRNA decapping proteins, Dcp1, Dcp2, and Dhh1, using subcellular fractionation. We found that decapping factors co-sediment in the polysome fraction of a sucrose gradient and do not alter their behaviour with stress, inhibition of translation or inhibition of the P body formation. Importantly, their localisation to the polysome fraction is independent of the RNA, suggesting that these factors may be constitutively localised to the polysome. Conversely, polysomal and post-polysomal sedimentation of the decapping proteins was abolished with the addition of a detergent, which shifts the factors to the non-translating RNP fraction and is consistent with membrane association. Using a membrane flotation assay, we observed the mRNA decapping factors in the lower density fractions at the buoyant density of membrane-associated proteins. These observations provide further evidence that mRNA decapping factors interact with subcellular membranes, and we suggest a model in which the mRNA decapping factors interact with membranes to facilitate regulation of mRNA degradation. PMID:27146487

  4. Stimulatory effect of luteinizing hormone, insulin-like growth factor-1, and epidermal growth factor on vascular endothelial growth factor production in cultured bubaline luteal cells.

    PubMed

    Chouhan, V S; Dangi, S S; Babitha, V; Verma, M R; Bag, S; Singh, G; Sarkar, M

    2015-10-15

    The purpose of this study was to evaluate the temporal (24, 48, and 72 hours) and dose-dependent (0, 5, 10, and 100 ng/mL of LH, insulin-like growth factor 1 [IGF-1], and EGF) in vitro expression and secretion patterns of vascular endothelial growth factor (VEGF) in luteal cell culture during different stages of estrous cycle in water buffaloes. Corpus luteum samples from ovaries of early luteal phase (ELP; Days 1-4), midluteal phase (Days 5-10), and late luteal phase (Days 11-16) were collected from a local slaughterhouse. The samples were then processed and cultured in (serum containing) appropriate cell culture medium and incubated separately with three factors (LH, IGF-1, or EGF) at the previously mentioned three dose-duration combinations. At the end of the respective incubation periods, VEGF was assayed in the spent culture medium by ELISA, whereas the cultured cells were used for VEGF mRNA expression by quantitative real-time polymerase chain reaction. The results of the present study disclosed dose- and time-dependent stimulatory effects of LH, IGF-1, and EGF on VEGF production in bubaline luteal cells. The VEGF expression and secretion from the cultured luteal cells were highest during the ELP, intermediate in the midluteal phase, and lowest in the late luteal phase of the estrous cycle for all the three tested factors. Comparison of the results of the three treatments depicted EGF as the most potent stimulating factor followed by IGF-1 and LH. Immunocytochemistry findings in luteal cell culture of ELP agreed with the VEGF expression and secretion. In conclusion, mRNA expression, protein secretion, and immunolocalization of VEGF data clearly indicated for the first time that LH, IGF-1, and EGF play an important role in stimulating luteal angiogenesis in buffalo CL. The highest expression and secretion of VEGF in the ELP might be associated with the development of blood vessels in early growth of CL, which in turn gets augmented by the aforementioned

  5. Epidermal growth factor, from gene organization to bedside

    PubMed Central

    Zeng, Fenghua; Harris, Raymond C.

    2014-01-01

    In 1962, epidermal growth factor (EGF) was discovered by Dr. Stanley Cohen while studying nerve growth factor (NGF). It was soon recognized that EGF is the prototypical member of a family of peptide growth factors that activate the EGF receptors, and that the EGF/EGF receptor signaling pathway plays important roles in proliferation, differentiation and migration of a variety of cell types, especially in epithelial cells. After the basic characterization of EGF function in the first decade or so after its discovery, the studies related to EGF and its signaling pathway have extended to a broad range of investigations concerning its biological and pathophysiological roles in development and in human diseases. In this review, we briefly describe the gene organization and tissue distribution of EGF, with emphasis on its biological and pathological roles in human diseases. PMID:24513230

  6. Multiple Transcription Factor Families Regulate Axon Growth and Regeneration

    PubMed Central

    Moore, Darcie L.; Goldberg, Jeffrey L.

    2011-01-01

    Understanding axon regenerative failure remains a major goal in neuroscience, and reversing this failure remains a major goal for clinical neurology. While an inhibitory CNS environment clearly plays a role, focus on molecular pathways within neurons has begun to yield fruitful insights. Initial steps forward investigated the receptors and signaling pathways immediately downstream of environmental cues, but recent work has also shed light on transcriptional control mechanisms that regulate intrinsic axon growth ability, presumably through whole cassettes of gene target regulation. Here we will discuss transcription factors that regulate neurite growth in vitro and in vivo, including p53, SnoN, E47, CREB, STAT3, NFAT, c-Jun, ATF3, Sox11, NFκB, and Kruppel-like factors (KLFs). Revealing the similarities and differences among the functions of these transcription factors may further our understanding of the mechanisms of transcriptional regulation in axon growth and regeneration. PMID:21674813

  7. Insulin-like growth factor-1: roles in androgenetic alopecia.

    PubMed

    Panchaprateep, Ratchathorn; Asawanonda, Pravit

    2014-03-01

    Of all the cytokines or growth factors that have been postulated to play a role in hair follicle, insulin-like growth factor-1 (IGF-1) is known to be regulated by androgens. However, how IGF-1 is altered in the balding scalp has not yet been investigated. In this study, expressions of IGF-1 and its binding proteins by dermal papilla (DP) cells obtained from balding versus non-balding hair follicles were quantified using growth factor array. DP cells from balding scalp follicles were found to secrete significantly less IGF-1, IGFBP-2 and IGFBP-4 (P < 0.05) than their non-balding counterparts. Our data confirmed that the downregulation of IGF-1 may be one of the important mechanisms contributing to male pattern baldness. PMID:24499417

  8. Growth factors with heparin binding affinity in human synovial fluid

    SciTech Connect

    Hamerman, D.; Taylor, S.; Kirschenbaum, I.; Klagsbrun, M.; Raines, E.W.; Ross, R.; Thomas, K.A.

    1987-12-01

    Synovial effusions were obtained from the knees of 15 subjects with joint trauma, menisceal or ligamentous injury, or osteoarthritis. Heparin-Sepharose affinity chromatography of these synovial fluids revealed, in general, three major peaks of mitogenic activity as measured by incorporation of /sup 3/H-thymidine into 3T3 cells. Gradient elution patterns showed activities at 0.5M NaCl, which is characteristic of platelet derived growth factor, and at 1.1 M NaCl and 1.6M NaCl, indicative of acidic and basic fibroblast growth factors, respectively. The identities of these mitogenic fractions were confirmed by specific immunologic and receptor-binding assays. The presence of platelet derived, acidic and basic fibroblast growth factors in the synovial fluid may contribute to wound healing in the arthritic joint.

  9. On the origin of size-dependent and size-independent crystal growth: Influence of advection and diffusion

    USGS Publications Warehouse

    Kile, D.E.; Eberl, D.D.

    2003-01-01

    Crystal growth experiments were conducted using potassium alum and calcite crystals in aqueous solution under both non-stirred and stirred conditions to elucidate the mechanism for size-dependent (proportionate) and size-independent (constant) crystal growth. Growth by these two laws can be distinguished from each other because the relative size difference among crystals is maintained during proportionate growth, leading to a constant crystal size variance (??2) for a crystal size distribution (CSD) as the mean size increases. The absolute size difference among crystals is maintained during constant growth, resulting in a decrease in size variance. Results of these experiments show that for centimeter-sized alum crystals, proportionate growth occurs in stirred systems, whereas constant growth occurs in non-stirred systems. Accordingly, the mechanism for proportionate growth is hypothesized to be related to the supply of reactants to the crystal surface by advection, whereas constant growth is related to supply by diffusion. Paradoxically, micrometer-sized calcite crystals showed proportionate growth both in stirred and in non-stirred systems. Such growth presumably results from the effects of convection and Brownian motion, which promote an advective environment and hence proportionate growth for minute crystals in non-stirred systems, thereby indicating the importance of solution velocity relative to crystal size. Calcite crystals grown in gels, where fluid motion was minimized, showed evidence for constant, diffusion-controlled growth. Additional investigations of CSDs of naturally occurring crystals indicate that proportionate growth is by far the most common growth law, thereby suggesting that advection, rather than diffusion, is the dominant process for supplying reactants to crystal surfaces.

  10. Cultured human foreskin fibroblasts produce a factor that stimulates their growth with properties similar to basic fibroblast growth factor

    SciTech Connect

    Story, M.T. )

    1989-05-01

    To determine if fibroblasts could be a source of fibroblast growth factor (FGF) in tissue, cells were initiated in culture from newborn human foreskin. Fibroblast cell lysates promoted radiolabeled thymidine uptake by cultured quiescent fibroblasts. Seventy-nine percent of the growth-promoting activity of lysates was recovered from heparin-Sepharose. The heparin-binding growth factor reacted on immunoblots with antiserum to human placenta-derived basic FGF and competed with iodinated basic FGF for binding to antiserum to (1-24)bFGF synthetic peptide. To confirm that fibroblasts were the source of the growth factor, cell lysates were prepared from cells incubated with radiolabeled methionine. Heparin affinity purified material was immunoprecipitated with basic FGF antiserum and electrophoresed. Radiolabeled material was detected on gel autoradiographs in the same molecular weight region as authentic iodinated basic FGF. The findings are consistant with the notion that cultured fibroblasts express basic FGF. As these cells also respond to the mitogen, it is possible that the regulation of their growth is under autocrine control. Fibroblasts may be an important source of the growth factor in tissue.

  11. The regulatory role of hepatoma-derived growth factor as an angiogenic factor in the eye

    PubMed Central

    LeBlanc, Michelle E.; Wang, Weiwen; Chen, Xiuping; Ji, Yanli; Shakya, Akhalesh; Shen, Chen; Zhang, Chenming; Gonzalez, Vivianne; Brewer, Megan; Ma, Jian-xing; Wen, Rong; Zhang, Fangliang

    2016-01-01

    Purpose Hepatoma-derived growth factor (HDGF) is a mitogen that promotes endothelial proliferation and neuronal survival. Using a unique technology of ligandomics, we recently identified HDGF as a retinal endothelial binding protein. The purpose of this study is to examine the role of HDGF in regulating ocular vasculature and the expression of HDGF in the retina. Methods HDGF expression in the retinal was analyzed with western blot and immunohistochemistry. Angiogenic activity was investigated in human retinal microvascular endothelial cells (HRMVECs) with in vitro endothelial proliferation, migration, and permeability assays. In vivo angiogenic activity was quantified with a corneal pocket assay. The Evans blue assay and western blot using anti-mouse albumin were performed to detect the capacity of HDGF to induce retinal vascular leakage. Results Immunohistochemistry revealed that HDGF is expressed in the retina with a distinct pattern. HDGF was detected in retinal ganglion cells and the inner nuclear layer but not in the inner plexiform layer, suggesting that HDGF is expressed in the nucleus, but not in the cytoplasm, of retinal neurons. In contrast to family member HDGF-related protein 3 (HRP-3) that has no expression in photoreceptors, HDGF is also present in the outer nuclear layer and the inner and outer segments of photoreceptors. This suggests that HDGF is expressed in the nucleus as well as the cytoplasm of photoreceptors. In vitro functional assays showed that HDGF induced the proliferation, migration, and permeability of HRMVECs. Corneal pocket assay indicated that HDGF directly stimulated angiogenesis in vivo. Intravitreal injection of HDGF significantly induced retinal vascular leakage. Conclusions These results suggest that HDGF is an angiogenic factor that regulates retinal vasculature in physiologic and pathological conditions. Identification of HDGF by ligandomics and its independent characterization in this study also support the validity of this

  12. The DEK oncogene activates VEGF expression and promotes tumor angiogenesis and growth in HIF-1α-dependent and -independent manners.

    PubMed

    Zhang, Yanan; Liu, Jie; Wang, Shibin; Luo, Xiaoli; Li, Yang; Lv, Zhaohui; Zhu, Jie; Lin, Jing; Ding, Lihua; Ye, Qinong

    2016-04-26

    The DEK oncogene is overexpressed in various cancers and overexpression of DEK correlates with poor clinical outcome. Vascular endothelial growth factor (VEGF) is the most important regulator of tumor angiogenesis, a process essential for tumor growth and metastasis. However, whether DEK enhances tumor angiogenesis remains unclear. Here, we show that DEK is a key regulator of VEGF expression and tumor angiogenesis. Using chromatin immunoprecipitation assay, we found that DEK promoted VEGF transcription in breast cancer cells (MCF7, ZR75-1 and MDA-MB-231) by directly binding to putative DEK-responsive element (DRE) of the VEGF promoter and indirectly binding to hypoxia response element (HRE) upstream of the DRE through its interaction with the transcription factor hypoxia-inducible factor 1α (HIF-1α), a master regulator of tumor angiogenesis and growth. DEK is responsible for recruitment of HIF-1α and the histone acetyltransferase p300 to the VEGF promoter. DEK-enhanced VEGF increases vascular endothelial cell proliferation, migration and tube formation as well as angiogenesis in the chick chorioallantoic membrane. DEK promotes tumor angiogenesis and growth in nude mice in HIF-1α-dependent and -independent manners. Immunohistochemical staining showed that DEK expression positively correlates with the expression of VEGF and microvessel number in 58 breast cancer patients. Our data establish DEK as a sequence-specific binding transcription factor, a novel coactivator for HIF-1α in regulation of VEGF transcription and a novel promoter of angiogenesis. PMID:26988756

  13. Expression and localization of epidermal growth factor, transforming growth factor-α and epidermal growth factor receptor in the canine testis

    PubMed Central

    TAMADA, Hiromichi; TAKEMOTO, Kohei; TOMINAGA, Masato; KAWATE, Noritoshi; TAKAHASHI, Masahiro; HATOYA, Shingo; MATSUYAMA, Satoshi; INABA, Toshio; SAWADA, Tsutomu

    2015-01-01

    Gene expression of epidermal growth factor (EGF), transforming growth factor-α (TGF-α) and EGF receptor (EGF-R) and the localization of the corresponding proteins in the canine testis were studied. Levels of mRNA expressions were determined by semiquantitative reverse transcription polymerase chain reaction in the testes of the peripubertal (4–6 months), young adult (3–4 years), advanced adult (7–8 years) and senescent (11–16 years) groups. The EGF-R mRNA level in the testes of the peripubertal group was significantly higher than those in the other groups, whereas there was no difference in EGF and TGF-α mRNA levels among groups. Immunohistochemical stainings for EGF, TGF-α and EGF-R in the testis revealed that immunoreactivity in the seminiferous epithelium and Sertoli cell was weak and nonspecific for the stage of spermatogenesis, and distinct staining was found in Leydig cells. These results suggest that the EGF family of growth factors may be involved in testicular maturation and function in the dog. PMID:26498203

  14. Nerve growth factor levels and localisation in human asthmatic bronchi.

    PubMed

    Olgart Höglund, C; de Blay, F; Oster, J P; Duvernelle, C; Kassel, O; Pauli, G; Frossard, N

    2002-11-01

    Nerve growth factor (NGF) has recently been suggested to be an important mediator of inflammation. In support of this, serum levels of NGF have been shown to be enhanced in asthmatics. However, it has not yet been shown whether the levels of NGF are also altered locally in asthmatic airways, when compared with healthy subjects, and the localisation of potential sources of NGF in the human bronchus have not yet been described. The aim of the present study was to assess NGF levels in bronchoalveolar lavage fluid (BALF) from asthmatics and to compare them to those of control subjects. Furthermore, the authors wanted to localise potential sources of NGF in bronchial tissue, and to number NGF-immunopositive infiltrating cells in the bronchial submucosa. BALF and bronchial biopsies were obtained from seven control subjects and seven asthmatic patients by fibreoptic bronchoscopy. NGF protein levels were quantified by enzyme-linked immunosorbent assay in BALF. NGF localisation was examined by immunohistochemistry on bronchial biopsy sections. The asthmatics exhibited significantly enhanced NGF levels in BALF. Intense NGF-immunoreactivity was observed in bronchial epithelium, smooth muscle cells and infiltrating inflammatory cells in the submucosa, and to a lesser extent in the connective tissue. The asthmatics exhibited a higher number of NGF-immunoreactive infiltrating cells in the bronchial submucosa than control subjects. This study provides evidence that nerve growth factor is locally produced in the airways, and shows that this production is enhanced in asthmatics. These findings suggest that nerve growth factor is produced by both structural cells and infiltrating inflammatory cells in human bronchus in vivo, and the authors suggest that the increase in nerve growth factor protein in bronchoalveolar lavage fluid observed in asthmatic patients may originate both from structural cells, producing increased nerve growth factor levels in inflammatory conditons, and from

  15. Effects of growth factors on temporomandibular joint disc cells.

    PubMed

    Detamore, Michael S; Athanasiou, Kyriacos A

    2004-07-01

    The effects of growth factors on cartilaginous tissues are well documented. An exception is the temporomandibular joint (TMJ) disc, where data for growth factor effects on proliferation and biosynthesis are very limited. The purpose of this study was to quantify proliferation of and synthesis by TMJ disc cells cultured in monolayer with either platelet derived growth factor-AB (PDGF), basic fibroblast growth factor (bFGF) or insulin-like growth factor-I (IGF), at either a low (10 ng/ml) or high (100 ng/ml) concentration. Proliferation was assessed with a DNA quantitation technique, collagen synthesis was measured via a hydroxyproline assay, and GAG synthesis was determined with a dimethylmethylene blue dye binding assay at 14 days. Overall, the most beneficial growth factor was bFGF, which was most potent in increasing proliferation and GAG synthesis, and also effective in promoting collagen synthesis. At the high concentration, bFGF resulted in 96% more cells than the control and 30 to 45% more cells than PDGF and IGF. PDGF and bFGF were the most potent upregulators of GAG synthesis, producing 2-3 times more GAG than the control. IGF had no significant effect on GAG production, although at its higher concentration it increased collagen production by 4.5 times over the control. Collagen synthesis was promoted by bFGF at its lower concentration, with levels 4.2 times higher than the control, whereas PDGF had no significant effect on collagen production. In general, higher concentrations increased proliferation, whereas lower concentrations favoured biosynthesis. PMID:15126139

  16. Molecular cloning and expression of an additional epidermal growth factor receptor-related gene.

    PubMed Central

    Plowman, G D; Whitney, G S; Neubauer, M G; Green, J M; McDonald, V L; Todaro, G J; Shoyab, M

    1990-01-01

    Epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), and amphiregulin are structurally and functionally related growth regulatory proteins. These secreted polypeptides all bind to the 170-kDa cell-surface EGF receptor, activating its intrinsic kinase activity. However, amphiregulin exhibits different activities than EGF and TGF-alpha in a number of biological assays. Amphiregulin only partially competes with EGF for binding EGF receptor, and amphiregulin does not induce anchorage-independent growth of normal rat kidney cells (NRK) in the presence of TGF-beta. Amphiregulin also appears to abrogate the stimulatory effect of TGF-alpha on the growth of several aggressive epithelial carcinomas that overexpress EGF receptor. These findings suggest that amphiregulin may interact with a separate receptor in certain cell types. Here we report the cloning of another member of the human EGF receptor (HER) family of receptor tyrosine kinases, which we have named "HER3/ERRB3." The cDNA was isolated from a human carcinoma cell line, and its 6-kilobase transcript was identified in various human tissues. We have generated peptide-specific antisera that recognizes the 160-kDa HER3 protein when transiently expressed in COS cells. These reagents will allow us to determine whether HER3 binds amphiregulin or other growth regulatory proteins and what role HER3 protein plays in the regulation of cell growth. Images PMID:2164210

  17. Small Is Beautiful: Insulin-Like Growth Factors and Their Role in Growth, Development, and Cancer

    PubMed Central

    Maki, Robert G.

    2010-01-01

    Insulin-like growth factors were discovered more than 50 years ago as mediators of growth hormone that effect growth and differentiation of bone and skeletal muscle. Interest of the role of insulin-like growth factors in cancer reached a peak in the 1990s, and then waned until the availability in the past 5 years of monoclonal antibodies and small molecules that block the insulin-like growth factor 1 receptor. In this article, we review the history of insulin-like growth factors and their role in growth, development, organism survival, and in cancer, both epithelial cancers and sarcomas. Recent developments regarding phase I to II clinical trials of such agents are discussed, as well as potential studies to consider in the future, given the lack of efficacy of one such monoclonal antibody in combination with cytotoxic chemotherapy in a first-line study in metastatic non–small-cell lung adenocarcinoma. Greater success with these agents clinically is expected when combining the agents with inhibitors of other cell signaling pathways in which cross-resistance has been observed. PMID:20975071

  18. Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer.

    PubMed

    Maki, Robert G

    2010-11-20

    Insulin-like growth factors were discovered more than 50 years ago as mediators of growth hormone that effect growth and differentiation of bone and skeletal muscle. Interest of the role of insulin-like growth factors in cancer reached a peak in the 1990s, and then waned until the availability in the past 5 years of monoclonal antibodies and small molecules that block the insulin-like growth factor 1 receptor. In this article, we review the history of insulin-like growth factors and their role in growth, development, organism survival, and in cancer, both epithelial cancers and sarcomas. Recent developments regarding phase I to II clinical trials of such agents are discussed, as well as potential studies to consider in the future, given the lack of efficacy of one such monoclonal antibody in combination with cytotoxic chemotherapy in a first-line study in metastatic non-small-cell lung adenocarcinoma. Greater success with these agents clinically is expected when combining the agents with inhibitors of other cell signaling pathways in which cross-resistance has been observed. PMID:20975071

  19. Vascular growth factors play critical roles in kidney glomeruli.

    PubMed

    Gnudi, Luigi; Benedetti, Sara; Woolf, Adrian S; Long, David A

    2015-12-01

    Kidney glomeruli ultrafilter blood to generate urine and they are dysfunctional in a variety of kidney diseases. There are two key vascular growth factor families implicated in glomerular biology and function, namely the vascular endothelial growth factors (VEGFs) and the angiopoietins (Angpt). We present examples showing not only how these molecules help generate and maintain healthy glomeruli but also how they drive disease when their expression is dysregulated. Finally, we review how manipulating VEGF and Angpt signalling may be used to treat glomerular disease. PMID:26561594

  20. The ethylene response factor Pti5 contributes to potato aphid resistance in tomato independent of ethylene signalling

    PubMed Central

    Wu, Chengjun; Avila, Carlos A.; Goggin, Fiona L.

    2015-01-01

    Ethylene response factors (ERFs) comprise a large family of transcription factors that regulate numerous biological processes including growth, development, and response to environmental stresses. Here, we report that Pti5, an ERF in tomato [Solanum lycopersicum (Linnaeus)] was transcriptionally upregulated in response to the potato aphid Macrosiphum euphorbiae (Thomas), and contributed to plant defences that limited the population growth of this phloem-feeding insect. Virus-induced gene silencing of Pti5 enhanced aphid population growth on tomato, both on an aphid-susceptible cultivar and on a near-isogenic genotype that carried the Mi-1.2 resistance (R) gene. These results indicate that Pti5 contributes to basal resistance in susceptible plants and also can synergize with other R gene-mediated defences to limit aphid survival and reproduction. Although Pti5 contains the ERF motif, induction of this gene by aphids was independent of ethylene, since the ACC deaminase (ACD) transgene, which inhibits ethylene synthesis, did not diminish the responsiveness of Pti5 to aphid infestation. Furthermore, experiments with inhibitors of ethylene synthesis revealed that Pti5 and ethylene have distinctly different roles in plant responses to aphids. Whereas Pti5 contributed to antibiotic plant defences that limited aphid survival and reproduction on both resistant (Mi-1.2+) and susceptible (Mi-1.2–) genotypes, ethylene signalling promoted aphid infestation on susceptible plants but contributed to antixenotic defences that deterred the early stages of aphid host selection on resistant plants. These findings suggest that the antixenotic defences that inhibit aphid settling and the antibiotic defences that depress fecundity and promote mortality are regulated through different signalling pathways. PMID:25504643

  1. The ethylene response factor Pti5 contributes to potato aphid resistance in tomato independent of ethylene signalling.

    PubMed

    Wu, Chengjun; Avila, Carlos A; Goggin, Fiona L

    2015-02-01

    Ethylene response factors (ERFs) comprise a large family of transcription factors that regulate numerous biological processes including growth, development, and response to environmental stresses. Here, we report that Pti5, an ERF in tomato [Solanum lycopersicum (Linnaeus)] was transcriptionally upregulated in response to the potato aphid Macrosiphum euphorbiae (Thomas), and contributed to plant defences that limited the population growth of this phloem-feeding insect. Virus-induced gene silencing of Pti5 enhanced aphid population growth on tomato, both on an aphid-susceptible cultivar and on a near-isogenic genotype that carried the Mi-1.2 resistance (R) gene. These results indicate that Pti5 contributes to basal resistance in susceptible plants and also can synergize with other R gene-mediated defences to limit aphid survival and reproduction. Although Pti5 contains the ERF motif, induction of this gene by aphids was independent of ethylene, since the ACC deaminase (ACD) transgene, which inhibits ethylene synthesis, did not diminish the responsiveness of Pti5 to aphid infestation. Furthermore, experiments with inhibitors of ethylene synthesis revealed that Pti5 and ethylene have distinctly different roles in plant responses to aphids. Whereas Pti5 contributed to antibiotic plant defences that limited aphid survival and reproduction on both resistant (Mi-1.2+) and susceptible (Mi-1.2-) genotypes, ethylene signalling promoted aphid infestation on susceptible plants but contributed to antixenotic defences that deterred the early stages of aphid host selection on resistant plants. These findings suggest that the antixenotic defences that inhibit aphid settling and the antibiotic defences that depress fecundity and promote mortality are regulated through different signalling pathways. PMID:25504643

  2. Haemorrheological abnormalities in unstable angina pectoris: a relation independent of risk factor profile and angiographic severity.

    PubMed Central

    Neumann, F J; Tillmanns, H; Roebruck, P; Zimmermann, R; Haupt, H M; Kübler, W

    1989-01-01

    Plasma viscosity, photometric erythrocyte aggregation index, and erythrocyte filterability were measured in 194 patients with coronary artery disease. Patients with unstable angina (n = 64) had a higher plasma viscosity and photometric erythrocyte aggregation index than patients with stable angina (95% confidence intervals for the mean difference: 0.052-0.100 mPa.s for plasma viscosity, and 43%-72% for the photometric erythrocyte aggregation index). Multiple regression with fibrinogen, cholesterol, high density lipoprotein cholesterol, triglycerides, blood pressure, smoking habits, coronary artery score, and left ventricular ejection fraction as independent variables showed a significant partial correlation between fibrinogen and the photometric erythrocyte aggregation index (r2 = 0.20) and plasma viscosity (r2 = 0.09), between triglycerides and plasma viscosity (r2 = 0.05), and between aortic pressure and erythrocyte filterability (r2 = 0.03). Logistic regression for unstable/stable angina with the haemorrheological variables as independent variables correctly identified 72% of the patients with stable angina and 78% of those with unstable angina. Inclusion of all the variables investigated did not substantially improve the discriminative potential of the logistic regression model. Unstable angina is associated with an impairment of blood fluidity that is essentially independent of risk factor profile and angiographic data. PMID:2690900

  3. Evidence for Multiple Mediator Complexes in Yeast Independently Recruited by Activated Heat Shock Factor.

    PubMed

    Anandhakumar, Jayamani; Moustafa, Yara W; Chowdhary, Surabhi; Kainth, Amoldeep S; Gross, David S

    2016-07-15

    Mediator is an evolutionarily conserved coactivator complex essential for RNA polymerase II transcription. Although it has been generally assumed that in Saccharomyces cerevisiae, Mediator is a stable trimodular complex, its structural state in vivo remains unclear. Using the "anchor away" (AA) technique to conditionally deplete select subunits within Mediator and its reversibly associated Cdk8 kinase module (CKM), we provide evidence that Mediator's tail module is highly dynamic and that a subcomplex consisting of Med2, Med3, and Med15 can be independently recruited to the regulatory regions of heat shock factor 1 (Hsf1)-activated genes. Fluorescence microscopy of a scaffold subunit (Med14)-anchored strain confirmed parallel cytoplasmic sequestration of core subunits located outside the tail triad. In addition, and contrary to current models, we provide evidence that Hsf1 can recruit the CKM independently of core Mediator and that core Mediator has a role in regulating postinitiation events. Collectively, our results suggest that yeast Mediator is not monolithic but potentially has a dynamic complexity heretofore unappreciated. Multiple species, including CKM-Mediator, the 21-subunit core complex, the Med2-Med3-Med15 tail triad, and the four-subunit CKM, can be independently recruited by activated Hsf1 to its target genes in AA strains. PMID:27185874

  4. 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. PMID:26831193

  5. Factor structure of the Smith irrational beliefs inventory: results of analyses on six independent samples.

    PubMed

    Smith, Jonathan C; Rausch, Sarah M; Kettmann, Julie D Jenks

    2004-10-01

    This study reports the results of six factor analyses (alpha factoring, direct oblimin rotation, Delta= .4) on six items from the Smith Irrational Beliefs Inventory. Six independent samples of 1851 college students (521 men, 1,280 women, 50 sex unstated) were tested. Three factors emerged with identical content for each analysis. Distorted Egocentrism was defined by two items reflecting feelings of entitlement and the naive assumption that events should always turn out favorably the way one desires; Task Exaggeration/Catastrophizing was defined by two items directly depicting a tendency to view challenges as overwhelming and catastrophic; and Isolated Low Self-esteem was defined by two items expressing the feeling that one has unacceptable feelings that could lead to isolation or rejection. Previous research on other irrational belief inventories has yielded inconsistent results, with multifactorial solutions emerging for clinical samples and unifactoral solutions for student samples. That the present six factor analytic studies yielded a consistent multifactoral set of irrational beliefs for a very large student sample suggests that factors do emerge when items are initially screened and the subject population is carefully defined. PMID:15587238

  6. Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF‐1

    PubMed Central

    Dobie, Ross; Ahmed, Syed F.; Staines, Katherine A.; Pass, Chloe; Jasim, Seema; MacRae, Vicky E.

