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Sample records for adaptation growth arrest

  1. Growth arrest specific protein (GAS) 6

    Haase, T N; Rasmussen, Morten; Jaksch, C A M; Gaarn, L W; Petersen, Camilla K; Billestrup, N; Nielsen, Jens Høiriis

    2013-01-01

    Aims/hypothesis Maternal low-protein (LP) diet during gestation results in a reduced beta cell mass in the offspring at birth and this may hamper the ability to adapt to high-energy food and sedentary lifestyle later in life. To investigate the biology behind the LP-offspring phenotype, this study...... using RNA microarray and quantitative PCR. The role of a differentially expressed gene, growth arrest specific protein 6 (GAS6), was evaluated in vitro using neonatal rat islets. Results The mRNA level of Gas6, known to be mitogenic in other tissues, was reduced in LP offspring. The mRNA content of Mafa...... was increased in LP offspring suggesting an early maturation of beta cells. When applied in vitro, GAS6 increased proliferation of neonatal pancreatic beta cells, while reducing glucose-stimulated insulin secretion without changing the total insulin content of the islets. In addition, GAS6 decreased...

  2. Translational arrest due to cytoplasmic redox stress delays adaptation to growth on methanol and heterologous protein expression in a typical fed-batch culture of Pichia pastoris.

    Bryn Edwards-Jones

    Full Text Available We have followed a typical fed-batch induction regime for heterologous protein production under the control of the AOX1 promoter using both microarray and metabolomic analysis. The genetic constructs involved 1 and 3 copies of the TRY1 gene, encoding human trypsinogen. In small-scale laboratory cultures, expression of the 3 copy-number construct induced the unfolded protein response (UPR sufficiently that titres of extracellular trypsinogen were lower in the 3-copy construct than with the 1-copy construct. In the fed-batch-culture, a similar pattern was observed, with higher expression from the 1-copy construct, but in this case there was no significant induction of UPR with the 3-copy strain. Analysis of the microarray and metabolomic information indicates that the 3-copy strain was undergoing cytoplasmic redox stress at the point of induction with methanol. In this Crabtree-negative yeast, this redox stress appeared to delay the adaptation to growth on methanol and supressed heterologous protein production, probably due to a block in translation.Although redox imbalance as a result of artificially imposed hypoxia has previously been described, this is the first time that it has been characterised as a result of a transient metabolic imbalance and shown to involve a stress response which can lead to translational arrest. Without detailed analysis of the underlying processes it could easily have been mis-interpreted as secretion stress, transmitted through the UPR.

  3. MRI in the assessment of growth arrest

    Lohman, Martina; Kivisaari, Arto; Kivisaari, Leena [Helsinki Univ. Central Hospital (Finland). Dept. of Radiology; Vehmas, Tapio [Finnish Institute of Occupational Health, Helsinki (Finland); Kallio, Pentti; Puntila, Juha [Department of Paediatric Surgery, Hospital for Children and Adolescents, University Central Hospital, Helsinki (Finland)

    2002-01-01

    Objective: To compare MRI with X-ray tomography in the assessment of bone bridges across the growth plate. Materials and methods: The investigation consisted of two parts. (1) Eleven children with 13 epiphyses suspected of physeal growth arrests were examined with conventional X-ray tomography and MRI. The bar was post-traumatic in eight children, postinfectious in two and due to a congenital, operated pes equinovarus in one. Three blinded radiologists separately evaluated the examinations retrospectively. (2) The images of four children with known physeal bars in the ankle were mixed with 36 normal examinations obtained 1-year after trauma and evaluated blindly by three radiologists. Results: In 5 of 13 epiphysis, the bony bridge was considered smaller on MRI than on X-ray tomography, in 7 of 13 it was considered equal, while it was larger only in one. The interobserver agreement (weighted kappa) was 0.8 (very good) for MRI, 0.76 (good) for X-ray tomography and 0.60 (moderate) for radiographs. The four bony bridges were easily detected on MRI. Conclusions: Compared to MRI, the size of bridges was estimated larger by tomography in about half of the patients. (orig.)

  4. Paclitaxel Arrests Growth of Intracellular Toxoplasma gondii

    Estes, Randee; Vogel, Nicolas; Mack, Douglas; McLeod, Rima

    1998-01-01

    Addition of paclitaxel (Taxol) at a concentration of 1 μM to Toxoplasma gondii-infected human foreskin fibroblasts arrested parasite multiplication. Division of the T. gondii tachyzoite nucleus was inhibited, leading to syncytium-like parasite structures within the fibroblasts by 24 h after infection and treatment of the cultures. By 4 days after infection and treatment of the cultures with paclitaxel, this inhibition was irreversible, since the arrested intracellular form was incapable of le...

  5. Cell cycle control after DNA damage: arrest, recovery and adaptation

    DNA damage triggers surveillance mechanisms, the DNA checkpoints, that control the genome integrity. The DNA checkpoints induce several responses, either cellular or transcriptional, that favor DNA repair. In particular, activation of the DNA checkpoints inhibits cell cycle progression in all phases, depending on the stage when lesions occur. These arrests are generally transient and cells ultimately reenter the cell division cycle whether lesions have been repaired (this process is termed 'recovery') or have proved un-repairable (this option is called 'adaptation'). The mechanisms controlling cell cycle arrests, recovery and adaptation are largely conserved among eukaryotes, and much information is now available for the yeast Saccharomyces cerevisiae, that is used as a model organism in these studies. (author)

  6. Cellular Growth Arrest and Persistence from Enzyme Saturation

    Ray, J. Christian J.; Wickersheim, Michelle L.; Jalihal, Ameya P.; Adeshina, Yusuf O.; Cooper, Tim F.; Balázsi, Gábor

    2016-01-01

    Metabolic efficiency depends on the balance between supply and demand of metabolites, which is sensitive to environmental and physiological fluctuations, or noise, causing shortages or surpluses in the metabolic pipeline. How cells can reliably optimize biomass production in the presence of metabolic fluctuations is a fundamental question that has not been fully answered. Here we use mathematical models to predict that enzyme saturation creates distinct regimes of cellular growth, including a phase of growth arrest resulting from toxicity of the metabolic process. Noise can drive entry of single cells into growth arrest while a fast-growing majority sustains the population. We confirmed these predictions by measuring the growth dynamics of Escherichia coli utilizing lactose as a sole carbon source. The predicted heterogeneous growth emerged at high lactose concentrations, and was associated with cell death and production of antibiotic-tolerant persister cells. These results suggest how metabolic networks may balance costs and benefits, with important implications for drug tolerance. PMID:27010473

  7. Total triterpenoids from Ganoderma Lucidum suppresses prostate cancer cell growth by inducing growth arrest and apoptosis.

    Wang, Tao; Xie, Zi-ping; Huang, Zhan-sen; Li, Hao; Wei, An-yang; Di, Jin-ming; Xiao, Heng-jun; Zhang, Zhi-gang; Cai, Liu-hong; Tao, Xin; Qi, Tao; Chen, Di-ling; Chen, Jun

    2015-10-01

    In this study, one immortalized human normal prostatic epithelial cell line (BPH) and four human prostate cancer cell lines (LNCaP, 22Rv1, PC-3, and DU-145) were treated with Ganoderma Lucidum triterpenoids (GLT) at different doses and for different time periods. Cell viability, apoptosis, and cell cycle were analyzed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR and Western blotting. It was found that GLT dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. GLT-induced apoptosis was due to activation of Caspases-9 and -3 and turning on the downstream apoptotic events. GLT-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and E2F1 expression at the late time. These findings demonstrate that GLT suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which might suggest that GLT or Ganoderma Lucidum could be used as a potential therapeutic drug for prostate cancer. PMID:26489631

  8. The SWI/SNF chromatin-remodeling gene AtCHR12 mediates temporary growth arrest in Arabidopsis thaliana upon perceiving environmental stress.

    Mlynárová, Ludmila; Nap, Jan-Peter; Bisseling, Ton

    2007-09-01

    One of the earliest responses of plants to environmental stress is establishing a temporary growth arrest that allows adaptation to adverse conditions. The response to abiotic stress requires the modulation of gene expression, which may be mediated by the alteration of chromatin structures. This alteration can be accomplished with the help of chromatin-remodeling enzymes, such as the various SWI/SNF classes of ATPases. Here, we investigate the role of the Arabidopsis SNF2/Brahma-type AtCHR12 chromatin-remodeling gene in plant growth and development in reaction to adverse environmental conditions. We show that the AtCHR12 chromatin-remodeling gene plays a vital role in mediating the temporary growth arrest of Arabidopsis that is induced upon perception of stress. Exposing an AtCHR12 overexpressing mutant to stress conditions leads to growth arrest of normally active primary buds, as well as to reduced growth of the primary stem. In contrast, the AtCHR12 knockout mutant shows less growth arrest than the wild-type when exposed to moderate stress. Without stress, mutant plants are indistinguishable from the wild-type, and the growth arrest response seems to depend on the severity of the stress applied. Modulation of AtCHR12 expression correlates with changes in expression of dormancy-associated genes. This is in agreement with the concept of AtCHR12 participation in priming the plants for the growth arrest response. Our data indicate that AtCHR12-associated growth arrest differs from DELLA-mediated growth restraint. This establishes AtCHR12 as a novel gene involved in the response repertoire of plants that permits flexible modulation of growth in adverse and/or otherwise limiting environments. PMID:17605754

  9. Growth arrest and differentiation-associated phosphoproteins in mesenchymal stem cells

    Cancer is thought to result from the expression of defects in the control of both cell proliferation and differentiation. In murine mesenchymal stem cells they have established that differentiation and proliferation can be mediated at a variety of distinct states in the G1 phase of the cell cycle. In order to evaluate the role of cellular phosphoprotein (PP) expression in these regulatory processes, five different growth and differentiation-dependent states were compared. Cells in the following states were studied: (1) exponential growth; (2) arrest in serum-deficient medium; (3) arrest at the predifferentiation arrest state; (4) arrest at a state of nonterminal differentiation; and (5) arrest at a state of terminal differentiation. Whole cell lysates from each group were phosphorylated in vitro using [γ-32P]ATP and analyzed by SDS-polyacrylamide gel electrophoresis. Two most interesting observations were established. First, a distinct PP with a molecular weight of 37 kD was expressed in all growth arrested cells but was not evident in rapidly growing cells. Second, two distinct differentiation-associated PP with molecular weights of 72 kD and 29 kD were expressed exclusively in nonterminally and terminally differentiated cells. Since the identification of the 37 kD cell cycle-dependent growth arrest-associated PP could be of great significance, they plan to further investigate the functional role of this phosphoprotein in the control of cellular proliferation

  10. Gene expression signature in organized and growth arrested mammaryacini predicts good outcome in breast cancer

    Fournier, Marcia V.; Martin, Katherine J.; Kenny, Paraic A.; Xhaja, Kris; Bosch, Irene; Yaswen, Paul; Bissell, Mina J.

    2006-02-08

    To understand how non-malignant human mammary epithelial cells (HMEC) transit from a disorganized proliferating to an organized growth arrested state, and to relate this process to the changes that occur in breast cancer, we studied gene expression changes in non-malignant HMEC grown in three-dimensional cultures, and in a previously published panel of microarray data for 295 breast cancer samples. We hypothesized that the gene expression pattern of organized and growth arrested mammary acini would share similarities with breast tumors with good prognoses. Using Affymetrix HG-U133A microarrays, we analyzed the expression of 22,283 gene transcripts in two HMEC cell lines, 184 (finite life span) and HMT3522 S1 (immortal non-malignant), on successive days post-seeding in a laminin-rich extracellular matrix assay. Both HMECs underwent growth arrest in G0/G1 and differentiated into polarized acini between days 5 and 7. We identified gene expression changes with the same temporal pattern in both lines. We show that genes that are significantly lower in the organized, growth arrested HMEC than in their proliferating counterparts can be used to classify breast cancer patients into poor and good prognosis groups with high accuracy. This study represents a novel unsupervised approach to identifying breast cancer markers that may be of use clinically.

  11. The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line

    Suzuki, Harukazu; Forrest, Alistair R R; van Nimwegen, Erik;

    2009-01-01

    Using deep sequencing (deepCAGE), the FANTOM4 study measured the genome-wide dynamics of transcription-start-site usage in the human monocytic cell line THP-1 throughout a time course of growth arrest and differentiation. Modeling the expression dynamics in terms of predicted cis-regulatory sites...

  12. Withaferin-A induces mitotic catastrophe and growth arrest in prostate cancer cells

    Roy, Ram V; Suman, Suman; Das, Trinath P; Luevano, Joe; Damodaran, Chendil

    2013-01-01

    Cell cycle deregulation is strongly associated with the pathogenesis of prostate cancer (CaP). Clinical trials of cell cycle regulators that target either the G0/G1 or G2/M phase to inhibit the growth of cancers including CaP are increasing. In this study, we determined the cell-cycle regulatory potential of the herbal molecule Withaferin-A (WA) on CaP cells. WA induced irreversible G2/M arrest in both CaP cell lines (PC3 and DU145) for 48 h. The G2/M arrest was accompanied by upregulation of...

  13. p53-Induced Growth Arrest Is Regulated by the Mitochondrial SirT3 Deacetylase

    SiDe Li; Michaela Banck; Shiraz Mujtaba; Ming-Ming Zhou; Mary M Sugrue; Walsh, Martin J

    2010-01-01

    A hallmark of p53 function is to regulate a transcriptional program in response to extracellular and intracellular stress that directs cell cycle arrest, apoptosis, and cellular senescence. Independent of the role of p53 in the nucleus, some of the anti-proliferative functions of p53 reside within the mitochondria [1]. p53 can arrest cell growth in response to mitochondrial p53 in an EJ bladder carcinoma cell environment that is naïve of p53 function until induced to express p53 [2]. TP53 can...

  14. Prolyl oligopeptidase inhibition-induced growth arrest of human gastric cancer cells

    Suzuki, Kanayo [Laboratory of Cell Biology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094 (Japan); Sakaguchi, Minoru, E-mail: sakaguti@gly.oups.ac.jp [Laboratory of Cell Biology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094 (Japan); Tanaka, Satoshi [Laboratory of Cell Biology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094 (Japan); Yoshimoto, Tadashi [Department of Life Science, Setsunan University, 17-8 Ikeda-Nakamachi, Neyagawa, Osaka 572-8508 (Japan); Takaoka, Masanori [Laboratory of Cell Biology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094 (Japan)

    2014-01-03

    Highlights: •We examined the effects of prolyl oligopeptidase (POP) inhibition on p53 null gastric cancer cell growth. •POP inhibition-induced cell growth suppression was associated with an increase in a quiescent G{sub 0} state. •POP might regulate the exit from and/or reentry into the cell cycle. -- Abstract: Prolyl oligopeptidase (POP) is a serine endopeptidase that hydrolyzes post-proline peptide bonds in peptides that are <30 amino acids in length. We recently reported that POP inhibition suppressed the growth of human neuroblastoma cells. The growth suppression was associated with pronounced G{sub 0}/G{sub 1} cell cycle arrest and increased levels of the CDK inhibitor p27{sup kip1} and the tumor suppressor p53. In this study, we investigated the mechanism of POP inhibition-induced cell growth arrest using a human gastric cancer cell line, KATO III cells, which had a p53 gene deletion. POP specific inhibitors, 3-((4-[2-(E)-styrylphenoxy]butanoyl)-L-4-hydroxyprolyl)-thiazolidine (SUAM-14746) and benzyloxycarbonyl-thioprolyl-thioprolinal, or RNAi-mediated POP knockdown inhibited the growth of KATO III cells irrespective of their p53 status. SUAM-14746-induced growth inhibition was associated with G{sub 0}/G{sub 1} cell cycle phase arrest and increased levels of p27{sup kip1} in the nuclei and the pRb2/p130 protein expression. Moreover, SUAM-14746-mediated cell cycle arrest of KATO III cells was associated with an increase in the quiescent G{sub 0} state, defined by low level staining for the proliferation marker, Ki-67. These results indicate that POP may be a positive regulator of cell cycle progression by regulating the exit from and/or reentry into the cell cycle by KATO III cells.

  15. Physeal growth arrest after tibial lengthening in achondroplasia

    Song, Sang-Heon; Agashe, Mandar Vikas; Huh, Young-Jae; Hwang, Soon-Young; Song, Hae-Ryong

    2012-01-01

    Background and purpose Bilateral tibial lengthening has become one of the standard treatments for upper segment-lower segment disproportion and to improve quality of life in achondroplasia. We determined the effect of tibial lengthening on the tibial physis and compared tibial growth that occurred at the physis with that in non-operated patients with acondroplasia. Methods We performed a retrospective analysis of serial radiographs until skeletal maturity in 23 achondroplasia patients who und...

  16. Somatostatin receptor-1 induces cell cycle arrest and inhibits tumor growth in pancreatic cancer.

    Li, Min; Wang, Xiaochi; Li, Wei; Li, Fei; Yang, Hui; Wang, Hao; Brunicardi, F Charles; Chen, Changyi; Yao, Qizhi; Fisher, William E

    2008-11-01

    Functional somatostatin receptors (SSTR) are lost in human pancreatic cancer. Transfection of SSTR-1 inhibited pancreatic cancer cell proliferation in vitro. We hypothesize that stable transfection of SSTR-1 may inhibit pancreatic cancer growth in vivo possibly through cell cycle arrest. In this study, we examined the expression of SSTR-1 mRNA in human pancreatic cancer tissue specimens, and investigated the effect of SSTR-1 overexpression on cell proliferation, cell cycle, and tumor growth in a subcutaneous nude mouse model. We found that SSTR-1 mRNA was downregulated in the majority of pancreatic cancer tissue specimens. Transfection of SSTR-1 caused cell cycle arrest at the G(0)/G(1) growth phase, with a corresponding decline of cells in the S (mitotic) phase. The overexpression of SSTR-1 significantly inhibited subcutaneous tumor size by 71% and 43% (n = 5, P < 0.05, Student's t-test), and inhibited tumor weight by 69% and 47% (n = 5, P < 0.05, Student's t-test), in Panc-SSTR-1 and MIA-SSTR-1 groups, respectively, indicating the potent inhibitory effect of SSTR-1 on pancreatic cancer growth. Our data demonstrate that overexpression of SSTR-1 significantly inhibits pancreatic cancer growth possibly through cell cycle arrest. This study suggests that gene therapy with SSTR-1 may be a potential adjuvant treatment for pancreatic cancer. PMID:18823376

  17. Physeal growth arrest after tibial lengthening in achondroplasia

    2012-01-01

    Background and purpose Bilateral tibial lengthening has become one of the standard treatments for upper segment-lower segment disproportion and to improve quality of life in achondroplasia. We determined the effect of tibial lengthening on the tibial physis and compared tibial growth that occurred at the physis with that in non-operated patients with acondroplasia. Methods We performed a retrospective analysis of serial radiographs until skeletal maturity in 23 achondroplasia patients who underwent bilateral tibial lengthening before skeletal maturity (lengthening group L) and 12 achondroplasia patients of similar height and age who did not undergo tibial lengthening (control group C). The mean amount of lengthening of tibia in group L was 9.2 cm (lengthening percentage: 60%) and the mean age at the time of lengthening was 8.2 years. The mean duration of follow-up was 9.8 years. Results Skeletal maturity (fusion of physis) occurred at 15.2 years in group L and at 16.0 years in group C. The actual length of tibia (without distraction) at skeletal maturity was 238 mm in group L and 277 mm in group C (p = 0.03). The mean growth rates showed a decrease in group L relative to group C from about 2 years after surgery. Physeal closure was most pronounced on the anterolateral proximal tibial physis, with relative preservation of the distal physis. Interpretation Our findings indicate that physeal growth rate can be disturbed after tibial lengthening in achondroplasia, and a close watch should be kept for such an occurrence—especially when lengthening of more than 50% is attempted. PMID:22489887

  18. Die Rolle von growth arrest specific protein 6 im Aldosteron induzierten Endorganschaden

    Theuer, Stefanie

    2013-01-01

    Growth arrest specific protein 6 (Gas 6) is involved in inflammatory kidney diseases, vascular remodeling, cell adhesion, and thrombus formation. We explored a role for Gas 6 in aldosterone-induced target organ damage. We observed that Gas 6 was upregulated in rats with high aldosterone levels. Mineralocorticoid receptor blockade prevented target organ damage and decreased the elevated Gas 6 expression. Vascular smooth muscle cells given aldosterone increased their Gas 6 expression in vitro. ...

  19. Growth arrest-specific protein 6 plasma concentrations during septic shock

    Gibot, Sébastien; Massin, Frédéric; Cravoisy, Aurélie; Dupays, Rachel; Barraud, Damien; Nace, Lionel; Bollaert, Pierre-Edouard

    2007-01-01

    Introduction The product of growth arrest-specific gene 6 (Gas6) is a vitamin K dependent protein that is secreted by leucocytes and endothelial cells in response to injury and participates in cell survival, proliferation, migration and adhesion. Our purpose was to investigate plasma Gas6 concentration and its relation to organ dysfunction in patients with septic shock. Methods Forty-five patients with septic shock admitted to a medical adult intensive care unit were enrolled. Plasma Gas6 con...

  20. RRR-α-tocopheryl succinate inhibits human gastric cancer SGC-7901 cell growth by inducing apoptosis and DNA synthesis arrest

    Wu, Kun; ZHAO Yan; Liu, Bai-He; Li, Yao; Liu, Fang; Guo, Jian; Yu, Wei-Ping

    2002-01-01

    AIM: To investigate the effects of growth inhibition of human gastric cancer SGC-7901 cell with RRR-α-tocopheryl succinate (VES), a derivative of natural Vitamin E, via inducing apoptosis and DNA synthesis arrest.

  1. MR imaging of pituitary hyperplasia in a child with growth arrest and primary hypothyroidism

    Magnetic resonance imaging of pituitary hyperplasia has been rarely described in children with primary hypothyroidism. We report a case of pituitary hyperplasia in a child presented with significant growth arrest and laboratory evidence of hypothyroidism. Magnetic resonance imaging revealed symmetrical pituitary enlargement simulating macroadenoma. After thyroid hormone replacement therapy, the child's height increased and pituitary enlargement regressed to normal. Awareness of MRI appearance of pituitary hyperplasia in children with laboratory evidence of hypothyroidism might avoid misdiagnosis for pituitary tumor, which may also manifest as growth disorder, obviating unnecessary surgery. (orig.)

