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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. 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

  9. 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

  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. 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

  15. 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

  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

    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 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

  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. 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

  15. 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

  16. 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

  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. 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.

  9. 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

  10. 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

  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. 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

  16. 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.

  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 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

  19. 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

  20. 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

  1. 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

  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. 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

  20. 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

  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. 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

  3. 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

  4. [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

  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. 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

  7. 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

  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. 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

  12. 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

  13. 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

  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. 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

  18. 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

  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 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

  4. 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

  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. 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

  15. 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

  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. 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

  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

    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

  6. 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

  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. 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

  10. 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

  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. 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…

  16. 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

  17. 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

  18. 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

  19. [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

  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. 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

  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. 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

  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. 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

  7. 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

  8. [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

  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. 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

  6. 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

  7. 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

  8. 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].

  9. 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

  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. 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 ...

  18. 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…

  19. 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

  20. 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

  1. 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.

  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. 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…

  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. 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

  6. 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.

  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. 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

  10. 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

  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. 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

  13. 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.

  14. 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.

  15. 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

  16. 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

  17. 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

  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. 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

  3. 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

  4. 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.

  5. 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

  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 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

  9. 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.

  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. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  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. 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

  2. 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

  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 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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.

  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