    2015-01-01

    Growth hormone (GH) signaling is essential for postnatal linear bone growth, but the relative importance of GHs actions on the liver and/or growth plate cartilage remains unclear. The importance of liver derived insulin like‐growth factor‐1 (IGF‐1) for endochondral growth has recently been challenged. Here, we investigate linear growth in Suppressor of Cytokine Signaling‐2 (SOCS2) knockout mice, which have enhanced growth despite normal systemic GH/IGF‐1 levels. Wild‐type embryonic ex vivo metatarsals failed to exhibit increased linear growth in response to GH, but displayed increased Socs2 transcript levels (P < 0.01). In the absence of SOCS2, GH treatment enhanced metatarsal linear growth over a 12 day period. Despite this increase, IGF‐1 transcript and protein levels were not increased in response to GH. In accordance with these data, IGF‐1 levels were unchanged in GH‐challenged postnatal Socs2‐/‐ conditioned medium despite metatarsals showing enhanced linear growth. Growth‐plate Igf1 mRNA levels were not elevated in juvenile Socs2‐/‐ mice. GH did however elevate IGF‐binding protein 3 levels in conditioned medium from GH challenged metatarsals and this was more apparent in Socs2‐/‐ metatarsals. GH did not enhance the growth of Socs2‐/‐ metatarsals when the IGF receptor was inhibited, suggesting that IGF receptor mediated mechanisms are required. IGF‐2 may be responsible as IGF‐2 promoted metatarsal growth and Igf2 expression was elevated in Socs2‐/‐ (but not WT) metatarsals in response to GH. These studies emphasise the critical importance of SOCS2 in regulating GHs ability to promote bone growth. Also, GH appears to act directly on the metatarsals of Socs2‐/‐ mice, promoting growth via a mechanism that is independent of IGF‐1. J. Cell. Physiol. 9999: 2796–2806, 2015. © 2015 Wiley Periodicals, Inc. PMID:25833299

  7. 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.

  8. Independent Verification and Validation of Complex User Interfaces: A Human Factors Approach

    NASA Technical Reports Server (NTRS)

    Whitmore, Mihriban; Berman, Andrea; Chmielewski, Cynthia

    1996-01-01

    The Usability Testing and Analysis Facility (UTAF) at the NASA Johnson Space Center has identified and evaluated a potential automated software interface inspection tool capable of assessing the degree to which space-related critical and high-risk software system user interfaces meet objective human factors standards across each NASA program and project. Testing consisted of two distinct phases. Phase 1 compared analysis times and similarity of results for the automated tool and for human-computer interface (HCI) experts. In Phase 2, HCI experts critiqued the prototype tool's user interface. Based on this evaluation, it appears that a more fully developed version of the tool will be a promising complement to a human factors-oriented independent verification and validation (IV&V) process.

  9. Stress and body mass index each contributes independently to tumor necrosis factor-alpha production in prepubescent Latino children.

    PubMed

    Dixon, Denise; Meng, Hongdao; Goldberg, Ronald; Schneiderman, Neil; Delamater, Alan

    2009-10-01

    This investigation extended prior work by determining if stress and body mass index (BMI) contributed independently to tumor necrosis factor-alpha (TNF-alpha) levels among prepubescent Latino children and if sex and family history of type 2 diabetes mellitus (T2DM) modified these relationships. Data were collected in South Florida from 112 nondiabetic school-aged Hispanic children, of whom 43.8% were obese (BMI >/= 95th percentile) and 51.8% presented with a family history of T2DM. Stressful life events were assessed via parental report using a life events scale. Plasma TNF-alpha levels were determined with enzyme-linked immunosorbent assay. The relative contributions of stress and BMI with TNF-alpha levels and the potential interaction effects of sex and family history of T2DM were analyzed with multiple linear regression analyses. Stress and BMI each accounted for a significant proportion of the unique variance associated with TNF-alpha. The association between stress and TNF-alpha was not modified by sex or family history of T2DM. These findings implicate BMI and stress as independent determinants of TNF-alpha (an inflammatory cytokine and adipocytokine) among Latino children. Future investigations should examine the potential roles of exercise, nutritional status, age, and growth hormone in explicating the relationship between TNF-alpha production and psychosocial distress and risk for infection among obese children. PMID:19782896

  10. von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

    PubMed Central

    Chauhan, Anil K.; Kisucka, Janka; Lamb, Colin B.; Bergmeier, Wolfgang

    2007-01-01

    von Willebrand factor (VWF) protects factor VIII (FVIII) from proteolysis and mediates the initial contact of platelets with the injured vessel wall, thus playing an important role in hemostasis and thrombosis. VWF is crucial for the formation of occlusive thrombi at arterial shear rates. However, with only a few conflicting studies published, the role of VWF in venous thrombosis is still unclear. Using gene-targeted mice, we show that in ferric chloride–injured veins platelet adhesion to subendothelium is decreased and thrombus growth is impaired in VWF−/− mice when compared with wild type (WT). We also observed increased embolization in the VWF−/− mice, which was due to lower FVIII levels in these mice as recombinant factor VIII (r-FVIII) restored thrombus stability. Despite normalization of blood clotting time and thrombus stability after r-FVIII infusion, the VWF−/− venules did not occlude. Transgenic platelets lacking the VWF receptor GPIbα extracellular domain showed decreased adhesion to injured veins. But, after a delay, all the injured venules occluded in these transgenic mice. Thus, VWF likely uses other adhesion receptors besides GPIbα in thrombus growth under venous shear conditions. Our studies document crucial roles for VWF and FVIII in experimental thrombosis under venous flow conditions in vivo. PMID:17119108

  11. 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. PMID:26066416

  12. Growth factors in the treatment of early osteoarthritis

    PubMed Central

    Civinini, Roberto; Nistri, Lorenzo; Martini, Caterina; Redl, Birgit; Ristori, Gabriele; Innocenti, Massimo

    2013-01-01

    Summary Regenerative medicine is the science that studies the regeneration of biological tissues obtained through use of cells, with the aid of support structures and with biomolecules such as growth factors. As regards the growth factors the PRP, or the platelet-rich plasma, obtained from a withdrawal of autologous blood, concentrating the platelets, represents a safe, economical, easy to prepare and easy to apply source of growth factors. Numerous growth factors are in fact within the platelets and in particular a large number of them have a specific activity on neo-proliferation, on cartilage regeneration and in particular also an antiapoptotic effect on chondroblasts: - The PDGF which regulates the secretion and synthesis of collagen;- The EGF that causes cellular proliferation, endothelial chemotaxis and angiogenesis;- The VEGF that increases angiogenesis and vascular permeability;- The TGF-beta that stimulates the proliferation of undifferentiated MSC, stimulates chemotaxis of endothelial cells and angiogenesis;- The bFGF that promotes the growth and differentiation of chondrocytes and osteoblasts stimulates mitogenesis of mesenchymal cells, chondrocytes and osteoblasts. These properties have led to the development of studies that evaluated the efficacy of treatment of infiltrations in the knee and hip with platelet-derived growth factors. Regarding the knee it was demonstrated that in patients with moderate degree of gonarthrosis, the PRP is able to significantly reduce the pain and improve joint function, both on placebo and towards infiltrations with hyaluronic acid. The success of the treatment was proportional to the age of and inversely proportional to the severity of osteoarthritis according to Kellgren and Lawrence classification. The possibility of infiltrations guided with ultrasound into the hip led us to extend the indications also to hip arthrosis, as already showed by Sanchez. Even in coxarthrosis preliminary results at 6 and 12 months show that

  13. Vitamin D Status Is an Independent Risk Factor for Global Cognitive Impairment in Peritoneal Dialysis Patients

    PubMed Central

    Liu, Gui-Ling; Pi, Hai-Chen; Hao, Li; Li, Dan-Dan; Wu, Yong-Gui; Dong, Jie

    2015-01-01

    Objective Vitamin D (VD) deficiency is an independent risk factor for cognitive impairment (CI) in the general population, but VD status in peritoneal dialysis (PD) patients has not been investigated. In this study, we aimed to investigate the relationship between serum VD levels and global and specific cognitive functions in PD patients. Design and Setting Cross-sectional study, simultaneously conducted at two PD centers. Patients Clinically stable patients (n = 273) undergoing PD for at least 3 months were enrolled over a period of one year. Main outcome Measures Demographic and comorbidity data were recorded, and routine biochemical parameters and serum 25-hydroxyvitamin D (25(OH) D) levels of overnight fasted patients were determined. Global cognitive function was assessed by the Modified Mini-Mental State Examination (3MS) score; executive function, by the trail making tests (Trails A and B); and immediate memory, delayed memory, and language ability by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) sub-tests. Results In the univariate analysis, serum 25(OH) D levels significantly correlated with 3MS scores (r = -0.139; P = 0.02), and Trail A (r = -0.188; P = 0.002) and B (r = -0.154; P = 0.01) completion times. In the multivariate analysis, 25(OH) D was found to be independently associated with global CI, but not with executive dysfunction. Serum 25(OH) D could not predict scores of immediate/delayed memory and language ability. Conclusions VD deficiency is highly prevalent in PD patients and is an independent risk factor for global CI in this patient cohort. PMID:26630385

  14. Involvement of reactive oxygen species in stimuli-induced shedding of heparin-binding epidermal growth factor-like growth factor.

    PubMed

    Umata, Toshiyuki

    2014-06-01

    Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a critical growth factor for a number of physiological and pathological processes, such as wound healing, atherosclerosis and cancer proliferation. HB-EGF is synthesized as a membrane form (proHB-EGF), and is shedded at the cell surface to yield soluble HB-EGF, resulting in making it active. In this study, the involvement of reactive oxygen species (ROS) in stimuli-induced shedding of HB-EGF was investigated using monkey kidney Vero cells overexpressing HB-EGF (Vero-H cells). 12-O-tetradecanoylphorbol-13-acetate (TPA), lysophosphatidic acid (LPA) as a ligand for seventransmembrane G protein coupled receptors (GPCR) and sorbitol as stress induced shedding of HB-EGF mediated protein kinase C (PKC)-δ, mitogen-activated protein kinase (MAPK) and p38MAPK, respectively. These stimuli-induced sheddings of HB-EGF were inhibited by N-acetyl-L-cysteine (NAC), suggesting the involvement of ROS. As specific inhibitors of these protein kinases inhibited the shedding of HB-EGF, these signaling pathways seem to be independent, respectively. In contrast, γ-ray irradiation did not induce shedding although it did increase intracellular ROS levels. Taken together, these results suggest that the synergistic generation of ROS and the activation of protein kinase are required to promote stimuli-induced shedding of HB-EGF. PMID:24930874

  15. 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

  16. 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. PMID:26798059

  17. 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.

  18. Heparin-Binding Epidermal Growth Factor-like Growth Factor/Diphtheria Toxin Receptor in Normal and Neoplastic Hematopoiesis

    PubMed Central

    Vinante, Fabrizio; Rigo, Antonella

    2013-01-01

    Heparin-binding EGF-like growth factor (HB-EGF) belongs to the EGF family of growth factors. It is biologically active either as a molecule anchored to the membrane or as a soluble form released by proteolytic cleavage of the extracellular domain. HB-EGF is involved in relevant physiological and pathological processes spanning from proliferation and apoptosis to morphogenesis. We outline here the main activities of HB-EGF in connection with normal or neoplastic differentiative or proliferative events taking place primitively in the hematopoietic microenvironment. PMID:23888518

  19. 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. PMID:17117475

  20. The role of hematopoietic growth factors in transfusion medicine.

    PubMed

    Whitsett, C F

    1995-02-01

    Hematopoietic growth factors have already had an enormous impact on transfusion practice by eliminating or reducing the need for red blood cell transfusions in a variety of anemic states characterized by an absolute or relative decrease in erythropoietin. In addition, GM-CSF and G-CSF have stimulated the production of autologous neutrophils in febrile neutropenic patients in whom granulocyte transfusions had been considered ineffective. With the discovery of c-Mpl ligand and the promising results obtained with IL-11 and IL-3, a combination of growth factors that successfully stimulate platelet production may soon be identified. This first era in the clinical application of hematopoietic growth factors has been characterized largely by treatment of the patient to stimulate production of autologous cells or to enhance the ability of transplanted hematopoietic progenitor cells to repopulate the patient. The use of G-CSF to increase the yield of granulocytes harvested by apheresis procedures and to mobilize peripheral blood stem cells in allogeneic donors has initiated a new era in which the cell donor is treated to enhance cell production and enhance the repopulating ability of hematopoietic progenitor cells. As our understanding of hematopoiesis grows, scientists will be able to identify growth factors to overcome or correct deficient hematopoiesis. Increasingly, component transfusions will be reserved for life-threatening situations in which endogenous cell production cannot be stimulated or cell production will be too slow to prevent life-threatening events. PMID:7737944

  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. NEUROBIOLOGICAL EFFECTS OF COLCHICINE: MODULATION BY NERVE GROWTH FACTOR

    EPA Science Inventory

    To study the effects of exogenously applied nerve growth factor (NGF) on colchicine-induced neurodegeneration in the dentate gyrus of the rat hippocampal formation, male Fischer 344 rats (n=75) weighing 275-325 grams received colchicine [COLCH; 2.5 ug/site in 0.5 ul of artificial...

  3. Role of fibroblast growth factors in organ regeneration and repair.

    PubMed

    El Agha, Elie; Kosanovic, Djuro; Schermuly, Ralph T; Bellusci, Saverio

    2016-05-01

    In its broad sense, regeneration refers to the renewal of lost cells, tissues or organs as part of the normal life cycle (skin, hair, endometrium etc.) or as part of an adaptive mechanism that organisms have developed throughout evolution. For example, worms, starfish and amphibians have developed remarkable regenerative capabilities allowing them to voluntarily shed body parts, in a process called autotomy, only to replace the lost parts afterwards. The bizarre myth of the fireproof homicidal salamander that can survive fire and poison apple trees has persisted until the 20th century. Salamanders possess one of the most robust regenerative machineries in vertebrates and attempting to draw lessons from limb regeneration in these animals and extrapolate the knowledge to mammals is a never-ending endeavor. Fibroblast growth factors are potent morphogens and mitogens that are highly conserved among the animal kingdom. These growth factors play key roles in organogenesis during embryonic development as well as homeostatic balance during postnatal life. In this review, we provide a summary about the current knowledge regarding the involvement of fibroblast growth factor signaling in organ regeneration and repair. We also shed light on the use of these growth factors in previous and current clinical trials in a wide array of human diseases. PMID:26459973

  4. Total Chemical Synthesis of Biologically Active Vascular Endothelial Growth Factor

    SciTech Connect

    Mandal, Kalyaneswar; Kent, Stephen B.H.

    2011-09-15

    The 204-residue covalent-dimer vascular endothelial growth factor (VEGF, see picture) with full mitogenic activity was prepared from three unprotected peptide segments by one-pot native chemical ligations. The covalent structure of the synthetic VEGF was confirmed by precise mass measurement, and the three-dimensional structure of the synthetic protein was determined by high-resolution X-ray crystallography.

  5. Regulation of liver regeneration by growth factors and cytokines

    PubMed Central

    Böhm, Friederike; Köhler, Ulrike A; Speicher, Tobias; Werner, Sabine

    2010-01-01

    The capability of the liver to fully regenerate after injury is a unique phenomenon essential for the maintenance of its important functions in the control of metabolism and xenobiotic detoxification. The regeneration process is histologically well described, but the genes that orchestrate liver regeneration have been only partially characterized. Of particular interest are cytokines and growth factors, which control different phases of liver regeneration. Historically, their potential functions in this process were addressed by analyzing their expression in the regenerating liver of rodents. Some of the predicted roles were confirmed using functional studies, including systemic delivery of recombinant growth factors, neutralizing antibodies or siRNAs prior to liver injury or during liver regeneration. In particular, the availability of genetically modified mice and their use in liver regeneration studies has unraveled novel and often unexpected functions of growth factors, cytokines and their downstream signalling targets in liver regeneration. This review summarizes the results obtained by functional studies that have addressed the roles and mechanisms of action of growth factors and cytokines in liver regeneration after acute injury to this organ. PMID:20652897

  6. Fibroblast Growth Factor-2 Alters the Nature of Extinction

    ERIC Educational Resources Information Center

    Graham, Bronwyn M.; Richardson, Rick

    2011-01-01

    These experiments examined the effects of the NMDA-receptor (NMDAr) antagonist MK801 on reacquisition and re-extinction of a conditioned fear that had been previously extinguished before injection of fibroblast growth factor-2 (FGF2) or vehicle. Recent findings have shown that relearning and re-extinction, unlike initial learning and extinction,…

  7. Characterization and estrogen regulation of uterine growth factor activity

    SciTech Connect

    Beck, C.A.

    1988-01-01

    Acid extracts of rat, bovine and rabbit uterus stimulated glucose transport, measured by phosphorylation of 2-deoxyglucose and DNA synthesis, measured by {sup 3}H-thymidne incorporation, in uterine tumor cells and in primary cultures of rat uterine cells. The stimulation of glucose transport was of the same magnitude and followed the same time course as estradiol stimulation in vivo. Uteri from estradiol-treated rat uteri contained 4 times more glucose transport-stimulating activity as control uteri. DNA synthetic activity in rat uterine homogenates was elevated 3-fold within 18-24 h after estradiol injection. Gel filtration showed molecular weight heterogeneity with activity eluting between 10-30 kDA. Both activities were acid and heat stable, were reduced by trypsin but not by dextran-coated charcoal. The effect of purified growth factors on DNA synthesis in primary cultures of rat uterine cells was examined. Epidermal growth factor (EGF), basic fibroblasts growth factor (bFGF), and transforming growth factor-{beta} (TGF{beta}) had no effect on {sup 3}H-thymidine incorporation.

  8. [Expression of tissue factor and vascular endothelial growth factor in colorectal carcinoma].

    PubMed

    Altomare, D F; Rotelli, M T; Memeo, V; Martinelli, E; Guglielmi, A; DeFazio, M; D'Elia, G; Pentimone, A; Colucci, M; Semeraro, N

    2003-01-01

    Tissue factor (TF) and vascular endothelial growth factor (VEGF) play an important role in tumor progression and metastasis. We analyzed their expression in the carcinoma and normal mucosa of 53 colorectal cancer patients. VEGF levels were significantly higher in the tumor and correlated with TF expression. No correlation was found with tumor stage. TF may influence tumor growth and metastasis by modulating VEGF expression and neoangiogenesis. PMID:12903530

  9. Carbachol stimulates a different phospholipid metabolism than nerve growth factor and basic fibroblast growth factor in PC12 cells.

    PubMed Central

    Pessin, M S; Altin, J G; Jarpe, M; Tansley, F; Bradshaw, R A; Raben, D M

    1991-01-01

    We have examined 1,2-diglycerides (DGs) generated in PC12 cells in response to the muscarinic agonist carbachol and compared them with those generated in response to the differentiation factors nerve growth factor and basic fibroblast growth factor. Whereas carbachol stimulates a greater release of inositol phosphates, all three agonists generate similar levels of DGs. In this report, we have analyzed the molecular species of PC12 DGs generated in response to these three agonists. Additionally, we have analyzed the molecular species of PC12 phospholipids. The data indicate that 1) after 1 min of either nerve growth factor or basic fibroblast growth factor stimulation, DGs arise primarily from phosphoinositide hydrolysis; 2) in contrast, after 1 min of carbachol stimulation, DG are generated equally by both phosphoinositide and phosphatidylcholine hydrolysis; and 3) after 15 min of stimulation by any of these agonists, DGs are generated largely by phosphatidylcholine hydrolysis, with a smaller component arising from the phosphoinositides. These results suggest that at least part of the mechanism by which PC12 cells distinguish between different agonists is via alterations in phospholipid sources and kinetics of DG generation. PMID:1892912

  10. Myogenin induces the myocyte-specific enhancer binding factor MEF-2 independently of other muscle-specific gene products.

    PubMed Central

    Cserjesi, P; Olson, E N

    1991-01-01

    The myocyte-specific enhancer-binding factor MEF-2 is a nuclear factor that interacts with a conserved element in the muscle creatine kinase and myosin light-chain 1/3 enhancers (L. A. Gossett, D. J. Kelvin, E. A. Sternberg, and E. N. Olson, Mol. Cell. Biol. 9:5022-5033, 1989). We show in this study that MEF-2 is regulated by the myogenic regulatory factor myogenin and that mitogenic signals block this regulatory interaction. Induction of MEF-2 by myogenin occurs in transfected 10T1/2 cells that have been converted to myoblasts by myogenin, as well as in CV-1 kidney cells that do not activate the myogenic program in response to myogenin. Through mutagenesis of the MEF-2 site, we further defined the binding site requirements for MEF-2 and identified potential MEF-2 sites within numerous muscle-specific regulatory regions. The MEF-2 site was also found to bind a ubiquitous nuclear factor whose binding specificity was similar to but distinct from that of MEF-2. Our results reveal that MEF-2 is controlled, either directly or indirectly, by a myogenin-dependent regulatory pathway and suggest that growth factor signals suppress MEF-2 expression through repression of myogenin expression or activity. The ability of myogenin to induce MEF-2 activity in CV-1 cells, which do not activate downstream genes associated with terminal differentiation, also demonstrates that myogenin retains limited function within cell types that are nonpermissive for myogenesis and suggests that MEF-2 is regulated independently of other muscle-specific genes. Images PMID:1656214

  11. Age as an independent factor for the development of neuropathy in diabetic patients

    PubMed Central

    Popescu, Simona; Timar, Bogdan; Baderca, Flavia; Simu, Mihaela; Diaconu, Laura; Velea, Iulian; Timar, Romulus

    2016-01-01

    Population aging is unprecedented, without parallel in the history of humanity. As type 2 diabetes mellitus is predominantly more prevalent in aging populations, this creates a major public health burden. Older adults with diabetes have the highest rates of major lower-extremity amputation, myocardial infarction, visual impairment, and end-stage renal disease of any age group. The aims of our study were to assess whether age is an independent factor for the occurrence of diabetic neuropathy (DN), and to evaluate the relationship between the presence and the severity of DN and the diabetes duration and blood glucose level. In this study, we enrolled 198 patients, previously diagnosed with type 2 diabetes mellitus. For all patients, we measured hemoglobin A1c (HbA1c), lipid profile, and body mass index and we assessed the presence and severity of DN using the evaluation of clinical signs and symptoms. Patients had a median age of 62 years, with a median of diabetes duration of 7 years; 55.1% of the patients were men and the average HbA1c in the cohort was 8.2%. The prevalence of DN according to Michigan Neuropathy Screening Instrument was 28.8%, being significantly and positively correlated with higher age (65 vs 59 years; P=0.001) and HbA1c (8.6% vs 8.0%; P=0.027). No significant correlations were observed between the severity of DN and diabetes duration, body mass index (31.9 vs 29.9 kg/m2), or the number of centimeters exceeding the normal waist circumference (25.2 vs 17.3 cm; P=0.003). In conclusion, age influences the presence of DN, independent on other risk factors. This influence persists even after adjusting for other, very important risk factors, like blood glucose level or diabetes duration. PMID:27042031

  12. 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. PMID:11953652

  13. 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.

  14. Role of hypoxia and vascular endothelial growth factors in lymphangiogenesis

    PubMed Central

    Morfoisse, Florent; Renaud, Edith; Hantelys, Fransky; Prats, Anne-Catherine; Garmy-Susini, Barbara

    2014-01-01

    Hypoxia is known to be a major factor in the induction of angiogenesis during tumor development but its role in lymphangiogenesis remains unclear. Blood and lymphatic vasculatures are stimulated by the vascular endothelial family of growth factors – the VEGFs. In this review, we investigate the role of hypoxia in the molecular regulation of synthesis of the lymphangiogenic growth factors VEGF-A, VEGF-C, and VEGF-D. Gene expression can be regulated by hypoxia at either transcriptional or translational levels. In contrast to strong induction of DNA transcription by hypoxia-inducible factors (HIFs), the majority of cellular stresses such as hypoxia lead to inhibition of cap-dependent translation of mRNA and downregulation of protein synthesis. Here, we describe how initiation of translation of VEGF mRNA is induced by hypoxia through an internal ribosome entry site (IRES)-dependent mechanism. Considering the implications of the lymphatic vasculature for metastatic dissemination, it is crucial to understand the molecular regulation of lymphangiogenic growth factors by hypoxia to obtain new insights into cancer therapy. PMID:27308316

  15. ATPase inhibitory factor 1 expression is an independent prognostic factor in non-small cell lung cancer

    PubMed Central

    Gao, Yi-Xing; Chen, Lu; Hu, Xu-Gang; Wu, Hai-Bo; Cui, You-Hong; Zhang, Xia; Wang, Yan; Liu, Xin-Dong; Bian, Xiu-Wu

    2016-01-01

    ATPase inhibitory factor 1 (IF1), an inhibitor of the mitochondrial H+-adenosine triphosphate (ATP) synthase, is putatively involved in tumor progression. This study aimed to evaluate the expression levels of IF1 in non-small cell lung cancer (NSCLC) and the prognostic value for the patients. IF1 protein expression levels were detected in 149 cases of NSCLC by using immunohistochemistry. Kaplan-Meier analysis showed that NSCLC patients with high expression of IF1 possessed poorer outcome than those with low expression of IF1 (P=0.007). Moreover, IF1 was also prognostic in the patients with early stages (stage I/II) (P=0.042) and low grade (grade I/II) (P=0.002). Multivariable Cox-regression analysis showed that high expression of IF1 (HR=1.67, P=0.034), tumor size (HR=1.79, P=0.001), and lymph node metastasis (HR=2.66, P=0.000) were independent indicators for NSCLC patients. In conclusion, our study demonstrated that elevated expression of IF1 may associated with lymph node metastasis of NSCLC and served as an independent prognostic and recurrent indicator for the patients. PMID:27294006

  16. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth.

    PubMed Central

    Nakshatri, H; Bhat-Nakshatri, P; Martin, D A; Goulet, R J; Sledge, G W

    1997-01-01

    Breast cancers often progress from a hormone-dependent, nonmetastatic, antiestrogen-sensitive phenotype to a hormone-independent, antiestrogen- and chemotherapy-resistant phenotype with highly invasive and metastatic growth properties. This progression is usually accompanied by altered function of the estrogen receptor (ER) or outgrowth of ER-negative cancer cells. To understand the molecular mechanisms responsible for metastatic growth of ER-negative breast cancers, the activities of the transcription factor NF-kappaB (which modulates the expression of genes involved in cell proliferation, differentiation, apoptosis, and metastasis) were compared in ER-positive (MCF-7 and T47-D) and ER-negative (MDA-MB-231 and MDA-MB-435) human breast cancer cell lines. NF-kappaB, which is usually maintained in an inactive state by protein-protein interaction with inhibitor IkappaBs, was found to be constitutively active in ER-negative breast cancer cell lines. Constitutive DNA binding of NF-kappaB was also observed with extracts from ER-negative, poorly differentiated primary breast tumors. Progression of the rat mammary carcinoma cell line RM22-F5 from an ER-positive, nonmalignant phenotype (E phenotype) to an ER-negative, malignant phenotype (F phenotype) was also accompanied by constitutive activation of NF-kappaB. Analysis of individual subunits of NF-kappaB revealed that all ER-negative cell lines, including RM22-F5 cells of F phenotype, contain a unique 37-kDa protein which is antigenically related to the RelA subunit. Cell-type-specific differences in IkappaB alpha, -beta, and -gamma were also observed. In transient-transfection experiments, constitutive activity of an NF-kappaB-dependent promoter was observed in MDA-MB-231 and RM22-F5 cells of F phenotype, and this activity was efficiently repressed by cotransfected ER. Since ER inhibits the constitutive as well as inducible activation function of NF-kappaB in a dose-dependent manner, we propose that breast cancers that

  17. Correlation of vascular endothelial growth factor expression with fibroblast growth factor-8 expression and clinico-pathologic parameters in human prostate cancer

    PubMed Central

    West, A F; O'Donnell, M; Charlton, R G; Neal, D E; Leung, H Y

    2001-01-01

    Vascular endothelial growth factor (VEGF) mediates neo-angiogenesis during tumour progression and is known to cooperate with the fibroblast growth factor (FGF) system to facilitate angiogenesis in a synergistic manner. In view of this, we have investigated VEGF expression in 67 cases of prostate cancer previously characterized for fibroblast growth factor-8 (FGF-8) expression. Cytoplasmic VEGF staining was detected in malignant cells in 45 out of 67 cases. Cytoplasmic staining was found in adjacent stromal cells in 32 cases, being particularly strong around nests of invasive tumour. Positive VEGF immunoreactivity in benign glands was restricted to basal epithelium. A significant association was observed between tumour VEGF and FGF-8 expression (P = 0.004). We identified increased VEGF immunoreactivity in both malignant epithelium and adjacent stroma and both were found to be significantly associated with high tumour stage (P = 0.0047 and P = 0.0002, respectively). VEGF expression also correlated with increased serum PSA levels (P = 0.01). Among positively stained tumours, VEGF expression showed a significant association with Gleason score (P = 0.04). Cases showing positive VEGF immunoreactivity in the stroma had a significantly reduced survival rate compared to those with negative staining (P = 0.037). Cases with tumours expressing both FGF-8 in the malignant epithelium and VEGF in the adjacent stroma had a significantly worse survival rate than those with tumours negative for both, or only expressing one of the two growth factors (P = 0.029). Cox multivariate regression analysis of survival demonstrated that stromal VEGF and tumour stage were the most significant independent predictors of survival. In conclusion, we report for the first time a correlation of both tumour and stromal VEGF expression in prostate cancer with clinical parameters as well as its correlation to FGF-8 expression. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11506499

  18. Vascular Endothelial growth factor signaling in hypoxia and Inflammation

    PubMed Central

    Ramakrishnan, S.; Anand, Vidhu; Roy, Sabita

    2014-01-01

    Infection, cancer and cardiovascular diseases are the major causes for morbidity and mortality in the United States according to the Center for Disease Control. The underlying etiology that contributes to the severity of these diseases is either hypoxia induced inflammation or inflammation resulting in hypoxia. Therefore, molecular mechanisms that regulate hypoxia-induced adaptive responses in cells are important areas of investigation. Oxygen availability is sensed by molecular switches which regulate synthesis and secretion of growth factors and inflammatory mediators. As a consequence, tissue microenvironment is altered by reprogramming metabolic pathways, angiogenesis, vascular permeability, pH homeostasis to facilitate tissue remodeling. Hypoxia inducible factor (HIF) is the central mediator of hypoxic response. HIF regulates several hundred genes and vascular endothelial growth factor (VEGF) is one of the primary target genes. Understanding the regulation of HIF and its influence on inflammatory response offers unique opportunities for drug development to modulate inflammation and ischemia in pathological conditions. PMID:24610033

  19. Induction of nerve growth factor receptors on cultured human melanocytes

    SciTech Connect

    Peacocke, M.; Yaar, M.; Mansur, C.P.; Chao, M.V.; Gilchrest, B.A. )

    1988-07-01

    Normal differentiation and malignant transformation of human melanocytes involve a complex series of interactions during which both genetic and environmental factors play roles. At present, the regulation of these processes is poorly understood. The authors have induced the expression of nerve growth factor (NGF) receptors on cultured human melanocytes with phorbol 12-tetradecanoate 13-acetate and have correlated this event with the appearance of a more differentiated, dendritic morphology. Criteria for NGF receptor expression included protein accumulation and cell-surface immunofluorescent staining with a monoclonal antibody directed against the human receptor and induction of the messenger RNA species as determined by blot-hybridization studies. The presence of the receptor could also be induced by UV irradiation or growth factor deprivation. The NGF receptor is inducible in cultured human melanocytes, and they suggest that NGF may modulate the behavior of this neural crest-derived cell in the skin.