  2. Direct inhibition of Retinoblastoma phosphorylation by Nimbolide causes cell cycle arrest and suppresses glioblastoma growth

    Anderson, Jane; Liu, Xiaona; Henry, Heather; Gasilina, Anjelika; Nassar, Nicholas; Ghosh, Jayeeta; Clark, Jason P; Kumar, Ashish; Pauletti, Giovanni M.; Ghosh, Pradip K; Dasgupta, Biplab

    2013-01-01

    Purpose Classical pharmacology allows the use and development of conventional phytomedicine faster and more economically than conventional drugs. This approach should be tested for their efficacy in terms of complementarity and disease control. The purpose of this study was to determine the molecular mechanisms by which nimbolide, a triterpenoid found in the well-known medicinal plant Azadirachta indica controls glioblastoma (GBM) growth. Experimental Design Using in vitro signaling, anchorage-independent growth, kinase assays, and xenograft models, we investigated the mechanisms of its growth inhibition in glioblastoma. Results We show that nimbolide or an ethanol soluble fraction of A. indica leaves (Azt) that contains nimbolide as the principal cytotoxic agent is highly cytotoxic against GBM in vitro and in vivo. Azt caused cell cycle arrest, most prominently at the G1-S stage in GBM cells expressing EGFRvIII, an oncogene present in about 20-25% of GBMs. Azt/nimbolide directly inhibited CDK4/CDK6 kinase activity leading to hypophosphorylation of the retinoblastoma (RB) protein, cell cycle arrest at G1-S and cell death. Independent of RB hypophosphorylation, Azt also significantly reduced proliferative and survival advantage of GBM cells in vitro and in tumor xenografts by downregulating Bcl2 and blocking growth factor induced phosphorylation of Akt, Erk1/2 and STAT3. These effects were specific since Azt did not affect mTOR or other cell cycle regulators. In vivo, Azt completely prevented initiation and inhibited progression of GBM growth. Conclusions Our preclinical findings demonstrate Nimbolide as a potent anti-glioma agent that blocks cell cycle and inhibits glioma growth in vitro and in vivo. PMID:24170547

  3. Placental Adaptations in Growth Restriction

    Song Zhang

    2015-01-01

    Full Text Available The placenta is the primary interface between the fetus and mother and plays an important role in maintaining fetal development and growth by facilitating the transfer of substrates and participating in modulating the maternal immune response to prevent immunological rejection of the conceptus. The major substrates required for fetal growth include oxygen, glucose, amino acids and fatty acids, and their transport processes depend on morphological characteristics of the placenta, such as placental size, morphology, blood flow and vascularity. Other factors including insulin-like growth factors, apoptosis, autophagy and glucocorticoid exposure also affect placental growth and substrate transport capacity. Intrauterine growth restriction (IUGR is often a consequence of insufficiency, and is associated with a high incidence of perinatal morbidity and mortality, as well as increased risk of cardiovascular and metabolic diseases in later life. Several different experimental methods have been used to induce placental insufficiency and IUGR in animal models and a range of factors that regulate placental growth and substrate transport capacity have been demonstrated. While no model system completely recapitulates human IUGR, these animal models allow us to carefully dissect cellular and molecular mechanisms to improve our understanding and facilitate development of therapeutic interventions.

  4. Necdin, a p53-target gene, is an inhibitor of p53-mediated growth arrest.

    Julie Lafontaine

    Full Text Available In vitro, cellular immortalization and transformation define a model for multistep carcinogenesis and current ongoing challenges include the identification of specific molecular events associated with steps along this oncogenic pathway. Here, using NIH3T3 cells, we identified transcriptionally related events associated with the expression of Polyomavirus Large-T antigen (PyLT, a potent viral oncogene. We propose that a subset of these alterations in gene expression may be related to the early events that contribute to carcinogenesis. The proposed tumor suppressor Necdin, known to be regulated by p53, was within a group of genes that was consistently upregulated in the presence of PyLT. While Necdin is induced following p53 activation with different genotoxic stresses, Necdin induction by PyLT did not involve p53 activation or the Rb-binding site of PyLT. Necdin depletion by shRNA conferred a proliferative advantage to NIH3T3 and PyLT-expressing NIH3T3 (NIHLT cells. In contrast, our results demonstrate that although overexpression of Necdin induced a growth arrest in NIH3T3 and NIHLT cells, a growing population rapidly emerged from these arrested cells. This population no longer showed significant proliferation defects despite high Necdin expression. Moreover, we established that Necdin is a negative regulator of p53-mediated growth arrest induced by nutlin-3, suggesting that Necdin upregulation could contribute to the bypass of a p53-response in p53 wild type tumors. To support this, we characterized Necdin expression in low malignant potential ovarian cancer (LMP where p53 mutations rarely occur. Elevated levels of Necdin expression were observed in LMP when compared to aggressive serous ovarian cancers. We propose that in some contexts, the constitutive expression of Necdin could contribute to cancer promotion by delaying appropriate p53 responses and potentially promote genomic instability.

  5. Adapting RRT growth for heterogeneous environments

    Denny, Jory

    2013-11-01

    Rapidly-exploring Random Trees (RRTs) are effective for a wide range of applications ranging from kinodynamic planning to motion planning under uncertainty. However, RRTs are not as efficient when exploring heterogeneous environments and do not adapt to the space. For example, in difficult areas an expensive RRT growth method might be appropriate, while in open areas inexpensive growth methods should be chosen. In this paper, we present a novel algorithm, Adaptive RRT, that adapts RRT growth to the current exploration area using a two level growth selection mechanism. At the first level, we select groups of expansion methods according to the visibility of the node being expanded. Second, we use a cost-sensitive learning approach to select a sampler from the group of expansion methods chosen. Also, we propose a novel definition of visibility for RRT nodes which can be computed in an online manner and used by Adaptive RRT to select an appropriate expansion method. We present the algorithm and experimental analysis on a broad range of problems showing not only its adaptability, but efficiency gains achieved by adapting exploration methods appropriately. © 2013 IEEE.

  6. Growth inhibitory effect of 4-phenyl butyric acid on human gastric cancer cells is associated with cell cycle arrest

    Long-Zhu Li; Hong-Xia Deng; Wen-Zhu Lou; Xue-Yan Sun; Meng-Wan Song; Jing Tao; Bing-Xiu Xiao; Jun-Ming Guo

    2012-01-01

    AIM: To investigate the growth effects of 4-phenyl butyric acid (PBA) on human gastric carcinoma cells and their mechanisms. METHODS: Moderately-differentiated human gastric carcinoma SGC-7901 and lowly-differentiated MGC-803 cells were treated with 5, 10, 20, 40, and 60 μmol/L PBA for 1-4 d. Cell proliferation was detected using the MTT colorimetric assay. Cell cycle distributions were examined using flow cytometry. RESULTS: The proliferation of gastric carcinoma cells was inhibited by PBA in a dose- and time-dependent fashion. Flow cytometry showed that SGC-7901 cells treated with low concentrations of PBA were arrested at the G0/G1 phase, whereas cells treated with high concentrations of PBA were arrested at the G2/M phase. Although MGC-803 cells treated with low concentrations of PBA were also arrested at the G0/G1 phase, cells treated with high concentrations of PBA were arrested at the S phase. CONCLUSION: The growth inhibitory effect of PBA on gastric cancer cells is associated with alteration of the cell cycle. For moderately-differentiated gastric cancer cells, the cell cycle was arrested at the G0/G1 and G2/M phases. For lowly-differentiated gastric cancer cells, the cell cycle was arrested at the G0/G1 and S phases.

  7. Withaferin-A induces mitotic catastrophe and growth arrest in prostate cancer cells

    Roy, Ram V; Suman, Suman; Das, Trinath P.; Luevano, Joe; Damodaran, Chendil

    2014-01-01

    Cell cycle deregulation is strongly associated with the pathogenesis of prostate cancer (CaP). Clinical trials of cell cycle regulators that target either the G0/G1 or G2/M phase to inhibit the growth of cancers including CaP are increasing. In this study, we determined the cell-cycle regulatory potential of the herbal molecule Withaferin-A (WA) on CaP cells. WA induced irreversible G2/M arrest in both CaP cell lines (PC3 and DU145) for 48 h. The G2/M arrest was accompanied by upregulation of phosphorylated Wee1, phophorylated histone H3, p21 and Aurora-B. On the other hand, downregulation of cyclins (E2, A, and B1) and phorphorylated Cdc2 (Tyr15) was observed in WA-treated CaP cells. In addition, decreased levels of phosphorylated Chk1 (Ser345) and Chk2 (Thr68) were evident in WA-treated CaP cells. Our results suggest that activation of Cdc2 leads to accumulation in M-phase, with abnormal duplication, and initiation of mitotic catastrophe that results in cell death. In conclusion, these results clearly highlight the potential of WA as a regulator of the G2/M phase of the cell cycle and as a therapeutic agent for CaP. PMID:24079846

  8. Arrested chain growth during magnetic directed particle assembly in yield stress matrix fluids.

    Rich, Jason P; McKinley, Gareth H; Doyle, Patrick S

    2012-02-28

    The process of assembling particles into organized functional structures is influenced by the rheological properties of the matrix fluid in which the assembly takes place. Therefore, tuning these properties represents a viable and as yet unexplored approach for controlling particle assembly. In this Letter, we examine the effect of the matrix fluid yield stress on the directed assembly of polarizable particles into linear chains under a uniform external magnetic field. Using particle-level simulations with a simple yield stress model, we find that chain growth follows the same trajectory as in Newtonian matrix fluids up to a critical time that depends on the balance between the yield stress and the strength of magnetic interactions between particles; subsequently, the system undergoes structural arrest. Appropriate dimensionless groups for characterizing the arresting behavior are determined and relationships between these groups and the resulting structural properties are presented. Since field-induced structures can be indefinitely stabilized by the matrix fluid yield stress and "frozen" into place as desired, this approach may facilitate the assembly of more complex and sophisticated structures. PMID:22335399

  9. Type-1-cytokines synergize with oncogene inhibition to induce tumor growth arrest

    Acquavella, Nicolas; Clever, David; Yu, Zhiya; Roelke-Parker, Melody; Palmer, Douglas C.; Xi, Liqiang; Pflicke, Holger; Ji, Yun; Gros, Alena; Hanada, Ken-ichi; Goldlust, Ian S.; Mehta, Gautam U.; Klebanoff, Christopher A.; Crompton, Joseph G.; Sukumar, Madhusudhanan; Morrow, James J.; Franco, Zulmarie; Gattinoni, Luca; Liu, Hui; Wang, Ena; Marincola, Francesco; Stroncek, David F.; Lee, Chyi-Chia R.; Raffeld, Mark; Bosenberg, Marcus W.; Roychoudhuri, Rahul; Restifo, Nicholas P.

    2014-01-01

    Both targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer but responses can be either short-lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAFV600E-mutant murine melanoma model (SB-3123), we explore potential mechanisms of synergy between the selective BRAFV600E inhibitor vemurafenib and adoptive cell transfer (ACT)-based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression without significantly affecting tumor infiltration or effector function of endogenous or adoptively transferred CD8+ T cells as previously observed. Instead, we found that the T-cell cytokines IFNγ and TNFα synergized with vemurafenib to induce cell-cycle arrest of tumor cells in vitro. This combinatorial effect was recapitulated in human melanoma-derived cell lines and was restricted to cancers bearing a BRAFV600E-mutation. Molecular profiling of treated SB-3123 indicated that the provision of vemurafenib promoted the sensitization of SB-3123 to the anti-proliferative effects of T-cell effector cytokines. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest have major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer. PMID:25358764

  10. The Role of Telomere Maintenance in the Spontaneous Growth Arrest of Pediatric Low-Grade Gliomas

    Uri Tabori

    2006-02-01

    Full Text Available Spontaneous tumor regression is a unique feature of pediatric low-grade gliomas (PLGG. We speculated that lack of telomere maintenance is responsible for this behavior. We first looked for evidence of telomerase activity and alternative-lengthening telomeres (ALT in 56 PLGG. Telomerase activity was observed in 0 of 11 PLGG in contrast to 10 of 13 high-grade pediatric brain tumors. There was no ALT in 45 of 45 samples. We applied Q-FISH to eight patients whose indolent PLGG underwent two metachronous biopsies over a lag of several years. Telomere shortening was observed in the second biopsy in all tumors but not in a normal brain control (P 8.0 conferred a high likelihood of late recurrences in PLGG. Our findings provide a plausible biological mechanism to explain the tendency of PLGG to exhibit growth arrest and spontaneous regression. Telomere maintenance may therefore represent the first known biologic prognostic marker in PLGG.

  11. Parafibromin inhibits cancer cell growth and causes G1 phase arrest

    The HRPT2 (hereditary hyperparathyroidism type 2) tumor suppressor gene encodes a ubiquitously expressed 531 amino acid protein termed parafibromin. Inactivation of parafibromin predisposes one to the development of HPT-JT syndrome. To date, the role of parafibromin in tumorigenesis is largely unknown. Here, we report that parafibromin is a nuclear protein that possesses anti-proliferative properties. We show that overexpression of parafibromin inhibits colony formation and cellular proliferation, and induces cell cycle arrest in the G1 phase. Moreover, HPT-JT syndrome-derived mutations in HRPT2 behave in a dominant-negative manner by abolishing the ability of parafibromin to suppress cell proliferation. These findings suggest that parafibromin has a critical role in cell growth, and mutations in HRPT2 can directly inhibit this role

  12. Silencing NOTCH signaling causes growth arrest in both breast cancer stem cells and breast cancer cells

    Suman, S; Das, T P; Damodaran, C

    2013-01-01

    Background: Breast cancer stem cells (BCSCs) are characterized by high aldehyde dehydrogenase (ALDH) enzyme activity and are refractory to current treatment modalities, show a higher risk for metastasis, and influence the epithelial to mesenchymal transition (EMT), leading to a shorter time to recurrence and death. In this study, we focused on examination of the mechanism of action of a small herbal molecule, psoralidin (Pso) that has been shown to effectively suppress the growth of BSCSs and breast cancer cells (BCCs), in breast cancer (BC) models. Methods: ALDH− and ALDH+ BCCs were isolated from MDA-MB-231 cells, and the anticancer effects of Pso were measured using cell viability, apoptosis, colony formation, invasion, migration, mammosphere formation, immunofluorescence, and western blot analysis. Results: Psoralidin significantly downregulated NOTCH1 signaling, and this downregulation resulted in growth inhibition and induction of apoptosis in both ALDH− and ALDH+ cells. Molecularly, Pso inhibited NOTCH1 signaling, which facilitated inhibition of EMT markers (β-catenin and vimentin) and upregulated E-cadherin expression, resulting in reduced migration and invasion of both ALDH− and ALDH+ cells. Conclusion: Together, our results suggest that inhibition of NOTCH1 by Pso resulted in growth arrest and inhibition of EMT in BCSCs and BCCs. Psoralidin appears to be a novel agent that targets both BCSCs and BCCs. PMID:24129237

  13. Understanding the functional difference between growth arrest-specific protein 6 and protein S : an evolutionary approach

    Studer, Romain A.; Opperdoes, Fred R.; Nicolaes, Gerry A. F.; Mulder, Andre B.; Mulder, Rene

    2014-01-01

    Although protein S (PROS1) and growth arrest-specific protein 6 (GAS6) proteins are homologous with a high degree of structural similarity, they are functionally different. The objectives of this study were to identify the evolutionary origins from which these functional differences arose. Bioinform

  14. Analysis of HIV-1 Vpr determinants responsible for cell growth arrest in Saccharomyces cerevisiae

    Yao Xiao-Jian

    2004-08-01

    Full Text Available Abstract Background The HIV-1 genome encodes a well-conserved accessory gene product, Vpr, that serves multiple functions in the retroviral life cycle, including the enhancement of viral replication in nondividing macrophages, the induction of G2 cell-cycle arrest, and the modulation of HIV-1-induced apoptosis. We previously reported the genetic selection of a panel of di-tryptophan (W-containing peptides capable of interacting with HIV-1 Vpr and inhibiting its cytostatic activity in Saccharomyces cerevisiae (Yao, X.-J., J. Lemay, N. Rougeau, M. Clément, S. Kurtz, P. Belhumeur, and E. A. Cohen, J. Biol. Chem. v. 277, p. 48816–48826, 2002. In this study, we performed a mutagenic analysis of Vpr to identify sequence and/or structural determinants implicated in the interaction with di-W-containing peptides and assessed the effect of mutations on Vpr-induced cytostatic activity in S. cerevisiae. Results Our data clearly shows that integrity of N-terminal α-helix I (17–33 and α-helix III (53–83 is crucial for Vpr interaction with di-W-containing peptides as well as for the protein-induced cytostatic effect in budding yeast. Interestingly, several Vpr mutants, mainly in the N- and C-terminal domains, which were previously reported to be defective for cell-cycle arrest or apoptosis in human cells, still displayed a cytostatic activity in S. cerevisiae and remained sensitive to the inhibitory effect of di-W-containing peptides. Conclusions Vpr-induced growth arrest in budding yeast can be effectively inhibited by GST-fused di-W peptide through a specific interaction of di-W peptide with Vpr functional domain, which includes α-helix I (17–33 and α-helix III (53–83. Furthermore, the mechanism(s underlying Vpr-induced cytostatic effect in budding yeast are likely to be distinct from those implicated in cell-cycle alteration and apoptosis in human cells.

  15. The lag-phase during diauxic growth is a trade-off between fast adaptation and high growth rate

    Chu, Dominique; Barnes, David J.

    2016-04-01

    Bi-phasic or diauxic growth is often observed when microbes are grown in a chemically defined medium containing two sugars (for example glucose and lactose). Typically, the two growth stages are separated by an often lengthy phase of arrested growth, the so-called lag-phase. Diauxic growth is usually interpreted as an adaptation to maximise population growth in multi-nutrient environments. However, the lag-phase implies a substantial loss of growth during the switch-over. It therefore remains unexplained why the lag-phase is adaptive. Here we show by means of a stochastic simulation model based on the bacterial PTS system that it is not possible to shorten the lag-phase without incurring a permanent growth-penalty. Mechanistically, this is due to the inherent and well established limitations of biological sensors to operate efficiently at a given resource cost. Hence, there is a trade-off between lost growth during the diauxic switch and the long-term growth potential of the cell. Using simulated evolution we predict that the lag-phase will evolve depending on the distribution of conditions experienced during adaptation. In environments where switching is less frequently required, the lag-phase will evolve to be longer whereas, in frequently changing environments, the lag-phase will evolve to be shorter.

  16. Three-dimensional MR imaging in the assessment of physeal growth arrest

    Sailhan, Frederic; Chotel, Franck; Gollogly, Sohrab; Adam, Philippe; Berard, Jerome [Department of Orthopaedics, Hopital Bebrousse, 29 rue Soeur Bouvier, 69005, Lyon (France); Guibal, Anne-Laure; Guibaud, Laurent [Department of Radiology, Hopital Bebrousse, 29 rue Soeur Bouvier, 69005, Lyon (France)

    2004-09-01

    The purpose of this study is to describe an imaging method for identifying and characterising physeal growth arrest following physeal plate aggression. The authors describe the use of three-dimensional MRI performed with fat-suppressed three-dimensional spoiled gradient-recalled echo sequences followed by manual image reconstruction to create a 3D model of the physeal plate. This retrospective series reports the analysis of 33 bony physeal bridges in 28 children (mean age 10.5 years) with the use of fat-suppressed three-dimensional spoiled gradient-recalled echo imaging and 3D reconstructions from the source images. 3D reconstructions were obtained after the outlining was done manually on each source image. Files of all patients were reviewed for clinical data at the time of MRI, type of injury, age at MRI and bone bridge characteristics on reconstructions. Twenty-one (63%) of the 33 bridges were post-traumatic and were mostly situated in the lower extremities (19/21). The distal tibia was involved in 66% (14/21) of the cases. Bridges due to causes other than trauma were located in the lower extremities in 10/12 cases, and the distal femur represented 60% of these cases. Of the 28 patients, five presented with two bridges involving two different growth plates making a total of 33 physeal bone bars. The location and shape of each bridge was accurately identified in each patient, and in post-traumatic cases, 89% of bone bars were of Ogden type III (central) or I (peripheral). Reconstructions were obtained in 15 min and are easy to interpret. Volumes of the physeal bone bridge(s) and of the remaining normal physis were calculated. The bone bridging represented less than 1% to 47% of the total physeal plate volume. The precise shape and location of the bridge can be visualised on the 3D reconstructions. This information is useful in the surgical management of these deformities; as for the eight patients who underwent bone bar resection, an excellent correspondence was

  17. Growth arrest specific protein 6 participates in DOCA-induced target-organ damage.

    Park, Joon-Keun; Theuer, Stefanie; Kirsch, Torsten; Lindschau, Carsten; Klinge, Uwe; Heuser, Arnd; Plehm, Ralph; Todiras, Mihai; Carmeliet, Peter; Haller, Hermann; Luft, Friedrich C; Muller, Dominik N; Fiebeler, Anette

    2009-08-01

    Growth arrest-specific protein 6 (Gas 6) is involved in inflammatory kidney diseases, vascular remodeling, cell adhesion, and thrombus formation. We explored a role for Gas 6 in aldosterone-induced target organ damage. We observed that Gas 6 was upregulated in rats with high aldosterone levels. Mineralocorticoid receptor blockade prevented target organ damage and decreased the elevated Gas 6 expression. Vascular smooth muscle cells given aldosterone increased their Gas 6 expression in vitro. To test the pathophysiological relevance, we investigated the effects of deoxycorticosterone acetate (DOCA) on Gas 6 gene-deleted ((-/-)) mice. After 6 weeks DOCA, Gas 6(-/-) mice developed similar telemetric blood pressure elevations compared to wild-type mice but were protected from cardiac hypertrophy. Cardiac expression of interleukin 6 and collagen IV was blunted in Gas 6(-/-) mice, indicating reduced inflammation and fibrosis. Gas 6(-/-) mice also had an improved renal function with reduced albuminuria, compared to wild-type mice. Renal fibrosis and fibronectin deposition in the kidney were also reduced. Gas 6 deficiency reduces the detrimental effects of aldosterone on cardiac and renal remodeling independent of blood pressure reduction. Gas 6 appears to play a role in mineralocorticoid receptor-mediated target organ damage. Furthermore, because warfarin interferes with Gas 6 protein expression, the findings could be of clinical relevance for anticoagulant choices. PMID:19564549

  18. Indole-3-carbinol inhibits nasopharyngeal carcinoma growth through cell cycle arrest in vivo and in vitro.

    Zhe Chen

    Full Text Available Nasopharyngeal carcinoma is a common malignant tumor in the head and neck. Because of frequent recurrence and distant metastasis which are the main causes of death, better treatment is needed. Indole-3-carbinol (I3C, a natural phytochemical found in the vegetables of the cruciferous family, shows anticancer effect through various signal pathways. I3C induces G1 arrest in NPC cell line with downregulation of cell cycle-related proteins, such as CDK4, CDK6, cyclin D1 and pRb. In vivo, nude mice receiving I3C protectively or therapeutically exhibited smaller tumors than control group after they were inoculated with nasopharyngeal carcinoma cells. The expression of CDK4, CDK6, cyclin D1 and pRb in preventive treatment group and drug treatment group both decreased compared with the control group. We conclude that I3C can inhibit the growth of NPC in vitro and in vivo by suppressing the expression of CDK and cyclin families. The drug was safe and had no toxic effects on normal tissues and organs.