  20. Is Obesity Predictive of Cardiovascular Dysfunction Independent of Cardiovascular Risk Factors?

    PubMed Central

    DeVallance, Evan; Fournier, Sara B.; Donley, David A.; Bonner, Daniel E.; Lee, Kyuwan; Frisbee, Jefferson C.; Chantler, Paul D.

    2015-01-01

    Introduction Obesity is thought to exert detrimental effects on the cardiovascular (CV) system. However, this relationship is impacted by the co-occurrence of CV risk factors, type II diabetes (T2DM), and overt disease. We examined the relationships between obesity, assessed by body mass index (BMI) and waist circumference (WC), and CV function in 102 subjects without overt CV disease. We hypothesized that obesity would be independently predictive of CV remodeling and functional differences, especially at peak exercise. Methods Brachial (bSBP) and central (cSBP) systolic pressure, carotid-to-femoral pulse wave velocity (PWVcf) augmentation index (AGI) (by SphygmoCor), and carotid remodeling (B-mode ultrasound) were examined at rest. Further, peak exercise cardiac imaging (Doppler ultrasound) was performed to measure the coupling between the heart and arterial system. Results In backward elimination regression models, accounting for CV risk factors, neither BMI nor WC were predictors of carotid thickness or PWVcf; rather age, triglycerides, and hypertension were the main determinants. However, BMI and WC predicted carotid cross-sectional area and lumen diameter. When examining the relationship between body size and SBP, BMI (β=0.32) and WC (β=0.25) were predictors of bSBP (p<0.05), whereas, BMI was the only predictor of cSBP (β=0.22, p<0.05) indicating a differential relationship between cSBP, bSBP and body size. Further, BMI (β=−0.26) and WC (β=−0.27) were independent predictors of AGI (p<0.05). As for resting cardiac diastolic function, WC seemed to be a better predictor than BMI. However, both BMI and WC were inversely and independently related to arterial elastance (net arterial load) and end-systolic elastance (cardiac contractility) at rest and peak exercise. Discussion These findings illustrate that obesity, without T2DM and overt CV disease, and after accounting for CV risk factors, is susceptible to pathophysiological adaptations that may

  1. 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

  2. High Myeloperoxidase Positive Cell Infiltration in Colorectal Cancer Is an Independent Favorable Prognostic Factor

    PubMed Central

    Eppenberger-Castori, Serenella; Zlobec, Inti; Viehl, Carsten T.; Frey, Daniel M.; Nebiker, Christian A.; Rosso, Raffaele; Zuber, Markus; Amicarella, Francesca; Iezzi, Giandomenica; Sconocchia, Giuseppe; Heberer, Michael; Lugli, Alessandro; Tornillo, Luigi; Oertli, Daniel

    2013-01-01

    Background Colorectal cancer (CRC) infiltration by adaptive immune system cells correlates with favorable prognosis. The role of the innate immune system is still debated. Here we addressed the prognostic impact of CRC infiltration by neutrophil granulocytes (NG). Methods A TMA including healthy mucosa and clinically annotated CRC specimens (n = 1491) was stained with MPO and CD15 specific antibodies. MPO+ and CD15+ positive immune cells were counted by three independent observers. Phenotypic profiles of CRC infiltrating MPO+ and CD15+ cells were validated by flow cytometry on cell suspensions derived from enzymatically digested surgical specimens. Survival analysis was performed by splitting randomized data in training and validation subsets. Results MPO+ and CD15+ cell infiltration were significantly correlated (p<0.0001; r = 0.76). However, only high density of MPO+ cell infiltration was associated with significantly improved survival in training (P = 0.038) and validation (P = 0.002) sets. In multivariate analysis including T and N stage, vascular invasion, tumor border configuration and microsatellite instability status, MPO+ cell infiltration proved an independent prognostic marker overall (P = 0.004; HR = 0.65; CI:±0.15) and in both training (P = 0.048) and validation (P = 0.036) sets. Flow-cytometry analysis of CRC cell suspensions derived from clinical specimens showed that while MPO+ cells were largely CD15+/CD66b+, sizeable percentages of CD15+ and CD66b+ cells were MPO−. Conclusions High density MPO+ cell infiltration is a novel independent favorable prognostic factor in CRC. PMID:23734221

  3. Type of gambling as an independent risk factor for suicidal events in pathological gamblers.

    PubMed

    Bischof, Anja; Meyer, Christian; Bischof, Gallus; John, Ulrich; Wurst, Friedrich Martin; Thon, Natasha; Lucht, Michael; Grabe, Hans-Joergen; Rumpf, Hans-Juergen

    2016-03-01

    Individuals with pathological gambling have an increased risk for suicidal events. Additionally, the prevalence of comorbid psychiatric disorders is high among pathological gamblers. This study analyzes whether the type of gambling is associated with suicidal events in pathological gamblers independently from comorbidity. Participants were recruited in 4 different ways: via random telephone sample from the general population, via individual invitation for study participation in gambling locations, through various media and the distribution of a leaflet in various settings, and via inpatient treatment facilities for pathological gambling. The final sample included 442 participants with a lifetime diagnosis of pathological gambling. A standardized clinical interview was conducted. High financial losses were associated with suicidal events (odds ratio [OR] = 1.94, 95% 95% confidence interval [CI], [1.11, 3.37]), as were mood disorders (OR = 7.70, 95% CI, [4.44, 13.37]) and female gender (OR = 2.52, 95% CI, [1.20, 5.28]). Gambling on electronic gambling machines in gambling halls or bars was associated with increased odds of suicidal events (OR = 2.94, 95% CI, [1.38, 6.24]). Other types of gambling, such as casino games or betting on sports, or the number of DSM-IV criteria for pathological gambling were not associated independently with suicidal events. Our findings suggest that gambling on electronic gambling machines in gambling halls or bars is associated with suicidal events in pathological gamblers independently of comorbidity. This result shows that the type of gambling needs to be considered as a relevant factor in gambling research. (PsycINFO Database Record PMID:26795395

  4. 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

  5. Model-independent determination of the astrophysical S factor in laser-induced fusion plasmas

    DOE PAGESBeta

    Lattuada, D.; Barbarino, M.; Bonasera, A.; Bang, W.; Quevedo, H. J.; Warren, M.; Consoli, F.; De Angelis, R.; Andreoli, P.; Kimura, S.; et al

    2016-04-19

    In this paper, we present a new and general method for measuring the astrophysical S factor of nuclear reactions in laser-induced plasmas and we apply it to 2H(d,n)3He. The experiment was performed with the Texas Petawatt Laser, which delivered 150–270 fs pulses of energy ranging from 90 to 180 J to D2 or CD4 molecular clusters (where D denotes 2H). After removing the background noise, we used the measured time-of-flight data of energetic deuterium ions to obtain their energy distribution. We derive the S factor using the measured energy distribution of the ions, the measured volume of the fusion plasma,more » and the measured fusion yields. This method is model independent in the sense that no assumption on the state of the system is required, but it requires an accurate measurement of the ion energy distribution, especially at high energies, and of the relevant fusion yields. In the 2H(d,n)3He and 3He(d,p)4He cases discussed here, it is very important to apply the background subtraction for the energetic ions and to measure the fusion yields with high precision. While the available data on both ion distribution and fusion yields allow us to determine with good precision the S factor in the d+d case (lower Gamow energies), for the d+3He case the data are not precise enough to obtain the S factor using this method. Our results agree with other experiments within the experimental error, even though smaller values of the S factor were obtained. This might be due to the plasma environment differing from the beam target conditions in a conventional accelerator experiment.« less

  6. Model-independent determination of the astrophysical S factor in laser-induced fusion plasmas

    NASA Astrophysics Data System (ADS)

    Lattuada, D.; Barbarino, M.; Bonasera, A.; Bang, W.; Quevedo, H. J.; Warren, M.; Consoli, F.; De Angelis, R.; Andreoli, P.; Kimura, S.; Dyer, G.; Bernstein, A. C.; Hagel, K.; Barbui, M.; Schmidt, K.; Gaul, E.; Donovan, M. E.; Natowitz, J. B.; Ditmire, T.

    2016-04-01

    In this work, we present a new and general method for measuring the astrophysical S factor of nuclear reactions in laser-induced plasmas and we apply it to :mmultiscripts>(d ,n )3He . The experiment was performed with the Texas Petawatt Laser, which delivered 150-270 fs pulses of energy ranging from 90 to 180 J to D2 or CD4 molecular clusters (where D denotes 2H ) . After removing the background noise, we used the measured time-of-flight data of energetic deuterium ions to obtain their energy distribution. We derive the S factor using the measured energy distribution of the ions, the measured volume of the fusion plasma, and the measured fusion yields. This method is model independent in the sense that no assumption on the state of the system is required, but it requires an accurate measurement of the ion energy distribution, especially at high energies, and of the relevant fusion yields. In the :mmultiscripts>(d ,n )3He and 3He(d ,p )4He cases discussed here, it is very important to apply the background subtraction for the energetic ions and to measure the fusion yields with high precision. While the available data on both ion distribution and fusion yields allow us to determine with good precision the S factor in the d +d case (lower Gamow energies), for the d +3He case the data are not precise enough to obtain the S factor using this method. Our results agree with other experiments within the experimental error, even though smaller values of the S factor were obtained. This might be due to the plasma environment differing from the beam target conditions in a conventional accelerator experiment.

  7. Pulmonary Hypertension an Independent Risk Factor for Death in Intensive Care Unit: Correlation of Hemodynamic Factors with Mortality

    PubMed Central

    Saydain, Ghulam; Awan, Aamir; Manickam, Palaniappan; Kleinow, Paul; Badr, Safwan

    2015-01-01

    OBJECTIVE Critically ill patients with pulmonary hypertension (PH) pose additional challenges due to the existence of right ventricular (RV) dysfunction. The purpose of this study was to assess the impact of hemodynamic factors on the outcome. METHODS We reviewed the records of patients with a diagnosis of PH admitted to the intensive care unit. In addition to evaluating traditional hemodynamic parameters, we defined severe PH as right atrial pressure >20 mmHg, mean pulmonary artery pressure >55 mmHg, or cardiac index (CI) <2 L/min/m2. We also defined the RV functional index (RFI) as pulmonary artery systolic pressure (PASP) adjusted for CI as PASP/CI; increasing values reflect RV dysfunction. RESULTS Fifty-three patients (mean age 60 years, 72% women, 79% Blacks), were included in the study. Severe PH was present in 68% of patients who had higher Sequential Organ Failure Assessment (SOFA) score (6.8 ± 3.3 vs 3.8 ± 1.6; P = 0.001) and overall in-hospital mortality (36% vs 6%; P = 0.02) compared to nonsevere patients, although Acute Physiology and Chronic Health Evaluation (APACHE) II scores (19.9 ± 7.5 vs 18.5 ± 6.04; P = 0.52) were similar and sepsis was more frequent among nonsevere PH patients (31 vs 64%; P = 0.02). Severe PH (P = 0.04), lower mean arterial pressure (P = 0.04), and CI (P = 0.01); need for invasive ventilation (P = 0.02) and vasopressors (P = 0.03); and higher SOFA (P = 0.001), APACHE II (P = 0.03), pulmonary vascular resistance index (PVRI) (P = 0.01), and RFI (P = 0.004) were associated with increased mortality. In a multivariate model, SOFA [OR = 1.45, 95% confidence interval (C.I.) = 1.09–1.93; P = 0.01], PVRI (OR = 1.12, 95% C.I. = 1.02–1.24; P = 0.02), and increasing RFI (OR = 1.06, 95% C.I. = 1.01–1.11; P = 0.01) were independently associated with mortality. CONCLUSION PH is an independent risk factor for mortality in critically ill patients. Composite factors rather than individual hemodynamic parameters are better predictors of

  8. MEK1-independent activation of MAPK and MEK1-dependent activation of p70 S6 kinase by stem cell factor (SCF) in ovarian cancer cells

    SciTech Connect

    Liu, Lian; Zhang, Xin; Du, Chao; Zhang, Xiaoning; Hou, Nan; Zhao, Di; Sun, Jianzhi; Li, Li; Wang, Xiuwen; Ma, Chunhong

    2009-05-01

    We discovered a stem cell factor (SCF)-triggered, MEK1-independent, and PI3K-dependent MAPK activation pathway in the Kit-expressing ovarian cancer cell line HEY. When we knocked down MEK1 with RNA interference (RNAi) to study the function of MEK1 on the proliferation and survival of ovarian cancer cells, we found that impaired cell growth still occurred after MEK1 expression had been suppressed, although MAPK activation remained intact. This suggests that there is MEK1-independent activation of MAPK in the SCF-induced ovarian cancer cell growth process, and that MEK1 still plays a crucial role in maintaining the malignant properties of ovarian cancer cells even when it fails to activate MAPK as expected.

  9. Vascular Endothelial Growth Factor Acts Primarily via Platelet-Derived Growth Factor Receptor α to Promote Proliferative Vitreoretinopathy

    PubMed Central

    Pennock, Steven; Haddock, Luis J.; Mukai, Shizuo; Kazlauskas, Andrius

    2015-01-01

    Proliferative vitreoretinopathy (PVR) is a nonneovascular blinding disease and the leading cause for failure in surgical repair of rhegmatogenous retinal detachments. Once formed, PVR is difficult to treat. Hence, there is an acute interest in developing approaches to prevent PVR. Of the many growth factors and cytokines that accumulate in vitreous as PVR develops, neutralizing vascular endothelial growth factor (VEGF) A has recently been found to prevent PVR in at least one animal model. The goal of this study was to test if Food and Drug Administration–approved agents could protect the eye from PVR in multiple animal models and to further investigate the underlying mechanisms. Neutralizing VEGF with aflibercept (VEGF Trap-Eye) safely and effectively protected rabbits from PVR in multiple models of disease. Furthermore, aflibercept reduced the bioactivity of both experimental and clinical PVR vitreous. Finally, although VEGF could promote some PVR-associated cellular responses via VEGF receptors expressed on the retinal pigment epithelial cells that drive this disease, VEGF's major contribution to vitreal bioactivity occurred via platelet-derived growth factor receptor α. Thus, VEGF promotes PVR by a noncanonical ability to engage platelet-derived growth factor receptor α. These findings indicate that VEGF contributes to nonangiogenic diseases and that anti–VEGF-based therapies may be effective on a wider spectrum of diseases than previously appreciated. PMID:25261788

  10. Epidermal growth factor (EGF) antagonizes transforming growth factor (TGF)-beta1-induced collagen lattice contraction by human skin fibroblasts.

    PubMed

    Park, J S; Kim, J Y; Cho, J Y; Kang, J S; Yu, Y H

    2000-12-01

    Wound contraction plays an important role in healing, but in extreme conditions, it may lead to excessive scar formation and pathological wound contracture. To date, the key regulator of excessive contracture is known to be transforming growth factor-beta (TGF-beta1). In this study, we have evaluated epidermal growth factor (EGF) antagonism in fibroblast-populated collagen lattice (FPCL) gel contraction, which has been generally used as an in vitro model thought to mimic wound contraction in vivo. As expected, TGF-beta1 treatment enhanced normal fibroblast-induced collagen gel contraction in a dose-dependent manner. In contrast, EGF did not affect normal gel formation, but significantly antagonized TGF-beta1-induced gel formation (p<0.05 at 100 ng/ml), whereas the other growth factor, platelet-derived growth factor (PDGF), did not altered either normal or TGF-beta1-induced gel contractions. Similarly, EGF treatment, but not PDGF, also significantly suppressed TGF-beta1 release that was autologously elicited by TGF-beta1 treatment (p<0.01 at 100 ng/ml). Therefore, the results suggest that EGF may negatively regulate the role of TGF-beta1 through attenuating autologous release of TGF-beta1. PMID:11145189

  11. Transforming growth factor-beta and transforming growth factor beta-receptor expression in human meningioma cells.

    PubMed Central

    Johnson, M. D.; Federspiel, C. F.; Gold, L. I.; Moses, H. L.

    1992-01-01

    The transforming growth factor-beta (TGF beta) family in mammals includes three closely related peptides that influence proliferation and numerous physiologic processes in most mesenchymal cells. In this study, Northern blots, immunohistochemistry, TGF beta radioreceptor assays, TGF beta receptor affinity labeling and [3H] thymidine incorporation were used to evaluate whether primary cell cultures of human meningiomas synthesize the three TGF beta isoforms, bear TGF beta receptors, and respond to TGF beta. Transcripts for TGF beta 1 and 2 were detected in the three cases analyzed. Transforming growth factor-beta 1 immunoreactivity was detected in three of six cases, and TGF beta 2 and 3 immunoreactivity were detected in each case analyzed. Media conditioned by cells cultured from six meningiomas also contained latent TGF beta-like activity. Transforming growth factor-beta receptor cross-linking studies identified TGF beta binding sites corresponding to the type 1, type 2, and type 3 receptors on meningioma cells. Treatment with active TGF beta 1 produced a statistically significant reduction in [3H] thymidine incorporation after stimulation with 10% fetal calf serum and epidermal growth factor in all six cases studied. Images Figure 1 Figure 2 Figure 4 PMID:1325741

  12. Induction of virulence factors in Giardia duodenalis independent of host attachment

    PubMed Central

    Emery, Samantha J.; Mirzaei, Mehdi; Vuong, Daniel; Pascovici, Dana; Chick, Joel M.; Lacey, Ernest; Haynes, Paul A.

    2016-01-01

    Giardia duodenalis is responsible for the majority of parasitic gastroenteritis in humans worldwide. Host-parasite interaction models in vitro provide insights into disease and virulence and help us to understand pathogenesis. Using HT-29 intestinal epithelial cells (IEC) as a model we have demonstrated that initial sensitisation by host secretions reduces proclivity for trophozoite attachment, while inducing virulence factors. Host soluble factors triggered up-regulation of membrane and secreted proteins, including Tenascins, Cathepsin-B precursor, cystatin, and numerous Variant-specific Surface Proteins (VSPs). By comparison, host-cell attached trophozoites up-regulated intracellular pathways for ubiquitination, reactive oxygen species (ROS) detoxification and production of pyridoxal phosphate (PLP). We reason that these results demonstrate early pathogenesis in Giardia involves two independent host-parasite interactions. Motile trophozoites respond to soluble secreted signals, which deter attachment and induce expression of virulence factors. Trophozoites attached to host cells, in contrast, respond by up-regulating intracellular pathways involved in clearance of ROS, thus anticipating the host defence response. PMID:26867958

  13. Induction of virulence factors in Giardia duodenalis independent of host attachment.

    PubMed

    Emery, Samantha J; Mirzaei, Mehdi; Vuong, Daniel; Pascovici, Dana; Chick, Joel M; Lacey, Ernest; Haynes, Paul A

    2016-01-01

    Giardia duodenalis is responsible for the majority of parasitic gastroenteritis in humans worldwide. Host-parasite interaction models in vitro provide insights into disease and virulence and help us to understand pathogenesis. Using HT-29 intestinal epithelial cells (IEC) as a model we have demonstrated that initial sensitisation by host secretions reduces proclivity for trophozoite attachment, while inducing virulence factors. Host soluble factors triggered up-regulation of membrane and secreted proteins, including Tenascins, Cathepsin-B precursor, cystatin, and numerous Variant-specific Surface Proteins (VSPs). By comparison, host-cell attached trophozoites up-regulated intracellular pathways for ubiquitination, reactive oxygen species (ROS) detoxification and production of pyridoxal phosphate (PLP). We reason that these results demonstrate early pathogenesis in Giardia involves two independent host-parasite interactions. Motile trophozoites respond to soluble secreted signals, which deter attachment and induce expression of virulence factors. Trophozoites attached to host cells, in contrast, respond by up-regulating intracellular pathways involved in clearance of ROS, thus anticipating the host defence response. PMID:26867958

  14. Examining factors involved in stress-related working memory impairments: Independent or conditional effects?

    PubMed

    Banks, Jonathan B; Tartar, Jaime L; Tamayo, Brittney A

    2015-12-01

    A large and growing body of research demonstrates the impact of psychological stress on working memory. However, the typical study approach tests the effects of a single biological or psychological factor on changes in working memory. The current study attempted to move beyond the standard single-factor assessment by examining the impact of 2 possible factors in stress-related working memory impairments. To this end, 60 participants completed a working memory task before and after either a psychological stressor writing task or a control writing task and completed measures of both cortisol and mind wandering. We also included a measure of state anxiety to examine the direct and indirect effect on working memory. We found that mind wandering mediated the relationship between state anxiety and working memory at the baseline measurement. This indirect relationship was moderated by cortisol, such that the impact of mind wandering on working memory increased as cortisol levels increased. No overall working memory impairment was observed following the stress manipulation, but increases in state anxiety and mind wandering were observed. State anxiety and mind wandering independently mediated the relationship between change in working memory and threat perception. The indirect paths resulted in opposing effects on working memory. Combined, the findings from this study suggest that cortisol enhances the impact of mind wandering on working memory, that state anxiety may not always result in stress-related working memory impairments, and that high working memory performance can protect against mind wandering. PMID:26098727

  15. 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

  16. Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas.

    PubMed Central

    Hatva, E.; Böhling, T.; Jääskeläinen, J.; Persico, M. G.; Haltia, M.; Alitalo, K.

    1996-01-01

    Capillary hemangioblastomas and hemangiopericytomas are highly vascular central nervous system tumors of controversial origin. Of interest in their pathogenesis are mechanisms regulating endothelial cell growth. The endothelial cell mitogen vascular endothelial growth factor (VEGF) stimulates angiogenesis, and together with its two receptor tyrosine kinases VEGFR-1(FLT1) and VEGFR-2(KDR), is up-regulated during the malignant progression of gliomas. We have analyzed the expression of VEGF and its receptors, the related placental growth factor (PlGF) and the endothelial receptors FLT4 and Tie by in situ hybridization in capillary hemangioblastomas and hemangiopericytomas. VEGF mRNA was up-regulated in all of the hemangiopericytomas studied and highly expressed in the stromal cells of hemangioblastomas. In addition, some hemangioblastoma tumor cells expressed high levels of PlGF. Significantly elevated levels of Tie mRNA, Tie protein, VEGFR-1, and VEGFR-2 but not FLT4 mRNAs were observed in the endothelia of both tumor types. In hemangioblastomas, however, the receptors were also highly expressed by a subpopulation of stromal cells. Consistent results were obtained for a human hemangioblastoma cell line in culture. Up-regulation of the endothelial growth factors and receptors may result in autocrine or paracrine stimulation of endothelial cells and their precursors involved in the genesis of these two vascular tumors. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8774132

  17. Transforming growth factor (TGF)-. alpha. in human milk

    SciTech Connect

    Okada, Masaki; Wakai, Kae; Shizume, Kazuo ); Iwashita, Mitsutoshi ); Ohmura, Eiji; Kamiya, Yoshinobu; Murakami, Hitomi; Onoda, Noritaka; Tsushima, Toshio

    1991-01-01

    Transforming growth factor (TGF)-{alpha} and epidermal growth factor (EGF) were measured in human milk by means of homologous radioimmunoassay. As previously reported, EGF concentration in the colostrum was approximately 200 ng/ml and decreased to 50 ng/ml by day 7 postpartum. The value of immunoreactive (IR)-TGF-{alpha} was 2.2-7.2 ng/ml, much lower than that of EGF. In contrast to EGF, the concentration of IR-TGF-{alpha} was fairly stable during the 7 postpartum days. There was no relationship between the concentrations of IR-TGF-{alpha} and IR-EGF, suggesting that the regulatory mechanism in the release of the two growth factors is different. On gel-chromatography using a Sephadex G-50 column, IR-EGF appeared in the fraction corresponding to that of authentic human EGF, while 70%-80% of the IR-TGF-{alpha} was eluted as a species with a molecular weight greater than that of authentic human TGF-{alpha}. Although the physiological role of TGF-{alpha} in milk is not known, it is possible that it is involved in the development of the mammary gland and/or the growth of newborn infants.

  18. Impact factor analysis of mixture spectra unmixing based on independent component analysis

    NASA Astrophysics Data System (ADS)

    Chen, Lei; Chen, Shengbo; Guo, Xulin; Zhou, Chao

    2016-01-01

    Based on spectral independence of different materials, independent component analysis (ICA), a blind source separation technique, can be applied to separate mixed hyperspectral signals. For the purpose of detecting objects on the sea and improving the precision of target recognition, an original ICA method is applied by analyzing the influence exerted by spectral features of different materials and mixture materials on spectral unmixing results. Due to the complexity of targets on the sea, several measured spectra of different materials have been mixed with water spectra to simulate mixed spectra for mixture spectra decomposition. Synthetic mixed spectra are generated by linear combinations of different materials and water spectra to obtain separated results. We then compared the separated results with the measured spectra of each endmember by coefficient of determination. We conclude that these factors that will change the original spectral characteristics of Gaussian distribution have significant influence on the separated results and selecting a proper initial matrix, and processing spectral data with lower noise can help improve the ICA method for more accurate separated results from hyperspectral data.

  19. STAT-Phosphorylation–Independent Induction of Interferon Regulatory Factor-9 by Interferon-β

    PubMed Central

    2010-01-01

    Type I interferon (IFN)-dependent STAT1 and STAT2 activation requires specific tyrosine residues (337Y and 512Y) located in the cytoplasmic domain of IFNAR-2c, the β-subunit of the human type I IFN receptor. To identify STAT activation-independent induction of ISGs, we used a mutant cell line in which both 337Y and 512Y were substituted with phenylalanine (337F512F or FF mutant). In these cells, type I IFN failed to activate STAT1, STAT2, and STAT3 did not induce well-characterized ISGs and did not exert antiviral or antiproliferative effects. Using Oligonucleotide array (Affymetrix™) analysis, we showed that interferon regulatory factor-9 (IRF-9) was the only gene induced by IFN-β in FF cells. Transient transfection analysis using an IRF-9 promoter–reporter luciferase construct in FF cells confirmed induction of the IRF-9 transcription unit by IFN-β. EMSA analysis using an IFN-stimulated response element (ISRE)-like sequence on the IRF-9 promoter detected 2 novel DNA-binding complexes induced in nuclear extracts of IFN-β-treated FF cells. Supershift experiments identified the proteins IRF-1 and C/EBP-β in the complex. These studies provide the first evidence that signaling pathways leading to gene transcription are activated by IFN-β independent of STAT phosphorylation. PMID:20038197

  20. The Independent Probabilistic Firing of Transcription Factors: A Paradigm for Clonal Variability in the Zebrafish Retina

    PubMed Central

    Boije, Henrik; Rulands, Steffen; Dudczig, Stefanie; Simons, Benjamin D.; Harris, William A.

    2015-01-01

    Summary Early retinal progenitor cells (RPCs) in vertebrates produce lineages that vary greatly both in terms of cell number and fate composition, yet how this variability is achieved remains unknown. One possibility is that these RPCs are individually distinct and that each gives rise to a unique lineage. Another is that stochastic mechanisms play upon the determinative machinery of equipotent early RPCs to drive clonal variability. Here we show that a simple model, based on the independent firing of key fate-influencing transcription factors, can quantitatively account for the intrinsic clonal variance in the zebrafish retina and predict the distributions of neuronal cell types in clones where one or more of these fates are made unavailable. PMID:26343455

  1. Meteorological factors and El Niño Southern Oscillation are independently associated with dengue infections.

    PubMed

    Earnest, A; Tan, S B; Wilder-Smith, A

    2012-07-01

    Our objective was to determine the association between temperature, humidity, rainfall and dengue activity in Singapore, after taking into account lag periods as well as long-term climate variability such as the El Niño Southern Oscillation Index (SOI). We used a Poisson model which allowed for autocorrelation and overdispersion in the data. We found weekly mean temperature and mean relative humidity as well as SOI to be significantly and independently associated with dengue notifications. There was an interaction effect by periods of dengue outbreaks, but periods where El Niño was present did not moderate the relationship between humidity and temperature with dengue notifications. Our results help to understand the temporal trends of dengue in Singapore, and further reinforce the findings that meteorological factors are important in the epidemiology of dengue. PMID:21906411

  2. Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin.

    PubMed

    Masuda, Takeshi; Wang, Xin; Maeda, Manami; Canver, Matthew C; Sher, Falak; Funnell, Alister P W; Fisher, Chris; Suciu, Maria; Martyn, Gabriella E; Norton, Laura J; Zhu, Catherine; Kurita, Ryo; Nakamura, Yukio; Xu, Jian; Higgs, Douglas R; Crossley, Merlin; Bauer, Daniel E; Orkin, Stuart H; Kharchenko, Peter V; Maeda, Takahiro

    2016-01-15

    Genes encoding human β-type globin undergo a developmental switch from embryonic to fetal to adult-type expression. Mutations in the adult form cause inherited hemoglobinopathies or globin disorders, including sickle cell disease and thalassemia. Some experimental results have suggested that these diseases could be treated by induction of fetal-type hemoglobin (HbF). However, the mechanisms that repress HbF in adults remain unclear. We found that the LRF/ZBTB7A transcription factor occupies fetal γ-globin genes and maintains the nucleosome density necessary for γ-globin gene silencing in adults, and that LRF confers its repressive activity through a NuRD repressor complex independent of the fetal globin repressor BCL11A. Our study may provide additional opportunities for therapeutic targeting in the treatment of hemoglobinopathies. PMID:26816381

  3. Expression and clinical significance of epidermal growth factor receptor and insulin-like growth factor receptor 1 in patients with ampullary adenocarcinoma.

    PubMed

    Xia, Michelle; Overman, Michael J; Rashid, Asif; Chatterjee, Deyali; Wang, Hua; Katz, Matthew H; Fleming, Jason B; Lee, Jeffery E; Varadhachary, Gauri R; Wolff, Robert A; Wang, Huamin

    2015-09-01

    Epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor 1 (IGF-1R) play important roles in cell proliferation, antiapoptosis, angiogenesis, and metastasis and have been used for targeted therapies for patients with advanced colorectal and lung cancers. However, the expression and function of EGFR and IGF-1R in ampullary adenocarcinoma (AA) have not been examined in detail. We examined the expression of EGFR and IGF-1R in 106 AA patients at our institution using tissue microarrays and immunohistochemistry. The results were correlated with the clinicopathological parameters and survival. Overexpression of EGFR and IGF-1R was detected in 18 (17%) and 26 (25%) of AAs, respectively. Patients with EGFR-high tumors had shorter overall survival (mean, 109.8 ± 22.3 months) than those patients whose tumors were EGFR-low in overall study population (mean, 164.2 ± 10.6 months; P = .04). Overexpression of EGFR correlated with poor overall survival in patients with intestinal-type AA (P = .01) but not in those with pancreaticobiliary-type AAs (P = .47). In multivariate analysis, EGFR overexpression was an independent prognostic factor for overall survival (P = .02). In addition, we found that overexpression of IGF-1R correlated with AAs of pancreaticobiliary histology. No additional correlation between the expression of EGFR or IGF-1R and other clinicopathological factors was observed in our patient population. Our study demonstrates that EGFR and IGF-1R appear to be overexpressed in a subset of AAs and that strong membranous expression of EGFR is an independent predictor for overall survival in patients with AA. EGFR and IGF-1R represent potential therapeutic targets for treatment of patient with AAs. PMID:26165226

  4. Stromal inhibition of prostatic epithelial cell proliferation not mediated by transforming growth factor beta.

    PubMed Central

    Kooistra, A.; van den Eijnden-van Raaij, A. J.; Klaij, I. A.; Romijn, J. C.; Schröder, F. H.

    1995-01-01

    The paracrine influence of prostatic stroma on the proliferation of prostatic epithelial cells was investigated. Stromal cells from the human prostate have previously been shown to inhibit anchorage-dependent as well as anchorage-independent growth of the prostatic tumour epithelial cell lines PC-3 and LNCaP. Antiproliferative activity, mediated by a diffusible factor in the stromal cell conditioned medium, was found to be produced specifically by prostatic stromal cells. In the present study the characteristics of this factor were examined. It is demonstrated that prostate stroma-derived inhibiting factor is an acid- and heat-labile, dithiothreitol-sensitive protein. Although some similarities with type beta transforming growth factor (TGF-beta)-like inhibitors are apparent, evidence is presented that the factor is not identical to TGF-beta or to the TGF-beta-like factors activin and inhibin. Absence of TGF-beta activity was shown by the lack of inhibitory response of the TGF-beta-sensitive mink lung cell line CCL-64 to prostate stromal cell conditioned medium and to concentrated, partially purified preparations of the inhibitor. Furthermore, neutralising antibodies against TGF-beta 1 or TGF-beta 2 did not cause a decline in the level of PC-3 growth inhibition caused by partially purified inhibitor. Using Northern blot analyses, we excluded the involvement of inhibin or activin. It is concluded that the prostate stroma-derived factor may be a novel growth inhibitor different from any of the currently described inhibiting factors. Images Figure 5 PMID:7543773

  5. Upregulation of nemo-like kinase is an independent prognostic factor in colorectal cancer

    PubMed Central

    Zhang, Wei; He, Jian; Du, Yan; Gao, Xian-Hua; Liu, Yan; Liu, Qi-Zhi; Chang, Wen-Jun; Cao, Guang-Wen; Fu, Chuan-Gang

    2015-01-01

    AIM: To investigate the expression and oncogenic role of nemo-like kinase (NLK) in colorectal cancer. METHODS: Expression of NLK protein was assessed by immunohistochemistry in tissue specimens from 56 cases of normal colorectal mucosa, 51 cases of colorectal adenoma, and 712 cases of colorectal cancer. In addition, NLK expression was knocked down using a lentivirus carrying NLK small hairpin RNA in colorectal cancer cells. Cell viability methylthiazoletetrazolium assays, colony formation assays, flow cytometry cell cycle assays, Transwell migration assays, and gene expression assays were performed to explore its role on proliferation and migration of colorectal cancer. RESULTS: Expression of NLK protein progressively increased in tissues from the normal mucosa through adenoma to various stages of colorectal cancer. Overexpression of NLK protein was associated with advanced tumor-lymph node-metastasis stages, poor differentiation, lymph node and distant metastases, and a higher recurrence rate of colorectal cancer (P < 0.05). Multivariate analyses showed that NLK expression was an independent prognostic factor to predict overall survival (hazard ratio 2.57, 95% confidence interval: 1.66-3.98; P < 0.001) and disease-free survival (hazard ratio 1.96, 95% confidence interval: 1.40-2.74: P < 0.001) of colorectal cancer patients. Furthermore, knockdown of NLK expression in colorectal cancer cell lines reduced cell viability, colony formation, and migration, and arrested tumor cells at the G0/G1 phase of the cell cycle. At the gene level, knockdown of NLK expression inhibited matrix metalloproteinase-2 expression in colorectal cancer cells. CONCLUSION: NLK overexpression is an independent prognostic factor in colorectal cancer and knockdown of NLK expression inhibits colorectal cancer progression and metastasis. PMID:26269673

  6. The influence of site factors on eucalypt growth in Karnataka

    SciTech Connect

    Dury, S.J.; Manjunath, B.E.

    1992-12-31

    The effect of site factors on the growth of E. tereticornis hybrid plantations in Karnataka, southern India, is investigated. Sites have been characterized and classified on the basis of the physical and chemical conditions of the soil, topography and climate. Growth data have been collected from two sources: permanent sample plots, to relate growth to site conditions and to detect site change over time, and fertilizer trials, to investigate which nutrients or combination of nutrients enhance growth rates. Site indices calculated from the permanent sample plots are used as the basis for relating growth rates to soil type. The lower than expected mean annual increments of the plantations, which vary between 0.2 and 7 m{sup 3} ha{sup {minus}1} yr{sup {minus}1} at six years of age, are considered to be primarily the result of water stress. Three of the areas studied have similar soil characteristics, as confirmed by discriminant analysis, but have quite different average site indices. This is shown to be related to differences in average rainfall. Practices for reducing moisture stress are therefore recommended to improve productivity. The fertilizer trials show no clear growth response to nitrogen or phosphorus; possible reasons for this are outlined. Evidence of potassium deficiency is presented. The need for a combined fertilizer/irrigation trial is discussed.

  7. Divergent effects of epidermal growth factor and transforming growth factors on a human endometrial carcinoma cell line.

    PubMed

    Korc, M; Haussler, C A; Trookman, N S

    1987-09-15

    Epidermal growth factor (EGF), at concentrations ranging from 0.83 to 4.98 nM, markedly inhibited the proliferation of RL95-2 cells that were seeded at low plating densities (4.7 X 10(3) cells/cm2). Under the same incubation conditions, 16.6 pM EGF enhanced cell proliferation. At high plating densities (2.5 X 10(4) cells/cm2) 0.83 nM EGF also stimulated cell proliferation. Both the inhibitory and stimulatory effects of EGF were mimicked by transforming growth factor-alpha (TGF-alpha). However, the inhibitory action of TGF-alpha was always greater that of EGF. Binding studies with 125I-labeled TGF-alpha indicated that maximal cell surface binding of TGF-alpha occurred at 15 min, whereas maximal internalization occurred at 45 min. Both cell surface and internalized radioactivity declined sharply thereafter. Analysis of radioactivity released into the incubation medium during pulse-chase experiments indicated that RL95-2 cells extensively degraded both TGF-alpha and EGF. The lysosomotropic compound methylamine arrested the generation of low-molecular-weight degradation products of EGF, but not of TGF-alpha. In contrast to EGF and TGF-alpha, transforming growth factor-beta (TGF-beta) inhibited the proliferation of RL95-2 cells that were seeded at either low or high plating densities. Further, transforming growth factor-beta induced the appearance of large cuboidal cells that were readily distinguished from cells treated with either EGF or TGF-alpha. These findings point to complex regulatory actions of growth factors on the proliferation of RL95-2 cells and suggest that the processing of TGF-alpha following EGF receptor activation is distinct from the processing of EGF. PMID:3497713

  8. Normoxic wound fluid contains high levels of vascular endothelial growth factor.

    PubMed Central

    Howdieshell, T R; Riegner, C; Gupta, V; Callaway, D; Grembowicz, K; Sathyanarayana; McNeil, P L

    1998-01-01

    OBJECTIVE: To examine the temporal integration of vascular endothelial growth factor (VEGF), which has been shown to be present in wound fluid, with the putatively related processes of wound fluid oxygen content, wound angiogenesis, and granulation tissue formation. SUMMARY BACKGROUND DATA: During cutaneous wound repair, new tissue formation starts with reepithelialization and is followed by granulation tissue formation, including neutrophil and macrophage accumulation, fibroblast ingrowth, matrix deposition, and angiogenesis. Because angiogenesis and increased vascular permeability are characteristic features of wound healing, VEGF may play an important role in tissue repair. METHODS: A ventral hernia, surgically created in the abdominal wall of female swine, was repaired using silicone sheeting and skin closure. Over time, a fluid-filled wound compartment formed, bounded by subcutaneous tissue and omentum. Ultrasonography was performed serially to examine the anatomy and dimensions of the subcutaneous tissue and wound compartment. Serial wound fluid samples, obtained by percutaneous aspiration, were analyzed for PO2, PCO2, pH, and growth factor concentrations. RESULTS: Three independent assays demonstrate that VEGF protein is present at substantially elevated levels in a wound fluid associated with the formation of abdominal granulation tissue. However, the wound fluid is not hypoxic at any time. Serial sampling reveals that transforming growth factor beta-1 protein appears in the wound fluid before VEGF. CONCLUSIONS: The results suggest that VEGF is a prominent regulator of wound angiogenesis and vessel permeability. A factor other than hypoxia, perhaps the earlier appearance of another growth factor, transforming growth factor beta-1, may positively regulate VEGF appearance in the wound fluid. Images Figure 1. Figure 2. Figure 3. Figure 5. Figure 7. PMID:9833810

  9. Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives.

    PubMed

    Dieci, Maria Vittoria; Arnedos, Monica; Andre, Fabrice; Soria, Jean Charles

    2013-03-01

    The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiologic processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifications, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, class-specific toxicity profiles and correctly designing clinical trials to address these different issues. PMID:23418312

  10. Role of hypoxia and vascular endothelial growth factors in lymphangiogenesis

    PubMed Central

    Morfoisse, Florent; Renaud, Edith; Hantelys, Fransky; Prats, Anne-Catherine; Garmy-Susini, Barbara

    2015-01-01

    Hypoxia is a major condition for the induction of angiogenesis during tumor development but its role in lymphangiogenesis remains unclear. Blood and lymphatic vasculatures are stimulated by growth factors from the vascular endothelial family: the VEGFs. In this review, we investigate the role of hypoxia in the molecular regulation of synthesis of lymphangiogenic growth factors VEGF-A, VEGF-C, and VEGF-D. Gene expression can be regulated at transcriptional and translational levels by hypoxia. Despite strong regulation of DNA transcription induced by hypoxia-inducible factors (HIFs), the majority of cellular stresses such as hypoxia lead to inhibition of cap-dependent translation of the mRNA, resulting in downregulation of protein synthesis. Here, we describe how translation initiation of VEGF mRNAs is induced by hypoxia through an internal ribosome entry site (IRES)-dependent mechanism. Considering the implication of the lymphatic vasculature in metastatic dissemination, it seems crucial to understand the hypoxia-induced molecular regulation of lymphangiogenic growth factors to obtain new insights for cancer therapy. PMID:27308508

  11. Growth factor choice is critical for successful functionalization of nanoparticles

    PubMed Central

    Pinkernelle, Josephine; Raffa, Vittoria; Calatayud, Maria P.; Goya, Gerado F.; Riggio, Cristina; Keilhoff, Gerburg

    2015-01-01

    Nanoparticles (NPs) show new characteristics compared to the corresponding bulk material. These nanoscale properties make them interesting for various applications in biomedicine and life sciences. One field of application is the use of magnetic NPs to support regeneration in the nervous system. Drug delivery requires a functionalization of NPs with bio-functional molecules. In our study, we functionalized self-made PEI-coated iron oxide NPs with nerve growth factor (NGF) and glial cell-line derived neurotrophic factor (GDNF). Next, we tested the bio-functionality of NGF in a rat pheochromocytoma cell line (PC12) and the bio-functionality of GDNF in an organotypic spinal cord culture. Covalent binding of NGF to PEI-NPs impaired bio-functionality of NGF, but non-covalent approach differentiated PC12 cells reliably. Non-covalent binding of GDNF showed a satisfying bio-functionality of GDNF:PEI-NPs, but turned out to be unstable in conjugation to the PEI-NPs. Taken together, our study showed the importance of assessing bio-functionality and binding stability of functionalized growth factors using proper biological models. It also shows that successful functionalization of magnetic NPs with growth factors is dependent on the used binding chemistry and that it is hardly predictable. For use as therapeutics, functionalization strategies have to be reproducible and future studies are needed. PMID:26388717

  12. Role of hypoxia and vascular endothelial growth factors in lymphangiogenesis.

    PubMed

    Morfoisse, Florent; Renaud, Edith; Hantelys, Fransky; Prats, Anne-Catherine; Garmy-Susini, Barbara

    2015-01-01

    Hypoxia is a major condition for the induction of angiogenesis during tumor development but its role in lymphangiogenesis remains unclear. Blood and lymphatic vasculatures are stimulated by growth factors from the vascular endothelial family: the VEGFs. In this review, we investigate the role of hypoxia in the molecular regulation of synthesis of lymphangiogenic growth factors VEGF-A, VEGF-C, and VEGF-D. Gene expression can be regulated at transcriptional and translational levels by hypoxia. Despite strong regulation of DNA transcription induced by hypoxia-inducible factors (HIFs), the majority of cellular stresses such as hypoxia lead to inhibition of cap-dependent translation of the mRNA, resulting in downregulation of protein synthesis. Here, we describe how translation initiation of VEGF mRNAs is induced by hypoxia through an internal ribosome entry site (IRES)-dependent mechanism. Considering the implication of the lymphatic vasculature in metastatic dissemination, it seems crucial to understand the hypoxia-induced molecular regulation of lymphangiogenic growth factors to obtain new insights for cancer therapy. PMID:27308508

  13. Model-independent plotting of the cosmological scale factor as a function of lookback time

    SciTech Connect

    Ringermacher, H. I.; Mead, L. R. E-mail: Lawrence.mead@usm.edu

    2014-11-01

    In this work we describe a model-independent method of developing a plot of scale factor a(t) versus lookback time t{sub L} from the usual Hubble diagram of modulus data against redshift. This is the first plot of this type. We follow the model-independent methodology of Daly and Djorgovski used for their radio-galaxy data. Once the a(t)data plot is completed, any model can be applied and will display as described in the standard literature. We then compile an extensive data set to z = 1.8 by combining Type Ia supernovae (SNe Ia) data from SNLS3 of Conley et al., high-z SNe data of Riess et al., and radio-galaxy data of Daly and Djorgovski to validate the new plot. We first display these data on a standard Hubble diagram to confirm the best fit for ΛCDM cosmology, and thus validate the joined data set. The scale factor plot is then developed from the data and the ΛCDM model is again displayed from a least-squares fit. The fit parameters are in agreement with the Hubble diagram fit confirming the validity of the new plot. Of special interest is the transition time of the universe, which in the scale factor plot will appear as an inflection point in the data set. Noise is more visible in this presentation, which is particularly sensitive to inflection points of any model displayed in the plot, unlike on a modulus-z diagram, where there are no inflection points and the transition-z is not at all obvious by inspection. We obtain a lower limit of z ≥ 0.6. It is evident from this presentation that there is a dearth of SNe data in the range z = 1-2, exactly the range necessary to confirm a ΛCDM transition-z around z = 0.76. We then compare a 'toy model' wherein dark matter is represented as a perfect fluid with an equation of state p = –(1/3) ρ to demonstrate the plot sensitivity to model choice. Its density varies as 1/t {sup 2} and it enters the Friedmann equations as Ω{sub dark}/t {sup 2}, replacing only the Ω{sub dark}/a {sup 3} term. The toy model is a

  14. Independence of buoyant cell density and growth rate in Escherichia coli

    SciTech Connect

    Kubitchek, H.E.; Baldwin, W.W.; Schroeter, S.J.; Graetzer, R.

    1984-04-01

    The relationship between growth rate and buoyant density was determined for cells from exponential-phase cultures of Escherichia coli B/r NC32 by equilibrium centrifugation in Percoll gradients at growth rates ranging from 0.15 to 2.3 doublings per h. The mean buoyant density did not change significantly with growth rate in any of three sets of experiments in which different gradient conditions were used. In addition, when cultures were allowed to enter the stationary phase of growth, mean cell volumes and buoyant densities usually remained unchanged for extended periods. These and earlier results support the existence of a highly regulated, discrete state of buoyant density during steady-state growth of E. coli and other cells that divide by equatorial fission. 11 references, 3 figures.

  15. The Growth Reduction Associated with Repressed Lignin Biosynthesis in Arabidopsis thaliana Is Independent of Flavonoids[C

    PubMed Central

    Li, Xu; Bonawitz, Nicholas D.; Weng, Jing-Ke; Chapple, Clint

    2010-01-01

    Defects in phenylpropanoid biosynthesis arising from deficiency in hydroxycinnamoyl CoA:shikimate hydroxycinnamoyl transferase (HCT) or p-coumaroyl shikimate 3′-hydroxylase (C3′H) lead to reduced lignin, hyperaccumulation of flavonoids, and growth inhibition in Arabidopsis thaliana. It was previously reported that flavonoid-mediated inhibition of auxin transport is responsible for growth reduction in HCT-RNA interference (RNAi) plants. This conclusion was based on the observation that simultaneous RNAi silencing of HCT and chalcone synthase (CHS), an enzyme essential for flavonoid biosynthesis, resulted in less severe dwarfing than silencing of HCT alone. In an attempt to extend these results using a C3′H mutant (ref8) and a CHS null mutant (tt4-2), we found that the growth phenotype of the ref8 tt4-2 double mutant, which lacks flavonoids, is indistinguishable from that of ref8. Moreover, using RNAi, we found that the relationship between HCT silencing and growth inhibition is identical in both the wild type and tt4-2. We conclude from these results that the growth inhibition observed in HCT-RNAi plants and the ref8 mutant is independent of flavonoids. Finally, we show that expression of a newly characterized gene bypassing HCT and C3′H partially restores both lignin biosynthesis and growth in HCT-RNAi plants, demonstrating that a biochemical pathway downstream of coniferaldehyde, probably lignification, is essential for normal plant growth. PMID:20511296

  16. Mammographic texture resemblance generalizes as an independent risk factor for breast cancer

    PubMed Central

    2014-01-01

    Introduction Breast density has been established as a major risk factor for breast cancer. We have previously demonstrated that mammographic texture resemblance (MTR), recognizing the local texture patterns of the mammogram, is also a risk factor for breast cancer, independent of percent breast density. We examine if these findings generalize to another population. Methods Texture patterns were recorded in digitalized pre-diagnosis (3.7 years) film mammograms of a nested case–control study within the Dutch screening program (S1) comprising of 245 breast cancers and 250 matched controls. The patterns were recognized in the same study using cross-validation to form resemblance scores associated with breast cancer. Texture patterns from S1 were examined in an independent nested case–control study within the Mayo Mammography Health Study cohort (S2) of 226 cases and 442 matched controls: mammograms on average 8.5 years prior to diagnosis, risk factor information and percent mammographic density (PD) estimated using Cumulus were available. MTR scores estimated from S1, S2 and S1 + S2 (the latter two as cross-validations) were evaluated in S2. MTR scores were analyzed as both quartiles and continuously for association with breast cancer using odds ratios (OR) and adjusting for known risk factors including age, body mass index (BMI), and hormone usage. Results The mean ages of S1 and S2 were 58.0 ± 5.7 years and 55.2 ± 10.5 years, respectively. The MTR scores on S1 showed significant capability to discriminate cancers from controls (area under the operator characteristics curve (AUC) = 0.63 ± 0.02, P <0.001), which persisted after adjustment for PD. S2 showed an AUC of 0.63, 0.61, and 0.60 based on PD, MTR scores trained on S2, and MTR scores trained on S1, respectively. When adjusted for PD, MTR scores of S2 trained on S1 showed an association with breast cancer for the highest quartile alone: OR in quartiles of controls as reference; 1

  17. Phosphoproteome analysis demonstrates the potential role of THRAP3 phosphorylation in androgen-independent prostate cancer cell growth.

    PubMed

    Ino, Yoko; Arakawa, Noriaki; Ishiguro, Hitoshi; Uemura, Hiroji; Kubota, Yoshinobu; Hirano, Hisashi; Toda, Tosifusa

    2016-04-01

    Elucidating the androgen-independent growth mechanism is critical for developing effective treatment strategies to combat androgen-independent prostate cancer. We performed a comparative phosphoproteome analysis using a prostate cancer cell line, LNCaP, and an LNCaP-derived androgen-independent cell line, LNCaP-AI, to identify phosphoproteins involved in this mechanism. We performed quantitative comparisons of the phosphopeptide levels in tryptic digests of protein extracts from these cell lines using MS. We found that the levels of 69 phosphopeptides in 66 proteins significantly differed between LNCaP and LNCaP-AI. In particular, we focused on thyroid hormone receptor associated protein 3 (THRAP3), which is a known transcriptional coactivator of the androgen receptor. The phosphorylation level of THRAP3 was significantly lower at S248 and S253 in LNCaP-AI cells. Furthermore, pull-down assays showed that 32 proteins uniquely bound to the nonphosphorylatable mutant form of THRAP3, whereas 31 other proteins uniquely bound to the phosphorylation-mimic form. Many of the differentially interacting proteins were identified as being involved with RNA splicing and processing. These results suggest that the phosphorylation state of THRAP3 at S248 and S253 might be involved in the mechanism of androgen-independent prostate cancer cell growth by changing the interaction partners. PMID:26841317

  18. Antitumor effect of hepatocyte growth factor on hepatoblastoma.

    PubMed

    Tsunoda, Y; Shibusawa, M; Tsunoda, A; Gomi, A; Yatsuzuka, M; Okamatsu, T

    1998-01-01

    A six month-old girl presented with an abdominal mass, and high serum level of alpha-fetoprotein. She was diagnosed as having a well-differentiated hepatoblastoma by open biopsy. The biopsy specimen was transplanted on a nude mouse, and a xenograft was successfully established. Because the xenograft maintained the characteristics of the original tumor, the effect of hepatocyte growth factor (HGF) on hepatoblastoma xenograft was investigated. Recently HGF was reported to be involved in growth, invasion, and metastasis of tumor cells. Contrary to our expectations, the treatment of hepatoblastoma xenograft with recombinant 20 ng/ml HGF produced a marked inhibition of cell growth and a suppression of producing alpha-fetoprotein. PMID:9891489

  19. A study of substrate factor on carbon nanotube forest growth

    NASA Astrophysics Data System (ADS)

    Read, Carlos; Call, Robert; Shen, T. C.

    2010-10-01

    Carbon Nanotube Forests (CNFs) are vertically grown carbon nanotubes. They can be as tall as millimeters with radii from less than one nm (single-walled) to more than a hundred nm (multi-walled). Their high surface to volume ratio provides a unique material system for EM radiation absorption, dry adhesive and biosensor applications. There have been numerous, but not all consistent reports on successful CNF growth. We find that the optimal growth conditions depend critically on the substrate, at least by the spray pyrolysis method we have adopted. To determine the substrate factor, we have investigated two grades of copper, stainless steel, silicon and quartz as substrates on which the catalytic particles and carbon source are delivered simultaneously by a ferrocine-xylene solution. We find that the interplay of lateral and in-diffusion of the iron atoms and interactions with existing gas molecules such as H2, O2, H2O on the substrates dictate the CNF growth.

  20. Modulation of epidermal growth factor receptors by human alpha interferon.

    PubMed Central

    Zoon, K C; Karasaki, Y; zur Nedden, D L; Hu, R Q; Arnheiter, H

    1986-01-01

    Treatment of Madin-Darby bovine kidney (MDBK) cells with human interferon (IFN)-alpha 2 at 37 degrees C results in a dose-dependent inhibition of cell growth and a reduction of the subsequent binding of 125I-labeled epidermal growth factor (EGF) at 4 degrees C. Human IFN-beta and -gamma, which exhibit little antiviral and antiproliferative activities on MDBK cells, have little effect on cell growth or the binding of 125I-labeled EGF to these cells. The binding of EGF is decreased after exposure to IFN-alpha for greater than 8 hr. Scatchard analyses of the EGF binding data indicate that a 20-hr exposure period results in a decrease in the apparent number of cell-surface EGF receptors and a reduction in the affinity of EGF for its receptor. The rate of internalization of EGF by MDBK cells does not appear to be affected by IFN treatment. PMID:3095830

  1. Modulation of epidermal growth factor receptors by human alpha interferon.

    PubMed

    Zoon, K C; Karasaki, Y; zur Nedden, D L; Hu, R Q; Arnheiter, H

    1986-11-01

    Treatment of Madin-Darby bovine kidney (MDBK) cells with human interferon (IFN)-alpha 2 at 37 degrees C results in a dose-dependent inhibition of cell growth and a reduction of the subsequent binding of 125I-labeled epidermal growth factor (EGF) at 4 degrees C. Human IFN-beta and -gamma, which exhibit little antiviral and antiproliferative activities on MDBK cells, have little effect on cell growth or the binding of 125I-labeled EGF to these cells. The binding of EGF is decreased after exposure to IFN-alpha for greater than 8 hr. Scatchard analyses of the EGF binding data indicate that a 20-hr exposure period results in a decrease in the apparent number of cell-surface EGF receptors and a reduction in the affinity of EGF for its receptor. The rate of internalization of EGF by MDBK cells does not appear to be affected by IFN treatment. PMID:3095830

  2. Insulin-like growth factor- I and factors affecting it in thalassemia major

    PubMed Central

    Soliman, Ashraf T.; Sanctis, Vincenzo De; Elalaily, Rania; Yassin, Mohamed

    2015-01-01

    Despite improvement of blood transfusion regimens and iron chelation therapy growth and maturational delay, cardiomyopathy, endocrinopathies and osteoporosis still occur in good number of thalassemic patients. Decreased IGF-1 secretion occurs in the majority of the thalassemic patients particularly those with growth and pubertal delay. Many factors contribute to this decreased synthesis of IGF-I including disturbed growth hormone (GH) - insulin-like growth factor - I (IGF-I) axis. The possible factors contributing to low IGF-I synthesis in thalassemia and the possible interaction between low IGF-I secretion and the occurrence of these complications is discussed in this mini-review. Improvement of IGF-I secretion in thalassemic patients should be intended to improve linear growth and bone mineral accretion in thalassemic patients. This can be attained through adequate correction of anemia and proper chelation, nutritional supplementation (increasing caloric intake), correction of vitamin D and zinc deficiencies, induction of puberty and correction of hypogonadism at the proper time and treating GH deficiency. This review paper provides a summary of the current state of knowledge regarding IGF-I and factors affecting it in patients with thalassaemia major (TM). Search on PubMed and reference lists of articles with the term ‘IGF-I, GH, growth, thalassemia, thyroxine, anemia, vitamin D, and zinc’ was carried out. A hundred and forty-eight articles were found and used in the write up and the data analyzed was included in this report. PMID:25729686

  3. The G Protein-Coupled Estrogen Receptor-1, GPER-1, Promotes Fibrillogenesis via a Shc-Dependent Pathway Resulting in Anchorage-Independent Growth

    PubMed Central

    Magruder, Hilary T.; Quinn, Jeffrey A.; Schwartzbauer, Jean E.; Reichner, Jonathan; Huang, Allan

    2016-01-01

    The G protein-coupled estrogen receptor-1, GPER-1, coordinates fibronectin (FN) matrix assembly and release of heparan-bound epidermal growth factor (HB-EGF). This mechanism of action results in the recruitment of FN-engaged integrin α5β1 to fibrillar adhesions and the formation of integrin α5β1-Shc adaptor protein complexes. Here, we show that GPER-1 stimulation of murine 4 T1 or human SKBR3 breast cancer cells with 17β-estradiol (E2β) promotes the formation of focal adhesions and actin stress fibers and results in increased cellular adhesion and haptotaxis on FN, but not collagen. These actions are also induced by the xenoestrogen, bisphenol A, and the estrogen receptor (ER) antagonist, ICI 182, 780, but not the inactive stereoisomer, 17α-estradiol (E2α). In addition, we show that GPER-1 stimulation of breast cancer cells allows for FN-dependent, anchorage-independent growth and FN fibril formation in “hanging drop” assays, indicating that these GPER-1-mediated actions occur independently of adhesion to solid substrata. Stable expression of Shc mutant Y317F lacking its primary tyrosyl phosphorylation site disrupts E2β-induced focal adhesion and actin stress fiber formation and abolishes E2β-enhanced haptotaxis on FN and anchorage-dependent growth. Collectively, these data demonstrate that E2β action via GPER-1 enhances cellular adhesivity and FN matrix assembly and allows for anchorage-independent growth, cellular events that may allow for cellular survival, and tumor progression. PMID:25096985

  4. Effects of medium flow on axon growth with or without nerve growth factor.

    PubMed

    Kumamoto, Junichi; Kitahata, Hiroyuki; Goto, Makiko; Nagayama, Masaharu; Denda, Mitsuhiro

    2015-09-11

    Axon growth is a crucial process in regeneration of damaged nerves. On the other hand, elongation of nerve fibers in the epidermis has been observed in skin of atopic dermatitis patients. Thus, regulation of nerve fiber extension might be an effective strategy to accelerate nerve regeneration and/or to reduce itching in pruritus dermatosis. We previously demonstrated that neurons and epidermal keratinocytes similarly contain multiple receptors that are activated by various environmental factors, and in particular, keratinocytes are influenced by shear stress. Thus, in the present study, we evaluated the effects of micro-flow of the medium on axon growth in the presence or absence of nerve growth factor (NGF), using cultured dorsal-root-ganglion (DRG) cells. The apparatus, AXIS™, consists of two chambers connected by a set of microgrooves, through which signaling molecules and axons, but not living cells, can pass. When DRG cells were present in chamber 1, NGF was present in chamber 2, and micro-flow was directed from chamber 1 to chamber 2, axon growth was significantly increased compared with other conditions. Acceleration of axon growth in the direction of the micro-flow was also observed in the absence of NGF. These results suggest that local micro-flow might significantly influence axon growth. PMID:26212442

  5. 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.