  19. Postmortem serum protein growth arrest-specific 6 levels in sepsis-related deaths.

    Palmiere, Cristian; Augsburger, Marc

    2015-09-01

    Growth arrest-specific 6 (Gas6) is widely expressed in leukocytes, platelets, endothelial cells, and monocytes. It regulates various processes including granulocyte adhesion to the endothelium, cell migration, thrombus stabilization, and cytokine release. In humans, increased plasma Gas6 levels have been described in patients with sepsis and septic shock. In this study, Gas6 concentrations were measured in postmortem serum from femoral blood in a series of sepsis-related fatalities and control cases. The aims were twofold: first, to determine whether Gas6 can be reliably determined in postmortem serum; and second, to assess its diagnostic potential in identifying sepsis-related deaths. Two study groups were prospectively formed, a sepsis-related fatalities group (24 cases) and a control group (24 cases) including cases of deep vein thrombosis and fatal pulmonary embolism, cases of systemic inflammatory response syndrome in severe trauma, cases of end-stage renal failure, and cases of hanging (non-septic, non-SIRS, non-end stage renal failure cases). The preliminary results of this study seem to indicate that Gas6 can be effectively measured in postmortem serum. However, Gas6 levels in sepsis-related fatalities do not appear to be clearly distinguishable from concentrations in pulmonary embolism, severe trauma, and end-stage renal failure cases. These findings tend to support previous reports that indicated that Gas6 behaves as an acute phase reactant and can be considered a general marker of inflammation rather than a specific biomarker of sepsis. PMID:26233610

  20. A novel peptide sansalvamide analogue inhibits pancreatic cancer cell growth through G0/G1 cell-cycle arrest

    Patients with pancreatic cancer have little hope for cure because no effective therapies are available. Sansalvamide A is a cyclic depsipeptide produced by a marine fungus. We investigated the effect of a novel sansalvamide A analogue on growth, cell-cycle phases, and induction of apoptosis in human pancreatic cancer cells in vitro. The sansalvamide analogue caused marked time- and concentration-dependent inhibition of DNA synthesis and cell proliferation of two human pancreatic cancer cell lines (AsPC-1 and S2-013). The analogue induced G0/G1 phase cell-cycle arrest and morphological changes suggesting induction of apoptosis. Apoptosis was confirmed by annexin V binding. This novel sansalvamide analogue inhibits growth of pancreatic cancer cells through G0/G1 arrest and induces apoptosis. Sansalvamide analogues may be valuable for the treatment of pancreatic cancer

  1. Mutation of Growth Arrest Specific 8 Reveals a Role in Motile Cilia Function and Human Disease.

    Lewis, Wesley R; Malarkey, Erik B; Tritschler, Douglas; Bower, Raqual; Pasek, Raymond C; Porath, Jonathan D; Birket, Susan E; Saunier, Sophie; Antignac, Corinne; Knowles, Michael R; Leigh, Margaret W; Zariwala, Maimoona A; Challa, Anil K; Kesterson, Robert A; Rowe, Steven M; Drummond, Iain A; Parant, John M; Hildebrandt, Friedhelm; Porter, Mary E; Yoder, Bradley K; Berbari, Nicolas F

    2016-07-01

    Ciliopathies are genetic disorders arising from dysfunction of microtubule-based cellular appendages called cilia. Different cilia types possess distinct stereotypic microtubule doublet arrangements with non-motile or 'primary' cilia having a 9+0 and motile cilia have a 9+2 array of microtubule doublets. Primary cilia are critical sensory and signaling centers needed for normal mammalian development. Defects in their structure/function result in a spectrum of clinical and developmental pathologies including abnormal neural tube and limb patterning. Altered patterning phenotypes in the limb and neural tube are due to perturbations in the hedgehog (Hh) signaling pathway. Motile cilia are important in fluid movement and defects in motility result in chronic respiratory infections, altered left-right asymmetry, and infertility. These features are the hallmarks of Primary Ciliary Dyskinesia (PCD, OMIM 244400). While mutations in several genes are associated with PCD in patients and animal models, the genetic lesion in many cases is unknown. We assessed the in vivo functions of Growth Arrest Specific 8 (GAS8). GAS8 shares strong sequence similarity with the Chlamydomonas Nexin-Dynein Regulatory Complex (NDRC) protein 4 (DRC4) where it is needed for proper flagella motility. In mammalian cells, the GAS8 protein localizes not only to the microtubule axoneme of motile cilia, but also to the base of non-motile cilia. Gas8 was recently implicated in the Hh signaling pathway as a regulator of Smoothened trafficking into the cilium. Here, we generate the first mouse with a Gas8 mutation and show that it causes severe PCD phenotypes; however, there were no overt Hh pathway phenotypes. In addition, we identified two human patients with missense variants in Gas8. Rescue experiments in Chlamydomonas revealed a subtle defect in swim velocity compared to controls. Further experiments using CRISPR/Cas9 homology driven repair (HDR) to generate one of these human missense variants in

  2. Overexpression of a novel gene, Cms1, can rescue the growth arrest of a Saccharomyces cerevisiae mcm10 suppressor

    2001-01-01

    MCM10 protein is an essential replication factor involved in the initiation of DNA replication. A mcm10 mutant (mcm10-1) of budding yeast shows a growth arrest at 37℃. In the present work, we have isolated a mcm10-1 suppressor strain, which grows at 37℃. Interestingly, this mcm10-1 suppressor undergoes cell cycle arrest at 14℃. A novel gene, YLR003c, is identified by high-copy complementation of this suppressor. We called it as Cmsl (Complementation of Mcm 10 Suppressor). Furthermore, the experiments of transformation show that cells of mcm10-1 suppressor with high-copy plasmid but not low-copy plasmid grow at 14℃, indicating that overexpression of Cmsl can rescue the growth arrest of this mcm10 suppressor at non-permissive temperature. These results suggest that CMS1 protein may functionally interact with MCM10 protein and play a role in the regulation of DNA replication and cell cycle control.

  3. Airway Delivery of Mesenchymal Stem Cells Prevents Arrested Alveolar Growth in Neonatal Lung Injury in Rats

    van Haaften, Timothy; Byrne, Roisin; Bonnet, Sebastien; Rochefort, Gael Y.; Akabutu, John; Bouchentouf, Manaf; Rey-Parra, Gloria J.; Galipeau, Jacques; Haromy, Alois; Eaton, Farah; Chen, Ming; Hashimoto, Kyoko; Abley, Doris; Korbutt, Greg; Archer, Stephen L.

    2009-01-01

    Rationale: Bronchopulmonary dysplasia (BPD) and emphysema are characterized by arrested alveolar development or loss of alveoli; both are significant global health problems and currently lack effective therapy. Bone marrow–derived mesenchymal stem cells (BMSCs) prevent adult lung injury, but their therapeutic potential in neonatal lung disease is unknown.

  4. RUNX1 and its fusion oncoprotein derivative RUNX1-ETO induce senescence-like growth arrest independently of replicative stress

    Wolyniec, Kamil; Wotton, Sandy; Kilbey, Anna; Jenkins, Alma; Terry, Anne; Peters, Gordon; Stocking, Carol; Cameron, Ewan; Neil, James C.

    2016-01-01

    A role for the RUNX genes in cancer failsafe processes has been suggested by their induction of senescence-like growth arrest in primary murine fibroblasts and the failure of RAS-induced senescence in Runx2 deficient cells. We now show that RUNX1 induces senescence in human primary fibroblasts. High affinity DNA binding is necessary but not sufficient, as shown by the functional attenuation of the truncated RUNX1/AML1a isoform and the TEL-RUNX1 fusion oncoprotein. However, a similar phenotype was potently induced by the RUNX1-ETO (AML1-ETO) oncoprotein, despite its dominant negative potential. Detailed comparison of H-RASV12, RUNX1 and RUNX1-ETO senescent phenotypes showed that the RUNX effectors induce earlier growth stasis with only low levels of DNA damage signalling and a lack of chromatin condensation, a marker of irreversible growth arrest. In human fibroblasts, all effectors induced p53 in the absence of detectable p14ARF, while only RUNX1-ETO induced senescence in p16INK4a null cells. Correlation was noted between induction of p53, reactive oxygen species and phospho-p38, while p38MAPK inhibition rescued cell growth markedly. These findings reveal a role for replication-independent pathways in RUNX and RUNX1-ETO senescence, and show that the context-specific oncogenic activity of RUNX1 fusion proteins are mirrored in their distinctive interactions with failsafe responses. PMID:19448675

  5. Dynamic analysis of crack growth and arrest in a pressure vessel subjected to thermal and pressure loading

    Predictions of crack arrest behaviour are performed for a cracked reactor pressure vessel under both thermal and pressure loading. The object is to compare static and dynamic calculations. The dynamic calculations are made using an explicit finite-element technique where crack growth is simulated by gradual nodal release. Three different load cases and the effect of different velocity dependence on the crack-propagation toughness are studied. It is found that for the analysed cases the static analysis is slightly conservative, thus justifying its use for these problems. (author)

  6. Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells

    Fournier, Marcia V.; Fata, Jimmie E.; Martin, Katherine J.; Yaswen, Paul; Bissell, Mina J.

    2009-06-03

    PTEN is a dual function phosphatase with tumor suppressor function compromised in a wide spectrum of cancers. Because tissue polarity and architecture are crucial modulators of normal and malignant behavior, we postulated that PTEN may play a role in maintenance of tissue integrity. We used two non-malignant human mammary epithelial cell lines (HMECs) that form polarized, growth-arrested structures (acini) when cultured in 3-dimensional laminin-rich extracellular matrix gels (3D lrECM). As acini begin to form, PTEN accumulates in both the cytoplasm, and at cell-cell contacts where it colocalizes with E-cadherin/{beta}-catenin complex. Reduction of PTEN levels by shRNA in lrECM prevents formation of organized breast acini and disrupts growth arrest. Importantly, disruption of acinar polarity and cell-cell contact by E-cadherin function-blocking antibodies reduces endogenous PTEN protein levels and inhibits its accumulation at cell-cell contacts. Conversely, in SKBR3 breast cancer cells lacking endogenous E-cadherin expression, exogenous introduction of E-cadherin gene causes induction of PTEN expression and its accumulation at sites of cell interactions. These studies provide evidence that E-cadherin regulates both the PTEN protein levels and its recruitment to cell-cell junctions in 3D lrECM indicating a dynamic reciprocity between architectural integrity and the levels and localization of PTEN. This interaction thus appears to be a critical integrator of proliferative and morphogenetic signaling in breast epithelial cells.

  7. Pharmacologic inhibition of cdk4/6 arrests the growth of glioblastoma multiforme intracranial xenografts

    Michaud, Karine; Solomon, David A.; Oermann, Eric; Kim, Jung-Sik; Zhong, Wei-Zhu; Prados, Michael D.; Ozawa, Tomoko; James, C. David; Waldman, Todd

    2010-01-01

    Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6 specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G1 cell cycle arrest and induc...

  8. Using growth and arrest of Richtmyer-Meshkov instabilities and Lagrangian simulations to study high-rate material strength

    Experiments applying a supported shock through mating surfaces (Atwood number = 1) with geometrical perturbations have been proposed for studying strength at strain rates up to 107/s using Richtmyer-Meshkov (RM) instabilities. Buttler et al. recently reported experimental results for RM instability growth in copper but with an unsupported shock applied by high explosives and the geometrical perturbations on the opposite free surface (Atwood number = −1). This novel configuration allowed detailed experimental observation of the instability growth and arrest. We present results and interpretation from numerical simulations of the Buttler RM instability experiments. Highly-resolved, two-dimensional simulations were performed using a Lagrangian hydrocode and the Preston-Tonks-Wallace (PTW) strength model. The model predictions show good agreement with the data. The numerical simulations are used to examine various assumptions previously made in an analytical model and to estimate the sensitivity of such experiments to material strength.

  9. Platycodin D Induces Tumor Growth Arrest by Activating FOXO3a Expression in Prostate Cancer in vitro and in vivo

    Zhou, Rui; Lu, Zongliang; Liu, Kai; Guo, Jing; Liu, Jie; Zhou, Yong; Yang, Jian; Mi, Mantian; Xu, Hongxia

    2014-01-01

    Platycodin D (PD), a major saponin derived from Platycodin grandiflorum, exerted cytotoxicity against prostate cancer cell lines (PC3, DU145 and LNCaP cells) with IC50 values in the range of 11.17 to 26.13μmol/L, whereas RWPE-1cells (a non-malignant human prostate epithelial cell line) were not significantly affected. A further study in these cell lines showed that PD could potently affect cell proliferation (indicated by the bromodeoxyuridine assay), induce cell apoptosis (determined by Annexin V-FITC flow cytometry) and cause cell cycle arrest (indicated by PI staining). After being treated with PD for 48 hours, DU145 and LNCaP cells were arrested in the G0 /G1 phase, and PC3 cells were arrested in the G2/M phase. A Western blotting analysis indicated that PD increased the expression of the FOXO3a transcription factor, decreased the expression of p-FOXO3a and MDM2 and increased the expression of FOXO-responsive genes, p21 and p27. MDM2 silencing (transiently by siRNA-MDM2) increased the PD-induced FOXO3a protein expression, while MDM2 overexpression (in cells transiently transfected with a pcDNA3-MDM2 plasmid) decreased the PD-induced expression of the FOXO3a protein. Moreover, PD dose-dependently inhibited the growth of PC3 xenograft tumors in BALB/c nude mice. A Western blotting analysis of the excised xenograft tumors indicated that similar changes in protein expression also occurred in vivo. These results suggest that PD exhibits significant activity against prostate cancer in vitro and in vivo. The FOXO3a transcription factor appears to be involved in the activity of PD. Together, all of these findings provide a basis for the future development of this agent for human prostate cancer therapy. PMID:25431082

  10. Bypass of hexavalent chromium-induced growth arrest by a protein tyrosine phosphatase inhibitor: Enhanced survival and mutagenesis

    Although the consequences of genotoxic injury include cell cycle arrest and apoptosis, cell survival responses after genotoxic injury can produce intrinsic death-resistance and contribute to the development of a transformed phenotype. Protein tyrosine phosphatases (PTPs) are integral components of key survival pathways, and are responsible for their inactivation, while PTP inhibition is often associated with enhanced cell proliferation. Our aim was to elucidate signaling events that modulate cell survival after genotoxin exposure. Diploid human lung fibroblasts (HLF) were treated with Cr(VI) (as Na2CrO4), the soluble oxyanionic dissolution product of certain particulate chromates, which are well-documented human respiratory carcinogens. In vitro soluble Cr(VI) induces a wide spectrum of DNA damage, in both the presence and absence of a broad-range PTP inhibitor, sodium orthovanadate (SOV). Notably, SOV abrogated Cr(VI)-induced clonogenic lethality. The enhanced survival of Cr(VI)-exposed cells after SOV treatment was predominantly due to a bypass of cell cycle arrest, as there was no effect of the PTP inhibitor on Cr-induced apoptosis. Moreover, the SOV effect was not due to decreased Cr uptake as evidenced by unchanged Cr-DNA adduct burden. Additionally, the bypass of Cr-induced growth arrest by SOV was accompanied by a decrease in Cr(VI)-induced expression of cell cycle inhibiting genes, and an increase in Cr(VI)-induced expression of cell cycle promoting genes. Importantly, SOV resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PTP inhibition in the presence of certain types of DNA damage may lead to increased genomic instability, via bypass of cell cycle checkpoints

  11. Bypass of hexavalent chromium-induced growth arrest by a protein tyrosine phosphatase inhibitor: Enhanced survival and mutagenesis

    Bae, Dongsoon; Camilli, Tura C. [Department of Pharmacology and Physiology, George Washington University Medical Center, Washington, DC (United States); Chun, Gina; Lal, Madhu; Wright, Kristen [Department of Pharmacology and Physiology, George Washington University Medical Center, Washington, DC (United States); Program in Molecular Medicine, George Washington University Medical Center, Washington, DC (United States); O' Brien, Travis J. [Department of Pharmacology and Physiology, George Washington University Medical Center, Washington, DC (United States); Program in Molecular Medicine, George Washington University Medical Center, Washington, DC (United States); GW Cancer Institute, George Washington University Medical Center, Washington, DC (United States); Patierno, Steven R. [Department of Pharmacology and Physiology, George Washington University Medical Center, Washington, DC (United States); Department of Medicine, George Washington University Medical Center, Washington, DC (United States); Program in Molecular Medicine, George Washington University Medical Center, Washington, DC (United States); GW Cancer Institute, George Washington University Medical Center, Washington, DC (United States); Ceryak, Susan [Department of Pharmacology and Physiology, George Washington University Medical Center, Washington, DC (United States); Department of Medicine, George Washington University Medical Center, Washington, DC (United States); Program in Molecular Medicine, George Washington University Medical Center, Washington, DC (United States); GW Cancer Institute, George Washington University Medical Center, Washington, DC (United States)], E-mail: phmsmc@gwumc.edu

    2009-01-15

    Although the consequences of genotoxic injury include cell cycle arrest and apoptosis, cell survival responses after genotoxic injury can produce intrinsic death-resistance and contribute to the development of a transformed phenotype. Protein tyrosine phosphatases (PTPs) are integral components of key survival pathways, and are responsible for their inactivation, while PTP inhibition is often associated with enhanced cell proliferation. Our aim was to elucidate signaling events that modulate cell survival after genotoxin exposure. Diploid human lung fibroblasts (HLF) were treated with Cr(VI) (as Na{sub 2}CrO{sub 4}), the soluble oxyanionic dissolution product of certain particulate chromates, which are well-documented human respiratory carcinogens. In vitro soluble Cr(VI) induces a wide spectrum of DNA damage, in both the presence and absence of a broad-range PTP inhibitor, sodium orthovanadate (SOV). Notably, SOV abrogated Cr(VI)-induced clonogenic lethality. The enhanced survival of Cr(VI)-exposed cells after SOV treatment was predominantly due to a bypass of cell cycle arrest, as there was no effect of the PTP inhibitor on Cr-induced apoptosis. Moreover, the SOV effect was not due to decreased Cr uptake as evidenced by unchanged Cr-DNA adduct burden. Additionally, the bypass of Cr-induced growth arrest by SOV was accompanied by a decrease in Cr(VI)-induced expression of cell cycle inhibiting genes, and an increase in Cr(VI)-induced expression of cell cycle promoting genes. Importantly, SOV resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PTP inhibition in the presence of certain types of DNA damage may lead to increased genomic instability, via bypass of cell cycle checkpoints.

  12. A low-dose hypersensitive keratinocyte loss in response to fractionated radiotherapy is associated with growth arrest and apoptosis

    Background and purpose: The existence of a hypersensitive radiation response to doses below 0.5 Gy is well established for many normal and tumour cell lines. There is also evidence for hypersensitive tissue responses in acute skin damage and kidney function in mice. Recently, we have identified that a hypersensitive γH2AX response exists in human epidermis. The aim of this study was to investigate the dose-response of basal clonogenic keratinocytes in normal skin to fractionated radiotherapy with low dose fractions. Materials: Skin punch biopsies were taken before and during radiotherapy from prostate cancer patients undergoing radiotherapy with a curative intent. Areas of epidermis receiving daily fractions of approximately 0.1, 0.2, 0.45 and 1.1 Gy were biopsied on the same occasion to determine dose-response for each individual patient. In total, 89 cases were assessed either at 1, 2.5, 3, 4, 5 or 6.5 weeks in the treatment course. Biopsy sampling of another 25 patients was performed from areas receiving 0.45 and 1.1 Gy per fraction at regular intervals throughout the 7-week treatment period. The number of basal keratinocytes per mm of the interfollicular epidermis was determined. The DNA damage response of the basal keratinocytes was investigated by immunohistochemical staining for molecular markers of growth arrest, mitosis and cell death, using p21, phospho-H3 and γH2AX, respectively. The number of stained keratinocytes in the basal layer was counted manually. The p21 staining was also quantified by digital image analysis. Results: The individual dose-response relationships revealed a low-dose hypersensitivity for reduction of basal keratinocytes throughout 7 weeks of radiotherapy (p < 0.01). Growth arrest and cell proliferation assessed at 1 week and 6.5 weeks showed, in both cases, hypersensitive increase of p21 (p < 0.01) and hypersensitive depression of mitosis (p < 0.01). Manual counting and digital image analysis of p21 showed good agreement. Cell

  13. Differential regulation of vitamin D receptor expression in distinct leukemic cell lines upon phorbol ester-induced growth arrest

    Folgueira M.A.A.K.

    2000-01-01

    Full Text Available A close correlation between vitamin D receptor (VDR abundance and cell proliferation rate has been shown in NIH-3T3 fibroblasts, MCF-7 breast cancer and in HL-60 myeloblastic cells. We have now determined if this association occurs in other leukemic cell lines, U937 and K562, and if VDR content is related to c-myc expression, which is also linked to cell growth state. Upon phorbol myristate acetate (PMA treatment, cells from the three lineages (HL-60, U937 and K562 differentiated and expressed specific surface antigens. All cell lines analyzed were growth inhibited by PMA and the doubling time was increased, mainly due to an increased fraction of cells in the G0/G1 phase, as determined by flow cytometry measurements of incorporated bromodeoxyuridine and cell DNA content. C-myc mRNA expression was down-regulated and closely correlated to cell growth arrest. However, VDR expression in leukemic cell lines, as determined by immunofluorescence and Northern blot assays, was not consistently changed upon inhibition of cell proliferation since VDR levels were down-regulated only in HL-60 cells. Our data suggest that VDR expression cannot be explained simply as a reflection of the leukemic cell growth state.

  14. NBM-T-BBX-OS01, Semisynthesized from Osthole, Induced G1 Growth Arrest through HDAC6 Inhibition in Lung Cancer Cells.

    Pai, Jih-Tung; Hsu, Chia-Yun; Hua, Kuo-Tai; Yu, Sheng-Yung; Huang, Chung-Yang; Chen, Chia-Nan; Liao, Chiung-Ho; Weng, Meng-Shih

    2015-01-01

    Disrupting lung tumor growth via histone deacetylases (HDACs) inhibition is a strategy for cancer therapy or prevention. Targeting HDAC6 may disturb the maturation of heat shock protein 90 (Hsp90) mediated cell cycle regulation. In this study, we demonstrated the effects of semisynthesized NBM-T-BBX-OS01 (TBBX) from osthole on HDAC6-mediated growth arrest in lung cancer cells. The results exhibited that the anti-proliferative activity of TBBX in numerous lung cancer cells was more potent than suberoylanilide hydroxamic acid (SAHA), a clinically approved pan-HDAC inhibitor, and the growth inhibitory effect has been mediated through G1 growth arrest. Furthermore, the protein levels of cyclin D1, CDK2 and CDK4 were reduced while cyclin E and CDK inhibitor, p21Waf1/Cip1, were up-regulated in TBBX-treated H1299 cells. The results also displayed that TBBX inhibited HDAC6 activity via down-regulation HDAC6 protein expression. TBBX induced Hsp90 hyper-acetylation and led to the disruption of cyclin D1/Hsp90 and CDK4/Hsp90 association following the degradation of cyclin D1 and CDK4 proteins through proteasome. Ectopic expression of HDAC6 rescued TBBX-induced G1 arrest in H1299 cells. Conclusively, the data suggested that TBBX induced G1 growth arrest may mediate HDAC6-caused Hsp90 hyper-acetylation and consequently increased the degradation of cyclin D1 and CDK4. PMID:25946558

  15. The Forkhead Transcription Factor FOXP2 Is Required for Regulation of p21WAF1/CIP1 in 143B Osteosarcoma Cell Growth Arrest.

    Duncan M Gascoyne

    Full Text Available Mutations of the forkhead transcription factor FOXP2 gene have been implicated in inherited speech-and-language disorders, and specific Foxp2 expression patterns in neuronal populations and neuronal phenotypes arising from Foxp2 disruption have been described. However, molecular functions of FOXP2 are not completely understood. Here we report a requirement for FOXP2 in growth arrest of the osteosarcoma cell line 143B. We observed endogenous expression of this transcription factor both transiently in normally developing murine osteoblasts and constitutively in human SAOS-2 osteosarcoma cells blocked in early osteoblast development. Critically, we demonstrate that in 143B osteosarcoma cells with minimal endogenous expression, FOXP2 induced by growth arrest is required for up-regulation of p21WAF1/CIP1. Upon growth factor withdrawal, FOXP2 induction occurs rapidly and precedes p21WAF1/CIP1 activation. Additionally, FOXP2 expression could be induced by MAPK pathway inhibition in growth-arrested 143B cells, but not in traditional cell line models of osteoblast differentiation (MG-63, C2C12, MC3T3-E1. Our data are consistent with a model in which transient upregulation of Foxp2 in pre-osteoblast mesenchymal cells regulates a p21-dependent growth arrest checkpoint, which may have implications for normal mesenchymal and osteosarcoma biology.

  16. Shocks and growth: adaptation, precaution and compensation.

    Collier, Paul; Goderis, Benedikt; Hoeffler, Anke

    2006-01-01

    In this paper we investigate how a wide array of types of shock arising from world prices, natural events, and political violence affect growth. Our results suggest that the impact from political shocks are far greater than from natural shocks. However, our preliminary cointegration results suggest that the cost from primary commodity exporting are very large. Potentially shocks can affect growth either due to their impact, or due to the volatility that repeated shocks generate. In our empiri...

  17. Natural variation in small molecule-induced TIR-NB-LRR signaling induces root growth arrest via EDS1- and PAD4-complexed R protein VICTR in Arabidopsis.

    Kim, Tae-Houn; Kunz, Hans-Henning; Bhattacharjee, Saikat; Hauser, Felix; Park, Jiyoung; Engineer, Cawas; Liu, Amy; Ha, Tracy; Parker, Jane E; Gassmann, Walter; Schroeder, Julian I

    2012-12-01

    In a chemical genetics screen we identified the small-molecule [5-(3,4-dichlorophenyl)furan-2-yl]-piperidine-1-ylmethanethione (DFPM) that triggers rapid inhibition of early abscisic acid signal transduction via PHYTOALEXIN DEFICIENT4 (PAD4)- and ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1)-dependent immune signaling mechanisms. However, mechanisms upstream of EDS1 and PAD4 in DFPM-mediated signaling remain unknown. Here, we report that DFPM generates an Arabidopsis thaliana accession-specific root growth arrest in Columbia-0 (Col-0) plants. The genetic locus responsible for this natural variant, VICTR (VARIATION IN COMPOUND TRIGGERED ROOT growth response), encodes a TIR-NB-LRR (for Toll-Interleukin1 Receptor-nucleotide binding-Leucine-rich repeat) protein. Analyses of T-DNA insertion victr alleles showed that VICTR is necessary for DFPM-induced root growth arrest and inhibition of abscisic acid-induced stomatal closing. Transgenic expression of the Col-0 VICTR allele in DFPM-insensitive Arabidopsis accessions recapitulated the DFPM-induced root growth arrest. EDS1 and PAD4, both central regulators of basal resistance and effector-triggered immunity, as well as HSP90 chaperones and their cochaperones RAR1 and SGT1B, are required for the DFPM-induced root growth arrest. Salicylic acid and jasmonic acid signaling pathway components are dispensable. We further demonstrate that VICTR associates with EDS1 and PAD4 in a nuclear protein complex. These findings show a previously unexplored association between a TIR-NB-LRR protein and PAD4 and identify functions of plant immune signaling components in the regulation of root meristematic zone-targeted growth arrest. PMID:23275581

  18. Growth arrest and apoptosis of human hepatocellular carcinoma cells induced by hexamethylene bisacetamide

    Ouyang, Gao-Liang; Cai, Qiu-Feng; Min LIU; Chen, Rui-Chuan; Huang, Zhi; Jiang, Rui-Sheng; Chen, Fu; Hong, Shui-Gen; Bao, Shi-Deng

    2004-01-01

    AIM: To investigate the cellular effects of hybrid polar compound hexamethylene bisacetamide (HMBA) on the growth and apoptosis of human hepatocellular carcinoma cells and to provide the molecular mechanism for potential application of HMBA in the treatment of liver cancer.

  19. Cellular Iron Depletion and the Mechanisms Involved in the Iron-dependent Regulation of the Growth Arrest and DNA Damage Family of Genes*

    Saletta, Federica; Rahmanto, Yohan Suryo; Siafakas, Aritee R.; Richardson, Des R.

    2011-01-01

    Iron plays a crucial part in proliferation while iron deficiency results in G1/S arrest, DNA damage, and apoptosis. However, the precise role of iron in cell cycle control remains unclear. We showed that iron depletion using the iron chelators, desferrioxamine (DFO), or 2-hydroxy-1-napthylaldehyde isonicotinoyl hydrazone (311), increased the mRNA levels of the growth arrest and DNA damage 45α gene, GADD45α (Darnell, G. and Richardson, D. R. (1999) Blood 94, 781–792). In this study, we examine...

  20. H4 histamine receptors mediate cell cycle arrest in growth factor-induced murine and human hematopoietic progenitor cells.

    Anne-France Petit-Bertron

    Full Text Available The most recently characterized H4 histamine receptor (H4R is expressed preferentially in the bone marrow, raising the question of its role during hematopoiesis. Here we show that both murine and human progenitor cell populations express this receptor subtype on transcriptional and protein levels and respond to its agonists by reduced growth factor-induced cell cycle progression that leads to decreased myeloid, erythroid and lymphoid colony formation. H4R activation prevents the induction of cell cycle genes through a cAMP/PKA-dependent pathway that is not associated with apoptosis. It is mediated specifically through H4R signaling since gene silencing or treatment with selective antagonists restores normal cell cycle progression. The arrest of growth factor-induced G1/S transition protects murine and human progenitor cells from the toxicity of the cell cycle-dependent anticancer drug Ara-C in vitro and reduces aplasia in a murine model of chemotherapy. This first evidence for functional H4R expression in hematopoietic progenitors opens new therapeutic perspectives for alleviating hematotoxic side effects of antineoplastic drugs.

  1. CSBF/C10orf99, a novel potential cytokine, inhibits colon cancer cell growth through inducing G1 arrest.

    Pan, Wen; Cheng, Yingying; Zhang, Heyu; Liu, Baocai; Mo, Xiaoning; Li, Ting; Li, Lin; Cheng, Xiaojing; Zhang, Lianhai; Ji, Jiafu; Wang, Pingzhang; Han, Wenling

    2014-01-01

    Cytokines are soluble proteins that exert their functions by binding specific receptors. Many cytokines play essential roles in carcinogenesis and have been developed for the treatment of cancer. In this study, we identified a novel potential cytokine using immunogenomics designated colon-derived SUSD2 binding factor (CSBF), also known as chromosome 10 open reading frame 99 (C10orf99). CSBF/C10orf99 is a classical secreted protein with predicted molecular mass of 6.5 kDa, and a functional ligand of Sushi Domain Containing 2 (SUSD2). CSBF/C10orf99 has the highest expression level in colon tissue. Both CSBF/C10orf99 and SUSD2 are down-regulated in colon cancer tissues and cell lines with different regulation mechanisms. CSBF/C10orf99 interacts with SUSD2 to inhibit colon cancer cell growth and induce G1 cell cycle arrest by down-regulating cyclin D and cyclin-dependent kinase 6 (CDK6). CSBF/C10orf99 displays a bell-shaped activity curve with the optimal effect at ~10 ng/ml. Its growth inhibitory effects can be blocked by sSUSD2-Fc soluble protein. Our results suggest that CSBF/C10orf99 is a novel potential cytokine with tumor suppressor functions. PMID:25351403

  2. Higher order nuclear organization in growth arrest of humanmammary epithelial cells: A novel role for telomere-associated proteinTIN2

    Kaminker, Patrick; Plachot, Cedric; Kim, Sahn-Ho; Chung, Peter; Crippen, Danielle; Petersen, Ole W.; Bissell, Mina J.; Campisi, Judith; Lelievre, Sophie A.

    2004-12-15

    Nuclear organization, such as the formation of specific nuclear subdomains, is generally thought to be involved in the control of cellular phenotype; however, there are relatively few specific examples of how mammalian nuclei organize during radical changes in phenotype, such as those which occur during differentiation and growth arrest. Using human mammary epithelial cells (HMECs) in which growth arrest is essential for morphological differentiation, we show that the arrest of cell proliferation is accompanied by a reorganization of the telomere-associated protein, TIN2, into one to three large nuclear subdomains. The large TIN2 domains do not contain telomeres and occur concomitant with the continued presence of TIN2 at telomeres. The TIN2 domains were sensitive to DNAse, but not RNAse, occurred frequently, but not exclusively near nucleoli, and overlapped often with dense domains containing heterochromatin protein l{gamma}. Expression of truncated forms of TIN2 simultaneously prevented the formation of TIN2 domains and relaxed the stringent morphogenesis-induced growth arrest in HMECs. Our findings reveal a novel extra-telomeric organization of TIN2 associated with the control of cell proliferation and identify TIN2 as an important regulator of mammary epithelial differentiation.

  3. Live-Cell Imaging Visualizes Frequent Mitotic Skipping During Senescence-Like Growth Arrest in Mammary Carcinoma Cells Exposed to Ionizing Radiation

    Purpose: Senescence-like growth arrest in human solid carcinomas is now recognized as the major outcome of radiotherapy. This study was designed to analyze cell cycle during the process of senescence-like growth arrest in mammary carcinoma cells exposed to X-rays. Methods and Materials: Fluorescent ubiquitination-based cell cycle indicators were introduced into the human mammary carcinoma cell line MCF-7. Cell cycle was sequentially monitored by live-cell imaging for up to 5 days after exposure to 10 Gy of X-rays. Results: Live-cell imaging revealed that cell cycle transition from G2 to G1 phase without mitosis, so-called mitotic skipping, was observed in 17.1% and 69.8% of G1- and G2-irradiated cells, respectively. Entry to G1 phase was confirmed by the nuclear accumulation of mKO2-hCdt1 as well as cyclin E, which was inversely correlated to the accumulation of G2-specific markers such as mAG-hGeminin and CENP-F. More than 90% of cells skipping mitosis were persistently arrested in G1 phase and showed positive staining for the senescent biochemical marker, which is senescence-associated ß-galactosidase, indicating induction of senescence-like growth arrest accompanied by mitotic skipping. While G2 irradiation with higher doses of X-rays induced mitotic skipping in approximately 80% of cells, transduction of short hairpin RNA (shRNA) for p53 significantly suppressed mitotic skipping, suggesting that ionizing radiation-induced mitotic skipping is associated with p53 function. Conclusions: The present study found the pathway of senescence-like growth arrest in G1 phase without mitotic entry following G2-irradiation.

  4. Live-Cell Imaging Visualizes Frequent Mitotic Skipping During Senescence-Like Growth Arrest in Mammary Carcinoma Cells Exposed to Ionizing Radiation

    Suzuki, Masatoshi, E-mail: msuzuki@nagasaki-u.ac.jp [Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (Japan); Yamauchi, Motohiro; Oka, Yasuyoshi; Suzuki, Keiji; Yamashita, Shunichi [Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (Japan)

    2012-06-01

    Purpose: Senescence-like growth arrest in human solid carcinomas is now recognized as the major outcome of radiotherapy. This study was designed to analyze cell cycle during the process of senescence-like growth arrest in mammary carcinoma cells exposed to X-rays. Methods and Materials: Fluorescent ubiquitination-based cell cycle indicators were introduced into the human mammary carcinoma cell line MCF-7. Cell cycle was sequentially monitored by live-cell imaging for up to 5 days after exposure to 10 Gy of X-rays. Results: Live-cell imaging revealed that cell cycle transition from G2 to G1 phase without mitosis, so-called mitotic skipping, was observed in 17.1% and 69.8% of G1- and G2-irradiated cells, respectively. Entry to G1 phase was confirmed by the nuclear accumulation of mKO{sub 2}-hCdt1 as well as cyclin E, which was inversely correlated to the accumulation of G2-specific markers such as mAG-hGeminin and CENP-F. More than 90% of cells skipping mitosis were persistently arrested in G1 phase and showed positive staining for the senescent biochemical marker, which is senescence-associated ss-galactosidase, indicating induction of senescence-like growth arrest accompanied by mitotic skipping. While G2 irradiation with higher doses of X-rays induced mitotic skipping in approximately 80% of cells, transduction of short hairpin RNA (shRNA) for p53 significantly suppressed mitotic skipping, suggesting that ionizing radiation-induced mitotic skipping is associated with p53 function. Conclusions: The present study found the pathway of senescence-like growth arrest in G1 phase without mitotic entry following G2-irradiation.

  5. Arrest of Myelination and Reduced Axon Growth when Schwann Cells Lack mTOR

    Sherman, Diane L.; Krols, Michiel; Wu, Lai-Man N.; Grove, Matthew; Nave, Klaus-Armin; Gangloff, Yann-Gaël; Brophy, Peter J.

    2012-01-01

    In developing peripheral nerves differentiating Schwann cells sort individual axons from bundles and ensheath them to generate multiple layers of myelin. In recent years there has been an increasing understanding of the extracellular and intracellular factors that initiate and stimulate Schwann cell myelination together with a growing appreciation of some of the signalling pathways involved. However, our knowledge of how Schwann cell growth is regulated during myelination is still incomplete....

  6. Nanotechnology and mesenchymal stem cells with chondrocytes in prevention of partial growth plate arrest in pigs

    Plánka, L.; Srnec, R.; Rauser, P.; Starý, D.; Filová, Eva; Jančář, J.; Juhásová, Jana; Křen, J.; Nečas, A.; Gál, P.

    2012-01-01

    Roč. 156, č. 2 (2012), s. 128-134. ISSN 1213-8118 R&D Projects: GA MZd(CZ) NS9896 Institutional research plan: CEZ:AV0Z50390512; CEZ:AV0Z50450515 Institutional support: RVO:68378041 ; RVO:67985904 Keywords : mesenchymal stem cells * growth plate defect * bone bridge Subject RIV: FI - Traumatology, Orthopedics Impact factor: 0.990, year: 2012

  7. Resistance to ultraviolet-induced apoptosis in DNA repair deficient growth arrested human fibroblasts is not related to recovery from RNA transcription blockage

    The impact of ultraviolet (UV-C) photoproducts on apoptosis induction was investigated in growth arrested (confluent) and proliferating human primary fibroblasts. Confluent fibroblasts were more resistant to UV-C-induced apoptosis than proliferating cells, and this was observed for normal human cells and for cells from patients with Cockayne and trichothiodystrophy syndromes, deficient in transcription coupled repair. This resistance was sustained for at least seven days and was not due to DNA repair efficiency, as the removal of CPDs in the genome was similar under both growth conditions. There was no correlation between reduced apoptosis and RNA synthesis recovery. Following UV-C treatment, proliferating and confluent fibroblasts showed a similar level of RNA synthesis inhibition and recovery from transcription blockage. These results support the hypothesis that the decrease of DNA replication, in growth arrested cells, protects cell from UV-C-induced apoptosis, even in the presence of DNA lesions

  8. Adaptation to optimal cell growth through self-organized criticality.

    Furusawa, Chikara; Kaneko, Kunihiko

    2012-05-18

    A simple cell model consisting of a catalytic reaction network is studied to show that cellular states are self-organized in a critical state for achieving optimal growth; we consider the catalytic network dynamics over a wide range of environmental conditions, through the spontaneous regulation of nutrient transport into the cell. Furthermore, we find that the adaptability of cellular growth to reach a critical state depends only on the extent of environmental changes, while all chemical species in the cell exhibit correlated partial adaptation. These results are in remarkable agreement with the recent experimental observations of the present cells. PMID:23003193

  9. Linear Growth Arrest Without Weight Gain Due to Overuse of Topical Clobetasol

    Zahra Razavi; Milad Sanginabadi

    2014-01-01

    Prolonged potent topical glucocorticoid therapy in infants can cause iatrogenic Cushing’s syndrome. This case highlights the rarity of poor weight gain in iatrogenic Cushing’s syndrome. A 17-month-old boy was referred to outpatients pediatric endocrine clinic for evaluation of growth failure. On presentation his weight was 9.7kg (5th percentile) and height was 72cm (-3.6 SD below mean for age and sex). Systemic examination revealed grossly moon-like face, hypertrichosis and thin skin in the g...

  10. Linear Growth Arrest Without Weight Gain Due to Overuse of Topical Clobetasol

    Zahra Razavi

    2014-11-01

    Full Text Available Prolonged potent topical glucocorticoid therapy in infants can cause iatrogenic Cushing’s syndrome. This case highlights the rarity of poor weight gain in iatrogenic Cushing’s syndrome. A 17-month-old boy was referred to outpatients pediatric endocrine clinic for evaluation of growth failure. On presentation his weight was 9.7kg (5th percentile and height was 72cm (-3.6 SD below mean for age and sex. Systemic examination revealed grossly moon-like face, hypertrichosis and thin skin in the genital area. His mother reported using local clobetasol for the previous seven months for his diaper dermatitis. Baseline plasma cortisol was low (0.3ng/ml, normal range: 60 to 280ng/ml. During standard dose of synthetic adrenocorticotropic hormone test, the peak cortisol level was 0.4ng/ml (N>180ng/ml and was consistent with hypothalamic–pituitary–adrenal axis suppression. The patient’s clinical presentation and laboratory investigations confirmed the diagnosis of secondary adrenal insufficiency and iatrogenic Cushing’s syndrome. He was treated successfully by discontinuing use of clobetasol. His appearance and growth returned to normal within two months. Morning cortisol was 101.2ng/ml after stopping the oral physiologic dose of hydrocortisone. Our case differed from other reports of iatrogenic Cushing’s syndrome by presenting in poor weight gain rather than obesity.

  11. Linear growth arrest without weight gain due to overuse of topical clobetasol.

    Razavi, Zahra; Sanginabadi, Milad

    2014-11-01

    Prolonged potent topical glucocorticoid therapy in infants can cause iatrogenic Cushing's syndrome. This case highlights the rarity of poor weight gain in iatrogenic Cushing's syndrome. A 17-month-old boy was referred to outpatients pediatric endocrine clinic for evaluation of growth failure. On presentation his weight was 9.7kg (5th percentile) and height was 72cm (-3.6 SD below mean for age and sex). Systemic examination revealed grossly moon-like face, hypertrichosis and thin skin in the genital area. His mother reported using local clobetasol for the previous seven months for his diaper dermatitis. Baseline plasma cortisol was low (0.3ng/ml, normal range: 60 to 280ng/ml). During standard dose of synthetic adrenocorticotropic hormone test, the peak cortisol level was 0.4ng/ml (N>180ng/ml) and was consistent with hypothalamic-pituitary-adrenal axis suppression. The patient's clinical presentation and laboratory investigations confirmed the diagnosis of secondary adrenal insufficiency and iatrogenic Cushing's syndrome. He was treated successfully by discontinuing use of clobetasol. His appearance and growth returned to normal within two months. Morning cortisol was 101.2ng/ml after stopping the oral physiologic dose of hydrocortisone. Our case differed from other reports of iatrogenic Cushing's syndrome by presenting in poor weight gain rather than obesity. PMID:25584165

  12. Silica Nanoparticles Sensitize Human Multiple Myeloma Cells to Snake (Walterinnesia aegyptia Venom-Induced Apoptosis and Growth Arrest

    Douaa Sayed

    2012-01-01

    Full Text Available Background. Multiple myeloma (MM, an almost incurable disease, is the second most common blood cancer. Initial chemotherapeutic treatment could be successful; however, resistance development urges the use of higher toxic doses accompanied by hematopoietic stem cell transplantation. The establishment of more effective treatments that can overcome or circumvent chemoresistance has become a priority. We recently demonstrated that venom extracted from Walterinnesia aegyptia (WEV either alone or in combination with silica nanoparticles (WEV+NPs mediated the growth arrest and apoptosis of prostate cancer cells. In the present study, we evaluated the impact of WEV alone and WEV+NP on proliferation and apoptosis of MM cells. Methods. The impacts of WEV alone and WEV+NP were monitored in MM cells from 70 diagnosed patients. The influences of WEV and WEV+NP were assessed with flow cytometry analysis. Results. WEV alone and WEV+NP decreased the viability of MM cells. Using a CFSE proliferation assay, we found that WEV+NP strongly inhibited MM cell proliferation. Furthermore, analysis of the cell cycle using the propidium iodide (PI staining method indicated that WEV+NP strongly altered the cell cycle of MM cells and enhanced the induction of apoptosis. Conclusions. Our data reveal the biological effects of WEV and WEV+NP on MM cells that enable these compounds to function as effective treatments for MM.

  13. Resveratrol oligomers isolated from Carex species inhibit growth of human colon tumorigenic cells mediated by cell cycle arrest.

    González-Sarrías, Antonio; Gromek, Samantha; Niesen, Daniel; Seeram, Navindra P; Henry, Geneive E

    2011-08-24

    Research has shown that members of the Carex genus produce biologically active stilbenoids including resveratrol oligomers. This is of great interest to the nutraceutical industry given that resveratrol, a constituent of grape and red wine, has attracted immense research attention due to its potential human health benefits. In the current study, five resveratrol oligomers (isolated from Carex folliculata and Carex gynandra ), along with resveratrol, were evaluated for antiproliferative effects against human colon cancer (HCT-116, HT-29, Caco-2) and normal human colon (CCD-18Co) cells. The resveratrol oligomers included one dimer, two trimers, and two tetramers: pallidol (1); α-viniferin (2) and trans-miyabenol C (3); and kobophenols A (4) and B (5), respectively. Although not cytotoxic, the resveratrol oligomers (1-5), as well as resveratrol, inhibited growth of the human colon cancer cells. Among the six stilbenoids, α-viniferin (2) was most active against the colon cancer cells with IC(50) values of 6-32 μM (>2-fold compared to normal colon cells). Moreover, α-viniferin (at 20 μM) did not induce apoptosis but arrested cell cycle (in the S-phase) for the colon cancer but not the normal colon cells. This study adds to the growing body of knowledge supporting the anticancer effects of resveratrol and its oligomers. Furthermore, Carex species should be investigated for their nutraceutical potential given that they produce biologically active stilbenoids such as α-viniferin. PMID:21761862

  14. Antisense oligonucleotide targeting at the initiator of hTERT arrests growth of hepatoma cells

    Su-Xia Liu; Wen-Sheng Sun; Ying-Lin Cao; Chun-Hong Ma; Li-Hui Han; Li-Ning Zhang; Zhen-Guang Wang; Fa-Liang Zhu

    2004-01-01

    AIM: To evaluate the inhibitory effect of antisense phosphorothioate oligonucleotide (asON) complementary to the initiator of human telomerase catalytic subunit (hTERT)on the growth of hepatoma cells.METHODS: The as-hTERT was synthesized by using a DNA synthesizer. HepG2.2.15 cells were treated with ashTERT at the concentration of 10 μmol/L. After 72 h, these cells were obtained for detecting growth inhibition,telomerase activity using the methods of MTT, TRAP-PCR-ELISA, respectively. BALB/c(nu/nu) mice were injected HepG2.2.15 cells and a human-nude mice model was obtained. There were three groups for anti-tumor activity study. Once tumors were established, these animals in the first group were administered as-hTERT and saline.Apoptosis of tumor cells was detected by FCM. In the 2nd group, the animals were injected HepG2.2.15 cells together with as-hTERT. In the third group, the animals were given as-hTERT 24 hours postinjection of HepG2.2.15 cells. The anti-HBV effects were assayed with ELISA ih vitro and in vivo.RESULTS: Growth inhibition was observed in cells treated with as-hTERT ih vitro. A significant different in the value of A570-A630 was found between cells treated with as-hTERT and control (P<0.01) by MTT method. The telomerase activity of tumor cells treated with as-hTERT was reduced,the value of A450 nm was 0.42 compared to control (1,49)with TRAP-PCR-ELISA. The peak of apoptosis in tumor cells given as-hTERT was 21. 12%, but not seen in saline-treated control. A prolonged period of carcinogenesis was observed in the second and third group animals. There was inhibitory effect on the expression of HBsAg and HBeAg ih vivo and in vitro.CONCLUSION: As-hTERT has an anti-tumor activity, which may be useful for gene therapy of tumors.

  15. Strategic Adaptation: A Key to Sustainable Business Growth

    Singh Satyendra Kumar

    2013-01-01

    Every organization operates in a business environment of its own. As the business environment is continually changing, the organization can grow and sustain its growth only if its strategy also changes in response to its business environment i.e. its strategy adapts to changing business environment. If the organization’s strategy remains static vis-à-vis its changing business environment, its growth is hampered, it suffers financial losses and may eventually become sick or die. This paper mak...

  16. Tris(2-chloroethyl)phosphate-induced cell growth arrest via attenuation of SIRT1-independent PI3K/Akt/mTOR pathway.

    Zhang, Wenjuan; Zhang, Youjian; Wang, Zhiyuan; Xu, Tian; Huang, Cheng; Yin, Wenjun; Wang, Jing; Xiong, Wei; Lu, Wenhong; Zheng, Hongyan; Yuan, Jing

    2016-07-01

    Tris(2-chloroethyl)phosphate (TCEP) as an organophosphorus flame retardant and plasticizer has been widely used in industrial and household products. It not only was detected in residential indoor air and dust, surface and drinking water, but also in human plasma and breast milk, and tissue samples of liver, kidneys and brain from rodents. TCEP is classified as carcinogenic category 2 and toxic for reproduction category 1B. Sufficient evidence from experimental animals indicated carcinogenicity of TCEP in the liver, and kidneys as well as cell loss in the brain. However, the underlying mechanisms of TCEP-induced hepatotoxicity are mostly unknown. We investigated the in vitro effects of TCEP as well as TCEP-induced cell growth in the L02 and HepG2 cells through the PI3K/Akt/mTOR pathway. We found that TCEP reduced cell viability of these cell lines, induced the cell growth arrest, upregulated mRNA and protein levels of SIRT1, and attenuated the PI3K/Akt/mTOR pathway. However, growth arrest of the L02 and HepG2 cells were aggravated after inhibiting the SIRT1 expression with EX-527. The findings above suggested that TCEP induced the cell growth arrest of L02 and HepG2 cells via attenuation of the SIRT1-independent PI3K/Akt/mTOR pathway. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26378621

  17. Growth arrest of lung carcinoma cells (A549) by polyacrylate-anchored peroxovanadate by activating Rac1-NADPH oxidase signalling axis.