  6. Uptake of inorganic phosphate is a limiting factor for Saccharomyces cerevisiae during growth at low temperatures.

    PubMed

    Vicent, Isabel; Navarro, Alfonso; Mulet, Jose M; Sharma, Sukesh; Serrano, Ramón

    2015-05-01

    The fermenting ability of Saccharomyces at low temperatures is crucial for the development of alcoholic beverages, but the key factors for the cold tolerance of yeast are not well known. In this report, we present the results of a screening for genes able to confer cold tolerance by overexpression in a laboratory yeast strain auxotrophic for tryptophan. We identified genes of tryptophan permeases (TAT1 and TAT2), suggesting that the first limiting factor in the growth of tryptophan auxotrophic yeast at low temperatures is tryptophan uptake. This fact is of little relevance to industrial strains which are prototrophic for tryptophan. Then, we screened for genes able to confer growth at low temperatures in tryptophan-rich media and found several genes related to phosphate uptake (PHO84, PHO87, PHO90 and GTR1). This suggests that without tryptophan limitation, uptake of inorganic phosphate becomes the limiting factor. We have found that overexpression of the previously uncharacterized ORF YCR015c/CTO1 increases the uptake of inorganic phosphate. Also, genes involved in ergosterol biosynthesis (NSG2) cause improvement of growth at 10°C, dependent on tryptophan uptake, while the gluconeogenesis gene PCK1 and the proline biosynthesis gene PRO2 cause an improvement in growth at 10°C, independent of tryptophan and phosphate uptake. PMID:25725023

  7. Heat Shock-Independent Induction of Multidrug Resistance by Heat Shock Factor 1†

    PubMed Central

    Tchénio, Thierry; Havard, Marilyne; Martinez, Luis A.; Dautry, François

    2006-01-01

    The screening of two different retroviral cDNA expression libraries to select genes that confer constitutive doxorubicin resistance has in both cases resulted in the isolation of the heat shock factor 1 (HSF1) transcription factor. We show that HSF1 induces a multidrug resistance phenotype that occurs in the absence of heat shock or cellular stress and is mediated at least in part through the constitutive activation of the multidrug resistance gene 1 (MDR-1). This drug resistance phenotype does not correlate with an increased expression of heat shock-responsive genes (heat shock protein genes, or HSPs). In addition, HSF1 mutants lacking HSP gene activation are also capable of conferring multidrug resistance, and only hypophosphorylated HSF1 complexes accumulate in transduced cells. Our results indicate that HSF1 can activate MDR-1 expression in a stress-independent manner that differs from the canonical heat shock-activated mechanism involved in HSP induction. We further provide evidence that the induction of MDR-1 expression occurs at a posttranscriptional level, revealing a novel undocumented role for hypophosphorylated HSF1 in posttranscriptional gene regulation. PMID:16382149

  8. Adipocytokines, gut hormones and growth factors in anorexia nervosa.

    PubMed

    Kowalska, Irina; Karczewska-Kupczewska, Monika; Strączkowski, Marek

    2011-09-18

    Anorexia nervosa is a complex eating disorder of unknown etiology which affects adolescent girls and young women and leads to chronic malnutrition. Clinical manifestations of prolonged semistarvation include a variety of physical features and psychiatric disorders. The study of different biological factors involved in the pathophysiology of anorexia nervosa is an area of active interest. In this review we have described the role of adipocytokines, neurotrophins, peptides of the gastrointestinal system and growth factors in appetite regulation, energy balance and insulin sensitivity in anorexia nervosa patients. PMID:21699889

  9. Nerve Growth Factor: A Focus on Neuroscience and Therapy

    PubMed Central

    Aloe, Luigi; Rocco, Maria Luisa; Omar Balzamino, Bijorn; Micera, Alessandra

    2015-01-01

    Nerve growth factor (NGF) is the firstly discovered and best characterized neurotrophic factor, known to play a critical protective role in the development and survival of sympathetic, sensory and forebrain cholinergic neurons. NGF promotes neuritis outgrowth both in vivo and in vitro and nerve cell recovery after ischemic, surgical or chemical injuries. Recently, the therapeutic property of NGF has been demonstrated on human cutaneous and corneal ulcers, pressure ulcer, glaucoma, maculopathy and retinitis pigmentosa. NGF eye drops administration is well tolerated, with no detectable clinical evidence of systemic or local adverse effects. The aim of this review is to summarize these biological properties and the potential clinical development of NGF. PMID:26411962

  10. EGF: new tricks for an old growth factor.

    PubMed

    Carpenter, G

    1993-04-01

    During the past year, the biology of epidermal growth factor (EGF) has been investigated in lower organisms (Caenorhabditis elegans, Drosophila and bacteria). These experiments have produced some surprising results: the identification of defects produced by mutation of EGF-like genes; the role of EGF receptors in bacterial invasion; and the role of EGF-like precursors as receptors for a bacteria toxin. PMID:8507498

  11. Harnessing endogenous growth factor activity modulates stem cell behavior

    PubMed Central

    Hudalla, Gregory A.; Kouris, Nicholas A.; Koepsel, Justin T.; Ogle, Brenda M.; Murphy, William L.

    2014-01-01

    The influence of specific serum-borne biomolecules (e.g. heparin) on growth factor-dependent cell behavior is often difficult to elucidate in traditional cell culture due to the random, non-specific nature of biomolecule adsorption from serum. We hypothesized that chemically well-defined cell culture substrates could be used to study the influence of sequestered heparin on human mesenchymal stem cell (hMSC) behavior. Specifically, we used bio-inert self-assembled monolayers (SAMs) chemically modified with a bioinspired heparin-binding peptide (termed “HEPpep”) and an integrin-binding peptide (RGDSP) as stem cell culture substrates. Our results demonstrate that purified heparin binds to HEPpep SAMs in a dose-dependent manner, and serum-borne heparin binds specifically and in a dose-dependent manner to HEPpep SAMs. These heparin-sequestering SAMs enhance hMSC proliferation by amplifying endogenous fibroblast growth factor (FGF) signaling, and enhance hMSC osteogenic differentiation by amplifying endogenous bone morphogenetic protein (BMP) signaling. The effects of heparin-sequestering are similar to the effects of supraphysiologic concentrations of recombinant FGF-2. hMSC phenotype is maintained over multiple population doublings on heparin-sequestering substrates in growth medium, while hMSC osteogenic differentiation is enhanced in a bone morphogenetic protein-dependent manner on the same substrates during culture in osteogenic induction medium. Together, these observations demonstrate that the influence of the substrate on stem cell phenotype is sensitive to the culture medium formulation. Our results also demonstrate that enhanced hMSC proliferation can be spatially localized by patterning the location of HEPpep on the substrate. Importantly, the use of chemically well-defined SAMs in this study eliminated the confounding factor of random, non-specific biomolecule adsorption, and identified serum-borne heparin as a key mediator of hMSC response to endogenous

  12. Cytokines and growth factors cross-link heparan sulfate

    PubMed Central

    Migliorini, Elisa; Thakar, Dhruv; Kühnle, Jens; Sadir, Rabia; Dyer, Douglas P.; Li, Yong; Sun, Changye; Volkman, Brian F.; Handel, Tracy M.; Coche-Guerente, Liliane; Fernig, David G.; Lortat-Jacob, Hugues; Richter, Ralf P.

    2015-01-01

    The glycosaminoglycan heparan sulfate (HS), present at the surface of most cells and ubiquitous in extracellular matrix, binds many soluble extracellular signalling molecules such as chemokines and growth factors, and regulates their transport and effector functions. It is, however, unknown whether upon binding HS these proteins can affect the long-range structure of HS. To test this idea, we interrogated a supramolecular model system, in which HS chains grafted to streptavidin-functionalized oligoethylene glycol monolayers or supported lipid bilayers mimic the HS-rich pericellular or extracellular matrix, with the biophysical techniques quartz crystal microbalance (QCM-D) and fluorescence recovery after photobleaching (FRAP). We were able to control and characterize the supramolecular presentation of HS chains—their local density, orientation, conformation and lateral mobility—and their interaction with proteins. The chemokine CXCL12α (or SDF-1α) rigidified the HS film, and this effect was due to protein-mediated cross-linking of HS chains. Complementary measurements with CXCL12α mutants and the CXCL12γ isoform provided insight into the molecular mechanism underlying cross-linking. Fibroblast growth factor 2 (FGF-2), which has three HS binding sites, was also found to cross-link HS, but FGF-9, which has just one binding site, did not. Based on these data, we propose that the ability to cross-link HS is a generic feature of many cytokines and growth factors, which depends on the architecture of their HS binding sites. The ability to change matrix organization and physico-chemical properties (e.g. permeability and rigidification) implies that the functions of cytokines and growth factors may not simply be confined to the activation of cognate cellular receptors. PMID:26269427

  13. Growth hormone releasing factor-like immunoreactivity in human milk.

    PubMed

    Werner, H; Amarant, T; Fridkin, M; Koch, Y

    1986-03-28

    The presence of immunoreactive growth hormone-releasing factor (GRF) in human milk has been demonstrated. By using sequential high performance liquid chromatography, it has been shown that most of the immunoreactivity co-elutes with the synthetic, hypothalamic-like, GRF (1-40). The concentrations of GRF detected (between 152 and 432 pg GRF/ml milk) exceed several fold its values in plasma. PMID:3083812

  14. Fibrochondrogenesis of hESCs: growth factor combinations and cocultures.

    PubMed

    Hoben, Gwendolyn M; Willard, Vincent P; Athanasiou, Kyriacos A

    2009-03-01

    The successful differentiation of human embryonic stem cells (hESCs) to fibrochondrocyte-like cells and characterization of these differentiated cells is a critical step toward tissue engineering of musculoskeletal fibrocartilages (e.g., knee meniscus, temporomandibular joint disc, and intervertebral disc). In this study, growth factors and primary cell cocultures were applied to hESC embryoid bodies (EBs) for 3 weeks and evaluated for their effect on the synthesis of critical fibrocartilage matrix components: glycosaminoglycans (GAG) and collagens (types I, II, and VI). Changes in surface markers (CD105, CD44, SSEA, PDGFR alpha) after the differentiation treatments were also analyzed. The study was conducted in three phases: (1) examination of growth factors (TGF-beta 3, BMP-2, BMP-4, BMP-6, PDGF-BB, sonic hedgehog protein); (2) comparison of two cocultures (primary chondrocytes or fibrochondrocytes); and (3) the combination of the most effective growth factor and coculture regimen. TGF-beta 3 with BMP-4 yielded EBs positive for collagens I, II, and VI, with up to 6.7- and 4.8-fold increases in GAG and collagen, respectively. Analysis of cell surface markers showed a significant increase in CD44 with the TGF-beta 3 + BMP-4 treatment compared to the controls. Coculture with fibrochondrocytes resulted in up to a 9.8-fold increase in collagen II production. The combination of the growth factors BMP-4 + TGF-beta 3 with the fibrochondrocyte coculture led to an increase in cell proliferation and GAG production compared to either treatment alone. This study determined two powerful treatments for inducing fibrocartilaginous differentiation of hESCs and provides a foundation for using flow cytometry to purify these differentiated cells. PMID:18454697

  15. Skeletal effects of growth hormone and insulin-like growth factor-I therapy.

    PubMed

    Lindsey, Richard C; Mohan, Subburaman

    2016-09-01

    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

  16. Nerve growth factor-induced migration of endothelial cells.

    PubMed

    Dollé, Jean-Pierre; Rezvan, Amir; Allen, Fred D; Lazarovici, Philip; Lelkes, Peter I

    2005-12-01

    Nerve growth factor (NGF) is a well known neurotropic and neurotrophic agonist in the nervous system, which recently was shown to also induce angiogenic effects in endothelial cells (ECs). To measure NGF effects on the migration of cultured ECs, an important step in neoangiogenesis, we optimized an omnidirectional migration assay using human aortic endothelial cells (HAECs) and validated the assay with human recombinant basic fibroblast growth factor (rhbFGF) and human recombinant vascular endothelial growth factor (rhVEGF). The potencies of nerve growth factor purified from various species (viper, mouse, and recombinant human) to stimulate HAEC migration was similar to that of VEGF and basic fibroblast growth factor (bFGF) (EC50 of approximately 0.5 ng/ml). Recombinant human bFGF was significantly more efficacious than either viper NGF or rhVEGF, both of which stimulated HAEC migration by approximately 30% over basal spontaneous migration. NGF-mediated stimulation of HAEC migration was completely blocked by the NGF/TrkA receptor antagonist K252a [(8R*,9S*,11S*)-(/)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,-8H,11H-2,7b,11a-triazadibenzo(a,g)cycloocta(c,d,e)trindene-1-one] (30 nM) but not by the VEGF/Flk receptor antagonist SU-5416 [3-[(2,4-dimethylpyrrol-5-yl) methylidenyl]-indolin-2-one] (250 nM), indicating a direct effect of NGF via TrkA receptor activation on HAEC migration. Viper NGF stimulation of HAEC migration was additively increased by either rhVEGF or rhbFGF, suggesting a potentiating interaction between their tyrosine kinase receptor signaling pathways. Viper NGF represents a novel pharmacological tool to investigate possible TrkA receptor subtypes in endothelial cells. The ability of NGF to stimulate migration of HAEC cells in vitro implies that this factor may play an important role in the cardiovascular system besides its well known effects in the nervous system. PMID:16123305

  17. Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy.

    PubMed

    Taniyama, Yoshiaki; Morishita, Ryuichi; Aoki, Motokuni; Hiraoka, Kazuya; Yamasaki, Keita; Hashiya, Naotaka; Matsumoto, Kunio; Nakamura, Toshikazu; Kaneda, Yasufumi; Ogihara, Toshio

    2002-07-01

    Impairment of cardiac function in cardiomyopathy has been postulated to be related to decreased blood blow and increased collagen synthesis. Therefore, a therapeutic approach to alter the blood flow or fibrosis directly by means of growth factors may open a new therapeutic concept in dilated cardiomyopathy. From this viewpoint, hepatocyte growth factor (HGF) is a unique growth factor with antifibrosis and angiogenesis effects. Using the hereditary cardiomyopathic Syrian hamster as a model of genetically determined cardiomyopathy and heart failure, the effects of overexpression of HGF on fibrosis and microvascular dysfunction were examined. HGF gene or control vector was injected by the Hemagglutinating Virus of Japan-liposome method into the anterior heart of cardiomyopathic hamsters (Bio 14.6) under echocardiography once a week, from 12 to 20 weeks of age (total, 8 times). Blood flow, as assessed by a laser Doppler imager score, and the capillary density in hearts, as assessed by alkaline phosphatase staining, were significantly increased in hamsters transfected with HGF gene compared with control-vector-transfected hamsters (P<0.01). In contrast, the fibrotic area was significantly decreased in hamsters transfected with HGF gene compared with control (P<0.01). Overall, in vivo experiments demonstrated that transfection of HGF gene into the myocardium of cardiomyopathic hamsters stimulated blood flow through the induction of angiogenesis and reduction of fibrosis. These results suggest that HGF gene transfer may be useful to protect against myocardial injury in cardiomyopathy through its cardioprotective effects such as antifibrosis and angiogenesis actions. PMID:12105137

  18. Epidermal growth factor receptor family in lung cancer and premalignancy.

    PubMed

    Franklin, Wilbur A; Veve, Robert; Hirsch, Fred R; Helfrich, Barbara A; Bunn, Paul A

    2002-02-01

    Lung cancer, like many other epithelial malignancies, is thought to be the outcome of genetic and epigenetic changes that result in a constellation of phenotypic abnormalities in bronchial epithelium. These include morphologic epithelial dysplasia, angiogenesis, increased proliferative rate, and changes in expression of cell surface proteins, particularly overexpression of epidermal growth factor receptor (EGFR) family proteins. The EFGR family is a group of four structurally similar tyrosine kinases (EGFR, HER2/neu, ErbB-3, and ErbB-4) that dimerize on binding with a number of ligands, including EGF and transforming growth factor alpha. Epidermal growth factor receptor overexpression is pronounced in virtually all squamous carcinomas and is also found in > or = 65% of large cell and adenocarcinomas. It is not expressed in situ by small cell lung carcinoma. Overexpression of EGFR is one of the earliest and most consistent abnormalities in bronchial epithelium of high-risk smokers. It is present at the stage of basal cell hyperplasia and persists through squamous metaplasia, dysplasia, and carcinoma in situ. Recent studies of the effect of inhibitors of receptor tyrosine kinases suggest that patterns of coexpression of multiple members of the EGFR family could be important in determining response. Intermediate endpoints of such trials could include monitoring of phosphorylation levels in signal transduction molecules downstream of the receptor dimers. These trials represent a new targeted approach to lung cancer treatment and chemoprevention that will require greater attention to molecular endpoints than required in past trials. PMID:11894009

  19. Growth-regulated synthesis and secretion of biologically active nerve growth factor by human keratinocytes.

    PubMed

    Di Marco, E; Marchisio, P C; Bondanza, S; Franzi, A T; Cancedda, R; De Luca, M

    1991-11-15

    Nerve growth factor (NGF) transcripts were identified in normal human keratinocytes in primary and secondary culture. The expression of the NGF mRNA was strongly down-regulated by corticosteroids and was maximal when keratinocytes were in the exponential phase of growth. Immunofluorescence studies on growing keratinocytes colonies and on elutriated keratinocytes obtained from growing colonies and mature stratified epithelium showed specific staining of the Golgi apparatus only in basal keratinocytes in the exponential phase of growth. The keratinocyte-derived NGF was secreted in a biologically active form as assessed by neurite induction in sensory neurons obtained from chick embryo dorsal root ganglia. Based on these data we suggest that the basal keratinocyte is the cell synthesizing and secreting NGF in the human adult epidermis. The paracrine secretion of NGF by keratinocytes might have a major role in regulating innervation, lymphocyte function, and melanocyte growth and differentiation in epidermal morphogenesis as well as during wound healing. PMID:1718982

  20. Measuring Growth Hormone and Insulin-like Growth Factor-I in Infants: What is Normal?

    PubMed Central

    Hawkes, Colin Patrick; Grimberg, Adda

    2014-01-01

    The role of growth hormone (GH) and insulin-like growth factor-I (IGF-I) change through early childhood. Whereas poor growth is a later presenting feature, infants with isolated GH deficiency have a normal birth weight and length, and often present with hypoglycemia. IGF-I plays an important role antenatally and post-natally in somatic and brain growth. In order to evaluate the GH/IGF-I axis in infancy, an understanding of the normal physiology is required. Measurements of GH and IGF-I in this population should be interpreted in the context of the assays used, as well as their limitations. In this review, we summarize our current understanding of normal GH and IGF-I secretion in children under 18 months of age, and describe variations in the reported assay-specific measurements. PMID:24575549

  1. Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer

    PubMed Central

    O'Byrne, K J; Koukourakis, M I; Giatromanolaki, A; Cox, G; Turley, H; Steward, W P; Gatter, K; Harris, A L

    2000-01-01

    High microvessel density, an indirect measure of angiogenesis, has been shown to correlate with increased tumour size, lymph node involvement and poor prognosis in non-small-cell lung cancer (NSCLC). Tumour cell vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) expression correlate with angiogenesis and a poor outcome in this disease. In a retrospective study VEGF and PD-ECGF expression and microvessel density were evaluated immunohistochemically in surgically resected specimens (T1–3, N0–2) from 223 patients with operable NSCLC using the VG1, P-GF.44C and JC70 monoclonal antibodies respectively. High VEGF immunoreactivity was seen in 104 (46.6%) and PD-ECGF in 72 (32.3%) cases and both were associated with high vascular grade tumours (P = 0.009 and P = 0.05 respectively). Linear regression analysis revealed a weak positive correlation between VEGF and PD-ECGF expression in cancer cells (r = 0.21;P = 0.002). Co-expression of VEGF and PD-ECGF was not associated with a higher microvessel density than VEGF or PD-ECGF only expressing tumours. Furthermore a proportion of high vascular grade tumours expressed neither growth factor. Univariate analysis revealed tumour size, nodal status, microvessel density and VEGF and PD-ECGF expression as significant prognostic factors. Tumour size (P< 0.02) and microvessel density (P< 0.04) remained significant on multivariate analysis. In conclusion, VEGF and PD-ECGF are important angiogenic growth factors and have prognostic significance in NSCLC. Furthermore the study underlines the prognostic significance of microvessel density in operable NSCLC. © 2000 Cancer Research Campaign PMID:10780522

  2. Haptoglobin-hemoglobin receptor independent killing of African trypanosomes by human serum and trypanosome lytic factors

    PubMed Central

    Bullard, Whitney; Kieft, Rudo; Capewell, Paul; Veitch, Nicola J.; Macleod, Annette; Hajduk, Stephen L.

    2012-01-01

    The haptoglobin-hemoglobin receptor (HpHbR) of African trypanosomes plays a critical role in human innate immunity against these parasites. Localized to the flagellar pocket of the veterinary pathogen Trypanosoma brucei brucei this receptor binds Trypanosome Lytic Factor-1 (TLF-1), a subclass of human high-density lipoprotein (HDL) facilitating endocytosis, lysosomal trafficking and subsequent killing. Recently, we found that group 1 Trypanosoma brucei gambiense does not express a functional HpHbR. We now show that loss of the TbbHpHbR reduces the susceptibility of T. b. brucei to human serum and TLF-1 by 100- and 10,000-fold, respectively. The relatively high concentrations of human serum and TLF-1 needed to kill trypanosomes lacking the HpHbR indicates that high affinity TbbHpHbR binding enhances the cytotoxicity; however, in the absence of TbbHpHbR, other receptors or fluid phase endocytosis are sufficient to provide some level of susceptibility. Human serum contains a second innate immune factor, TLF-2, that has been suggested to kill trypanosomes independently of the TbbHpHbR. We found that T. b. brucei killing by TLF-2 was reduced in TbbHpHbR-deficient cells but to a lesser extent than TLF-1. This suggests that both TLF-1 and TLF-2 can be taken up via the TbbHpHbR but that alternative pathways exist for the uptake of these toxins. Together the findings reported here extend our previously published studies and suggest that group 1 T. b. gambiense has evolved multiple mechanisms to avoid killing by trypanolytic human serum factors. PMID:22286709

  3. Haptoglobin-hemoglobin receptor independent killing of African trypanosomes by human serum and trypanosome lytic factors.

    PubMed

    Bullard, Whitney; Kieft, Rudo; Capewell, Paul; Veitch, Nicola J; Macleod, Annette; Hajduk, Stephen L

    2012-01-01

    The haptoglobin-hemoglobin receptor (HpHbR) of African trypanosomes plays a critical role in human innate immunity against these parasites. Localized to the flagellar pocket of the veterinary pathogen Trypanosoma brucei brucei this receptor binds Trypanosome Lytic Factor-1 (TLF-1), a subclass of human high-density lipoprotein (HDL) facilitating endocytosis, lysosomal trafficking and subsequent killing. Recently, we found that group 1 Trypanosoma brucei gambiense does not express a functional HpHbR. We now show that loss of the TbbHpHbR reduces the susceptibility of T. b. brucei to human serum and TLF-1 by 100- and 10,000-fold, respectively. The relatively high concentrations of human serum and TLF-1 needed to kill trypanosomes lacking the HpHbR indicates that high affinity TbbHpHbR binding enhances the cytotoxicity; however, in the absence of TbbHpHbR, other receptors or fluid phase endocytosis are sufficient to provide some level of susceptibility. Human serum contains a second innate immune factor, TLF-2, that has been suggested to kill trypanosomes independently of the TbbHpHbR. We found that T. b. brucei killing by TLF-2 was reduced in TbbHpHbR-deficient cells but to a lesser extent than TLF-1. This suggests that both TLF-1 and TLF-2 can be taken up via the TbbHpHbR but that alternative pathways exist for the uptake of these toxins. Together the findings reported here extend our previously published studies and suggest that group 1 T. b. gambiense has evolved multiple mechanisms to avoid killing by trypanolytic human serum factors. PMID:22286709

  4. Interhospital transfer: an independent risk factor for mortality in the surgical intensive care unit.

    PubMed

    Arthur, Katherine R; Kelz, Rachel R; Mills, Angela M; Reinke, Caroline E; Robertson, Mathew P; Sims, Carrie A; Pascual, Jose L; Reilly, Patrick M; Holena, Daniel N

    2013-09-01

    Interhospital transfer (IHT) is associated with mortality in medical and mixed intensive care units (ICUs), but few studies have examined this relationship in a surgical ICU (SICU) setting. We hypothesized that IHT is associated with increased mortality in SICU patients relative to ICU patients admitted within the hospital. We reviewed SICU and transfer center databases from a tertiary academic center over a 2-year period. Inclusion criteria included age 18 years or older and SICU admission 24 hours or greater. Demographic data, admission service, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were captured. The primary end point was ICU mortality. Univariate logistic regression was used to test the association between variables and mortality. Factors found to be associated with mortality at P < 0.1 were entered into a multivariable model. Of 4542 admissions, 416 arrived by IHT. Compared with the non-IHT group, the IHT group was older (age 58.3 years [interquartile range, 47.8 to 70.6] vs. 57.8 years [interquartile range, 44.1 to 68.8] years, P = 0.036), sicker (APACHE II score 16.5 [interquartile range, 12 to 23] vs. 14 [interquartile range, 10 to 20], P < 0.001), and more likely to be white (82% [n = 341] vs. 69% [n = 2865], P < 0.001). Mortality rates in IHT patients were highest on the emergency surgery (18%), transplant surgery (16%), and gastrointestinal surgery (8%) services. After adjusting for age and APACHE II score, IHT remained a risk factor for ICU mortality (odds ratio, 1.60; 95% confidence interval, 1.04 to 2.45; P = 0.032) in SICU patients. Interhospital transfer is an independent risk factor for mortality in the SICU population; this risk is unevenly distributed through service lines. Further efforts to determine the cause of this association are warranted. PMID:24069990

  5. Salicylates Inhibit Flavivirus Replication Independently of Blocking Nuclear Factor Kappa B Activation

    PubMed Central

    Liao, Ching-Len; Lin, Yi-Ling; Wu, Bi-Ching; Tsao, Chang-Huei; Wang, Mei-Chuan; Liu, Chiu-I; Huang, Yue-Ling; Chen, Jui-Hui; Wang, Jia-Pey; Chen, Li-Kuang

    2001-01-01

    Flaviviruses comprise a positive-sense RNA genome that replicates exclusively in the cytoplasm of infected cells. Whether flaviviruses require an activated nuclear factor(s) to complete their life cycle and trigger apoptosis in infected cells remains elusive. Flavivirus infections quickly activate nuclear factor kappa B (NF-κB), and salicylates have been shown to inhibit NF-κB activation. In this study, we investigated whether salicylates suppress flavivirus replication and virus-induced apoptosis in cultured cells. In a dose-dependent inhibition, we found salicylates within a range of 1 to 5 mM not only restricted flavivirus replication but also abrogated flavivirus-triggered apoptosis. However, flavivirus replication was not affected by a specific NF-κB peptide inhibitor, SN50, and a proteosome inhibitor, lactacystin. Flaviviruses also replicated and triggered apoptosis in cells stably expressing IκBα-ΔN, a dominant-negative mutant that antagonizes NF-κB activation, as readily as in wild-type BHK-21 cells, suggesting that NF-κB activation is not essential for either flavivirus replication or flavivirus-induced apoptosis. Salicylates still diminished flavivirus replication and blocked apoptosis in the same IκBα-ΔN cells. This inhibition of flaviviruses by salicylates could be partially reversed by a specific p38 mitogen-activated protein (MAP) kinase inhibitor, SB203580. Together, these results show that the mechanism by which salicylates suppress flavivirus infection may involve p38 MAP kinase activity but is independent of blocking the NF-κB pathway. PMID:11483726

  6. Heparin Binds Endothelial Cell Growth Factor, the Principal Endothelial Cell Mitogen in Bovine Brain

    NASA Astrophysics Data System (ADS)

    Maciag, Thomas; Mehlman, Tevie; Friesel, Robert; Schreiber, Alain B.

    1984-08-01

    Endothelial cell growth factor (ECGF), an anionic polypeptide mitogen, binds to immobilized heparin. The interaction between the acidic polypeptide and the anionic carbohydrate suggests a mechanism that is independent of ion exchange. Monoclonal antibodies to purified bovine ECGF inhibited the biological activity of ECGF in crude preparations of bovine brain. These data indicate that ECGF is the principal mitogen for endothelial cells from bovine brain, that heparin affinity chromatography may be used to purify and concentrate ECGF, and that the affinity of ECGF for heparin may have structural and perhaps biological significance.

  7. TERT Promoter Mutation Status as an Independent Prognostic Factor in Cutaneous Melanoma

    PubMed Central

    Murali, Rajmohan; Puig-Butille, Joan Anton; Schilling, Bastian; Livingstone, Elisabeth; Potrony, Miriam; Carrera, Cristina; Schimming, Tobias; Möller, Inga; Schwamborn, Marion; Sucker, Antje; Hillen, Uwe; Badenas, Celia; Malvehy, Josep; Zimmer, Lisa; Scherag, André; Puig, Susana

    2014-01-01

    Background Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics. Methods 410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed. Results TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006). Conclusions UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis. PMID:25217772

  8. Fruit Growth in Arabidopsis Occurs via DELLA-Dependent and DELLA-Independent Gibberellin Responses[W][OA

    PubMed Central

    Fuentes, Sara; Ljung, Karin; Sorefan, Karim; Alvey, Elizabeth; Harberd, Nicholas P.; Østergaard, Lars

    2012-01-01

    Fruit growth and development depend on highly coordinated hormonal activities. The phytohormone gibberellin (GA) promotes growth by inducing degradation of the growth-repressing DELLA proteins; however, the extent to which DELLA proteins contribute to GA-mediated gynoecium and fruit development remains to be clarified. Here, we provide an in-depth characterization of the role of DELLA proteins in Arabidopsis thaliana fruit growth. We show that DELLA proteins are key regulators of reproductive organ size and important for ensuring optimal fertilization. We demonstrate that the seedless fruit growth (parthenocarpy) observed in della mutants can be directly attributed to the constitutive activation of GA signaling. It has been known for >75 years that another hormone, auxin, can induce formation of seedless fruits. Using mutants with complete lack of DELLA activity, we show here that auxin-induced parthenocarpy occurs entirely through GA signaling in Arabidopsis. Finally, we uncover the existence of a DELLA-independent GA response that promotes fruit growth. This response requires GIBBERELLIN-INSENSITIVE DWARF1–mediated GA perception and a functional 26S proteasome and involves the basic helix-loop-helix protein SPATULA as a key component. Taken together, our results describe additional complexities in GA signaling during fruit development, which may be particularly important to optimize the conditions for successful reproduction. PMID:23064323

  9. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo

    NASA Astrophysics Data System (ADS)

    Plate, Karl H.; Breier, Georg; Weich, Herbert A.; Risau, Werner

    1992-10-01

    CLINICAL and experimental studies suggest that angiogenesis is a prerequisite for solid tumour growth1,2. Several growth factors with mitogenic or chemotactic activity for endothelial cells in vitro have been described, but it is not known whether these mediate tumour vascularization in vivo3,4. Glioblastoma, the most common and most malignant brain tumour in humans, is distinguished from astrocytoma by the presence of necroses and vascular prolifer-ations5'6. Here we show that expression of an endothelial cell-specific mitogen, vascular endothelial growth factor (VEGF), is induced in astrocytoma cells but is dramatically upregulated in two apparently different subsets of glioblastoma cells. The high-affinity tyrosine kinase receptor for VEGF, flt, although not expressed in normal brain endothelium, is upregulated in tumour endothelial cells in vivo. These observations strongly support the concept that tumour angiogenesis is regulated by paracrine mechanisms and identify VEGF as a potential tumour angiogenesis factor in vivo.

  10. Canine splenic haemangiosarcoma: influence of metastases, chemotherapy and growth pattern on post-splenectomy survival and expression of angiogenic factors.