    Chatterjee, Nirupama; Anwar, Tarique; Islam, Nashreen S; Ramasarma, T; Ramakrishna, Gayatri

    2016-09-01

    Hydrogen peroxide is often required in sublethal, millimolar concentrations to show its oxidant effects on cells in culture as it is easily destroyed by cellular catalase. Previously, we had shown that diperoxovanadate, a physiologically stable peroxovanadium compound, can substitute H2O2 effectively in peroxidation reactions. We report here that peroxovanadate when anchored to polyacrylic acid (PAPV) becomes a highly potent inhibitor of growth of lung carcinoma cells (A549). The early events associated with PAPV treatment included cytoskeletal modifications, increase in GTPase activity of Rac1, accumulation of the reactive oxygen species, and also increase in phosphorylation of H2AX (γH2AX), a marker of DNA damage. These effects persisted even at 24 h after removal of the compound and culminated in increased levels of p53 and p21 together with growth arrest. The PAPV-mediated growth arrest was significantly abrogated in cells pre-treated with the N-acetylcysteine, Rac1 knocked down by siRNA and DPI an inhibitor of NADPH oxidase. In conclusion, our results show that polyacrylate derivative of peroxovanadate efficiently arrests growth of A549 cancerous cells by activating the axis of Rac1-NADPH oxidase leading to oxidative stress and DNA damage. PMID:27435854

  18. Peptide nucleic acids arrest the growth of gastric cancer cells SGC7901

    王宽; 张岂凡; 王锡山; 薛英威; 庞达; 傅松滨

    2004-01-01

    Background Peptide nucleic acid (PNA) has many characteristics useful in molecular biology. This paper described an effective way to raise the cell ingestion rate of PNA so as to kill gastric cancer cells.Methods Heteroduplexes of PNAs and oligonucleotides, wrapped by Lipofectamine 2000, were used to infect SGC7901 cells. The inhibitive effect of heteroduplexes was evaluated by analyzing cell clone forming and cell growth rate. Telomerase activity of SGC7901 cells was detected by polymerase chain reaction enzyme-linked immunosorbent assay (PCR-ELISA) and silver staining assay.Results PNAs showed a dose-dependent inhibition of cell proliferation. The percentage of proliferation inhibition was 99.4% after 7 days; the rate of cloning inhibition was 98.2% after 8 days;whereas for oligonucleotide groups, at the same concentration, the percentages were 50. 1% and 67. 5% respectively. Antisense PNA-DNA-Lipofectamine 2000 group (AP-D-L group) exhibited significantly different percentages from the control groups (P<0.05). The test result indicated that telomerase activity of the AP-D-L group was inhibited (P<0.05). At the same time, the impact on cell morphology was observed.Conclusions The results showed that PNAs are potent antisense reagents. The telomeraseassociated therapies are very promising for the treatment of malignant tumours.

  19. Daily Arrests

    Montgomery County of Maryland — This dataset provides the public with arrest information from the Montgomery County Central Processing Unit (CPU) systems. The data presented is derived from every...

  20. Evaluation and prediction of the HIV-1 central polypurine tract influence on foamy viral vectors to transduce dividing and growth-arrested cells.

    Shityakov, Sergey; Förster, Carola; Rethwilm, Axel; Dandekar, Thomas

    2014-01-01

    Retroviral vectors are potent tools for gene delivery and various biomedical applications. To accomplish a gene transfer task successfully, retroviral vectors must effectively transduce diverse cell cultures at different phases of a cell cycle. However, very promising retroviral vectors based on the foamy viral (FV) backbone lack the capacity to efficiently transduce quiescent cells. It is hypothesized that this phenomenon might be explained as the inability of foamy viruses to form a pre-integration complex (PIC) with nuclear import activity in growth-arrested cells, which is the characteristic for lentiviruses (HIV-1). In this process, the HIV-1 central polypurine tract (cPPT) serves as a primer for plus-strand synthesis to produce a "flap" element and is believed to be crucial for the subsequent double-stranded cDNA formation of all retroviral RNA genomes. In this study, the effects of the lentiviral cPPT element on the FV transduction potential in dividing and growth-arrested (G1/S phase) adenocarcinomic human alveolar basal epithelial (A549) cells are investigated by experimental and theoretical methods. The results indicated that the HIV-1 cPPT element in a foamy viral vector background will lead to a significant reduction of the FV transduction and viral titre in growth-arrested cells due to the absence of PICs with nuclear import activity. PMID:25009830

  1. Adaptive evolution of synthetic cooperating communities improves growth performance.

    Xiaolin Zhang

    Full Text Available Symbiotic interactions between organisms are important for human health and biotechnological applications. Microbial mutualism is a widespread phenomenon and is important in maintaining natural microbial communities. Although cooperative interactions are prevalent in nature, little is known about the processes that allow their initial establishment, govern population dynamics and affect evolutionary processes. To investigate cooperative interactions between bacteria, we constructed, characterized, and adaptively evolved a synthetic community comprised of leucine and lysine Escherichia coli auxotrophs. The co-culture can grow in glucose minimal medium only if the two auxotrophs exchange essential metabolites - lysine and leucine (or its precursors. Our experiments showed that a viable co-culture using these two auxotrophs could be established and adaptively evolved to increase growth rates (by ∼3 fold and optical densities. While independently evolved co-cultures achieved similar improvements in growth, they took different evolutionary trajectories leading to different community compositions. Experiments with individual isolates from these evolved co-cultures showed that changes in both the leucine and lysine auxotrophs improved growth of the co-culture. Interestingly, while evolved isolates increased growth of co-cultures, they exhibited decreased growth in mono-culture (in the presence of leucine or lysine. A genome-scale metabolic model of the co-culture was also constructed and used to investigate the effects of amino acid (leucine or lysine release and uptake rates on growth and composition of the co-culture. When the metabolic model was constrained by the estimated leucine and lysine release rates, the model predictions agreed well with experimental growth rates and composition measurements. While this study and others have focused on cooperative interactions amongst community members, the adaptive evolution of communities with other

  2. A class of DNA-binding peptides from wheat bud causes growth inhibition, G2 cell cycle arrest and apoptosis induction in HeLa cells

    Elgjo Kjell

    2009-07-01

    Full Text Available Abstract Background Deproteinized DNA from eukaryotic and prokaryotic cells still contains a low-molecular weight peptidic fraction which can be dissociated by alkalinization of the medium. This fraction inhibits RNA transcription and tumor cell growth. Removal from DNA of normal cells causes amplification of DNA template activity. This effect is lower or absent in several cancer cell lines. Likewise, the amount of active peptides in cancer cell DNA extracts is lower than in DNA preparation of the corresponding normal cells. Such evidence, and their ubiquitous presence, suggests that they are a regulatory, conserved factor involved in the control of normal cell growth and gene expression. Results We report that peptides extracted from wheat bud chromatin induce growth inhibition, G2 arrest and caspase-dependent apoptosis in HeLa cells. The growth rate is decreased in cells treated during the S phase only and it is accompanied by DNA damage and DNA synthesis inhibition. In G2 cells, this treatment induces inactivation of the CDK1-cyclin B1 complex and an increase of active chk1 kinase expression. Conclusion The data indicate that the chromatin peptidic pool inhibits HeLa cell growth by causing defective DNA replication which, in turn, arrests cell cycle progression to mitosis via G2 checkpoint pathway activation.

  3. Effects of gamma-radiation on cell growth, cycle arrest, death, and superoxide dismutase expression by DU 145 human prostate cancer cells

    Vucic V.

    2006-01-01

    Full Text Available Gamma-irradiation (gamma-IR is extensively used in the treatment of hormone-resistant prostate carcinoma. The objective of the present study was to investigate the effects of 60Co gamma-IR on the growth, cell cycle arrest and cell death of the human prostate cancer cell line DU 145. The viability of DU 145 cells was measured by the Trypan blue exclusion assay and the 3(4,5-dimethylthiazol-2-yl-2,5,diphenyltetrazolium bromide test. Bromodeoxyuridine incorporation was used for the determination of cell proliferation. Cell cycle arrest and cell death were analyzed by flow cytometry. Superoxide dismutase (SOD, specifically CuZnSOD and MnSOD protein expression, after 10 Gy gamma-IR, was determined by Western immunoblotting analysis. gamma-IR treatment had a significant (P < 0.001 antiproliferative and cytotoxic effect on DU 145 cells. Both effects were time and dose dependent. Also, the dose of gamma-IR which inhibited DNA synthesis and cell proliferation by 50% was 9.7 Gy. Furthermore, gamma-IR induced cell cycle arrest in the G2/M phase and the percentage of cells in the G2/M phase was increased from 15% (control to 49% (IR cells, with a nonsignificant induction of apoptosis. Treatment with 10 Gy gamma-IR for 24, 48, and 72 h stimulated CuZnSOD and MnSOD protein expression in a time-dependent manner, approximately by 3- to 3.5-fold. These data suggest that CuZnSOD and MnSOD enzymes may play an important role in the gamma-IR-induced changes in DU 145 cell growth, cell cycle arrest and cell death.

  4. Sarsaparilla (Smilax Glabra Rhizome) Extract Inhibits Cancer Cell Growth by S Phase Arrest, Apoptosis, and Autophagy via Redox-Dependent ERK1/2 Pathway.

    She, Tiantian; Qu, Like; Wang, Lixin; Yang, Xingxin; Xu, Shuo; Feng, Junnan; Gao, Yujing; Zhao, Chuanke; Han, Yong; Cai, Shaoqing; Shou, Chengchao

    2015-05-01

    Cancer is still the major cause of death across the world. Regular approaches cannot effectively solve the emerging problems, including drug/radiation resistance, side effects, and therapeutic ineffectiveness. Natural dietary supplements have shown effectiveness in the prevention and treatment of cancer. Sarsaparilla (Smilax Glabra Rhizome) has growth-inhibitory effects on several cancer cell lines in vitro and in vivo, with little toxicity on normal cells. However, the mechanism underlying its function remains elusive. In the present study, we examined the anticancer activity of the supernatant of the water-soluble extract (SW) from sarsaparilla. Liquid chromatography/mass spectrometry-ion trap-time-of-flight (LC/MS-IT-TOF) analysis identified flavonoids, alkaloids, and phenylpropanoids as the major bioactive components of SW. SW was shown to markedly inhibit the growth of a broad spectrum of cancer cell lines in the in vitro and in vivo assays. S phase arrest, autophagy, or/and apoptosis were partly responsible for SW-induced growth inhibition. Results of microarray analysis and validation by quantitative RT-PCR indicated the involvement of oxidative stress and the MAPK1 pathway in SW-treated cells. We further found that SW destroyed intracellular-reduced glutathione/oxidized glutathione (GSH/GSSG) balance, and supplement with N-acetylcysteine (NAC) or glutathione (GSH) significantly antagonized SW-induced S phase arrest, apoptosis, and autophagy. In addition, SW-induced GSH/GSSG imbalance activated the ERK1/2 pathway, which contributed to SW-induced S phase arrest, apoptosis, autophagy, and resultant growth-inhibitory effect. Together, our results provide a molecular basis for sarsaparilla as an anticancer agent. PMID:25732255

  5. Curcumin induces growth-arrest and apoptosis in association with the inhibition of constitutively active JAK-STAT pathway in T cell leukemia

    Adult T cell leukemia is an aggressive and frequently fatal malignancy that expressess constitutively activated growth-signaling pathways in association with deregulated growth and resistance to apoptosis. Curcumin (diferuloylmethane) is a naturally occurring yellow pigment, isolated from the rhizomes of the plant Curcuma longa that has traditionally been used in the treatment of injury and inflammation. But the effect and mechanism of action of curcumin on T cell leukemia is not known. To investigate the antitumor activity of curcumin in T cell leukemia, we examined its effect on constitutive phosphorylation of JAK and STAT proteins, proliferation, and apoptosis in HTLV-I-transformed T cell lines. HTLV-I-transformed T cell leukemia lines, MT-2, HuT-102, and SLB-1, express constitutively phosphorylated JAK3, TYK2, STAT3, and STAT5 signaling proteins. In vitro treatment with curcumin induced a dose-dependent decrease in JAK and STAT phosphorylation resulting in the induction of growth-arrest and apoptosis in T cell leukemia. The induction of growth-arrest and apoptosis in association with the blockade of constitutively active JAK-STAT pathway suggests this be a mechanism by which curcumin induces antitumor activity in T cell leukemia

  6. Vitamin D Arrests Thyroid Carcinoma Cell Growth and Induces p27 Dephosphorylation and Accumulation through PTEN/Akt-Dependent and -Independent Pathways

    Wei LIU; Asa, Sylvia L.; Fantus, I. George; Walfish, Paul G.; Ezzat, Shereen

    2002-01-01

    We investigated the effects of 1,25-dihydroxycholecalciferol vitamin D3 (VD) and its noncalciomimetic analog EB1089 on thyroid carcinoma cell growth. VD and EB1089 exhibited anti-proliferative effects in a dose-dependent manner as determined by [3H]thymidine incorporation and MIB-1 immunolabeling. VD or EB1089 resulted in similar G1-phase arrest. Neither apoptosis nor differentiation was affected. VD and EB1089 induced increased nuclear protein expression of the cyclin-dependent kinase inhibi...

  7. A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor β-induced cell-cycle arrest

    Claassen, Gisela F.; Hann, Stephen R.

    2000-01-01

    c-Myc plays a vital role in cell-cycle progression. Deregulated expression of c-Myc can overcome cell-cycle arrest in order to promote cellular proliferation. Transforming growth factor β (TGFβ) treatment of immortalized human keratinocyte cells inhibits cell-cycle progression and is characterized by down-regulation of c-Myc followed by up-regulation of p21CIP1. A direct role of c-Myc in this pathway was demonstrated by the observation that ectopic expression of c-Myc overcame the cell-cycle ...

  8. Resistance to ursodeoxycholic acid-induced growth arrest can also result in resistance to deoxycholic acid-induced apoptosis and increased tumorgenicity

    There is a large body of evidence which suggests that bile acids increase the risk of colon cancer and act as tumor promoters, however, the mechanism(s) of bile acids mediated tumorigenesis is not clear. Previously we showed that deoxycholic acid (DCA), a tumorogenic bile acid, and ursodeoxycholic acid (UDCA), a putative chemopreventive agent, exhibited distinct biological effects, yet appeared to act on some of the same signaling molecules. The present study was carried out to determine whether there is overlap in signaling pathways activated by tumorogenic bile acid DCA and chemopreventive bile acid UDCA. To determine whether there was an overlap in activation of signaling pathways by DCA and UDCA, we mutagenized HCT116 cells and then isolated cell lines resistant to UDCA induced growth arrest. These lines were then tested for their response to DCA induced apoptosis. We found that a majority of the cell lines resistant to UDCA-induced growth arrest were also resistant to DCA-induced apoptosis, implying an overlap in DCA and UDCA mediated signaling. Moreover, the cell lines which were the most resistant to DCA-induced apoptosis also exhibited a greater capacity for anchorage independent growth. We conclude that UDCA and DCA have overlapping signaling activities and that disregulation of these pathways can lead to a more advanced neoplastic phenotype

  9. Platelet-derived growth factor stimulation of [3H]-glucosamine incorporation in density-arrested BALB/c-3T3 cells

    G0/G1 traverse in density-arrested BALB/c-3T3 cells is controlled by multiple serum-derived growth factors. Platelet-derived growth factor (PDGF) initiates a proliferative response, whereas factors present in plasma facilitate progression through G0/G1. In the absence of competence formation, progression factors are unable to stimulate cell cycle traverse. The authors have identified the stimulation of a biochemical process specific to competence formation in BALB/c-3T3 cells. PDGF treated BALB/c-3T3 cells incorporated 5-10 fold more [3H]-glucosamine (GlcN) into acid-insoluble material as compared to platelet-poor plasma (PPP) treated cultures. Increased GlcN incorporation occurred in density-arrested BALB/c-3T3 cells in response to treatment with other competence factors, fibroblast growth factor, and Ca3 (PO4)2 and was not due to cell-cycle traverse. Stimulation of [3H]-GlcN incorporation by PDGF was time dependent, and increased incorporation of [3H]-GlcN into protein required de novo protein synthesis. Several mechanisms through which PDGF could increase GlcN incorporation into cellular material were examined. Results of these studies suggest an increase in the cellular capacity to glycosylate proteins is a response to or a part of competence formation

  10. The click-compatible sugar 6-deoxy-alkynyl glucose metabolically incorporates into Arabidopsis root hair tips and arrests their growth.

    McClosky, Daniel D; Wang, Bo; Chen, Gong; Anderson, Charles T

    2016-03-01

    Plant cell walls are dynamic structures whose polysaccharide components are rearranged and recycled during growth and morphogenesis. Covalent fluorescent tagging of these polysaccharides following a metabolic labeling approach can help elucidate these changes. Herein reported are the synthesis and seedling-incorporation of a plant polysaccharide chemical reporter, 6-deoxy-alkynyl glucose (6dAG), that is modeled on D-glucose. Whereas fucose-alkyne, a previously reported chemical reporter for pectin, incorporates diffusely throughout growing cell walls, 6dAG incorporated specifically into root hair tips. This incorporation occurs in a time- and concentration-dependent manner. 6dAG exposure both induces and colocalizes with callose deposition in this tissue, and arrests both root hair and root growth. These results show that plants can incorporate an additional alkynyl-modified sugar analog into their metabolism, and into a discrete subcellular location. PMID:26833385

  11. Expression of the bacterial type III effector DspA/E in Saccharomyces cerevisiae down-regulates the sphingolipid biosynthetic pathway leading to growth arrest.

    Siamer, Sabrina; Guillas, Isabelle; Shimobayashi, Mitsugu; Kunz, Caroline; Hall, Michael N; Barny, Marie-Anne

    2014-06-27

    Erwinia amylovora, the bacterium responsible for fire blight, relies on a type III secretion system and a single injected effector, DspA/E, to induce disease in host plants. DspA/E belongs to the widespread AvrE family of type III effectors that suppress plant defense responses and promote bacterial growth following infection. Ectopic expression of DspA/E in plant or in Saccharomyces cerevisiae is toxic, indicating that DspA/E likely targets a cellular process conserved between yeast and plant. To unravel the mode of action of DspA/E, we screened the Euroscarf S. cerevisiae library for mutants resistant to DspA/E-induced growth arrest. The most resistant mutants (Δsur4, Δfen1, Δipt1, Δskn1, Δcsg1, Δcsg2, Δorm1, and Δorm2) were impaired in the sphingolipid biosynthetic pathway. Exogenously supplied sphingolipid precursors such as the long chain bases (LCBs) phytosphingosine and dihydrosphingosine also suppressed the DspA/E-induced yeast growth defect. Expression of DspA/E in yeast down-regulated LCB biosynthesis and induced a rapid decrease in LCB levels, indicating that serine palmitoyltransferase (SPT), the first and rate-limiting enzyme of the sphingolipid biosynthetic pathway, was repressed. SPT down-regulation was mediated by dephosphorylation and activation of Orm proteins that negatively regulate SPT. A Δcdc55 mutation affecting Cdc55-PP2A protein phosphatase activity prevented Orm dephosphorylation and suppressed DspA/E-induced growth arrest. PMID:24828506

  12. Identification of MicroRNAs Involved in Growth Arrest and Apoptosis in Hydrogen Peroxide-Treated Human Hepatocellular Carcinoma Cell Line HepG2

    Yuan Luo

    2016-01-01

    Full Text Available Although both oxidative stress and microRNAs (miRNAs play vital roles in physiological and pathological processes, little is known about the interactions between them. In this study, we first described the regulation of H2O2 in cell viability, proliferation, cycle, and apoptosis of human hepatocellular carcinoma cell line HepG2. Then, miRNAs expression was profiled after H2O2 treatment. The results showed that high concentration of H2O2 (600 μM could decrease cell viability, inhibit cell proliferation, induce cell cycle arrest, and finally promote cell apoptosis. Conversely, no significant effects could be found under treatment with low concentration (30 μM. miRNAs array analysis identified 131 differentially expressed miRNAs (125 were upregulated and 6 were downregulated and predicted 13504 putative target genes of the deregulated miRNAs. Gene ontology (GO analysis revealed that the putative target genes were associated with H2O2-induced cell growth arrest and apoptosis. The subsequent bioinformatics analysis indicated that H2O2-response pathways, including MAPK signaling pathway, apoptosis, and pathways in cancer and cell cycle, were significantly affected. Overall, these results provided comprehensive information on the biological function of H2O2 treatment in HepG2 cells. The identification of miRNAs and their putative targets may offer new diagnostic and therapeutic strategies for liver cancer.

  13. A novel muscarinic antagonist R2HBJJ inhibits non-small cell lung cancer cell growth and arrests the cell cycle in G0/G1.

    Nan Hua

    Full Text Available Lung cancers express the cholinergic autocrine loop, which facilitates the progression of cancer cells. The antagonists of mAChRs have been demonstrated to depress the growth of small cell lung cancers (SCLCs. In this study we intended to investigate the growth inhibitory effect of R2HBJJ, a novel muscarinic antagonist, on non-small cell lung cancer (NSCLC cells and the possible mechanisms. The competitive binding assay revealed that R2HBJJ had a high affinity to M3 and M1 AChRs. R2HBJJ presented a strong anticholinergic activity on carbachol-induced contraction of guinea-pig trachea. R2HBJJ markedly suppressed the growth of NSCLC cells, such as H1299, H460 and H157. In H1299 cells, both R2HBJJ and its leading compound R2-PHC displayed significant anti-proliferative activity as M3 receptor antagonist darifenacin. Exogenous replenish of ACh could attenuate R2HBJJ-induced growth inhibition. Silencing M3 receptor or ChAT by specific-siRNAs resulted in a growth inhibition of 55.5% and 37.9% on H1299 cells 96 h post transfection, respectively. Further studies revealed that treatment with R2HBJJ arrested the cell cycle in G0/G1 by down-regulation of cyclin D1-CDK4/6-Rb. Therefore, the current study reveals that NSCLC cells express an autocrine and paracrine cholinergic system which stimulates the growth of NSCLC cells. R2HBJJ, as a novel mAChRs antagonist, can block the local cholinergic loop by antagonizing predominantly M3 receptors and inhibit NSCLC cell growth, which suggest that M3 receptor antagonist might be a potential chemotherapeutic regimen for NSCLC.

  14. A novel muscarinic antagonist R2HBJJ inhibits non-small cell lung cancer cell growth and arrests the cell cycle in G0/G1.

    Hua, Nan; Wei, Xiaoli; Liu, Xiaoyan; Ma, Xiaoyun; He, Xinhua; Zhuo, Rengong; Zhao, Zhe; Wang, Liyun; Yan, Haitao; Zhong, Bohua; Zheng, Jianquan

    2012-01-01

    Lung cancers express the cholinergic autocrine loop, which facilitates the progression of cancer cells. The antagonists of mAChRs have been demonstrated to depress the growth of small cell lung cancers (SCLCs). In this study we intended to investigate the growth inhibitory effect of R2HBJJ, a novel muscarinic antagonist, on non-small cell lung cancer (NSCLC) cells and the possible mechanisms. The competitive binding assay revealed that R2HBJJ had a high affinity to M3 and M1 AChRs. R2HBJJ presented a strong anticholinergic activity on carbachol-induced contraction of guinea-pig trachea. R2HBJJ markedly suppressed the growth of NSCLC cells, such as H1299, H460 and H157. In H1299 cells, both R2HBJJ and its leading compound R2-PHC displayed significant anti-proliferative activity as M3 receptor antagonist darifenacin. Exogenous replenish of ACh could attenuate R2HBJJ-induced growth inhibition. Silencing M3 receptor or ChAT by specific-siRNAs resulted in a growth inhibition of 55.5% and 37.9% on H1299 cells 96 h post transfection, respectively. Further studies revealed that treatment with R2HBJJ arrested the cell cycle in G0/G1 by down-regulation of cyclin D1-CDK4/6-Rb. Therefore, the current study reveals that NSCLC cells express an autocrine and paracrine cholinergic system which stimulates the growth of NSCLC cells. R2HBJJ, as a novel mAChRs antagonist, can block the local cholinergic loop by antagonizing predominantly M3 receptors and inhibit NSCLC cell growth, which suggest that M3 receptor antagonist might be a potential chemotherapeutic regimen for NSCLC. PMID:23285263

  15. Curcumin-treated cancer cells show mitotic disturbances leading to growth arrest and induction of senescence phenotype.

    Mosieniak, Grażyna; Sliwinska, Małgorzata A; Przybylska, Dorota; Grabowska, Wioleta; Sunderland, Piotr; Bielak-Zmijewska, Anna; Sikora, Ewa

    2016-05-01

    Cellular senescence is recognized as a potent anticancer mechanism that inhibits carcinogenesis. Cancer cells can also undergo senescence upon chemo- or radiotherapy. Curcumin, a natural polyphenol derived from the rhizome of Curcuma longa, shows anticancer properties both in vitro and in vivo. Previously, we have shown that treatment with curcumin leads to senescence of human cancer cells. Now we identified the molecular mechanism underlying this phenomenon. We observed a time-dependent accumulation of mitotic cells upon curcumin treatment. The time-lapse analysis proved that those cells progressed through mitosis for a significantly longer period of time. A fraction of cells managed to divide or undergo mitotic slippage and then enter the next phase of the cell cycle. Cells arrested in mitosis had an improperly formed mitotic spindle and were positive for γH2AX, which shows that they acquired DNA damage during prolonged mitosis. Moreover, the DNA damage response pathway was activated upon curcumin treatment and the components of this pathway remained upregulated while cells were undergoing senescence. Inhibition of the DNA damage response decreased the number of senescent cells. Thus, our studies revealed that the induction of cell senescence upon curcumin treatment resulted from aberrant progression through the cell cycle. Moreover, the DNA damage acquired by cancer cells, due to mitotic disturbances, activates an important molecular mechanism that determines the potential anticancer activity of curcumin. PMID:26916504

  16. Notch Signaling Activation in Cervical Cancer Cells Induces Cell Growth Arrest with the Involvement of the Nuclear Receptor NR4A2

    Sun, Lichun; Liu, Mingqiu; Sun, Guang-Chun; Yang, Xu; Qian, Qingqing; Feng, Shuyu; Mackey, L. Vienna; Coy, David H.

    2016-01-01

    Cervical cancer is a second leading cancer death in women world-wide, with most cases in less developed countries. Notch signaling is highly conserved with its involvement in many cancers. In the present study, we established stable cervical cell lines with Notch activation and inactivation and found that Notch activation played a suppressive role in cervical cancer cells. Meanwhile, the transient overexpression of the active intracellular domain of all four Notch receptors (ICN1, 2, 3, and 4) also induced the suppression of cervical cancer Hela cell growth. ICN1 also induced cell cycle arrest at phase G1. Notch1 signaling activation affected the expression of serial genes, especially the genes associated with cAMP signaling, with an increase of genes like THBS1, VCL, p63, c-Myc and SCG2, a decrease of genes like NR4A2, PCK2 and BCL-2. Particularly, The nuclear receptor NR4A2 was observed to induce cell proliferation via MTT assay and reduce cell apoptosis via FACS assay. Furthermore, NR4A2's activation could reverse ICN1-induced suppression of cell growth while erasing ICN1-induced increase of tumor suppressor p63. These findings support that Notch signaling mediates cervical cancer cell growth suppression with the involvement of nuclear receptor NR4A2. Notably, Notch/NR4A2/p63 signaling cascade possibly is a new signling pathway undisclosed. PMID:27471554

  17. Using quantitative PCR to Identify Kinesin-3 Genes that are Upregulated During Growth Arrest in MouseNIH3T3 Cells

    Thorsteinsson, Rikke; Christensen, Søren Tvorup; Pedersen, Lotte Bang

    2009-01-01

    mouse NIH3T3 cells and those that might have cilia-related functions. We employed this method to specifically search for mouse kinesin-3 genes that are upregulated during growth arrest and identified three such genes (Kif13A, Kif13B, and Kif16A). In principle, however, the method can be extended to...

  18. Herbal diterpenoids induce growth arrest and apoptosis in colon cancer cells with increased expression of the nonsteroidal anti-inflammatory drug-activated gene.

    Ko, Joshua K S; Leung, Wan C; Ho, Wai K; Chiu, Pauline

    2007-03-15

    Novel chemotherapeutic agents derived from active phytochemicals could be used as adjuvants and improve the anti-carcinogenicity of standard drug treatments. However, their precise mechanisms of action are sometimes unclear. In this study, the anti-carcinogenic effect of the herbal diterpenoid pseudolaric acid B (PAB) on the growth and apoptosis of colon cancer cells was investigated, and to compare that with the more toxic compound triptolide. PAB induced growth inhibition and apoptosis in HT-29 cells, which were associated with cell cycle arrest at the G(2)/M phase, modulation of cyclin expression and downregulation of the protooncogene c-myc. In addition, PAB also inhibited bcl-x(L) expression, induced cleavage of procaspase-3 and its substrate poly(ADP-ribose) polymerase (PARP), which together caused DNA fragmentation and nuclear chromatin condensation. Concomitantly, the modulation of the growth-related and apoptotic factors by PAB was accompanied by the increased protein and gene expression of the nonsteroidal anti-inflammatory drug-activated gene (NAG-1), which occurred along with cyclooxygenase-2 inhibition. The effects of PAB on PARP cleavage and NAG-1 overexpression were not reversible upon removal of the drug from the culture medium. Similar cytotoxic and pro-apoptotic effects were also attained by treating the HT-29 cells with another diterpenoid triptolide, but its actions on cell cycle progression and on the upstream transcriptional regulation of NAG-1 both took place in a less coherent manner. These findings exemplify the potential of herbal terpenoids, particularly PAB, in modulating colon cancer carcinogenesis through known molecular targets and precise mechanism of action. PMID:17258704

  19. Upregulation of the growth arrest-specific-2 in recurrent colorectal cancers, and its susceptibility to chemotherapy in a model cell system.

    Huang, Chi-Jung; Lee, Chia-Long; Yang, Shung-Haur; Chien, Chih-Cheng; Huang, Chi-Cheng; Yang, Ruey-Neng; Chang, Chun-Chao

    2016-07-01

    Colorectal cancer (CRC) is one of the most common life-threatening malignances worldwide. CRC relapse markedly decreases the 5-year survival of patients following surgery. Aberrant expression of genes involved in pathways regulating the cell cycle, cell proliferation, or cell death are frequently reported in CRC tumorigenesis. We hypothesized that genes involved in CRC relapse might serve as prognostic indicators. We first evaluated the significance of gene sequences in the feces of patients with CRC relapse by consulting a public database. Tumorigenesis of target tissues was tested through tumor cell growth, cell cycle regulation, and chemotherapeutic efficacy. We found a highly significant correlation between CRC relapse and growth arrest-specific 2 (GAS2) gene expression. Based on cell models, the overexpressed GAS2 was associated with cellular growth rate, cell cycle regulation, and with chemotherapeutic sensitivity. Cell division was impaired by treating cells with 2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]-propionic acid (XK469), even when the cells were overexpressing GAS2. Thus, downregulation of GAS2 expression might control CRC relapse after curative resection. GAS2 could serve as a noninvasive marker from the feces of patients with prediagnosed CRC. Our findings suggest that GAS2 could have potential clinical applications for predicting early CRC relapse after radical resection, and that XK469 might impair tumor cell division by reducing GAS2 expression or blocking its cellular translocation. This will help in selecting the best therapeutic option, 5-fluorouracil in combination with XK469, for patients overexpressing GAS2 in CRC cells. Thus, GAS2 might act as a prognostic biomolecule and potential therapeutic target in patients with CRC relapse. PMID:27085973

  20. Induction of reactive oxygen species generation inhibits epithelial-mesenchymal transition and promotes growth arrest in prostate cancer cells.

    Das, Trinath P; Suman, Suman; Damodaran, Chendil

    2014-07-01

    Oxidative stress is one causative factor of the pathogenesis and aggressiveness of most of the cancer types, including prostate cancer (CaP). A moderate increase in reactive oxygen species (ROS) induces cell proliferation whereas excessive amounts of ROS promote apoptosis. In this study, we explored the pro-oxidant property of 3,9-dihydroxy-2-prenylcoumestan (psoralidin [pso]), a dietary agent, on CaP (PC-3 and C4-2B) cells. Pso greatly induced ROS generation (more than 20-fold) that resulted in the growth inhibition of CaP cells. Overexpression of anti-oxidant enzymes superoxide dismutase 1 (SOD1), SOD2, and catalase, or pretreatment with the pharmacological inhibitor N-acetylcysteine (NAC) significantly attenuated both pso-mediated ROS generation and pso-mediated growth inhibition in CaP cells. Furthermore, pso administration significantly inhibited the migratory and invasive property of CaP cells by decreasing the transcription of β-catenin, and slug, which promote epithelial-mesenchymal transition (EMT), and by concurrently inducing E-cadherin expression in CaP cells. Pso-induced ROS generation in CaP cells resulted in loss of mitochondrial membrane potential, cytochrome-c release, and activation of caspase-3 and -9 and poly (ADP-ribose) polymerase (PARP), which led to apoptosis. On the other hand, overexpression of anti-oxidants rescued pso-mediated effects on CaP cells. These findings suggest that increasing the threshold of intracellular ROS could prevent or treat CaP growth and metastasis. PMID:23475579

  1. On arresting the complex growth rates in ferromagnetic convection with magnetic field dependent viscosity in a rotating ferrofluid layer

    Prakash, Jyoti, E-mail: jpsmaths67@gmail.com; Gupta, Sanjay

    2013-11-15

    It is proved analytically that the complex growth rate ω=ω{sub r}+iω{sub i} (ω{sub r}andω{sub i} are respectively the real and imaginary parts of ω) of an arbitrary oscillatory motion of growing amplitude in ferromagnetic convection, with magnetic field dependent viscosity, in a rotating ferrofluid layer for the case of free boundaries, must lie inside a semicircle in the right half of the ω{sub r}ω{sub i}- plane whose center is at the origin and (radius){sup 2}=max{(RM_1/P_r),T_a}, where R is the Rayleigh number, M{sub 1} is the magnetic number, P{sub r} is the Prandtl number and T{sub a} is the Taylor number. Further, bounds for the case of rigid boundaries are also derived separately. - Highlights: • The linear stability analysis for a rotating ferrofluid layer with magnetic field dependent viscosity heated from below is made. • Upper bounds for the complex growth rates are obtained for free and rigid boundaries. • Bounds are important mainly when atleast one boundary is rigid so that exact solutions in closed form are not obtainable. • Results derived involve only nondimensional quantities and are independent of the wave number; are, thus, of uniform validity and applicability.

  2. On arresting the complex growth rates in ferromagnetic convection with magnetic field dependent viscosity in a rotating ferrofluid layer

    It is proved analytically that the complex growth rate ω=ωr+iωi (ωrandωi are respectively the real and imaginary parts of ω) of an arbitrary oscillatory motion of growing amplitude in ferromagnetic convection, with magnetic field dependent viscosity, in a rotating ferrofluid layer for the case of free boundaries, must lie inside a semicircle in the right half of the ωrωi- plane whose center is at the origin and (radius)2=max{(RM1/Pr),Ta}, where R is the Rayleigh number, M1 is the magnetic number, Pr is the Prandtl number and Ta is the Taylor number. Further, bounds for the case of rigid boundaries are also derived separately. - Highlights: • The linear stability analysis for a rotating ferrofluid layer with magnetic field dependent viscosity heated from below is made. • Upper bounds for the complex growth rates are obtained for free and rigid boundaries. • Bounds are important mainly when atleast one boundary is rigid so that exact solutions in closed form are not obtainable. • Results derived involve only nondimensional quantities and are independent of the wave number; are, thus, of uniform validity and applicability

  3. Arrest of cell cycle by inhibition of ribonucleotide reductase induces accumulation of NAD+ by Mn2+-supplemented growth of Corynebacterium ammoniagenes.

    Abbouni, Bouziane; Elhariry, Hesham M; Auling, Georg

    2003-01-01

    Cell division of the wild type strain Corynebacterium (formerly Brevibacterium) ammoniagenes ATCC 6872 which requires 1 microM Mn2+ for balanced growth was inhibited by addition of 20 mM hydroxyurea (HU) or 10 mM p-methoxyphenol (MP) to a Mn2+-supplemented fermentation medium at an appropriate time. Scanning electron microscopy (SEM) showed a restricted elongation characteristic of arrest of the cell cycle in coryneform bacteria. The cultures treated with HU or MP had, respectively, a fourfold or sixfold enhanced accumulation of NAD+ by a salvage biosynthetic pathway. An assay of nucleotide-permeable cells for ribonucleotide reductase activity using [3H-CDP] as substrate revealed a pre-early and complete decline of DNA precursor biosynthesis not found in the untreated control. Overproduction of NAD+ is an alternative to the conventional fermentation process using Mn2+ deficiency. A simple model is presented to discuss the metabolic regulation of the new process based on the presence of a manganese ribonucleotide reductase (Mn-RNR) in the producing strain. PMID:12882290

  4. Simultaneous Presence of Growth and Remodeling in the Bone Adaptation Theory

    Seyyed A.H. Ahmedi

    2009-01-01

    Full Text Available Mechanical forces acting on bone during growth affect their final shape and strength. Mechanoregulation of bone growth is maybe recognized in embryogenesis, and also in the adaptation of the adult skeleton to changes in mechanical loading. By combining equations describing bone remodeling and growth with an iterative finite element analysis, a computational model to simulate the simultaneous effects of bone remodeling and bone growth was proposed in this study. Strain-energy density was assumed as mechanical stimulus of bone adaptation process. Negative exponential decay function over time was considered as metabolic growth rate. Based upon numeric results, the model shows an acceptable behavior under various modes of loading, e.g. altering in trabeculas orientation or its thickness. This model also shows that by neglecting growth part in the adaptation model, a considerable error would result in both final density distribution and microstructural pattern of spongy bone.

  5. Ability of Group IVB metallocene polyethers containing dienestrol to arrest the growth of selected cancer cell lines

    Monomeric Group IVB (Ti, Zr and Hf) metallocenes represent a new class of antitumor compounds. There is literature on the general biological activities of some organotin compounds. Unfortunately, there is little information with respect to the molecular level activity of these organotin compounds. We recently started focusing on the anti-cancer activity of organotin polymers that we had made for other purposes and as part of our platinum anti-cancer effort. For this study, we synthesized a new series of metallocene-containing compounds coupling the metallocene unit with dienestrol, a synthetic, nonsteroidal estrogen. This is part of our effort to couple known moieties that offer antitumor activity with biologically active units hoping to increase the biological activity of the combination. The materials were confirmed to be polymeric using light scattering photometry and the structural repeat unit was verified employing matrix assisted laser desorption ionization mass spectrometry and infrared spectroscopy results. The polymers demonstrated the ability to suppress the growth of a series of tumor cell lines originating from breast, colon, prostrate, and lung cancers at concentrations generally lower than those required for inhibition of cell growth by the commonly used antitumor drug cisplatin. These drugs show great promise in vitro against a number of cancer cell lines and due to their polymeric nature will most likely be less toxic than currently used metal-containing drugs such as cisplatin. These drugs also offer several addition positive aspects. First, the reactants are commercially available so that additional synthetic steps are not needed. Second, synthesis of the polymer is rapid, occurring within about 15 seconds. Third, the interfacial synthetic system is already industrially employed in the synthesis of aromatic nylons and polycarbonates. Thus, the ability to synthesize large amounts of the drugs is straight forward

  6. Plant HDAC inhibitor chrysin arrest cell growth and induce p21WAF1 by altering chromatin of STAT response element in A375 cells

    Pal-Bhadra Manika

    2012-05-01

    Full Text Available Abstract Background Chrysin and its analogues, belongs to flavonoid family and possess potential anti-tumour activity. The aim of this study is to determine the molecular mechanism by which chrysin controls cell growth and induce apoptosis in A375 cells. Methods Effect of chrysin and its analogues on cell viability and cell cycle analysis was determined by MTT assay and flowcytometry. A series of Western blots was performed to determine the effect of chrysin on important cell cycle regulatory proteins (Cdk2, cyclin D1, p53, p21, p27. The fluorimetry and calorimetry based assays was conducted for characterization of chrysin as HDAC inhibitor. The changes in histone tail modification such as acetylation and methylation was studied after chrysin treatment was estimated by immuno-fluorescence and western blot analysis. The expression of Bcl-xL, survivin and caspase-3 was estimated in chrysin treated cells. The effect of chrysin on p21 promoter activity was studied by luciferase and ChIP assays. Results Chrysin cause G1 cell cycle arrest and found to inhibit HDAC-2 and HDAC-8. Chrysin treated cells have shown increase in the levels of H3acK14, H4acK12, H4acK16 and decrease in H3me2K9 methylation. The p21 induction by chrysin treatment was found to be independent of p53 status. The chromatin remodelling at p21WAF1 promoter induces p21 activity, increased STAT-1 expression and epigenetic modifications that are responsible for ultimate cell cycle arrest and apoptosis. Conclusion Chrysin shows in vitro anti-cancer activity that is correlated with induction of histone hyperacetylation and possible recruitment of STAT-1, 3, 5 proteins at STAT (−692 to −684 region of p21 promoter. Our results also support an unexpected action of chrysin on the chromatin organization of p21WAF1 promoter through histone methylation and hyper-acetylation. It proposes previously unknown sequence specific chromatin modulations in the STAT responsive elements for regulating

  7. Plant HDAC inhibitor chrysin arrest cell growth and induce p21WAF1 by altering chromatin of STAT response element in A375 cells

    Chrysin and its analogues, belongs to flavonoid family and possess potential anti-tumour activity. The aim of this study is to determine the molecular mechanism by which chrysin controls cell growth and induce apoptosis in A375 cells. Effect of chrysin and its analogues on cell viability and cell cycle analysis was determined by MTT assay and flowcytometry. A series of Western blots was performed to determine the effect of chrysin on important cell cycle regulatory proteins (Cdk2, cyclin D1, p53, p21, p27). The fluorimetry and calorimetry based assays was conducted for characterization of chrysin as HDAC inhibitor. The changes in histone tail modification such as acetylation and methylation was studied after chrysin treatment was estimated by immuno-fluorescence and western blot analysis. The expression of Bcl-xL, survivin and caspase-3 was estimated in chrysin treated cells. The effect of chrysin on p21 promoter activity was studied by luciferase and ChIP assays. Chrysin cause G1 cell cycle arrest and found to inhibit HDAC-2 and HDAC-8. Chrysin treated cells have shown increase in the levels of H3acK14, H4acK12, H4acK16 and decrease in H3me2K9 methylation. The p21 induction by chrysin treatment was found to be independent of p53 status. The chromatin remodelling at p21WAF1 promoter induces p21 activity, increased STAT-1 expression and epigenetic modifications that are responsible for ultimate cell cycle arrest and apoptosis. Chrysin shows in vitro anti-cancer activity that is correlated with induction of histone hyperacetylation and possible recruitment of STAT-1, 3, 5 proteins at STAT (−692 to −684) region of p21 promoter. Our results also support an unexpected action of chrysin on the chromatin organization of p21WAF1 promoter through histone methylation and hyper-acetylation. It proposes previously unknown sequence specific chromatin modulations in the STAT responsive elements for regulating cell cycle progression negatively via the induction of the CDK

  8. Treatment of mouse melanoma cells with phorbol 12-myristate 13-acetate counteracts mannosylerythritol lipid-induced growth arrest and apoptosis.

    Zhao, X; Geltinger, C; Kishikawa, S; Ohshima, K; Murata, T; Nomura, N; Nakahara, T; Yokoyama, K K

    2000-07-01

    Mannosylerythritol lipid (MEL), an extracellularglycolipid from yeast, induces the differentiation ofHL-60 promyelocytic leukemia cells towardsgranulocytes. We show here that MEL is also a potentinhibitor of the proliferation of mouse melanoma B16cells. Flow-cytometric analysis of the cell cycle ofMEL-treated B16 cells revealed the accumulation ofcells in the sub-G(0)/G(1) phase, which is a hallmark ofcells undergoing apoptosis. Treatment of B16 cellsfor 24 h with phorbol 12-myristate 13-acetate (PMA),an activator of protein kinase C (PKC), did notinterfere with the growth and survival of the cells,but it effectively counteracted the MEL-induced growtharrest and apoptosis. The activity of PKC was reducedin B16 cells treated with MEL at a concentration atwhich MEL induced apoptosis. However, incubation withPMA in addition to MEL reversed this reduction in theactivity of PKC. These results suggest thatconverging signaling pathways are triggeredindependently by MEL and PMA and that the signalsmight both be mediated by PKC. PMID:19002819

  9. Dual involvement of growth arrest-specific gene 6 in the early phase of human IgA nephropathy.

    Kojiro Nagai

    Full Text Available BACKGROUND: Gas6 is a growth factor that causes proliferation of mesangial cells in the development of glomerulonephritis. Gas6 can bind to three kinds of receptors; Axl, Dtk, and Mer. However, their expression and functions are not entirely clear in the different glomerular cell types. Meanwhile, representative cell cycle regulatory protein p27 has been reported to be expressed in podocytes in normal glomeruli with decreased expression in proliferating glomeruli, which inversely correlated with mesangial proliferation in human IgA nephropathy (IgAN. METHODS: The aim of this study is to clarify Gas6 involvement in the progression of IgAN. Expression of Gas6/Axl/Dtk was examined in 31 biopsy proven IgAN cases. We compared the expression levels with histological severity or clinical data. Moreover, we investigated the expression of Gas6 and its receptors in cultured podocytes. RESULTS: In 28 of 31 cases, Gas6 was upregulated mainly in podocytes. In the other 3 cases, Gas6 expression was induced in endothelial and mesangial cells, which was similar to animal nephritis models. Among 28 podocyte type cases, the expression level of Gas6 correlated with the mesangial hypercellularity score of IgAN Oxford classification and urine protein excretion. It also inversely correlated with p27 expression in glomeruli. As for the receptors, Axl was mainly expressed in endothelial and mesangial cells, while Dtk was expressed in podocytes. In vitro, Dtk was expressed in cultured murine podocytes, and the expression of p27 was decreased by Gas6 stimulation. CONCLUSIONS: Gas6 was uniquely upregulated in either endothelial/mesangial cells or podocytes in IgAN. The expression pattern can be used as a marker to classify IgAN. Gas6 has a possibility to be involved in not only mesangial proliferation via Axl, but also podocyte injury via Dtk in IgAN.

  10. Dehydroleucodine inhibits tumor growth in a preclinical melanoma model by inducing cell cycle arrest, senescence and apoptosis.