    PubMed

    Göritz, M; Müller, K; Krastel, D; Staudacher, G; Schmidt, P; Kühn, M; Nickel, R; Schoon, H-A

    2013-07-01

    Splenic haemangiosarcomas (HSAs) from 122 dogs were characterized and classified according to their patterns of growth, survival time post splenectomy, metastases and chemotherapy. The most common pattern of growth was a mixture of cavernous, capillary and solid tumour tissue. Survival time post splenectomy was independent of the growth pattern; however, it was influenced by chemotherapy and metastases. Immunohistochemical assessment of the expression of angiogenic factors (fetal liver kinase-1, angiopoietin-2, angiopoietin receptor-2 and vascular endothelial growth factor A) and conventional endothelial markers (CD31, factor VIII-related antigen) revealed variable expression, particularly in undifferentiated HSAs. Therefore, a combination of endothelial markers should be used to confirm the endothelial origin of splenic tumours. PMID:23276383

  11. ATP differentially upregulates fibroblast growth factor 2 and transforming growth factor α in neonatal and adult mice: effect on neuroproliferation.

    PubMed

    Jia, C; Cussen, A R; Hegg, C C

    2011-03-17

    Multiple neurotrophic factors play a role in proliferation, differentiation and survival in the olfactory epithelium (OE); however, the signaling cascade has not been fully elucidated. We tested the hypotheses that ATP induces the synthesis and secretion of two neurotrophic factors, fibroblast growth factor 2 (FGF2) and transforming growth factor alpha (TGFα), and that these neurotrophic factors have a role in inducing proliferation. Protein levels of FGF2 and TGFα were increased 20 h post-intranasal instillation of ATP compared to vehicle control in adult Swiss Webster mice. Pre-intranasal treatment with purinergic receptor antagonist pyridoxal-phosphate-6-azophenyl-20,40-disulfonic acid (PPADS) significantly blocked this ATP-induced increase, indicating that upregulation of FGF2 and TGFα expression is mediated by purinergic receptor activation. However, in neonatal mouse, intranasal instillation of ATP significantly increased the protein levels of FGF2, but not TGFα. Likewise, ATP evoked the secretion of FGF2, but not TGFα, from neonatal mouse olfactory epithelial slices and PPADS significantly blocked ATP-evoked FGF2 release. To determine the role of FGF2 and TGFα in inducing proliferation, 5-bromo-2-deoxyuridine (BrdU) incorporation was examined in adult olfactory epithelium. Intranasal treatment with FGF receptor inhibitor PD173074 or epidermal growth factor receptor inhibitor AG1478 following ATP instillation significantly blocked ATP-induced BrdU incorporation. Collectively, these data demonstrate that ATP induces proliferation in adult mouse olfactory epithelium by promoting FGF2 and TGFα synthesis and activation of their receptors. These data suggest that different mechanisms regulate neurogenesis in neonatal and adult OE, and FGF2 and TGFα may have different roles throughout development. PMID:21187124

  12. Inverse regulation of human ERBB2 and epidermal growth factor receptors by tumor necrosis factor alpha.

    PubMed Central

    Kalthoff, H; Roeder, C; Gieseking, J; Humburg, I; Schmiegel, W

    1993-01-01

    Recombinant human tumor necrosis factor (TNF) alpha decreased the expression of ERBB2 mRNA by stimulating p55 TNF receptors of pancreatic tumor cells. This decrease contrasts with an increase in epidermal growth factor receptor (EGFR) mRNA. Both effects were selectively achieved by TNF-alpha or -beta, whereas interferon alpha or gamma or transforming growth factor beta showed no such effects. The inverse regulatory effects of TNF on ERBB2 and EGFR mRNA levels were evoked by different signaling pathways of p55 TNF receptors. The TNF-mediated ERBB2 mRNA decrease was followed by a reduction in protein. Four of five pancreatic tumor cell lines exhibited this down-regulation. This decrease of ERBB2 is a singular example of a modulation of this growth factor receptor by TNF. Overexpression of ERBB2 has been reported to cause resistance to TNF and other cytotoxic cytokines. In our study we show that the TNF-mediated down-regulation of ERBB2 in pancreatic tumor cells is accompanied by an increase in growth inhibition at low doses of TNF. The simultaneous alteration of the ERBB2/EGFR balance by TNF represents a striking model of cytokine receptor transregulation in the growth control of malignant pancreatic epithelial cells. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8105469

  13. Maternal parity, fetal and childhood growth, and cardiometabolic risk factors.

    PubMed

    Gaillard, Romy; Rurangirwa, Akashi A; Williams, Michelle A; Hofman, Albert; Mackenbach, Johan P; Franco, Oscar H; Steegers, Eric A P; Jaddoe, Vincent W V

    2014-08-01

    We examined the associations of maternal parity with fetal and childhood growth characteristics and childhood cardiometabolic risk factors in a population-based prospective cohort study among 9031 mothers and their children. Fetal and childhood growth were repeatedly measured. We measured childhood anthropometrics, body fat distribution, left ventricular mass, blood pressure, blood lipids, and insulin levels at the age of 6 years. Compared with nulliparous mothers, multiparous mothers had children with higher third trimester fetal head circumference, length and weight growth, and lower risks of preterm birth and small-size-for-gestational-age at birth but a higher risk of large-size-for-gestational-age at birth (P<0.05). Children from multiparous mothers had lower rates of accelerated infant growth and lower levels of childhood body mass index, total fat mass percentage, and total and low-density lipoprotein cholesterol than children of nulliparous mothers (P<0.05). They also had a lower risk of childhood overweight (odds ratio, 0.75 [95% confidence interval, 0.63–0.88]). The risk of childhood clustering of cardiometabolic risk factors was not statistically significantly different (odds ratio, 0.82; 95% confidence interval, 0.64–1.05). Among children from multiparous mothers only, we observed consistent trends toward a lower risk of childhood overweight and lower cholesterol levels with increasing parity (P<0.05). In conclusion, offspring from nulliparous mothers have lower fetal but higher infant growth rates and higher risks of childhood overweight and adverse metabolic profile. Maternal nulliparity may have persistent cardiometabolic consequences for the offspring. PMID:24866145

  14. Influence of different growth factors on a rat choriocarcinoma cell line.

    PubMed

    Verstuyf, A; Goebels, J; Sobis, H; Vandeputte, M

    1993-01-01

    The influence of epidermal growth factor, insulin-like growth factors I and II, insulin, transforming growth factor beta 1 and transferrin on the growth of a postgestational rat choriocarcinoma was examined by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. The cell line was cultured in RPMI 1640 medium supplemented with fetal calf serum, beta-mercaptoethanol, glucose, sodium pyruvate and antibiotics. The experiments were done in media supplemented with 10% (optimal) or 3% (suboptimal) fetal calf serum. Among the different growth factors tested, only epidermal growth factor and to a certain extent insulin had a growth-promoting effect by themselves. The other growth factors had either an additive effect in the presence of epidermal growth factor or no effect at all. The cytotrophoblast cells expressed both epidermal growth factor and transferrin receptors whereas the more differentiated giant cells expressed only transferrin receptors. PMID:8493450

  15. Growth and differentiation in cultured human thyroid cells: effects of epidermal growth factor and thyrotropin.

    PubMed

    Errick, J E; Ing, K W; Eggo, M C; Burrow, G N

    1986-01-01

    Human thyroid cells were grown and subcultured in vitro to examine their responses to known hormones and growth factors, and to serum. The cells were obtained from surgical specimens and were either neoplastic or nonneoplastic. The effects of culture conditions on cell growth were measured by changes in cell numbers and by stimulation of [3H]thymidine incorporation. The results showed that serum (0.5%) was essential for cell proliferation, and that a mixture of insulin (10 micrograms/ml), transferrin (5 micrograms/ml), hydrocortisone (10 micrograms/ml), somatostatin (10 ng/ml), and glycyl-histidyl-lysine (10 ng/ml) enhanced the effect of serum. Maximum growth of the cells was obtained when epidermal growth factor was present at 10(-9) M. Differentiation was measured by production of thyroglobulin, which was found to be stimulated by thyrotropin. This system provides a means to study the hormonal control of growth and differentiation in human thyroid cells. PMID:3511027

  16. Immunolocalisation of vascular endothelial growth factor (VEGF) in human neonatal growth plate cartilage

    PubMed Central

    HORNER, A.; BISHOP, N. J.; BORD, S.; BEETON, C.; KELSALL, A. W.; COLEMAN, N.; COMPSTON, J. E.

    1999-01-01

    Angiogenesis is essential for the replacement of cartilage by bone during growth and repair. In order to obtain a better understanding of the mechanisms regulating vascular invasion at sites of endochondral ossification we have investigated the expression of the endothelial cell-specific mitogen, vascular endothelial growth factor (VEGF), by chondrocytes in human neonatal growth plates. VEGF was absent from chondrocytes in the resting zone and only weakly expressed by occasional chondrocytes in the proliferating region. In the hypertrophic zone the number of chondrocytes stained and the intensity of staining for VEGF increased with chondrocyte hypertrophy, maximum expression of VEGF being observed in chondrocytes in the lower hypertrophic and mineralised regions of the cartilage. These observations provide the first demonstration of the presence of VEGF in situ in developing human bone and are consistent with in vitro observations demonstrating the upregulation of proangiogenic growth factor production with increasing chondrocyte hypertrophy. The presence of numerous small blood vessels and vascular structures in the subchondral region where VEGF expression was maximal indicates that VEGF produced by hypertrophic chondrocytes may play a key role in the regulation of vascular invasion of the growth plate. PMID:10445820

  17. Integrin α5 promotes tumor progression and is an independent unfavorable prognostic factor in esophageal squamous cell carcinoma.

    PubMed

    Xie, Jian-Jun; Guo, Jin-Cheng; Wu, Zhi-Yong; Xu, Xiu-E; Wu, Jian-Yi; Chen, Bo; Ran, Li-Qiang; Liao, Lian-Di; Li, En-Min; Xu, Li-Yan

    2016-02-01

    The integrin family plays a major role in complex biological events such as differentiation, development, wound healing, and the altered adhesive and invasive properties of tumor cells. The expression and function of integrin α5 in esophageal squamous cell carcinoma (ESCC) are not clear. Here, by using tissue microarrays and immunohistochemical method, integrin α5 expression was retrospectively evaluated in 147 samples of human ESCC. Results showed that expression of integrin α5 was heterogeneous and varied from negative to intense expression in a membrane and cytoplasmic distribution manner. High expression of integrin α5 was significantly correlated with lymph node metastasis (P = .042) and tumor size (P = .042). Kaplan-Meier analysis revealed that high expression of integrin α5 was related to poor overall survival of ESCC patients (P = .018). Multivariate analysis suggested that integrin α5 expression status was an independent prognostic factor for ESCC (P = .003). Moreover, integrin α5 expression was associated with the survival of patients with lymph node metastasis (P = .020), but did not influence the survival of patients without lymph node metastasis. Finally, we found that RNAi-mediated knockdown of integrin α5 led to decreased growth, migration, and invasion of ESCC cells. Combined, integrin α5 might play important roles in the progression of ESCC. Integrin α5 is a novel biomarker to predict the prognosis of ESCC patients. PMID:26772401

  18. Role of growth factors in the growth of normal and transformed cells

    SciTech Connect

    Lokeshwar, V.B.

    1989-01-01

    Growth factors play an important role in the growth of normal cells. However, their untimely and/or excess production leads to neoplastic transformation. The role of growth factors in the growth of normal cells was studied by investigating the mechanism of transmodulation of the cell surface EGF receptor number by protamine. Protamine increased the EGF stimulated mitogenic response in Swiss mouse 3T3 cells and A431 cells by increasing the number of functionally active EGF receptors. Protamine also increased EGF receptor number in plasma membranes and solubilized membranes. This was evidenced by an increase in both {sup 125}I-EGF-EGF-receptor complex and EGF stimulated phosphorylation of the EGF receptor. The solubilized EGF receptor was retained on a protamine-agarose gel indicating that protamine might increase EGF receptor number by directly activating cryptic EGF receptors in the plasma membranes. The role of growth factors in neoplastic transformation was studied by investigating the role of the oncogene v-sis in the growth of Simian sarcoma virus (SSV) transformed cells. The product of the oncogene v-sis is 94% homologous to the B chain of PDGF. This study found that (i) v-sis gene product is synthesized as a 32 kDa unglycosylated monomer which is glycosylated, dimerized and proteolytically processed into p36, p72, p68, p58, p44 and p27 mol. wt. species respectively. (ii) p36, p72, p68 and p58 are very likely formed in the endoplasmic reticulum and/or Golgi complex. A fraction of newly synthesized p72, p68 and p58 is degraded intracellularly at a fast rate. (iii) p44 is a secretory product which remains tightly associated with the cell surface. p44 is recaptured by the cells through interaction with cell surface PDGF receptors and degraded into p27. (iv) During long term cultures p44 is extracellularly cleaved into a 27 kDa product.

  19. Vascular Endothelial Growth Factor A Regulates the Secretion of Different Angiogenic Factors in Lung Cancer Cells.

    PubMed

    Frezzetti, Daniela; Gallo, Marianna; Roma, Cristin; D'Alessio, Amelia; Maiello, Monica R; Bevilacqua, Simona; Normanno, Nicola; De Luca, Antonella

    2016-07-01

    Vascular endothelial growth factor A (VEGFA) is one of the main mediators of angiogenesis in non-small cell lung cancer (NSCLC). Recently, it has been described an autocrine feed-forward loop in NSCLC cells in which tumor-derived VEGFA promoted the secretion of VEGFA itself, amplifying the proangiogenic signal. In order to investigate the role of VEGFA in lung cancer progression, we assessed the effects of recombinant VEGFA on proliferation, migration, and secretion of other angiogenic factors in A549, H1975, and HCC827 NSCLC cell lines. We found that VEGFA did not affect NSCLC cell proliferation and migration. On the other hand, we demonstrated that VEGFA not only produced a strong and persistent increase of VEGFA itself but also significantly induced the secretion of a variety of angiogenic factors, including follistatin (FST), hepatocyte growth factor (HGF), angiopoietin-2 (ANGPT2), granulocyte-colony stimulating factor (G-CSF), interleukin (IL)-8, leptin (LEP), platelet/endothelial cell adhesion molecule 1 (PECAM-1), and platelet-derived growth factor bb (PDGF-BB). PI3K/AKT, RAS/ERK, and STAT3 signalling pathways were found to mediate the effects of VEGFA in NSCLC cell lines. We also observed that VEGFA regulation mainly occurred at post-transcriptional level and that NSCLC cells expressed different isoforms of VEGFA. Collectively, our data suggested that VEGFA contributes to lung cancer progression by inducing a network of angiogenic factors, which might offer potential for therapeutic intervention. PMID:26542886

  20. An expandable, inducible hemangioblast state regulated by fibroblast growth factor.

    PubMed

    Vereide, David T; Vickerman, Vernella; Swanson, Scott A; Chu, Li-Fang; McIntosh, Brian E; Thomson, James A

    2014-12-01

    During development, the hematopoietic and vascular lineages are thought to descend from common mesodermal progenitors called hemangioblasts. Here we identify six transcription factors, Gata2, Lmo2, Mycn, Pitx2, Sox17, and Tal1, that "trap" murine cells in a proliferative state and endow them with a hemangioblast potential. These "expandable" hemangioblasts (eHBs) are capable, once released from the control of the ectopic factors, to give rise to functional endothelial cells, multilineage hematopoietic cells, and smooth muscle cells. The eHBs can be derived from embryonic stem cells, from fetal liver cells, or poorly from fibroblasts. The eHBs reveal a central role for fibroblast growth factor, which not only promotes their expansion, but also facilitates their ability to give rise to endothelial cells and leukocytes, but not erythrocytes. This study serves as a demonstration that ephemeral progenitor states can be harnessed in vitro, enabling the creation of tractable progenitor cell lines. PMID:25458896

  1. Expression of transforming growth factor alpha and epidermal growth factor receptor in rat lung neoplasms induced by plutonium-239

    SciTech Connect

    Stegelmeier, B.L.; Gillett, N.A.; Hahn, F.F.; Kelly, G.; Rebar, A.H.

    1994-11-01

    Ninety-two rat lung proliferative lesions and neoplasms induced by inhaled {sup 239}PuO{sub 2} were evaluated for aberrant expression of transforming growth factor alpha (TGF-{alpha}) and epidermal growth factor receptor (EGFR). Expression of TGF-{alpha} protein, measured by immunohistochemistry, was higher in 94% of the squamous cell carcinomas and 87% of the foci of alveolar epithelial squamous metaplasia than that exhibited by the normal-appearing, adjacent lung parenchyma. In contrast, only 20% of adenocarcinomas and foci of epithelial hyperplasia expressed elevated levels of TGF-{alpha}. Many neoplasms expressing TGF-{alpha} also expressed excessive levels of EGFR mRNA. Southern and DNA slot blot analyses showed that the elevated EGFR expression was not due to amplification of the EGFR gene. These data suggest that increased amounts of TGF-{alpha} were early alterations in the progression of plutonium-induced squamous cell carcinoma, and these increases may occur in parallel with overexpression of the receptor for this growth factor. Together, these alterations create a potential autocrine loop for sustaining clonal expansion of cells initiated by high-LET radiation. 44 refs., 4 figs., 1 tab.

  2. Uptake and Intracellular Transport of Acidic Fibroblast Growth Factor: Evidence for Free and Cytoskeleton-anchored Fibroblast Growth Factor Receptors

    PubMed Central

    Citores, Lucía; Wesche, Jørgen; Kolpakova, Elona; Olsnes, Sjur

    1999-01-01

    Endocytic uptake and intracellular transport of acidic FGF was studied in cells transfected with FGF receptor 4 (FGFR4). Acidification of the cytosol to block endocytic uptake from coated pits did not inhibit endocytosis of the growth factor in COS cells transfected with FGFR4, indicating that it is to a large extent taken up by an alternative endocytic pathway. Fractionation of the cells demonstrated that part of the growth factor receptor was present in a low-density, caveolin-containing fraction, but we were unable to demonstrate binding to caveolin in immunoprecipitation studies. Upon treatment of the cells with acidic FGF, the activated receptor, together with the growth factor, moved to a juxtanuclear compartment, which was identified as the recycling endosome compartment. When the cells were lysed with Triton X-100, 3-([3-chloramidopropyl]dimethylammonio)-2-hydroxy-1-propanesulfonate, or 2-octyl glucoside, almost all surface-exposed and endocytosed FGFR4 was solubilized, but only a minor fraction of the total FGFR4 in the cells was found in the soluble fraction. The data indicate that the major part of FGFR4 is anchored to detergent-insoluble structures, presumably cytoskeletal elements associated with the recycling endosome compartment. PMID:10564275

  3. 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. PMID:26943480

  4. Production of human epidermal growth factor using adenoviral based system

    PubMed Central

    Negahdari, Babak; Shahosseini, Zahra; Baniasadi, Vahid

    2016-01-01

    Epidermal growth factor (EGF), a growth factor involved in cell growth and differentiation, is a small polypeptide with molecular weight of approximately 6 kDa known to be present in a number of different mammalian species. Experimental studies in animals and humans have demonstrated that the topical application of EGF accelerates the rate of epidermal regeneration of partial-thickness wounds and second-degree burns. Due to its commercial applications, Human EGF (hEGF) has been cloned in several forms. In the present study, adenoviral based expression system was used to produce biologically active recombinant hEGF. The presence of secreted recombinant hEGF was confirmed by a dot blot and its expression level was determined by enzyme-linked immuno-sorbent assay. Moreover, biological activity of secreted hEGF was evaluated by a proliferation assay performed on A549 cells. For production of hEGF in a secretory form, a chimeric gene coding for the hEGF fused to the signal peptide was expressed using adenoviral based method. This method enables the production of hEGF at the site of interest and moreover it could be used for cell proliferation and differentiation assays in tissue engineering research experiments instead of using commercially available EGF. PMID:27051431

  5. Fibroblast growth factor (FGF) signaling in development and skeletal diseases

    PubMed Central

    Teven, Chad M.; Farina, Evan M.; Rivas, Jane; Reid, Russell R.

    2014-01-01

    Fibroblast growth factors (FGF) and their receptors serve many functions in both the developing and adult organism. Humans contain 18 FGF ligands and four FGF receptors (FGFR). FGF ligands are polypeptide growth factors that regulate several developmental processes including cellular proliferation, differentiation, and migration, morphogenesis, and patterning. FGF-FGFR signaling is also critical to the developing axial and craniofacial skeleton. In particular, the signaling cascade has been implicated in intramembranous ossification of cranial bones as well as cranial suture homeostasis. In the adult, FGFs and FGFRs are crucial for tissue repair. FGF signaling generally follows one of three transduction pathways: RAS/MAP kinase, PI3/AKT, or PLCγ. Each pathway likely regulates specific cellular behaviors. Inappropriate expression of FGF and improper activation of FGFRs are associated with various pathologic conditions, unregulated cell growth, and tumorigenesis. Additionally, aberrant signaling has been implicated in many skeletal abnormalities including achondroplasia and craniosynostosis. The biology and mechanisms of the FGF family have been the subject of significant research over the past 30 years. Recently, work has focused on the therapeutic targeting and potential of FGF ligands and their associated receptors. The majority of FGF-related therapy is aimed at age-related disorders. Increased understanding of FGF signaling and biology may reveal additional therapeutic roles, both in utero and postnatally. This review discusses the role of FGF signaling in general physiologic and pathologic embryogenesis and further explores it within the context of skeletal development. PMID:25679016

  6. Recurrent growth factor starvation promotes drug resistance in human leukaemic cells

    PubMed Central

    Saeki, K; Okuma, E; Yuo, A

    2002-01-01

    Multi-drug resistance can be induced by various environmental stresses including an exposure to chemical drugs and X-ray irradiation. In addition, hypo-nutritive conditions are known to promote multi-drug resistance in solid tumours. To understand the importance of nutritive conditions in the development of drug resistance in non-solid tumours and to know whether a transient malnutrition could induce a permanent reduction in drug sensitivity, leukaemic cells were transiently cultured under growth factor-starved conditions. Granulocyte-macrophage colony-stimulating factor-dependent human leukaemic MO7e cells were cultured in the absence of granulocyte-macrophage colon-stimulating factor for 2 weeks, during which the majority of the cells died, and the minor viable cells were expanded in the presence of granulocyte-macrophage colon-stimulating factor for following 1 week. This procedure was repeated three times, and the surviving cells were cloned by limiting dilution. These clones underwent G1 arrest in the absence of granulocyte-macrophage colon-stimulating factor, while parental cells underwent apoptosis. Interestingly, activities of the downstream targets of granulocyte-macrophage colon-stimulating factor receptor were regulated in a granulocyte-macrophage colon-stimulating factor-independent manner, indicating that the ligand-independent activation of granulocyte-macrophage colon-stimulating factor receptor had not taken place. Moreover, the 4–7-fold increases in IC50 for etoposide and the 2–6-fold increase in IC90 for doxorubicin was observed. Furthermore, Bcl-2 protein expression was significantly up-regulated in the clones while no significant changes in Bax, Bcl-xL, P-glycoprotein and Hsp70 protein expression and no consistent changes in p53 expression were detected. We propose that recurrent growth factor starvation, which may occur in vivo when stromal function is damaged after intensive chemotherapy or bone marrow occupation by malignant cells, causes

  7. S6K1 controls pancreatic β cell size independently of intrauterine growth restriction.

    PubMed

    Um, Sung Hee; Sticker-Jantscheff, Melanie; Chau, Gia Cac; Vintersten, Kristina; Mueller, Matthias; Gangloff, Yann-Gael; Adams, Ralf H; Spetz, Jean-Francois; Elghazi, Lynda; Pfluger, Paul T; Pende, Mario; Bernal-Mizrachi, Ernesto; Tauler, Albert; Tschöp, Matthias H; Thomas, George; Kozma, Sara C

    2015-07-01

    Type 2 diabetes mellitus (T2DM) is a worldwide heath problem that is characterized by insulin resistance and the eventual loss of β cell function. As recent studies have shown that loss of ribosomal protein (RP) S6 kinase 1 (S6K1) increases systemic insulin sensitivity, S6K1 inhibitors are being pursued as potential agents for improving insulin resistance. Here we found that S6K1 deficiency in mice also leads to decreased β cell growth, intrauterine growth restriction (IUGR), and impaired placental development. IUGR is a common complication of human pregnancy that limits the supply of oxygen and nutrients to the developing fetus, leading to diminished embryonic β cell growth and the onset of T2DM later in life. However, restoration of placental development and the rescue of IUGR by tetraploid embryo complementation did not restore β cell size or insulin levels in S6K1-/- embryos, suggesting that loss of S6K1 leads to an intrinsic β cell lesion. Consistent with this hypothesis, reexpression of S6K1 in β cells of S6K1-/- mice restored embryonic β cell size, insulin levels, glucose tolerance, and RPS6 phosphorylation, without rescuing IUGR. Together, these data suggest that a nutrient-mediated reduction in intrinsic β cell S6K1 signaling, rather than IUGR, during fetal development may underlie reduced β cell growth and eventual development of T2DM later in life. PMID:26075820

  8. S6K1 controls pancreatic β cell size independently of intrauterine growth restriction

    PubMed Central

    Um, Sung Hee; Sticker-Jantscheff, Melanie; Chau, Gia Cac; Vintersten, Kristina; Mueller, Matthias; Gangloff, Yann-Gael; Adams, Ralf H.; Spetz, Jean-Francois; Elghazi, Lynda; Pfluger, Paul T.; Pende, Mario; Bernal-Mizrachi, Ernesto; Tauler, Albert; Tschöp, Matthias H.; Thomas, George; Kozma, Sara C.

    2015-01-01

    Type 2 diabetes mellitus (T2DM) is a worldwide heath problem that is characterized by insulin resistance and the eventual loss of β cell function. As recent studies have shown that loss of ribosomal protein (RP) S6 kinase 1 (S6K1) increases systemic insulin sensitivity, S6K1 inhibitors are being pursued as potential agents for improving insulin resistance. Here we found that S6K1 deficiency in mice also leads to decreased β cell growth, intrauterine growth restriction (IUGR), and impaired placental development. IUGR is a common complication of human pregnancy that limits the supply of oxygen and nutrients to the developing fetus, leading to diminished embryonic β cell growth and the onset of T2DM later in life. However, restoration of placental development and the rescue of IUGR by tetraploid embryo complementation did not restore β cell size or insulin levels in S6K1–/– embryos, suggesting that loss of S6K1 leads to an intrinsic β cell lesion. Consistent with this hypothesis, reexpression of S6K1 in β cells of S6K1–/– mice restored embryonic β cell size, insulin levels, glucose tolerance, and RPS6 phosphorylation, without rescuing IUGR. Together, these data suggest that a nutrient-mediated reduction in intrinsic β cell S6K1 signaling, rather than IUGR, during fetal development may underlie reduced β cell growth and eventual development of T2DM later in life. PMID:26075820

  9. Posttraumatic Growth and Depreciation as Independent Experiences and Predictors of Well-Being

    ERIC Educational Resources Information Center

    Cann, Arnie; Calhoun, Lawrence G.; Tedeschi, Richard G.; Solomon, David T.

    2010-01-01

    Positive changes (posttraumatic growth [PTG]) and negative changes (posttraumatic depreciation [PTD]) were assessed using the PTGI-42 with persons reporting changes from a stressful event. PTG and PTD were uncorrelated, and PTG was much greater than PTD. PTG was positively related to disruption of core beliefs and recent deliberate rumination and…

  10. Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome.

    PubMed

    Foster, Christopher S; Falconer, Alison; Dodson, Andrew R; Norman, Andrew R; Dennis, Nening; Fletcher, Anne; Southgate, Christine; Dowe, Anna; Dearnaley, David; Jhavar, Sameer; Eeles, Rosalind; Feber, Andrew; Cooper, Colin S

    2004-08-01

    E2F transcription factors, including E2F3, directly modulate expression of EZH2. Recently, overexpression of the EZH2 gene has been implicated in the development of human prostate cancer. In tissue microrarray studies we now show that expression of high levels of nuclear E2F3 occurs in a high proportion (98/147, 67%) of human prostate cancers, but is a rare event in non-neoplastic prostatic epithelium suggesting a role for E2F3 overexpression in prostate carcinogenesis. Patients with prostate cancer exhibiting immunohistochemically detectable nuclear E2F3 expression have poorer overall survival (P=0.0022) and cause-specific survival (P=0.0047) than patients without detectable E2F3 expression. When patients are stratified according to the maximum percentage of E2F3-positive nuclei identified within their prostate cancers (up to 20, 21-40%, etc.), there is an increasingly significant association between E2F3 staining and risk of death both for overall survival (P=0.0014) and for cause-specific survival (P=0.0004). Multivariate analyses select E2F3 expression as an independent factor predicting overall survival (unstratified P=0.0103, stratified P=0.0086) and cause-specific survival (unstratified P=0.0288, stratified P=0.0072). When these results are considered together with published data on EZH2 and on the E2F3 control protein pRB, we conclude that the pRB-E2F3-EZH2 control axis may have a critical role in modulating aggressiveness of individual human prostate cancer. PMID:15184867

  11. Sarcopenia is an independent prognostic factor in male patients with diffuse large B-cell lymphoma.

    PubMed

    Nakamura, Nobuhiko; Hara, Takeshi; Shibata, Yuhei; Matsumoto, Takuro; Nakamura, Hiroshi; Ninomiya, Soranobu; Kito, Yusuke; Kitagawa, Junichi; Kanemura, Nobuhiro; Goto, Naoe; Shiraki, Makoto; Miyazaki, Tatsuhiko; Takeuchi, Tamotsu; Shimizu, Masahito; Tsurumi, Hisashi

    2015-12-01

    Sarcopenia reportedly predicts poor outcomes in elderly patients with diffuse large B-cell lymphoma (DLBCL). However, because previous studies only involved elderly patients, it is difficult to generalize these results to all patients with DLBCL. We retrospectively analyzed 207 patients with DLBCL who received the R-CHOP or R-THP-COP regimen between June 2004 and May 2014. Sarcopenia was measured by the analysis of CT images at the L3 level before treatment. The surface of muscular tissues was selected according to the CT Hounsfield unit. This value was normalized for stature in order to calculate the L3 skeletal muscle index (L3 SMI, cm(2)/m(2)). Median age at diagnosis in the 121 males and 86 females was 67 years (range, 19-86 years). The sex-specific cutoffs for the L3 SMI were determined by receiver operator curve (ROC) analysis. Sarcopenic patients were older than non-sarcopenic patients, with a median age of 70 and 65 years, respectively (p < 0.001). Other International Prognostic Index factors were not significantly different when comparing sarcopenic and non-sarcopenic patients. With a median follow-up of 50.4 months, the 3-year overall survival (OS) was 70 % in the sarcopenic group and 85 % in the non-sarcopenic group (p = 0.0260). In a subgroup analysis by gender, there was a significant difference in the OS when comparing sarcopenic and non-sarcopenic patients in males but not in females (p = 0.0003, p = 0.4440, respectively). Sarcopenia is an independent prognostic factor in male patients with DLBCL. PMID:26385388

  12. Glutathione S Transferases Polymorphisms Are Independent Prognostic Factors in Lupus Nephritis Treated with Cyclophosphamide

    PubMed Central

    Verstuyft, Céline; Costedoat-Chalumeau, Nathalie; Hummel, Aurélie; Le Guern, Véronique; Sacré, Karim; Meyer, Olivier; Daugas, Eric; Goujard, Cécile; Sultan, Audrey; Lobbedez, Thierry; Galicier, Lionel; Pourrat, Jacques; Le Hello, Claire; Godin, Michel; Morello, Rémy; Lambert, Marc; Hachulla, Eric; Vanhille, Philippe; Queffeulou, Guillaume; Potier, Jacky; Dion, Jean-Jacques; Bataille, Pierre; Chauveau, Dominique; Moulis, Guillaume; Farge-Bancel, Dominique; Duhaut, Pierre; Saint-Marcoux, Bernadette; Deroux, Alban; Manuzak, Jennifer; Francès, Camille; Aumaitre, Olivier; Bezanahary, Holy; Becquemont, Laurent; Bienvenu, Boris

    2016-01-01

    Objective To investigate association between genetic polymorphisms of GST, CYP and renal outcome or occurrence of adverse drug reactions (ADRs) in lupus nephritis (LN) treated with cyclophosphamide (CYC). CYC, as a pro-drug, requires bioactivation through multiple hepatic cytochrome P450s and glutathione S transferases (GST). Methods We carried out a multicentric retrospective study including 70 patients with proliferative LN treated with CYC. Patients were genotyped for polymorphisms of the CYP2B6, CYP2C19, GSTP1, GSTM1 and GSTT1 genes. Complete remission (CR) was defined as proteinuria ≤0.33g/day and serum creatinine ≤124 µmol/l. Partial remission (PR) was defined as proteinuria ≤1.5g/day with a 50% decrease of the baseline proteinuria value and serum creatinine no greater than 25% above baseline. Results Most patients were women (84%) and 77% were Caucasian. The mean age at LN diagnosis was 41 ± 10 years. The frequency of patients carrying the GST null genotype GSTT1-, GSTM1-, and the Ile→105Val GSTP1 genotype were respectively 38%, 60% and 44%. In multivariate analysis, the Ile→105Val GSTP1 genotype was an independent factor of poor renal outcome (achievement of CR or PR) (OR = 5.01 95% CI [1.02–24.51]) and the sole factor that influenced occurrence of ADRs was the GSTM1 null genotype (OR = 3.34 95% CI [1.064–10.58]). No association between polymorphisms of cytochrome P450s gene and efficacy or ADRs was observed. Conclusion This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients. PMID:27002825

  13. Effects of transforming growth factor-beta on growth and differentiation of the continuous rat thyroid follicular cell line, FRTL-5

    SciTech Connect

    Morris, J.C. III; Ranganathan, G.; Hay, I.D.; Nelson, R.E.; Jiang, N.S.