    Costantino, Valeria V; Lobos-Gonzalez, Lorena; Ibañez, Jorge; Fernandez, Dario; Cuello-Carrión, F Darío; Valenzuela, Manuel A; Barbieri, Manuel A; Semino, Silvana N; Jahn, Graciela A; Quest, Andrew F G; Lopez, Luis A

    2016-03-01

    Malignant melanoma represents the fastest growing public health risk of all cancer types worldwide. Several strategies and anti-cancer drugs have been used in an effort to improve treatments, but the development of resistance to anti-neoplastic drugs remains the major cause of chemotherapy failure in melanomas. Previously, we showed that the sesquiterpene lactone, dehydroleucodine (DhL), promotes the accumulation of DNA damage markers, such as H2AX and 53BP1, in human tumor cells. Also DhL was shown to trigger either cell senescence or apoptosis in a concentration-dependent manner in HeLa and MCF7 cells. Here, we evaluated the effects of DhL on B16F0 mouse melanoma cells in vitro and in a pre-clinical melanoma model. DhL inhibited the proliferation of B16F0 cells by inducing senescence or apoptosis in a concentration-dependent manner. Also, DhL reduced the expression of the cell cycle proteins cyclin D1 and B1 and the inhibitor of apoptosis protein, survivin. In melanomas generated by subcutaneous injection of B16F0 cells into C57/BL6 mice, the treatment with 20 mg DhL /Kg/day in preventive, simultaneous and therapeutic protocols reduced tumor volumes by 70%, 60% and 50%, respectively. DhL treatments reduced the number of proliferating, while increasing the number of senescent and apoptotic tumor cells. To estimate the long-term effects of DhL, a mathematical model was applied to fit experimental data. Extrapolation beyond experimental time points revealed that DhL administration following preventive and therapeutic protocols is predicted to be more effective than simultaneous treatments with DhL in restricting tumor growth. PMID:26718258

  11. Prediction of solution structures of the Ca2+-bound gamma-carboxyglutamic acid domains of protein S and homolog growth arrest specific protein 6: use of the particle mesh Ewald method.

    Perera, L; Li, L.; Darden, T.; Monroe, D M; Pedersen, L G

    1997-01-01

    The solution structures of the N-terminal domains of protein S, a plasma vitamin K-dependent glycoprotein, and its homolog growth arrest specific protein 6 (Gas6) were predicted by molecular dynamics computer simulations. The initial structures were based on the x-ray crystallographic structure of the corresponding region of bovine prothrombin fragment 1. The subsequent molecular dynamics trajectories were calculated using the second-generation AMBER force field. The long-range electrostatic ...

  12. Growth arrest-specific transcript 5 associated snoRNA levels are related to p53 expression and DNA damage in colorectal cancer.

    Jonathan Krell

    Full Text Available The growth arrest-specific transcript 5 gene (GAS5 encodes a long noncoding RNA (lncRNA and hosts a number of small nucleolar RNAs (snoRNAs that have recently been implicated in multiple cellular processes and cancer. Here, we investigate the relationship between DNA damage, p53, and the GAS5 snoRNAs to gain further insight into the potential role of this locus in cell survival and oncogenesis both in vivo and in vitro.We used quantitative techniques to analyse the effect of DNA damage on GAS5 snoRNA expression and to assess the relationship between p53 and the GAS5 snoRNAs in cancer cell lines and in normal, pre-malignant, and malignant human colorectal tissue and used biological techniques to suggest potential roles for these snoRNAs in the DNA damage response.GAS5-derived snoRNA expression was induced by DNA damage in a p53-dependent manner in colorectal cancer cell lines and their levels were not affected by DICER. Furthermore, p53 levels strongly correlated with GAS5-derived snoRNA expression in colorectal tissue.In aggregate, these data suggest that the GAS5-derived snoRNAs are under control of p53 and that they have an important role in mediating the p53 response to DNA damage, which may not relate to their function in the ribosome. We suggest that these snoRNAs are not processed by DICER to form smaller snoRNA-derived RNAs with microRNA (miRNA-like functions, but their precise role requires further evaluation. Furthermore, since GAS5 host snoRNAs are often used as endogenous controls in qPCR quantifications we show that their use as housekeeping genes in DNA damage experiments can lead to inaccurate results.

  13. Hwanggeumchal sorghum induces cell cycle arrest, and suppresses tumor growth and metastasis through Jak2/STAT pathways in breast cancer xenografts.

    Jin Hee Park

    Full Text Available BACKGROUND: Cancer is one of the highly virulent diseases known to humankind with a high mortality rate. Breast cancer is the most common cancer in women worldwide. Sorghum is a principal cereal food in many parts of the world, and is critical in folk medicine of Asia and Africa. In the present study, we analyzed the effects of HSE in metastatic breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: Preliminary studies conducted on MDA-MB 231 and MCF-7 xenograft models showed tumor growth suppression by HSE. Western blotting studies conducted both in vivo and in vitro to check the effect of HSE in Jak/STAT pathways. Anti-metastatic effects of HSE were confirmed using both MDA-MB 231 and MCF-7 metastatic animal models. These studies showed that HSE can modulate Jak/STAT pathways, and it hindered the STAT5b/IGF-1R and STAT3/VEGF pathways not only by down-regulating the expression of these signal molecules and but also by preventing their phosphorylation. The expression of angiogenic factors like VEGF, VEGF-R2 and cell cycle regulators like cyclin D, cyclin E, and pRb were found down-regulated by HSE. In addition, it also targets Brk, p53, and HIF-1α for anti-cancer effects. HSE induced G1 phase arrest and migration inhibition in MDA-MB 231 cells. The metastasis of breast cancer to the lungs also found blocked by HSE in the metastatic animal model. CONCLUSIONS/SIGNIFICANCE: Usage of HS as a dietary supplement is an inexpensive natural cancer therapy, without any side effects. We strongly recommend the use of HS as an edible therapeutic agent as it possesses tumor suppression, migration inhibition, and anti-metastatic effects on breast cancer.

  14. N-Methyl-N'-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNA

    Narayan Satya

    2004-01-01

    Full Text Available Abstract Background Cellular senescence is a state in which mammalian cells enter into an irreversible growth arrest and altered biological functions. The senescence response in mammalian cells can be elicited by DNA-damaging agents. In the present study we report that the DNA-damaging agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG is able to induce senescence in the HCT-116 colon cancer cell line. Results Cells treated with lower concentrations of MNNG (0–25 microM for 50 h showed a dose-dependent increase in G2/M phase arrest and apoptosis; however, cells treated with higher concentrations of MNNG (50–100 microM showed a senescence-like G0/G1 phase arrest which was confirmed by increased expression of β-galactosidase, a senescence induced marker. The G2/M phase arrest and apoptosis were found to be associated with increased levels of p53 protein, but the senescence-like G0/G1 phase arrest was dissociated with p53 protein levels, since the p53 protein levels decreased in senescence-like arrested cells. We further, determined whether the decreased level of p53 was a transcriptional or a translational phenomenon. The results revealed that the decreased level of p53 protein in senescence-like arrested cells was a transcriptional phenomenon since p53 mRNA levels simultaneously decreased after treatment with higher concentrations of MNNG. We also examined the effect of MNNG treatment on other cell cycle-related proteins such as p21, p27, cyclin B1, Cdc2, c-Myc and max. The expression levels of these proteins were increased in cells treated with lower concentrations of MNNG, which supported the G2/M phase arrest. However, cells treated with higher concentrations of MNNG showed decreased levels of these proteins, and hence, may not play a role in cell cycle arrest. We then examined a possible association of the expression of APC protein and telomeric DNA signals with cellular senescence in MNNG-treated cells. We found that protein and m

  15. Growth arrest by the antitumor steroidal lactone withaferin A in human breast cancer cells is associated with down-regulation and covalent binding at cysteine 303 of β-tubulin.

    Antony, Marie L; Lee, Joomin; Hahm, Eun-Ryeong; Kim, Su-Hyeong; Marcus, Adam I; Kumari, Vandana; Ji, Xinhua; Yang, Zhen; Vowell, Courtney L; Wipf, Peter; Uechi, Guy T; Yates, Nathan A; Romero, Guillermo; Sarkar, Saumendra N; Singh, Shivendra V

    2014-01-17

    Withaferin A (WA), a C5,C6-epoxy steroidal lactone derived from a medicinal plant (Withania somnifera), inhibits growth of human breast cancer cells in vitro and in vivo and prevents mammary cancer development in a transgenic mouse model. However, the mechanisms underlying the anticancer effect of WA are not fully understood. Herein, we report that tubulin is a novel target of WA-mediated growth arrest in human breast cancer cells. The G2 and mitotic arrest resulting from WA exposure in MCF-7, SUM159, and SK-BR-3 cells was associated with a marked decrease in protein levels of β-tubulin. These effects were not observed with the naturally occurring C6,C7-epoxy analogs of WA (withanone and withanolide A). A non-tumorigenic normal mammary epithelial cell line (MCF-10A) was markedly more resistant to mitotic arrest by WA compared with breast cancer cells. Vehicle-treated control cells exhibited a normal bipolar spindle with chromosomes aligned along the metaphase plate. In contrast, WA treatment led to a severe disruption of normal spindle morphology. NMR analyses revealed that the A-ring enone in WA, but not in withanone or withanolide A, was highly reactive with cysteamine and rapidly succumbed to irreversible nucleophilic addition. Mass spectrometry demonstrated direct covalent binding of WA to Cys(303) of β-tubulin in MCF-7 cells. Molecular docking indicated that the WA-binding pocket is located on the surface of β-tubulin and characterized by a hydrophobic floor, a hydrophobic wall, and a charge-balanced hydrophilic entrance. These results provide novel insights into the mechanism of growth arrest by WA in breast cancer cells. PMID:24297176

  16. Sonic Hedgehog Opposes Epithelial Cell Cycle Arrest

    Fan, Hongran; Khavari, Paul A

    1999-01-01

    Stratified epithelium displays an equilibrium between proliferation and cell cycle arrest, a balance that is disrupted in basal cell carcinoma (BCC). Sonic hedgehog (Shh) pathway activation appears sufficient to induce BCC, however, the way it does so is unknown. Shh-induced epidermal hyperplasia is accompanied by continued cell proliferation in normally growth arrested suprabasal cells in vivo. Shh-expressing cells fail to exit S and G2/M phases in response to calcium-induced differentiation...

  17. Deterrence and arrest ratios.

    Carmichael, Stephanie E; Piquero, Alex R

    2006-02-01

    In the limited research on the origins of sanction threat perceptions, researchers have focused on either the effects of actively engaging in crime or the effects of formal sanctioning but rarely on both (i.e., the arrest ratio or the number of arrests relative to the number of crimes committed). This article extends this line of research by using a sample of Colorado inmates and measures arrest ratios and sanction perceptions for eight different crime types. Analyses reveal that the offenders report both significant experiential and arrest ratio effects. Theoretical and policy implications, limitations, and directions for future research are outlined. PMID:16397123

  18. High-density growth arrest in Ras-transformed cells: low Cdk kinase activities in spite of absence of p27Kip Cdk-complexes

    Groth, Anja; Willumsen, Berthe Marie

    2005-01-01

    and Cdk2 complexes, as these kinases were inactivated. Ras-transformed cells failed to arrest at normal saturation density and showed no significant alterations in cell control complexes at this point. Yet, at an elevated density the Ras-transformed cells ceased to proliferate and entered a quiescent......-like state with low Cdk4 and Cdk2 activity. Surprisingly, this delayed arrest was molecularly distinct from contact inhibition of normal cells, as it occurred in the absence of p27Kip1 induction and cyclin D1 levels remained high. This demonstrates that although oncogenic Ras efficiently disabled the normal...

  19. A novel site contributing to growth-arrest-specific gene 6 binding to its receptors as revealed by a human monoclonal antibody

    2004-01-01

    Gas6 (growth-arrest-specific gene 6) is a vitamin K-dependent protein known to activate the Axl family of receptor tyrosine kinases. It is an important regulator of thrombosis and many other biological functions. The C-terminus of Gas6 binds to receptors and consists of two laminin-like globular domains LG1 and LG2. It has been reported that a Ca2+-binding site at the junction of LG1 and LG2 domains and a hydrophobic patch at the LG2 domain are important for receptor binding [Sasaki, Knyazev, Cheburkin, Gohring, Tisi, Ullrich, Timpl and Hohenester (2002) J. Biol. Chem. 277, 44164–44170]. In the present study, we developed a neutralizing human monoclonal antibody, named CNTO300, for Gas6. The antibody was generated by immunization of human IgG-expressing transgenic mice with recombinant human Gas6 protein and the anti-Gas6 IgG sequences were rescued from an unstable hybridoma clone. Binding of Gas6 to its receptors was partially inhibited by the CNTO300 antibody in a dose-dependent manner. To characterize further the interaction between Gas6 and this antibody, the binding kinetics of CNTO300 for recombinant Gas6 were compared with independently expressed LG1 and LG2. The CNTO300 antibody showed comparable binding affinity, yet different dependence on Ca2+, to Gas6 and LG1. No binding to LG2 was detected. In the presence of EDTA, binding of the antibody to Gas6 was disrupted, but no significant effect of EDTA on LG1 binding was evident. Further epitope mapping identified a Gas6 peptide sequence recognized by the CNTO300 antibody. This peptide sequence was found to be located at the LG1 domain distant from the Ca2+-binding site and the hydrophobic patch. Co-interaction of Gas6 with its receptor and CNTO300 antibody was detected by BIAcore analysis, suggesting a second receptor-binding site on the LG1 domain. This hypothesis was further supported by direct binding of Gas6 receptors to an independently expressed LG1 domain. Our results revealed, for the first time, a

  20. Fetal hemodynamic adaptive changes related to intrauterine growth the generation R study

    Verburg, Bero Olof; JADDOE, Vincent; Wladimiroff, Juriy; Hofman, Albert; Witteman, Jacqueline; Steegers-Theunissen, Régine

    2008-01-01

    textabstractBackground-It has been suggested that an adverse fetal environment increases susceptibility to hypertension and cardiovascular disease in adult life. This increased risk may result from suboptimal development of the heart and main arteries in utero and from adaptive cardiovascular changes in conditions of reduced fetal growth. The aim of the present study was to evaluate whether reduced fetal growth is associated with fetal circulatory changes and cardiac dysfunction. Methods and ...

  1. Climate Change Adaptation. Challenges and Opportunities for a Smart Urban Growth

    Adriana Galderisi

    2014-04-01

    Full Text Available Climate change is one of the main environmental issues challenging cities in the 21th century. At present, more than half of the world population lives in cities and the latter are responsible for 60% to 80% of global energy consumption and greenhouse gas (GHG emissions, which are the main causes of the change in climate conditions. In the meantime, they are seriously threatened by the heterogeneous climate-related phenomena, very often exacerbated by the features of the cities themselves. In the last decade, international and European efforts have been mainly focused on mitigation rather than on adaptation strategies. Europe is one of the world leaders in global mitigation policies, while the issue of adaptation has gained growing importance in the last years. As underlined by the EU Strategy on adaptation to climate change, even though climate change mitigation still remains a priority for the global community, large room has to be devoted to adaptation measures, in order to effectively face the unavoidable impacts and related economic, environmental and social costs of climate change (EC, 2013. Thus, measures for adaptation to climate change are receiving an increasing financial support and a growing number of European countries are implementing national and urban adaptation strategies to deal with the actual and potential climate change impacts. According to the above considerations, this paper explores strengths and weaknesses of current adaptation strategies in European cities. First the main suggestions of the European Community to improve urban adaptation to climate change are examined; then, some recent Adaptation Plans are analyzed, in order to highlight challenges and opportunities arising from the adaptation processes at urban level and to explore the potential of Adaptation Plans to promote a smart growth in the European cities.

  2. Growth rate regulates membrane fluidity and membrane cold adaptation in .i.Bacillus subtilis./i

    Beranová, J.; Jemiola-Rzeminska, M.; Elhottová, Dana; Strzalka, K.; Konopásek, I.

    2007-01-01

    Roč. 48, - (2007), s. 85. ISSN 0009-0646. [Kongres Československé společnosti mikrobiologické /24./. 02.10.2007-05.10.2007, Liberec] Institutional research plan: CEZ:AV0Z60660521 Keywords : growth rate * membrane fluidity * membrane cold adaptation Subject RIV: EH - Ecology, Behaviour

  3. Growth arrest- and DNA-damage-inducible 45beta gene inhibits c-Jun N-terminal kinase and extracellular signal-regulated kinase and decreases IL-1beta-induced apoptosis in insulin-producing INS-1E cells

    Larsen, Claus Morten; Døssing, M G; Papa, S;

    2006-01-01

    IL-1beta is a candidate mediator of apoptotic beta cell destruction, a process that leads to type 1 diabetes and progression of type 2 diabetes. IL-1beta activates beta cell c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38, all of which are members of the mitogen......-activated protein kinase (MAPK) family. Inhibition of JNK prevents IL-1beta-mediated beta cell destruction. In mouse embryo fibroblasts and 3DO T cells, overexpression of the gene encoding growth arrest and DNA-damage-inducible 45beta (Gadd45b) downregulates pro-apoptotic JNK signalling. The aim of this study...

  4. Sudden Cardiac Arrest

    ... scan, or MUGA, which shows how well your heart is pumping blood. Magnetic resonance imaging (MRI) which gives doctors detailed pictures of your heart. How is SCA treated? Sudden cardiac arrest should ...

  5. Cardiac arrest in children

    Tress Erika

    2010-01-01

    Full Text Available Major advances in the field of pediatric cardiac arrest (CA were made during the last decade, starting with the publication of pediatric Utstein guidelines, the 2005 recommendations by the International Liaison Committee on Resuscitation, and culminating in multicenter collaborations. The epidemiology and pathophysiology of in-hospital and out-of-hospital CA are now well described. Four phases of CA are described and the term "post-cardiac arrest syndrome" has been proposed, along with treatment goals for each of its four phases: immediate post-arrest, early post-arrest, intermediate and recovery phase. Hypothermia is recommended to be considered as a therapy for post-CA syndrome in comatose patients after CA, and large multicenter prospective studies are underway. We reviewed landmark articles related to pediatric CA published during the last decade. We present the current knowledge of epidemiology, pathophysiology and treatment of CA relevant to pre-hospital and acute care health practitioners.

  6. Cardiac arrest in children.

    Tress, Erika E; Kochanek, Patrick M; Saladino, Richard A; Manole, Mioara D

    2010-07-01

    Major advances in the field of pediatric cardiac arrest (CA) were made during the last decade, starting with the publication of pediatric Utstein guidelines, the 2005 recommendations by the International Liaison Committee on Resuscitation, and culminating in multicenter collaborations. The epidemiology and pathophysiology of in-hospital and out-of-hospital CA are now well described. Four phases of CA are described and the term "post-cardiac arrest syndrome" has been proposed, along with treatment goals for each of its four phases: immediate post-arrest, early post-arrest, intermediate and recovery phase. Hypothermia is recommended to be considered as a therapy for post-CA syndrome in comatose patients after CA, and large multicenter prospective studies are underway. We reviewed landmark articles related to pediatric CA published during the last decade. We present the current knowledge of epidemiology, pathophysiology and treatment of CA relevant to pre-hospital and acute care health practitioners. PMID:20930971

  7. Sudden Cardiac Arrest

    ... Heart Risk Factors & Prevention Heart Diseases & Disorders Atrial Fibrillation (AFib) Sudden Cardiac Arrest (SCA) SCA: Who's At Risk? Prevention of SCA What Causes SCA? SCA Awareness Atrial Flutter Heart Block Heart Failure Sick Sinus Syndrome Substances & Heart Rhythm Disorders Symptoms & ...

  8. Sudden Cardiac Arrest

    ... often are found in public places, such as shopping malls, golf courses, businesses, airports, airplanes, casinos, ... arrest In a study published online today in the New England Journal of Medicine , ...

  9. Cardiac arrest - cardiopulmonary resuscitation

    Basri Lenjani; Besnik Elshani; Nehat Baftiu; Kelmend Pallaska; Kadir Hyseni; Njazi Gashi; Nexhbedin Karemani; Ilaz Bunjaku; Taxhidin Zaimi; Arianit Jakupi

    2014-01-01

    Objective:To investigate application of cardiopulmonary resuscitation(CPR) measures within the golden minutes inEurope.Methods:The material was taken from theUniversityClinical Center ofKosovo -EmergencyCentre inPristina, during the two(2) year period(2010-2011).The collected date belong to the patients with cardiac arrest have been recorded in the patients' log book protocol at the emergency clinic.Results:During the2010 to2011 in the emergency center of theCUCK inPristina have been treated a total of269 patients with cardiac arrest, of whom159 or59.1% have been treated in2010, and110 patients or40.9% in2011.Of the269 patients treated in the emergency centre,93 or34.6% have exited lethally in the emergency centre, and176 or 65.4% have been transferred to other clinics.In the total number of patients with cardiac arrest, males have dominated with186 cases, or69.1%.The average age of patients included in the survey was56.7 year oldSD±16.0 years.Of the269 patients with cardiac arrest, defibrillation has been applied for93 or34.6% of patients.In the outpatient settings defibrillation has been applied for3 or3.2% of patients.Patients were defibrillated with application of one to four shocks. Of27 cases with who have survived cardiac arrest, none of them have suffered cardiac arrest at home,3 or11.1% of them have suffered cardiac arrest on the street, and24 or88.9% of them have suffered cardiac arrest in the hospital.5 out of27 patients survived have ended with neurological impairment.Cardiac arrest cases were present during all days of the week, but frequently most reported cases have been onMonday with32.0% of cases, and onFriday with24.5% of cases. Conclusions:All survivors from cardiac arrest have received appropriate medical assistance within10 min from attack, which implies that if cardiac arrest occurs near an institution health care(with an opportunity to provide the emergent health care) the rate of survival is higher.

  10. Plasma membrane proteomics in the maize primary root growth zone: novel insights into root growth adaptation to water stress.

    Voothuluru, Priyamvada; Anderson, Jeffrey C; Sharp, Robert E; Peck, Scott C

    2016-09-01

    Previous work on maize (Zea mays L.) primary root growth under water stress showed that cell elongation is maintained in the apical region of the growth zone but progressively inhibited further from the apex. These responses involve spatially differential and coordinated regulation of osmotic adjustment, modification of cell wall extensibility, and other cellular growth processes that are required for root growth under water-stressed conditions. As the interface between the cytoplasm and the apoplast (including the cell wall), the plasma membrane likely plays critical roles in these responses. Using a simplified method for enrichment of plasma membrane proteins, the developmental distribution of plasma membrane proteins was analysed in the growth zone of well-watered and water-stressed maize primary roots. The results identified 432 proteins with differential abundances in well-watered and water-stressed roots. The majority of changes involved region-specific patterns of response, and the identities of the water stress-responsive proteins suggest involvement in diverse biological processes including modification of sugar and nutrient transport, ion homeostasis, lipid metabolism, and cell wall composition. Integration of the distinct, region-specific plasma membrane protein abundance patterns with results from previous physiological, transcriptomic and cell wall proteomic studies reveals novel insights into root growth adaptation to water stress. PMID:27341663

  11. Effect of a Previous Acid Adaptation of Zygosaccharomyces bailii on its Growth Kinetic in Acidic Media

    Alex Tchuenchieu

    2014-11-01

    Full Text Available The growth response of Zygosaccharomyces bailii acid adapted cells was assessed in acidified media. Yeast cells were first pre-cultured in nutrient broth adjusted with hydrochloric, citric and malic acid to pH 4; 4.5; 5; 5.5; 6 and 6.5. Moreover, they were also grown in two controls consisting of nutrient broth and nutrient broth supplemented with 1% of glucose both adjusted at pH 7. The variation of pH before and after the growth along with yeast concentration was measured. The cells pre-cultured in controls conditions and in the three conditions at pH 5 were then each inoculated in six BHI medium consisting of BHI adjusted with hydrochloric, citric and malic acid at pH 5.5 and 3.5. The growth was monitored by spectrophotometry and the yeast concentration after incubation was obtained by microscopy using a Thoma cell chamber. DMFit 2.1 was used to plot the growth curves and to estimate the growth parameters. All the pre-cultures and cultures were made at 37°C during 24 hours. During the pre-cultures, an important decrease of pH was noted in nutrient broth supplemented with glucose, moving from 7 to 3.81. In all the other pre-cultures, just a little variation was observed ranging from -0.57 to 0.50. Growth was observed in all the conditions, except at pH4. By growing the cells coming from the selected pre-cultures conditions in the different acidic BHI media, it appears that acid adaptation enhance the growth at pH 5.5 no matter the acid contains in the medium and the acid to which the cells were adapted. However, this acid adaptation was not sufficient to initiate growth at pH 3.5 after 24 hours of incubation at 37°C. Growth rate was significantly affected by the pH of the pre-culture medium and the acid present in the culture medium. Pre-culture with glucose supplementation was the only parameter studied affecting the latency.