    1988-09-01

    Transforming growth factor-beta (TGF beta) has been shown to influence the growth and differentiation of many widely varied cell types in vitro, including some that are endocrinologically active. We have investigated the previously unknown effects of this unique growth factor in the differentiated rat thyroid follicular cell line FRTL-5. The cells demonstrated specific, high affinity binding of TGF beta, and as with other epithelial cells, the growth of these thyroid follicular cells was potently inhibited by addition of TGF beta to the culture medium. TGF beta caused a significant reduction in TSH-sensitive adenylate cyclase activity in the cells. The addition of (Bu)2cAMP along with the growth factor to cultures partially reversed the characteristic morphological changes seen with TGF beta, but did not reverse the growth inhibition. To further investigate the possible mechanisms of the effects of TGF beta on the cells, we measured the influence of the growth factor on (125I)TSH binding. TGF beta did not compete for specific TSH-binding sites; however, exposure of the cells to TGF beta for 12 or more h resulted in a dose-dependent down-regulation of TSH receptors that was fully reversible. While cellular proliferation was potently inhibited by TGF beta, differentiated function, as manifest by iodine-trapping ability, was stimulated by the growth factor. This stimulation of iodine uptake was independent of, and additive to, the stimulatory effects of TSH. Finally, FRTL-5 cells in serum-free medium and in response to TSH were shown to secrete TGF beta-like activity that competed for (125I)TGF beta in a RRA. These studies suggest that TGF beta may represent an autocrine mechanism of controlling the growth response to TSH in thyroid follicular cells, while allowing the continuance of differentiated function.

  14. Hyperhomocysteinaemia is an independent risk factor of abdominal aortic aneurysm in a Chinese Han population

    PubMed Central

    Liu, Jie; Wei Zuo, Shang; Li, Yue; Jia, Xin; Jia, Sen Hao; Zhang, Tao; Xiang Song, Yu; Qi Wei, Ying; Xiong, Jiang; Hua Hu, Yong; Guo, Wei

    2016-01-01

    The associations between hyperhomocysteinaemia (HHcy), methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, and abdominal aortic aneurysm (AAA) remain controversial, with only few studies focused on these associations within the Chinese population. We performed subgroup and interaction analyses in a Chinese Han population to investigate these associations. In all, 155 AAA patients and 310 control subjects were evaluated for serum total homocysteine levels and MTHFR C677T polymorphisms. Multiple logistic regression models were used to evaluate the aforementioned associations. Interaction and stratified analyses were conducted according to age, sex, smoking status, drinking status, and chronic disease histories. The multiple logistic analyses showed a significant association between HHcy and AAA but no significant association between MTHFR C677T polymorphism and AAA. The interaction analysis showed that age and peripheral arterial disease played an interactive role in the association between HHcy and AAA, while drinking status played an interactive role in the association between MTHFR C677T polymorphism and AAA. In conclusion, HHcy is an independent risk factor of AAA in a Chinese Han population, especially in the elderly and peripheral arterial disease subgroups. Longitudinal studies and clinical trials aimed to reduce homocysteine levels are warranted to assess the causal nature of these relationships PMID:26865327

  15. Hyperhomocysteinaemia is an independent risk factor of abdominal aortic aneurysm in a Chinese Han population.

    PubMed

    Liu, Jie; Wei Zuo, Shang; Li, Yue; Jia, Xin; Jia, Sen Hao; Zhang, Tao; Xiang Song, Yu; Qi Wei, Ying; Xiong, Jiang; Hua Hu, Yong; Guo, Wei

    2016-01-01

    The associations between hyperhomocysteinaemia (HHcy), methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, and abdominal aortic aneurysm (AAA) remain controversial, with only few studies focused on these associations within the Chinese population. We performed subgroup and interaction analyses in a Chinese Han population to investigate these associations. In all, 155 AAA patients and 310 control subjects were evaluated for serum total homocysteine levels and MTHFR C677T polymorphisms. Multiple logistic regression models were used to evaluate the aforementioned associations. Interaction and stratified analyses were conducted according to age, sex, smoking status, drinking status, and chronic disease histories. The multiple logistic analyses showed a significant association between HHcy and AAA but no significant association between MTHFR C677T polymorphism and AAA. The interaction analysis showed that age and peripheral arterial disease played an interactive role in the association between HHcy and AAA, while drinking status played an interactive role in the association between MTHFR C677T polymorphism and AAA. In conclusion, HHcy is an independent risk factor of AAA in a Chinese Han population, especially in the elderly and peripheral arterial disease subgroups. Longitudinal studies and clinical trials aimed to reduce homocysteine levels are warranted to assess the causal nature of these relationships. PMID:26865327

  16. Environmental exposure as an independent risk factor of chronic bronchitis in northwest Russia

    PubMed Central

    Nieminen, Pentti; Panychev, Dmitry; Lyalyushkin, Sergei; Komarov, German; Nikanov, Alexander; Borisenko, Mark; Kinnula, Vuokko L.; Toljamo, Tuula

    2013-01-01

    Background In some parts of the northwest Russia, Murmansk region, high exposures to heavy mining and refining industrial air pollution, especially sulphur dioxide, have been documented. Objective Our aim was to evaluate whether living in the mining area would be an independent risk factor of the respiratory symptoms. Design A cross-sectional survey of 200 Murmansk region adult citizens was performed. The main outcome variable was prolonged cough with sputum production that fulfilled the criteria of chronic bronchitis. Results Of the 200 participants, 53 (26.5%) stated that they had experienced chronic cough with phlegm during the last 2 years. The prevalence was higher among those subjects living in the mining area with its high pollution compared to those living outside this region (35% vs. 18%). Multivariable regression model confirmed that the risk for the chronic cough with sputum production was elevated in a statistical significant manner in the mining and refining area (adjusted OR 2.16, 95% CI 1.07–4.35) after adjustment for smoking status, age and sex. Conclusions The increased level of sulphur dioxide emitted during nickel mining and refining may explain these adverse health effects. This information is important for medical authorities when they make recommendations and issue guidelines regarding the relationship between environmental pollution and health outcomes. PMID:23440671

  17. Model-independent structure factors from powder X-ray diffraction: a novel approach.

    PubMed

    Straasø, Tine; Dippel, Ann-Christin; Becker, Jacob; Als-Nielsen, Jens

    2014-01-01

    Under the experimental condition that all Bragg peaks in a powder X-ray diffraction (PXRD) pattern have the same shape, one can readily obtain the Bragg intensities without fitting any parameters. This condition is fulfilled at the P02.1 beamline at PETRA III using the seventh harmonic from a 23 mm-period undulator (60 keV) at a distance of 65 m. For grain sizes of the order of 1 µm, the Bragg peak shape in the PXRD is entirely determined by the diameter of the capillary containing the powder sample and the pixel size of the image plate detector, and consequently it is independent of the scattering angle. As an example, a diamond powder has been chosen and structure factors derived which are in accordance with those calculated from density functional theory methods of the WIEN2k package to within an accuracy that allows a detailed electron density analysis. PMID:24365925

  18. Sequence-independent induction of Sp1 transcription factor activity by phosphorothioate oligodeoxynucleotides.

    PubMed Central

    Perez, J R; Li, Y; Stein, C A; Majumder, S; van Oorschot, A; Narayanan, R

    1994-01-01

    Modified analogues of antisense oligodeoxynucleotides (ODNs), particularly phosphorothioates ([S]ODNs), have been extensively used to inhibit gene expression. The potential sequence specificity of antisense oligomers makes them attractive as molecular drugs for human diseases. The use of antisense [S]ODNs to inhibit gene expression has been complicated by frequent nonspecific effects. In this study we show in diverse cell types that [S]ODNs, independent of their base sequence, mediated the induction of an Sp1 nuclear transcription factor. The [S]ODN-mediated Sp1 induction was rapid and was associated with elevated levels of Sp1 protein. This induction was dependent on NF-kappa B activity, since inhibition of NF-kappa B activity abolished the [S]ODN-induced Sp1 activity. [S]ODN-induced Sp1 activity was seen in mouse spleen cells following in vivo administration. Sp1 activity induced by [S]ODNs required the tyrosine kinase pathway and did not have transactivating potential. These results may help to explain some of the non-specific effects often seen with [S]ODNs. Images PMID:8016096

  19. Effects of transforming growth factor beta and epidermal growth factor on cell proliferation and the formation of bone nodules in isolated fetal rat calvaria cells.

    PubMed

    Antosz, M E; Bellows, C G; Aubin, J E

    1989-08-01

    When cells enzymatically isolated from fetal rat calvaria (RC cells) are cultured in vitro in the presence of ascorbic acid and Na beta-glycerophosphate, discrete three-dimensional nodules form with the histologic, immunohistochemical, and ultrastructural characteristics of bone (Bellows et al; Calcified Tissue International 38:143-154, 1986; Bhargava et al., Bone, 9:155-163, 1988). Quantitation of the number of bone nodules that forms provides a colony assay for osteoprogenitor cells present in the RC population (Bellows and Aubin, Develop. Biol., 133:8-13, 1989). Continuous culture with either epidermal growth factor (EGF) or transforming growth factor beta (TGF-beta) results in dose-dependent inhibition of bone nodule formation; however, the former causes increased proliferation and saturation density, while the latter reduces both parameters. Addition of EGF (48 h pulse, 2-200 ng/ml) to RC cells at day 1 after plating results in increased proliferation and population saturation density and an increased number of bone nodules formed. Similar pulses at confluence and in postconfluent multilayered cultures when nodules first begin forming (approx. day 11) inhibited bone nodule formation and resulted in a smaller stimulation of cell proliferation. Forty-eight hour pulses of TGF-beta (0.01-1 ng/ml) reduced bone nodule formation and proliferation at all times examined, with pulses on day 1 causing maximum inhibition. The effects of pulses with TGF-beta and EGF on inhibition of nodule formation are independent of the presence of serum in the culture medium during the pulse. The data suggest that whereas EGF can either stimulate or inhibit the formation of bone nodules depending upon the time and duration of exposure, TGF-B inhibits bone nodule formation under all conditions tested. Moreover, these effects on osteoprogenitor cell differentiation do not always correlate with the effects of the growth factors on RC cell proliferation. PMID:2787326

  20. Activation of phospholipase D by growth factors and oncogenes in murine fibroblasts follow alternative but cross-talking pathways.

    PubMed Central

    del Peso, L; Lucas, L; Esteve, P; Lacal, J C

    1997-01-01

    Phospholipase D (PLD) is activated by a variety of stimuli, including mitogenic stimulation by growth factors and oncogene transformation. Activation of PLD by growth factors requires protein kinase C (PKC) since depletion of the enzyme by down-regulation or direct inhibition by specific drugs completely abrogates this effect. Transformation by the ras and src oncogenes is also associated with an increase in basal PLD activity. However, this effect is not dependent on PKC, suggesting that growth factors and oncogenes may activate PLD by two independent mechanisms. Here we demonstrate that activation of PLD by phorbol esters is greatly enhanced in ras-transformed cells, suggesting synergistic activation of PLD by ras oncogenes and PKC. Also, ras-transformed cells showed a dramatic attenuation of the PLD activation induced by growth factors, although receptor function was still detectable. This attenuation paralleled the specific uncoupling of the phosphatidylinositol-specific phospholipase C (PI-PLC) pathway, indicating that activation of PLD by growth factors may be mediated by PI-PLC and PKC activation. Attenuation of PLD activation by platelet-derived growth factor was also observed in several oncogene-transformed cells, as well as the uncoupling of the PI-PLC pathway. Neither the co-operation with PKC activation nor the attenuation of the PLD response to growth factors in ras-transformed cells was a general consequence of cell transformation, since cells transformed by other oncogenes showed a normal response to either treatment. These results support the existence of at least two alternative signalling routes for the activation of PLD, one mediated by the PI-PLC/diacylglycerol/PKC pathway and a second one mediated by several oncogenes, independent of the PKC pathway, which synergizes with the PI-PLC/PKC-dependent pathway. PMID:9065772

  1. Interaction of phosphatidylinositol 3-kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors.

    PubMed Central

    Hu, P; Margolis, B; Skolnik, E Y; Lammers, R; Ullrich, A; Schlessinger, J

    1992-01-01

    One of the immediate cellular responses to stimulation by various growth factors is the activation of a phosphatidylinositol (PI) 3-kinase. We recently cloned the 85-kDa subunit of PI 3-kinase (p85) from a lambda gt11 expression library, using the tyrosine-phosphorylated carboxy terminus of the epidermal growth factor (EGF) receptor as a probe (E. Y. Skolnik, B. Margolis, M. Mohammadi, E. Lowenstein, R. Fischer, A. Drepps, A. Ullrich, and J. Schlessinger, Cell 65:83-90, 1991). In this study, we have examined the association of p85 with EGF and platelet-derived growth factor (PDGF) receptors and the tyrosine phosphorylation of p85 in 3T3 (HER14) cells in response to EGF and PDGF treatment. Treatment of cells with EGF or PDGF markedly increased the amount of p85 associated with EGF and PDGF receptors. Binding assays with glutathione S-transferase (GST) fusion proteins demonstrated that either Src homology region 2 (SH2) domain of p85 is sufficient for binding to EGF and PDGF receptors and that receptor tyrosine autophosphorylation is required for binding. Binding of a GST fusion protein expressing the N-terminal SH2 domain of p85 (GST-N-SH2) to EGF and PDGF receptors was half-maximally inhibited by 2 and 24 mM phosphotyrosine (P-Tyr), respectively, suggesting that the N-SH2 domain interacts more stably with PDGF receptors than with EGF receptors. The amount of receptor-p85 complex detected in HER14 cells treated with EGF or PDGF. Growth factor treatment also increased the amount of p85 found in anti-PDGF-treated HER14 cells, suggesting that the vast majority of p85 in the anti-P-Tyr fraction is receptor associated but not phosphorylated on tyrosine residues. Only upon transient overexpression of p85 and PDGF receptor did p85 become tyrosine phosphorylated. These are consistent with the hypothesis that p85 functions as an adaptor molecule that targets PI 3-kinase to activated growth factor receptors. Images PMID:1372091

  2. The emerging role of hepatocyte growth factor in renal diseases.

    PubMed

    Mao, Song; Zhang, Jianhua

    2016-06-01

    Hepatocyte growth factor (HGF), a kringle-containing polypeptide, acts on various epithelial cells to regulate cell growth, cell motility, and morphogenesis. HGF also accelerates tissue regeneration of injured organs and is regarded as a key molecule in organ regeneration. Besides the regeneration of the liver, HGF also plays a role in the renal regeneration. In addition, an adaptive alteration of HGF status in various renal diseases occurs. However, the precise role of HGF in various renal diseases remains elusive. The signaling pathways of HGF may be associated with renal diseases. In this review, we will try to provide an in-depth understanding of the underlying role of HGF and its possible interactions with other molecules in renal diseases. PMID:26460681

  3. Anti-Vascular Endothelial Growth Factor Therapy in Breast Cancer

    PubMed Central

    Kristensen, Tina Bøgelund; Knutsson, Malin L. T.; Wehland, Markus; Laursen, Britt Elmedal; Grimm, Daniela; Warnke, Elisabeth; Magnusson, Nils E.

    2014-01-01

    Neo-angiogenesis is a critical process for tumor growth and invasion and has become a promising target in cancer therapy. This manuscript reviews three currently relevant anti-angiogenic agents targeting the vascular endothelial growth factor system: bevacizumab, ramucirumab and sorafenib. The efficacy of anti-angiogenic drugs in adjuvant therapy or as neo-adjuvant treatment has been estimated in clinical trials of advanced breast cancer. To date, the overall observed clinical improvements are unconvincing, and further research is required to demonstrate the efficacy of anti-angiogenic drugs in breast cancer treatments. The outcomes of anti-angiogenic therapy have been highly variable in terms of tumor response. New methods are needed to identify patients who will benefit from this regimen. The development of biomarkers and molecular profiling are relevant research areas that may strengthen the ability to focus anti-angiogenic therapy towards suitable patients, thereby increase the cost-effectiveness, currently estimated to be inadequate. PMID:25514409

  4. Release characteristics of encapsulated formulations incorporating plant growth factors.

    PubMed

    Wybraniec, Slawomir; Schwartz, Liliana; Wiesman, Zeev; Markus, Arie; Wolf, David

    2002-05-01

    The release characteristics of encapsulated formulations containing a combination of plant growth factors (PGF)--plant hormones (IBA, paclobutrazol), nutrients (fertilizers, microelements), and fungicide (prochloraz)--were studied. The formulations were prepared by encapsulating the active ingredients in a polyethylene matrix and, in some cases, subsequently coating the product with polyurethane. Dissolution experiments were carried out with both coated and non-coated formulations to determine the sustained release patterns of the active ingredients. The PGF controlled-release systems obtained have been shown to promote development of root systems, vegetative growth, and reproductive development in cuttings, potted plants, or garden plants of various plant species. These beneficial effects are attributable to the lasting and balanced PGF availability provided by these systems. PMID:12009194

  5. Interdependent epidermal growth factor receptor signalling and trafficking.

    PubMed

    Jones, Sylwia; Rappoport, Joshua Z

    2014-06-01

    Epidermal growth factor (EGF) receptor (EGFR) signalling regulates diverse cellular functions, promoting cell proliferation, differentiation, migration, cell growth and survival. EGFR signalling is critical during embryogenesis, in particular in epithelial development, and disruption of the EGFR gene results in epithelial immaturity and perinatal death. EGFR signalling also functions during wound healing responses through accelerating wound re-epithelialisation, inducing cell migration, proliferation and angiogenesis. Upregulation of EGFR signalling is often observed in carcinomas and has been shown to promote uncontrolled cell proliferation and metastasis. Therefore aberrant EGFR signalling is a common target for anticancer therapies. Various reports indicate that EGFR signalling primarily occurs at the plasma membrane and EGFR degradation following endocytosis greatly attenuates signalling. Other studies argue that EGFR internalisation is essential for complete activation of downstream signalling cascades and that endosomes can serve as signalling platforms. The aim of this review is to discuss current understanding of intersection between EGFR signalling and trafficking. PMID:24681003

  6. Independent signaling by Drosophila insulin receptor for axon guidance and growth

    PubMed Central

    Li, Caroline R.; Guo, Dongyu; Pick, Leslie

    2014-01-01

    The Drosophila insulin receptor (DInR) regulates a diverse array of biological processes including growth, axon guidance, and sugar homeostasis. Growth regulation by DInR is mediated by Chico, the Drosophila homolog of vertebrate insulin receptor substrate proteins IRS1–4. In contrast, DInR regulation of photoreceptor axon guidance in the developing visual system is mediated by the SH2-SH3 domain adaptor protein Dreadlocks (Dock). In vitro studies by others identified five NPXY motifs, one in the juxtamembrane region and four in the signaling C-terminal tail (C-tail), important for interaction with Chico. Here we used yeast two-hybrid assays to identify regions in the DInR C-tail that interact with Dock. These Dock binding sites were in separate portions of the C-tail from the previously identified Chico binding sites. To test whether these sites are required for growth or axon guidance in whole animals, a panel of DInR proteins, in which the putative Chico and Dock interaction sites had been mutated individually or in combination, were tested for their ability to rescue viability, growth and axon guidance defects of dinr mutant flies. Sites required for viability were identified. Unexpectedly, mutation of both putative Dock binding sites, either individually or in combination, did not lead to defects in photoreceptor axon guidance. Thus, either sites also required for viability are necessary for DInR function in axon guidance and/or there is redundancy built into the DInR/Dock interaction such that Dock is able to interact with multiple regions of DInR. We also found that simultaneous mutation of all five NPXY motifs implicated in Chico interaction drastically decreased growth in both male and female adult flies. These animals resembled chico mutants, supporting the notion that DInR interacts directly with Chico in vivo to control body size. Mutation of these five NPXY motifs did not affect photoreceptor axon guidance, segregating the roles of DInR in the

  7. Independent signaling by Drosophila insulin receptor for axon guidance and growth.

    PubMed

    Li, Caroline R; Guo, Dongyu; Pick, Leslie

    2013-01-01

    The Drosophila insulin receptor (DInR) regulates a diverse array of biological processes including growth, axon guidance, and sugar homeostasis. Growth regulation by DInR is mediated by Chico, the Drosophila homolog of vertebrate insulin receptor substrate proteins IRS1-4. In contrast, DInR regulation of photoreceptor axon guidance in the developing visual system is mediated by the SH2-SH3 domain adaptor protein Dreadlocks (Dock). In vitro studies by others identified five NPXY motifs, one in the juxtamembrane region and four in the signaling C-terminal tail (C-tail), important for interaction with Chico. Here we used yeast two-hybrid assays to identify regions in the DInR C-tail that interact with Dock. These Dock binding sites were in separate portions of the C-tail from the previously identified Chico binding sites. To test whether these sites are required for growth or axon guidance in whole animals, a panel of DInR proteins, in which the putative Chico and Dock interaction sites had been mutated individually or in combination, were tested for their ability to rescue viability, growth and axon guidance defects of dinr mutant flies. Sites required for viability were identified. Unexpectedly, mutation of both putative Dock binding sites, either individually or in combination, did not lead to defects in photoreceptor axon guidance. Thus, either sites also required for viability are necessary for DInR function in axon guidance and/or there is redundancy built into the DInR/Dock interaction such that Dock is able to interact with multiple regions of DInR. We also found that simultaneous mutation of all five NPXY motifs implicated in Chico interaction drastically decreased growth in both male and female adult flies. These animals resembled chico mutants, supporting the notion that DInR interacts directly with Chico in vivo to control body size. Mutation of these five NPXY motifs did not affect photoreceptor axon guidance, segregating the roles of DInR in the

  8. Fibroblast growth factor 15 deficiency impairs liver regeneration in mice

    PubMed Central

    Kong, Bo; Huang, Jiansheng; Zhu, Yan; Li, Guodong; Williams, Jessica; Shen, Steven; Aleksunes, Lauren M.; Richardson, Jason R.; Apte, Udayan; Rudnick, David A.

    2014-01-01

    Fibroblast growth factor (FGF) 15 (human homolog, FGF19) is an endocrine FGF highly expressed in the small intestine of mice. Emerging evidence suggests that FGF15 is critical for regulating hepatic functions; however, the role of FGF15 in liver regeneration is unclear. This study assessed whether liver regeneration is altered in FGF15 knockout (KO) mice following 2/3 partial hepatectomy (PHx). The results showed that FGF15 KO mice had marked mortality, with the survival rate influenced by genetic background. Compared with wild-type mice, the KO mice displayed extensive liver necrosis and marked elevation of serum bile acids and bilirubin. Furthermore, hepatocyte proliferation was reduced in the KO mice because of impaired cell cycle progression. After PHx, the KO mice had weaker activation of signaling pathways that are important for liver regeneration, including signal transducer and activator of transcription 3, nuclear factor-κB, and mitogen-activated protein kinase. Examination of the KO mice at early time points after PHx revealed a reduced and/or delayed induction of immediate-early response genes, including growth-control transcription factors that are critical for liver regeneration. In conclusion, the results suggest that FGF15 deficiency severely impairs liver regeneration in mice after PHx. The underlying mechanism is likely the result of disrupted bile acid homeostasis and impaired priming of hepatocyte proliferation. PMID:24699334

  9. The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ERα, and is an independent prognostic factor in node-negative breast cancer.

    PubMed

    Brennan, D J; O'Connor, D P; Laursen, H; McGee, S F; McCarthy, S; Zagozdzon, R; Rexhepaj, E; Culhane, A C; Martin, F M; Duffy, M J; Landberg, G; Ryden, L; Hewitt, S M; Kuhar, M J; Bernards, R; Millikan, R C; Crown, J P; Jirström, K; Gallagher, W M

    2012-07-26

    Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n=690; P=0.002, 0.013). We also show that CART increases the transcriptional activity of ERα in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy. PMID:22139072

  10. Effects of Hypergravity Rearing on Growth Hormone and Insulin-Like Growth Factor in Rat Pups

    NASA Technical Reports Server (NTRS)

    Baer, L. A.; Chowdhury, J. H.; Grindeland, R. E.; Wade, C. E.; Ronca, A. E.

    2003-01-01

    Body weights of rat pups reared during exposure to hypergravity (hg) are significantly reduced relative to 1 g controls. In the present study, we examined in hg-reared rat pups two major contributors to growth and development, namely growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Beginning on Gestational day (G)11 of the rats 22 day pregnancy, rat dams and their litters were continuously exposed to either 1.5-g or 2.0-g. On Postnatal day (P)l0, plasma GH and IGF-1 were analyzed using radioimmunoassay (RIA). Both hormones were significantly elevated in hg pups relative to 1-g control pups. Together, these findings suggest that GH and IGF-1 are not primary determinants of reduced body weights observed in hg-reared pups. The significant elevations in pup GH and IGF-1 may be related to increased physical stimulation in hypergravity.

  11. Identification of Two Independent Risk Factors for Lupus within the MHC in United Kingdom Families

    PubMed Central

    Fernando, Michelle M. A; Stevens, Christine R; Sabeti, Pardis C; Walsh, Emily C; McWhinnie, Alasdair J. M; Shah, Anila; Green, Todd; Rioux, John D; Vyse, Timothy J

    2007-01-01

    The association of the major histocompatibility complex (MHC) with SLE is well established yet the causal variants arising from this region remain to be identified, largely due to inadequate study design and the strong linkage disequilibrium demonstrated by genes across this locus. The majority of studies thus far have identified strong association with classical class II alleles, in particular HLA-DRB1*0301 and HLA-DRB1*1501. Additional associations have been reported with class III alleles; specifically, complement C4 null alleles and a tumor necrosis factor promoter SNP (TNF-308G/A). However, the relative effects of these class II and class III variants have not been determined. We have thus used a family-based approach to map association signals across the MHC class II and class III regions in a cohort of 314 complete United Kingdom Caucasian SLE trios by typing tagging SNPs together with classical typing of the HLA-DRB1 locus. Using TDT and conditional regression analyses, we have demonstrated the presence of two distinct and independent association signals in SLE: HLA-DRB1*0301 (nominal p = 4.9 × 10−8, permuted p < 0.0001, OR = 2.3) and the T allele of SNP rs419788 (nominal p = 4.3 × 10−8, permuted p < 0.0001, OR = 2.0) in intron 6 of the class III region gene SKIV2L. Assessment of genotypic risk demonstrates a likely dominant model of inheritance for HLA-DRB1*0301, while rs419788-T confers susceptibility in an additive manner. Furthermore, by comparing transmitted and untransmitted parental chromosomes, we have delimited our class II signal to a 180 kb region encompassing the alleles HLA-DRB1*0301-HLA-DQA1*0501-HLA-DQB1*0201 alone. Our class III signal importantly excludes independent association at the TNF promoter polymorphism, TNF-308G/A, in our SLE cohort and provides a potentially novel locus for future genetic and functional studies. PMID:17997607

  12. Iron-independent induction of ferritin H chain by tumor necrosis factor.

    PubMed Central

    Miller, L L; Miller, S C; Torti, S V; Tsuji, Y; Torti, F M

    1991-01-01

    Iron increases the synthesis of the iron-storage protein, ferritin, largely by promoting translation of preexisting mRNAs for both the H and L ferritin isoforms (H, heavy, heart, acidic; L, light, liver, basic). We have recently cloned and sequenced a full-length cDNA to murine ferritin H and identified ferritin H as a gene induced by tumor necrosis factor alpha (TNF-alpha, cachectin). Using primary human myoblasts, we have now examined the relationship between TNF-alpha and iron in regulating ferritin. Four lines of evidence suggest that TNF-alpha regulates ferritin independently of iron. First, evaluation of mRNA showed that TNF-alpha increased ferritin H chain specifically, provoking no change in steady-state levels of ferritin L mRNA; iron, in contrast, increased the mRNA of both isoforms. Second, the increase in ferritin H protein synthesis observed during TNF-alpha treatment was dependent on an increase in ferritin H mRNA: actinomycin D blocked the TNF-alpha-induced changes in ferritin H but did not inhibit the translational induction of ferritin seen with iron treatment. Third, equal ferritin mRNA induction was observed in iron-loaded cells and in cells depleted of iron by a permeant chelator, 2,2'-dipyridyl. Fourth, ferritin H induction by TNF-alpha and iron was additive over the entire range of iron concentrations, even at TNF-alpha doses known to maximally stimulate ferritin H mRNA levels. Nonetheless, the role of iron in translational regulation of ferritin was retained in TNF-alpha-treated cells; effective biosynthesis of TNF-alpha-induced, H-subunit-predominant ferritin protein required iron and could be enhanced by treatment of the cells with additional iron or blocked by 2,2'-dipyridyl. Finally, we observed that the TNF-alpha-mediated increase in ferritin synthesis peaked at 8 hr and was followed by a decrease in both H and L isoferritin synthesis; the addition of iron, however, reversed the late-occurring depression in ferritin synthesis. This

  13. Expression of cyr61, a growth factor-inducible immediate-early gene.

    PubMed Central

    O'Brien, T P; Yang, G P; Sanders, L; Lau, L F

    1990-01-01

    A set of immediate-early genes that are rapidly activated by serum or purified platelet-derived growth factor in mouse 3T3 fibroblasts has been previously identified. Among these genes, several are related to known or putative transcription factors and growth factors, supporting the notion that some of these genes encode regulatory molecules important to cell growth. We show here that a member of this set of genes, cyr61 (originally identified by its cDNA 3CH61), encodes a 379-amino-acid polypeptide rich in cysteine residues. cyr61 can be induced through protein kinase C-dependent and -independent pathways. Unlike many immediate-early genes that are transiently expressed, the cyr61 mRNA is accumulated from the G0/G1 transition through mid-G1. This expression pattern is due to persistent transcription, while the mRNA is rapidly turned over during the G0/G1 transition and in mid-G1 at the same rate. In logarithmically growing cells, the cyr61 mRNA level is constant throughout the cell cycle. Cyr61 contains an N-terminal secretory signal sequence; however, it is not detected in the culture medium by immunoprecipitation. Cyr61 is synthesized maximally at 1 to 2 h after serum stimulation and has a short half-life within the cell. Images PMID:2355916

  14. Human fetal and adult chondrocytes. Effect of insulinlike growth factors I and II, insulin, and growth hormone on clonal growth.

    PubMed Central

    Vetter, U; Zapf, J; Heit, W; Helbing, G; Heinze, E; Froesch, E R; Teller, W M

    1986-01-01

    Clonal proliferation of freshly isolated human fetal chondrocytes and adult chondrocytes in response to human insulinlike growth factors I and II (IGF I, IGF II), human biosynthetic insulin, and human growth hormone (GH) was assessed. IGF I (25 ng/ml) stimulated clonal growth of fetal chondrocytes (54 +/- 12 colonies/1,000 inserted cells, mean +/- 1 SD), but IGF II (25 ng/ml) was significantly more effective (106 +/- 12 colonies/1,000 inserted cells, P less than 0.05, unstimulated control: 14 +/- 4 colonies/1,000 inserted cells). In contrast, IGF I (25 ng/ml) was more effective in adult chondrocytes (42 +/- 6 colonies/1,000 inserted cells) than IGF II (25 ng/ml) (21 +/- 6 colonies/1,000 inserted cells; P less than 0.05, unstimulated control: 6 +/- 3 colonies/1,000 inserted cells). GH and human biosynthetic insulin did not affect clonal growth of fetal or adult chondrocytes. The clonal growth pattern of IGF-stimulated fetal and adult chondrocytes was not significantly changed when chondrocytes were first grown in monolayer culture, harvested, and then inserted in the clonal culture system. However, the adult chondrocytes showed a time-dependent decrease of stimulation of clonal growth by IGF I and II. This was not true for fetal chondrocytes. The results are compatible with the concept that IGF II is a more potent stimulant of clonal growth of chondrocytes during fetal life, whereas IGF I is more effective in stimulating clonal growth of chondrocytes during postnatal life. Images PMID:3519682

  15. Tumor associated osteoclast-like giant cells promote tumor growth and lymphangiogenesis by secreting vascular endothelial growth factor-C

    SciTech Connect

    Hatano, Yu; Nakahama, Ken-ichi; Isobe, Mitsuaki; Morita, Ikuo

    2014-03-28

    Highlights: • M-CSF and RANKL expressing HeLa cells induced osteoclastogenesis in vitro. • We established OGC-containing tumor model in vivo. • OGC-containing tumor became larger independent of M-CSF or RANKL effect. • VEGF-C secreted from OGCs was a one of candidates for OGC-containing tumor growth. - Abstract: Tumors with osteoclast-like giant cells (OGCs) have been reported in a variety of organs and exert an invasive and prometastatic phenotype, but the functional role of OGCs in the tumor environment has not been fully clarified. We established tumors containing OGCs to clarify the role of OGCs in tumor phenotype. A mixture of HeLa cells expressing macrophage colony-stimulating factor (M-CSF, HeLa-M) and receptor activator of nuclear factor-κB ligand (RANKL, HeLa-R) effectively supported the differentiation of osteoclast-like cells from bone marrow macrophages in vitro. Moreover, a xenograft study showed OGC formation in a tumor composed of HeLa-M and HeLa-R. Surprisingly, the tumors containing OGCs were significantly larger than the tumors without OGCs, although the growth rates were not different in vitro. Histological analysis showed that lymphangiogenesis and macrophage infiltration in the tumor containing OGCs, but not in other tumors were accelerated. According to quantitative PCR analysis, vascular endothelial growth factor (VEGF)-C mRNA expression increased with differentiation of osteoclast-like cells. To investigate whether VEGF-C expression is responsible for tumor growth and macrophage infiltration, HeLa cells overexpressing VEGF-C (HeLa-VC) were established and transplanted into mice. Tumors composed of HeLa-VC mimicked the phenotype of the tumors containing OGCs. Furthermore, the vascular permeability of tumor microvessels also increased in tumors containing OGCs and to some extent in VEGF-C-expressing tumors. These results suggest that macrophage infiltration and vascular permeability are possible mediators in these tumors. These

  16. Myoferlin is required for insulin-like growth factor response and muscle growth

    PubMed Central

    Demonbreun, Alexis R.; Posey, Avery D.; Heretis, Konstantina; Swaggart, Kayleigh A.; Earley, Judy U.; Pytel, Peter; McNally, Elizabeth M.

    2010-01-01

    Insulin-like growth factor (IGF) is a potent stimulus of muscle growth. Myoferlin is a membrane-associated protein important for muscle development and regeneration. Myoferlin-null mice have smaller muscles and defective myoblast fusion. To understand the mechanism by which myoferlin loss retards muscle growth, we found that myoferlin-null muscle does not respond to IGF1. In vivo after IGF1 infusion, control muscle increased myofiber diameter by 25%, but myoferlin-null muscle was unresponsive. Myoblasts cultured from myoferlin-null muscle and treated with IGF1 also failed to show the expected increase in fusion to multinucleate myotubes. The IGF1 receptor colocalized with myoferlin at sites of myoblast fusion. The lack of IGF1 responsiveness in myoferlin-null myoblasts was linked directly to IGF1 receptor mistrafficking as well as decreased IGF1 signaling. In myoferlin-null myoblasts, the IGF1 receptor accumulated into large vesicular structures. These vesicles colocalized with a marker of late endosomes/lysosomes, LAMP2, specifying redirection from a recycling to a degradative pathway. Furthermore, ultrastructural analysis showed a marked increase in vacuoles in myoferlin-null muscle. These data demonstrate that IGF1 receptor recycling is required for normal myogenesis and that myoferlin is a critical mediator of postnatal muscle growth mediated by IGF1.—Demonbreun, A. R., Posey, A. D., Heretis, K., Swaggart, K. A., Earley, J. U., Pytel, P., McNally, E. M. Myoferlin is required for insulin-like growth factor response and muscle growth. PMID:20008164

  17. The cutaneous epidermal growth factor network: Can it be translated clinically to stimulate hair growth?

    PubMed

    Alexandrescu, Doru T; Kauffman, C Lisa; Dasanu, Constantin A

    2009-01-01

    The influences exerted by the epidermal growth factor receptor (EGFR) on the skin act at multiple levels, which involve compartments that normally express EGFR. These include the basal and suprabasal layers of the epidermis, sebaceous glands, and the outer root sheath of the hair follicles. The physiological roles of EGFR ensure epidermal renewal and integrity, along with a gatekeeping and function and hair growth stimulation functions. Important cellular functions that are altered during EGF receptor blocking therapy consist of epidermal differentiation, proliferation, apoptosis, and migration, with an overall dominating effect of inducing growth arrest and terminal differentiation of the keratinocytes in the basal layers. The effects of EGFR blockage on the hair cycle include terminal differentiation of the hair follicle, which in certain cases may be associated with trichomegaly. Trichomegaly of the eyelashes may occur as an isolated occurrence or, frequently, as part of a generalized phenomenon that may be associated with the use of the EGFR inhibitors. Molecular changes associated with EGFR blockage are discussed, relevant to their association with hair growth. Modulation of Akt, AP2alpha, CDK4, Notch-1, p27KIP1, and Hedgehog expression are involved in the initiation of the hair cycle and inducement of the anagen phase, followed by proliferation and differentiation of the hair follicles. Epidermal growth factor receptor inhibitors have been developed as therapeutic molecules directed against cancer; in these regimens the knowledge of EGF receptor signaling functions has been translated into significant clinical results. However, among their various collateral effects on the skin, hair growth is observed to occur in certain patients. A particular "wavy" hair phenotype is observed during the pharmacological EGFR receptor blockade, just as in murine transgenic models that carry loss of function of TGF-alpha or EGFR genes. A better characterization of the

  18. Vascular Endothelial Growth Factor Receptor -2 in Breast Cancer

    PubMed Central

    Guo, Shanchun; Colbert, Laronna S.; Fuller, Miles; Zhang, Yuanyuan; Gonzalez-Perez, Ruben R.

    2010-01-01

    Investigations over the last decade have established the essential role of growth factors and their receptors during angiogenesis and carcinogenesis. The vascular endothelial growth factor receptor (VEGFR) family in mammals contains three members, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4), which are transmembrane tyrosine kinase receptors that regulate the formation of blood and lymphatic vessels. In the early 1990s, the above VEGFR were structurally characterized by cDNA cloning. Among these three receptors, VEGFR-2 is generally recognized to have a principal role in mediating VEGF-induced responses. VEGFR-2 is considered as the earliest marker for endothelial cell development. Importantly, VEGFR-2 directly regulates tumor angiogenesis. Therefore, several inhibitors of VEGFR-2 have been developed and many of them are now in clinical trials. In addition to targeting endothelial cells, the VEGF/VEGFR-2 system works as an essential autocrine/paracrine process for cancer cell proliferation and survival. Recent studies mark the continuous and increased interest in this related, but distinct, function of VEGF/VEGFR-2 in cancer cells: the autocrine/paracrine loop. Several mechanisms regulate VEGFR-2 levels and modulate its role in tumor angiogenesis and physiologic functions, i.e.: cellular localization/trafficking, regulation of cis-elements of promoter, epigenetic regulation and signaling from Notch, cytokines/growth factors and estrogen, etc. In this review, we will focus on updated information regarding VEGFR-2 research with respect to the molecular mechanisms of VEGFR-2 regulation in human breast cancer. Investigations in the activation, function, and regulation of VEGFR-2 in breast cancer will allow the development of new pharmacological strategies aimed at directly targeting cancer cell proliferation and survival. PMID:20462514

  19. Defining human insulin-like growth factor I gene regulation.

    PubMed

    Mukherjee, Aditi; Alzhanov, Damir; Rotwein, Peter

    2016-08-01

    Growth hormone (GH) plays an essential role in controlling somatic growth and in regulating multiple physiological processes in humans and other species. Insulin-like growth factor I (IGF-I), a conserved, secreted 70-amino acid peptide, is a critical mediator of many of the biological effects of GH. Previous studies have demonstrated that GH rapidly and potently promotes IGF-I gene expression in rodents and in some other mammals through the transcription factor STAT5b, leading to accumulation of IGF-I mRNAs and production of IGF-I. Despite this progress, very little is known about how GH or other trophic factors control human IGF1 gene expression, in large part because of the absence of any cellular model systems that robustly express IGF-I. Here, we have addressed mechanisms of regulation of human IGF-I by GH after generating cells in which the IGF1 chromosomal locus has been incorporated into a mouse cell line. Using this model, we found that physiological levels of GH rapidly stimulate human IGF1 gene transcription and identify several potential transcriptional enhancers in chromatin that bind STAT5b in a GH-regulated way. Each of the putative enhancers also activates a human IGF1 gene promoter in reconstitution experiments in the presence of the GH receptor, STAT5b, and GH. Thus we have developed a novel experimental platform that now may be used to determine how human IGF1 gene expression is controlled under different physiological and pathological conditions. PMID:27406741

  20. 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.

  1. CD166-mediated epidermal growth factor receptor phosphorylation promotes the growth of oral squamous cell carcinoma.

    PubMed

    Jia, Guodong; Wang, Xu; Yan, Ming; Chen, Wantao; Zhang, Ping

    2016-08-01

    CD166 has been considered a relatively specific marker of stem cells and cancer stem cells, and the altered expression of CD166 has also been reported as a prognostic marker of several other types of cancer. However, the molecular functions of CD166 in these cancer cells are largely unknown. In this study, we found that CD166 significantly enhanced epidermal growth factor receptor (EGFR) phosphorylation and prolonged epidermal growth factor (EGF)/EGFR signalling activation. In addition, EGF stimulation in CD166-overexpressing oral squamous carcinoma cells led to enhanced colony formation, invasion capacity and cytoskeletal re-organization in vitro and elevated tumourigenesis in vivo. Taken together, the results of our study identify CD166 as an intriguing therapeutic target for patients suffering from oral squamous cell carcinoma (OSCC). PMID:27424177

  2. Modulation of growth and differentiation in normal human keratinocytes by transforming growth factor-beta

    SciTech Connect

    Matsumoto, K.; Hashimoto, K.; Hashiro, M.; Yoshimasa, H.; Yoshikawa, K. )

    1990-10-01

    The effect of transforming growth factor-type beta 1(TGF-beta) on the growth and differentiation of normal human skin keratinocytes cultured in serum-free medium was investigated. TGF-beta markedly inhibited the growth of keratinocytes at the concentrations greater than 2 ng/ml under low Ca2+ conditions (0.1 mM). Growth inhibition was accompanied by changes in cell functions related to proliferation. Remarkable inhibition of DNA synthesis was demonstrated by the decrease of (3H)thymidine incorporation. The decrease of (3H)thymidine incorporation was observed as early as 3 hr after addition of TGF-beta. TGF-beta also decreased c-myc messenger RNA (mRNA) expression 30 min after addition of TGF-beta. This rapid reduction of c-myc mRNA expression by TGF-beta treatment is possibly one of the main factors in the process of TGF-beta-induced growth inhibition of human keratinocytes. Since growth inhibition and induction of differentiation are closely related in human keratinocytes, the growth-inhibitory effect of TGF-beta under high Ca2+ conditions was examined. TGF-beta inhibited the growth of keratinocytes under high Ca2+ conditions in the same manner as under low Ca2+ conditions, suggesting that it is a strong growth inhibitor in both low and high Ca2+ environments. The induction of keratinocyte differentiation was evaluated by measuring involucrin expression and cornified envelope formation: TGF-beta at 20 ng/ml increased involucrin expression from 9.3% to 18.8% under high Ca2+ conditions, while it decreased involucrin expression from 7.0% to 3.3% under low Ca2+ conditions. Cornified envelope formation was modulated in a similar way by addition of TGF-beta: TGF-beta at 20 ng/ml decreased cornified envelope formation by 53% under low Ca2+ conditions, while it enhanced cornified envelope formation by 30.7% under high Ca2+ conditions.

  3. Hepatoma-derived growth factor stimulates smooth muscle cell growth and is expressed in vascular development

    PubMed Central

    Everett, Allen D.; Lobe, David R.; Matsumura, Martin E.; Nakamura, Hideji; McNamara, Coleen A.

    2000-01-01

    Hepatoma-derived growth factor (HDGF) is the first member identified of a new family of secreted heparin-binding growth factors highly expressed in the fetal aorta. The biologic role of HDGF in vascular growth is unknown. Here, we demonstrate that HDGF mRNA is expressed in smooth muscle cells (SMCs), most prominently in proliferating SMCs, 8–24 hours after serum stimulation. Exogenous HDGF and endogenous overexpression of HDGF stimulated a significant increase in SMC number and DNA synthesis. Rat aortic SMCs transfected with a hemagglutinin-epitope–tagged rat HDGF cDNA contain HA-HDGF in their nuclei during S-phase. We also detected native HDGF in nuclei of cultured SMCs, of SMCs and endothelial cells from 19-day fetal (but not in the adult) rat aorta, of SMCs proximal to abdominal aortic constriction in adult rats, and of SMCs in the neointima formed after endothelial denudation of the rat common carotid artery. Moreover, HDGF colocalizes with the proliferating cell nuclear antigen (PCNA) in SMCs in human atherosclerotic carotid arteries, suggesting that HDGF helps regulate SMC growth during development and in response to vascular injury. PMID:10712428

  4. Vascular endothelial growth factor antagonist therapy for retinopathy of prematurity.

    PubMed

    Hartnett, M Elizabeth

    2014-12-01

    In this article, the growing problem of retinopathy of prematurity (ROP) worldwide, treatments for severe ROP including standard-of-care laser treatment, and the need for new treatments are discussed. Also discussed are the reasons to consider inhibiting the vascular endothelial growth factor (VEGF) signaling pathway in severe ROP and the concerns about broad VEGF inhibition. Finally, the potential role of VEGF in ROP based on studies in animal models of oxygen-induced retinopathy, the effects of anti-VEGF based on basic research data, and the clinical relevance of these data are covered. PMID:25459781

  5. Ten years of anti-vascular endothelial growth factor therapy.

    PubMed

    Ferrara, Napoleone; Adamis, Anthony P

    2016-06-01

    The targeting of vascular endothelial growth factor A (VEGFA), a crucial regulator of both normal and pathological angiogenesis, has revealed innovative therapeutic approaches in oncology and ophthalmology. The first VEGFA inhibitor, bevacizumab, was approved by the US Food and Drug Administration in 2004 for the first-line treatment of metastatic colorectal cancer, and the first VEGFA inhibitors in ophthalmology, pegaptanib and ranibizumab, were approved in 2004 and 2006, respectively. To mark this tenth anniversary of anti-VEGFA therapy, we discuss the discovery of VEGFA, the successes and challenges in the development of VEGFA inhibitors and the impact of these agents on the treatment of cancers and ophthalmic diseases. PMID:26775688

  6. Fibroblast Growth Factor 21 Analogs for Treating Metabolic Disorders

    PubMed Central

    Zhang, Jun; Li, Yang

    2015-01-01

    Fibroblast growth factor (FGF) 21 is a member of the endocrine FGF subfamily. FGF21 expression is induced under different disease conditions, such as type 2 diabetes, obesity, chronic kidney diseases, and cardiovascular diseases, and it has a broad spectrum of functions in regulating various metabolic parameters. Many different approaches have been pursued targeting FGF21 and its receptors to develop therapeutics for treating type 2 diabetes and other aspects of metabolic conditions. In this article, we summarize some of these key approaches and highlight the potential challenges in the development of these agents. PMID:26594197

  7. Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma

    PubMed Central

    Furnari, Frank B.; Cloughesy, Timothy F.; Cavenee, Webster K.; Mischel, Paul S.

    2016-01-01

    As tumours evolve, the daughter cells of the initiating cell often become molecularly heterogeneous and develop different functional properties and therapeutic vulnerabilities. In glioblastoma (GBM), a lethal form of brain cancer, the heterogeneous expression of the epidermal growth factor receptor (EGFR) poses a substantial challenge for the effective use of EGFR-targeted therapies. Understanding the mechanisms that cause EGFR heterogeneity in GBM should provide better insights into how they, and possibly other amplified receptor tyrosine kinases, affect cellular signalling, metabolism and drug resistance. PMID:25855404

  8. Stochastic contribution to the growth factor in the LCDM model

    SciTech Connect

    Ribeiro, A. L.B.; Andrade, A. P.A.; Letelier, P. S.

    2009-01-01

    We study the effect of noise on the evolution of the growth factor of density perturbations in the context of the LCDM model. Stochasticity is introduced as a Wiener process amplified by an intensity parameter alpha. By comparing the evolution of deterministic and stochastic cases for different values of alpha we estimate the intensity level necessary to make noise relevant for cosmological tests based on large-scale structure data. Our results indicate that the presence of random forces underlying the fluid description can lead to significant deviations from the nonstochastic solution at late times for alpha>0.001.

  9. Both epidermal growth factor and insulin-like growth factor receptors are dispensable for structural intestinal adaptation

    PubMed Central

    Sun, Raphael C.; Diaz-Miron, Jose L.; Choi, Pamela M.; Sommovilla, Joshua; Guo, Jun; Erwin, Christopher R.; Warner, Brad W.

    2015-01-01

    Purpose Intestinal adaptation structurally represents increases in crypt depth and villus height in response to small bowel resection (SBR). Previously, we found that neither epidermal growth factor receptor (EGFR) nor insulin-like growth factor 1 receptor (IGF1R) function was individually required for normal adaptation. In this study, we sought to determine the effect of disrupting both EGFR and IGF1R expression on resection-induced adaptation. Methods Intestinal-specific EGFR and IGF1R double knockout mice (EGFR/IGF1R-IKO) (n=6) and wild-type (WT) control mice (n=7) underwent 50% proximal SBR. On postoperative day (POD) 7, structural adaptation was scored by measuring crypt depth and villus height. Rates of crypt cell proliferation, apoptosis, and submucosal capillary density were also compared. Results After 50% SBR, normal adaptation occurred in both WT and EGFR/IGF1R-IKO. Rates of proliferation and apoptosis were no different between the two groups. The angiogenic response was less in the EGFR/IGF1R-IKO compared to WT mice. Conclusion Disrupted expression of EGFR and IGF1R in the intestinal epithelial cells does not affect resection-induced structural adaptation but attenuates angiogenesis after SBR. These findings suggest that villus growth is driven by receptors and pathways that occur outside the epithelial cell component, while angiogenic responses may be influenced by epithelial-endothelial crosstalk. PMID:25818318

  10. The spectral analysis of photoplethysmography to evaluate an independent cardiovascular risk factor

    PubMed Central

    Gandhi, Pratiksha G; Rao, Gundu HR

    2014-01-01

    Background In this study, we evaluate homeostatic markers correlated to autonomic nervous and endothelial functions in a population of coronary artery disease (CAD) patients versus a control group. Since CAD is the highest risk marker for sudden cardiac death, the study objective is to determine whether an independent cardiovascular risk score based on these markers can be used alongside known conventional cardiovascular risk markers to strengthen the understanding of a patient’s vascular state. Materials and methods Sixty-five subjects (13 women) with a mean age of 62.9 years (range 40–80 years) who were diagnosed with CAD using coronary angiography (group 1) and seventy-two subjects (29 women) with a mean age of 45.1 years (range 18–85 years) who claimed they were healthy (group 2) were included in the study. These subjects underwent examination with the TM-Oxi and SudoPath systems at IPC Heart Care Centers in Mumbai, India. The TM-Oxi system takes measurements from a blood pressure device and a pulse oximeter. The SudoPath measures galvanic skin response to assess the sudomotor pathway function. Spectral analysis of the photoplethysmograph (PTG) waveform and electrochemical galvanic skin response allow the TM-Oxi and SudoPath systems to calculate several homeostatic markers, such as the PTG index (PTGi), PTG very low frequency index (PTGVLFi), and PTG ratio (PTGr). The focus of this study was to evaluate these markers (PTGi, PTGVLFi, and PTGr) in CAD patients against a control group, and to calculate an independent cardiovascular risk factor score: the PTG cardiovascular disease risk score (PTG CVD), calculated solely from these markers. We compared PTGi, PTGVLFi, PTGr, and PTG CVD scores between the CAD patient group and the healthy control group. Statistical analyses were performed using receiver operating characteristic curves to determine the specificity and sensitivity of the markers to detect CAD at optimal cutoff values for PTGi, PTGVLFi, PTGr, and

  11. 1α,25-Dihydroxyvitamin D3 Inhibits C4-2 Prostate Cancer Cell Growth via a Retinoblastoma Protein (Rb)-Independent G1 Arrest

    PubMed Central

    Washington, Michele N.; Kim, Jung-Sun; Weigel, Nancy L.

    2010-01-01

    BACKGROUND The active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D) reduces the growth of several prostate cancer cell lines, most commonly by inducing a cell cycle arrest in G1. This is mediated, in part, through down-regulation of c-Myc, a positive regulator of the transcription factor, E2F. There is evidence that prostate cancer cells lacking functional retinoblastoma protein (Rb), a negative regulator of E2F activity, are poorly responsive to 1,25D treatment. Since up to 60% of prostate cancers demonstrate a loss of heterozygosity for Rb, we sought to determine whether Rb is required for the growth inhibitory effects of 1,25D. METHODS Using siRNA, Rb was reduced in C4-2 prostate cancer cells, and the response of cells to 1,25D treatment or depletion of c-myc measured by [3H]-thymidine incorporation and flow cytometry. The effects of 1,25D treatment on E2F levels and activity, and E2F target gene expression were also measured. RESULTS 1,25D treatment and c-Myc depletion both cause a G1 arrest inhibiting C4-2 cell proliferation independently of Rb. 1,25D reduces c-Myc expression and causes a decrease in E2F and E2F target genes. Bcl-2, an E2F target and positive regulator of C4-2 cell growth, also is down-regulated by 1,25D independently of Rb. CONCLUSIONS Redundant growth inhibitory pathways compensate for the loss of Rb, and tumors lacking functional Rb may be responsive to 1,25D. PMID:20632309

  12. Prognostic Significance of Vascular Endothelial Growth Factor Serum Determination in Women with Ovarian Cancer

    PubMed Central

    Bandiera, Elisabetta; Franceschini, Roberta; Specchia, Claudia; Bignotti, Eliana; Trevisiol, Chiara; Gion, Massimo; Pecorelli, Sergio; Santin, Alessandro Davide; Ravaggi, Antonella

    2012-01-01

    Introduction. We performed a review of the literature to elucidate the potential prognostic significance of serum vascular endothelial growth factor (sVEGF) levels in ovarian cancer. Methods. Eligible studies in English and Italian were identified in MEDLINE/PubMed from VEGF discovery to October 2011. All studies evaluating: (i) sVEGF levels before any surgical and chemotherapeutic treatment; (ii) the association between sVEGF levels and the established prognostic variables; (iii) the value of sVEGF levels in predicting patients' outcomes, were selected for this review. Results. The search resulted in 758 titles. Nine studies met the inclusion criteria. A statistically significant association between the level of sVEGF and FIGO stage, tumour grade, residual tumour size, lymph node involvement, and presence of ascites was found in at least one study. sVEGF, in comparison with the established prognostic factors, appears to be the best prognostic marker for overall survival, since it stands out as an independent prognostic factor in most of the studies considered. Moreover, sVEGF levels were shown to be independent prognostic factors by 2 out of the 3 studies that considered DFS as an end point. Conclusion. High levels of sVEGF identify a subgroup of patients with higher risk of death and/or recurrence. These patients should be eligible for individually tailored therapeutic interventions. PMID:22792477

  13. Trophic effect of human pericardial fluid on adult cardiac myocytes. Differential role of fibroblast growth factor-2 and factors related to ventricular hypertrophy.

    PubMed

    Corda, S; Mebazaa, A; Gandolfini, M P; Fitting, C; Marotte, F; Peynet, J; Charlemagne, D; Cavaillon, J M; Payen, D; Rappaport, L; Samuel, J L

    1997-11-01

    Pericardial fluid (PF) may contain myocardial growth factors that exert paracrine actions on cardiac myocytes. The aims of this study were (1) to investigate the effects of human PF and serum, collected from patients undergoing cardiac surgery, on the growth of cultured adult rat cardiac myocytes and (2) to relate the growth activity of both fluids to the adaptive changes in overloaded human hearts. Both PF and serum increased the rate of protein synthesis, measured by [14C]phenylalanine incorporation in adult rat cardiomyocytes (PF, +71.9 +/- 8.2% [n = 17]; serum, +14.9 +/- 6.5% [n = 13]; both P < .01 versus control medium). The effects of both PF and serum on cardiomyocyte growth correlated positively with the respective left ventricular (LV) mass. However, the magnitude of change with PF was 3-fold greater than with serum (P < .01). These trophic effects of PF were mimicked by exogenous basic fibroblast growth factor (FGF2) and inhibited by anti-FGF2 antibodies and transforming growth factor-beta (TGF-beta), suggesting a relationship to FGF2. In addition, FGF2 concentration in PF was 20 times greater than in serum. On the other hand, the LV mass-dependent trophic effect, present in both fluids, was independent of FGF2 concentration or other factors, such as angiotensin II, atrial natriuretic factor, and TGF-beta. These data suggest that FGF2 in human PF is a major determining factor in normal myocyte growth, whereas unidentified LV mass-dependent factor(s), present in both PF and serum, participates in the development of ventricular hypertrophy. PMID:9351441

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

    PubMed Central

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

    2015-01-01

    Significance: Growth factors are very promising molecules for the treatment of skin wounds. However, their translation to clinical use has been seriously limited, facing issues related to safety and cost-effectiveness. These problems may derive from the fact that growth factors are used at vastly supra-physiological levels without optimized delivery systems. Recent Advances: The extracellular matrix (ECM) plays a fundamental role in coordinating growth factor signaling. Therefore, understanding the mechanisms by which the ECM modulates growth factor activity is key for designing efficient growth factor-based therapies. Recently, several growth factor-binding domains have been discovered within various ECM proteins, and growth factor delivery systems integrating these ECM growth factor-binding domains showed promising results in animal models of skin wound healing. Moreover, a novel strategy consisting of engineering growth factors to target endogenous ECM could substantially enhance their efficacy, even when used at low doses. Critical Issues: Optimal delivery of growth factors often requires complex engineered biomaterial matrices, which can face regulatory issues for clinical translation. To simplify delivery systems and render strategies more applicable, growth factors can be engineered to optimally function with clinically approved biomaterials or with endogenous ECM present at the delivery site. Future Directions: Further development and clinical trials will reveal whether growth factor-based therapies can be used as main therapeutic approaches for skin wound healing. The future impact of these therapies will depend on our capacity to deliver growth factors more precisely, to improve efficacy, safety, and cost-effectiveness. PMID:26244104