  12. Vagal afferents are essential for maximal resection-induced intestinal adaptive growth in orally fed rats

    Nelson, David W; Liu, Xiaowen; Holst, Jens Juul; Raybould, Helen E; Ney, Denise M

    2006-01-01

    in mucosal mass, protein, DNA, and histology. Both systemic and perivagal capsaicin significantly attenuated by 48-100% resection-induced increases in ileal mucosal mass, protein, and DNA in rats fed orally. Villus height was significantly reduced in resected rats given capsaicin compared with...... of bioactive GLP-2 resulting from resection in orally fed rats. Ablation of spinal/splanchnic innervation by ganglionectomy failed to attenuate resection-induced adaptive growth. In TPN rats, capsaicin did not attenuate resection-induced mucosal growth. We conclude that vagal afferents are not...... essential for maximal resection-induced intestinal growth. Rats received systemic or perivagal capsaicin or ganglionectomy before 70% midjejunoileal resection or transection and were fed orally or by total parenteral nutrition (TPN) for 7 days after surgery. Growth of residual bowel was assessed by changes...

  13. Adaptation of the European crop growth monitoring system to the Belgian conditions.

    Buffet, D.; Dehem, Didier; Wouters, K.; Tychon, Bernard; Oger, Robert; Veroustraete, F.

    1999-01-01

    The aim of the Belgian Crop Growth Monitoring System (B-CGMS) is the elaboration of an integrated information system predicting reliable, timely and objective estimates of crop yields and monitoring calamity sites at regional scales. Seven major crops are concerned by the project : winter wheat, winter barley, fodder maize, winter rape seed, potatoes, sugar beet and permanent meadow. The main tasks in the adaptation of the European model come down to the completion and the improvement of the ...

  14. Vitamin K2 and cotylenin A synergistically induce monocytic differentiation and growth arrest along with the suppression of c-MYC expression and induction of cyclin G2 expression in human leukemia HL-60 cells.

    Maniwa, Yasuhisa; Kasukabe, Takashi; Kumakura, Shunichi

    2015-08-01

    Although all-trans retinoic acid (ATRA) is a standard and effective drug used for differentiation therapy in acute promyelocytic leukemia, ATRA-resistant leukemia cells ultimately emerge during this treatment. Therefore, the development of new drugs or effective combination therapy is urgently needed. We demonstrate that the combined treatment of vitamin K2 and cotylenin A synergistically induced monocytic differentiation in HL-60 cells. This combined treatment also synergistically induced NBT-reducing activity and non-specific esterase-positive cells as well as morphological changes to monocyte/macrophage-like cells. Vitamin K2 and cotylenin A cooperatively inhibited the proliferation of HL-60 cells in short-term and long-term cultures. This treatment also induced growth arrest at the G1 phase. Although 5 µg/ml cotylenin A or 5 µM vitamin K2 alone reduced c-MYC gene expression in HL-60 cells to approximately 45% or 80% that of control cells, respectively, the combined treatment almost completely suppressed c-MYC gene expression. We also demonstrated that the combined treatment of vitamin K2 and cotylenin A synergistically induced the expression of cyclin G2, which had a positive effect on the promotion and maintenance of cell cycle arrest. These results suggest that the combination of vitamin K2 and cotylenin A has therapeutic value in the treatment of acute myeloid leukemia. PMID:26046133

  15. 4β-Hydroxywithanolide E from Physalis peruviana (golden berry) inhibits growth of human lung cancer cells through DNA damage, apoptosis and G2/M arrest

    The crude extract of the fruit bearing plant, Physalis peruviana (golden berry), demonstrated anti-hepatoma and anti-inflammatory activities. However, the cellular mechanism involved in this process is still unknown. Herein, we isolated the main pure compound, 4β-Hydroxywithanolide (4βHWE) derived from golden berries, and investigated its antiproliferative effect on a human lung cancer cell line (H1299) using survival, cell cycle, and apoptosis analyses. An alkaline comet-nuclear extract (NE) assay was used to evaluate the DNA damage due to the drug. It was shown that DNA damage was significantly induced by 1, 5, and 10 μg/mL 4βHWE for 2 h in a dose-dependent manner (p < 0.005). A trypan blue exclusion assay showed that the proliferation of cells was inhibited by 4βHWE in both dose- and time-dependent manners (p < 0.05 and 0.001 for 24 and 48 h, respectively). The half maximal inhibitory concentrations (IC50) of 4βHWE in H1299 cells for 24 and 48 h were 0.6 and 0.71 μg/mL, respectively, suggesting it could be a potential therapeutic agent against lung cancer. In a flow cytometric analysis, 4βHWE produced cell cycle perturbation in the form of sub-G1 accumulation and slight arrest at the G2/M phase with 1 μg/mL for 12 and 24 h, respectively. Using flow cytometric and annexin V/propidium iodide immunofluorescence double-staining techniques, these phenomena were proven to be apoptosis and complete G2/M arrest for H1299 cells treated with 5 μg/mL for 24 h. In this study, we demonstrated that golden berry-derived 4βHWE is a potential DNA-damaging and chemotherapeutic agent against lung cancer

  16. 4β-Hydroxywithanolide E from Physalis peruviana (golden berry inhibits growth of human lung cancer cells through DNA damage, apoptosis and G2/M arrest

    Guo Zong-Lun

    2010-02-01

    Full Text Available Abstract Background The crude extract of the fruit bearing plant, Physalis peruviana (golden berry, demonstrated anti-hepatoma and anti-inflammatory activities. However, the cellular mechanism involved in this process is still unknown. Methods Herein, we isolated the main pure compound, 4β-Hydroxywithanolide (4βHWE derived from golden berries, and investigated its antiproliferative effect on a human lung cancer cell line (H1299 using survival, cell cycle, and apoptosis analyses. An alkaline comet-nuclear extract (NE assay was used to evaluate the DNA damage due to the drug. Results It was shown that DNA damage was significantly induced by 1, 5, and 10 μg/mL 4βHWE for 2 h in a dose-dependent manner (p p 50 of 4βHWE in H1299 cells for 24 and 48 h were 0.6 and 0.71 μg/mL, respectively, suggesting it could be a potential therapeutic agent against lung cancer. In a flow cytometric analysis, 4βHWE produced cell cycle perturbation in the form of sub-G1 accumulation and slight arrest at the G2/M phase with 1 μg/mL for 12 and 24 h, respectively. Using flow cytometric and annexin V/propidium iodide immunofluorescence double-staining techniques, these phenomena were proven to be apoptosis and complete G2/M arrest for H1299 cells treated with 5 μg/mL for 24 h. Conclusions In this study, we demonstrated that golden berry-derived 4βHWE is a potential DNA-damaging and chemotherapeutic agent against lung cancer.

  17. Crack-arrest technology

    Over the last several years, the Heavy Section Steel Technology (HSST) Program has conducted several fracture mechanics experiments on large specimens that produced crack-arrest fracture-toughness values above 220 MPa·√m, which is the limit imposed by the ASME Code and the limit included in the Issues on Pressurized Thermal Shock studies. It is therefore appropriate and timely to investigate the influence that these high crack-arrest data have on the integrity assessment of nuclear Reactor Pressure Vessels (RPVs). A review of the evolution of the Pressurized Thermal Shock (PTS) issue and current methods of analysis provides insight into the motivation for the HSST Program performing the large-specimen fracture mechanics experiments. During the early 1970s, it was recognized that RPVs could be subjected to severe thermal shock as the result of a large-break loss-of-coolant accident (LBLOCA). Analyses performed at that time indicated that thermal shock alone would not result in failure (through-wall cracking) of the vessel. However, a combination of pressure and a less severe thermal shock, the result of some postulated transients, could result in vessel failure. In March 1978, such a transient occurred at the Rancho Seco nuclear power plant. As a result of these events, parametric PTS studies were undertaken. Because of the apparent need for and the existence of high-temperature crack-arrest capability, the NRC HSST Program and others began to investigate the effect of higher crack-arrest values on the probability of failure and to determine if these values actually exist for prototypical RPV materials. This report describes the results of HSST Program large-specimen crack-arrest testing

  18. Adaptive algorithms for estimation of multiple biomass growth rates and biomass concentration in a class of bioprocesses

    Lubenova, V.; Ferreira, E.C.

    2000-01-01

    An approach for multiple biomass growth rates and biomass concentration estimation is proposed for a class of bioprocesses characterizing by on-line measurements of dissolved oxygen concentration and off-line measurements of biomass concentration. The approach is based on adaptive observer theory and includes two steps. In the first one, an adaptive estimator of two biomass growth rates is designed using on-line measurements of dissolved oxygen concentration. In the second step...

  19. Resveratrol analogue 3,4,4′,5-tetramethoxystilbene inhibits growth, arrests cell cycle and induces apoptosis in ovarian SKOV‐3 and A-2780 cancer cells

    In the screening studies, cytotoxicity of 12 methylated resveratrol analogues on 11 human cancer cell lines was examined. The most active compound 3,4,4′5-tetramethoxystilbene (DMU-212) and two ovarian cancer cell lines A-2780 (IC50 = 0.71 μM) and SKOV-3 (IC50 = 11.51 μM) were selected for further investigation. To determine the mechanism of DMU-212 cytotoxicity, its ability to induce apoptosis was examined. DMU-212 arrested cell cycle in the G2/M or G0/G1 phase which resulted in apoptosis of both cell lines. The expression level of 84 apoptosis-related genes was investigated. In SKOV-3 cells DMU-212 caused up-regulation of pro-apoptotic Bax, Apaf-1 and p53 genes, specific to intrinsic pathway of apoptosis, and a decrease in Bcl-2 and Bcl 2110 mRNA expressions. Conversely, in A-2780 cells an increased expression of pro-apoptotic genes Fas, FasL, TNF, TNFRSF10A, TNFRSF21, TNFRSF16 specific to extracellular mechanism of apoptosis was observed. There are no data published so far regarding the receptor mediated apoptosis induced by DMU-212. The activation of caspase-3/7 was correlated with decreased TRAF-1 and BIRC-2 expression level in A-2780 cells exposed to DMU-212. DMU-212 caused a decrease in CYP1A1 and CYP1B1 mRNA levels in A-2780 by 50% and 75%, and in SKOV-3 cells by 15% and 45%, respectively. The protein expression was also reduced in both cell lines. It is noteworthy that the expression of CYP1B1 protein was entirely inhibited in A-2780 cells treated with DMU-212. It can be suggested that different CYP1B1 expression patterns in either ovarian cell line may affect their sensitivity to cytotoxic activity of DMU-212. -- Highlights: ► DMU-212 was the most cytotoxic among 12 O-methylated resveratrol analogues. ► DMU-212 arrested cell cycle at G2/M and G0/G1phase ► DMU-212 triggered mitochondria- and receptor‐mediated apoptosis. ► DMU-212 entirely inhibited CYP1B1 protein expression in A-2780 cells.

  20. Resveratrol analogue 3,4,4′,5-tetramethoxystilbene inhibits growth, arrests cell cycle and induces apoptosis in ovarian SKOV‐3 and A-2780 cancer cells

    Piotrowska, Hanna; Myszkowski, Krzysztof; Ziółkowska, Alicja [Department of Toxicology, Poznan University of Medical Sciences, Poznan (Poland); Kulcenty, Katarzyna [Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan (Poland); Wierzchowski, Marcin [Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Poznan (Poland); Kaczmarek, Mariusz [Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan (Poland); Murias, Marek [Department of Toxicology, Poznan University of Medical Sciences, Poznan (Poland); Kwiatkowska-Borowczyk, Eliza [Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan (Poland); Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, Poznan (Poland); Jodynis-Liebert, Jadwiga, E-mail: liebert@ump.edu.pl [Department of Toxicology, Poznan University of Medical Sciences, Poznan (Poland)

    2012-08-15

    In the screening studies, cytotoxicity of 12 methylated resveratrol analogues on 11 human cancer cell lines was examined. The most active compound 3,4,4′5-tetramethoxystilbene (DMU-212) and two ovarian cancer cell lines A-2780 (IC{sub 50} = 0.71 μM) and SKOV-3 (IC{sub 50} = 11.51 μM) were selected for further investigation. To determine the mechanism of DMU-212 cytotoxicity, its ability to induce apoptosis was examined. DMU-212 arrested cell cycle in the G2/M or G0/G1 phase which resulted in apoptosis of both cell lines. The expression level of 84 apoptosis-related genes was investigated. In SKOV-3 cells DMU-212 caused up-regulation of pro-apoptotic Bax, Apaf-1 and p53 genes, specific to intrinsic pathway of apoptosis, and a decrease in Bcl-2 and Bcl 2110 mRNA expressions. Conversely, in A-2780 cells an increased expression of pro-apoptotic genes Fas, FasL, TNF, TNFRSF10A, TNFRSF21, TNFRSF16 specific to extracellular mechanism of apoptosis was observed. There are no data published so far regarding the receptor mediated apoptosis induced by DMU-212. The activation of caspase-3/7 was correlated with decreased TRAF-1 and BIRC-2 expression level in A-2780 cells exposed to DMU-212. DMU-212 caused a decrease in CYP1A1 and CYP1B1 mRNA levels in A-2780 by 50% and 75%, and in SKOV-3 cells by 15% and 45%, respectively. The protein expression was also reduced in both cell lines. It is noteworthy that the expression of CYP1B1 protein was entirely inhibited in A-2780 cells treated with DMU-212. It can be suggested that different CYP1B1 expression patterns in either ovarian cell line may affect their sensitivity to cytotoxic activity of DMU-212. -- Highlights: ► DMU-212 was the most cytotoxic among 12 O-methylated resveratrol analogues. ► DMU-212 arrested cell cycle at G2/M and G0/G1phase ► DMU-212 triggered mitochondria- and receptor‐mediated apoptosis. ► DMU-212 entirely inhibited CYP1B1 protein expression in A-2780 cells.

  1. Dactylone inhibits epidermal growth factor-induced transformation and phenotype expression of human cancer cells and induces G1-S arrest and apoptosis.

    Fedorov, Sergey N; Shubina, Larisa K; Bode, Ann M; Stonik, Valentin A; Dong, Zigang

    2007-06-15

    The marine natural chamigrane-type sesquiterpenoid, dactylone, is closely related to secondary metabolites of some edible species of red algae. In the present study, the effect of dactylone was tested on the mouse skin epidermal JB6 P+ Cl41 cell line and its stable transfectants as well as on several human tumor cell lines, including lung (H460), colon (HCT-116), and skin melanomas (SK-MEL-5 and SK-MEL-28). This natural product was effective at nontoxic doses as a cancer-preventive agent, which exerted its actions, at least in part, through the inhibition of cyclin D3 and Cdk4 expression and retinoblastoma tumor suppressor protein (Rb) phosphorylation. The inhibition of these cell cycle components was followed by cell cycle arrest at the G1-S transition with subsequent p53-independent apoptosis. Therefore, these data showed that application of dactylone and related compounds may lead to decreased malignant cell transformation and/or decreased tumor cell proliferation. PMID:17575161

  2. CARI III Inhibits Tumor Growth in a Melanoma-Bearing Mouse Model through Induction of G0/G1 Cell Cycle Arrest

    Hye-Jin Park

    2014-09-01

    Full Text Available Mushroom-derived natural products have been used to prevent or treat cancer for millennia. In this study, we evaluated the anticancer effects of CARI (Cell Activation Research Institute III, which consists of a blend of mushroom mycelia from Phellinus linteus grown on germinated brown rice, Inonotus obliquus grown on germinated brown rice, Antrodia camphorata grown on germinated brown rice and Ganoderma lucidum. Here, we showed that CARI III exerted anti-cancer activity, which is comparable to Dox against melanoma in vivo. B16F10 cells were intraperitoneally injected into C57BL6 mice to develop solid intra-abdominal tumors. Three hundred milligrams of the CARI III/kg/day p.o. regimen reduced tumor weight, comparable to the doxorubicin (Dox-treated group. An increase in life span (ILS% = 50.88% was observed in the CARI III-administered group, compared to the tumor control group. CARI III demonstrates anti-proliferative activity against B16F10 melanoma cells through inducing G0/G1 cell cycle arrest. CARI III inhibits the expression of cyclin D1, CDK4 and CDK2 and induces p21. Therefore, CARI III could be a potential chemopreventive supplement to melanoma patients.

  3. CARI III inhibits tumor growth in a melanoma-bearing mouse model through induction of G0/G1 cell cycle arrest.

    Park, Hye-Jin

    2014-01-01

    Mushroom-derived natural products have been used to prevent or treat cancer for millennia. In this study, we evaluated the anticancer effects of CARI (Cell Activation Research Institute) III, which consists of a blend of mushroom mycelia from Phellinus linteus grown on germinated brown rice, Inonotus obliquus grown on germinated brown rice, Antrodia camphorata grown on germinated brown rice and Ganoderma lucidum. Here, we showed that CARI III exerted anti-cancer activity, which is comparable to Dox against melanoma in vivo. B16F10 cells were intraperitoneally injected into C57BL6 mice to develop solid intra-abdominal tumors. Three hundred milligrams of the CARI III/kg/day p.o. regimen reduced tumor weight, comparable to the doxorubicin (Dox)-treated group. An increase in life span (ILS% = 50.88%) was observed in the CARI III-administered group, compared to the tumor control group. CARI III demonstrates anti-proliferative activity against B16F10 melanoma cells through inducing G0/G1 cell cycle arrest. CARI III inhibits the expression of cyclin D1, CDK4 and CDK2 and induces p21. Therefore, CARI III could be a potential chemopreventive supplement to melanoma patients. PMID:25221864

  4. Adapt

    Bargatze, L. F.

    2015-12-01

    Active Data Archive Product Tracking (ADAPT) is a collection of software routines that permits one to generate XML metadata files to describe and register data products in support of the NASA Heliophysics Virtual Observatory VxO effort. ADAPT is also a philosophy. The ADAPT concept is to use any and all available metadata associated with scientific data to produce XML metadata descriptions in a consistent, uniform, and organized fashion to provide blanket access to the full complement of data stored on a targeted data server. In this poster, we present an application of ADAPT to describe all of the data products that are stored by using the Common Data File (CDF) format served out by the CDAWEB and SPDF data servers hosted at the NASA Goddard Space Flight Center. These data servers are the primary repositories for NASA Heliophysics data. For this purpose, the ADAPT routines have been used to generate data resource descriptions by using an XML schema named Space Physics Archive, Search, and Extract (SPASE). SPASE is the designated standard for documenting Heliophysics data products, as adopted by the Heliophysics Data and Model Consortium. The set of SPASE XML resource descriptions produced by ADAPT includes high-level descriptions of numerical data products, display data products, or catalogs and also includes low-level "Granule" descriptions. A SPASE Granule is effectively a universal access metadata resource; a Granule associates an individual data file (e.g. a CDF file) with a "parent" high-level data resource description, assigns a resource identifier to the file, and lists the corresponding assess URL(s). The CDAWEB and SPDF file systems were queried to provide the input required by the ADAPT software to create an initial set of SPASE metadata resource descriptions. Then, the CDAWEB and SPDF data repositories were queried subsequently on a nightly basis and the CDF file lists were checked for any changes such as the occurrence of new, modified, or deleted

  5. Quantitative analysis of population heterogeneity of the adaptive salt stress response and growth capacity of Bacillus cereus ATCC 14579

    Besten, den H.M.W.; Ingham, C.J.; Hylckama Vlieg, van J.E.T.; Beerthuyzen, M.M.; Zwietering, M.H.; Abee, T.

    2007-01-01

    Bacterial populations can display heterogeneity with respect to both the adaptive stress response and growth capacity of individual cells. The growth dynamics of Bacillus cereus ATCC 14579 during mild and severe salt stress exposure were investigated for the population as a whole in liquid culture.

  6. Lentivirus-mediated knockdown of TSP50 suppresses the growth of non-small cell lung cancer cells via G0/G1 phase arrest.

    Qiao, Wen-Liang; Hu, Hai-Yang; Shi, Bo-Wen; Zang, Li-Juan; Jin, Wei; Lin, Qiang

    2016-06-01

    Non-small cell lung cancer (NSCLC) as the most frequently diagnosed lethal cancer remains the major cause of overall cancer-related death worldwide. Testes-specific protease 50 (TSP50) has been proved as a critical biomarker in various cancers, and we previously reported that TSP50 protein expression is overexpressed in clinical resected NSCLC tumor tissues and related to poor prognosis in NSCLC patients. Hence, the present study was designed to further investigate the potential oncogenesis mechanism of TSP50 in NSCLC cells. Real-time quantitative PCR, immunohistochemical assay and western blot analysis were used to analyze the TSP50 mRNA and protein expression in 20 NSCLC cases, and TSP50 expression was observed to have high levels in the NSCLC specimens and paired metastatic lymph node tissues when compared to the levels in corresponding normal lung tissues and normal lymph nodes. In the experiments in NSCLC cell lines, lentiviral short hairpin RNA (shRNA) delivery system was applied to knock down TSP50 in 95D cells, and the following investigations revealed that downregulation of TSP50 expression markedly reduced cell proliferation, colony formation and migration ability in vitro. Furthermore, the inhibition of TSP50 induced G0/G1-phase arrest and decreased expression levels of cell cycle relative markers CDK4, CDK6, and CyclinD1 and increased expression of p21 and p53 in 95D cells. In conclusion, this study indicates that TSP50 plays a significant role in NSCLC cell proliferation and may act as a novel oncogene in the development and progression of NSCLC, offering a potential cancer therapeutic target for the treatment of NSCLC. PMID:27109614

  7. Direct targeting of MEK1/2 and RSK2 by silybin induces cell cycle arrest and inhibits melanoma cell growth

    Lee, Mee-Hyun; Huang, Zunnan; Kim, Dong Joon; Kim, Sung-Hyun; Kim, Myoung Ok; Lee, Sung-Young; Xie, Hua; Park, Si Jun; Kim, Jae Young; Kundu, Joydeb Kumar; Bode, Ann M.; Surh, Young-Joon; Dong, Zigang

    2013-01-01

    Abnormal functioning of multiple gene products underlies the neoplastic transformation of cells. Thus, chemopreventive and/or chemotherapeutic agents with multigene targets hold promise in the development of effective anticancer drugs. Silybin, a component of milk thistle, is a natural anticancer agent. In the present study, we investigated the effect of silybin on melanoma cell growth and elucidated its molecular targets. Our study revealed that silybin attenuated the growth of melanoma xeno...

  8. Arrest Decisions as Precludes To? An Evaluation of Policy Related Research. Volume I: Administrative Summary and Training Script.

    Neithercutt, M. G.; And Others

    The document is the first part of a study conducted to evaluate policy-related research on police arrest discretion as an alternative solution to arrest. It presents the administrative summary of the Arrest Decisions as Preludes To? (ADAPT) project and contains scripts intended for use by police departments as a staff training device. The…

  9. Adaptation of BAp crystal orientation to stress distribution in rat mandible during bone growth

    Biological apatite (BAp) c-axis orientation strongly depends on stress distribution in vivo and tends to align along the principal stress direction in bones. Dentulous mandible is subjected to a complicated stress condition in vivo during chewing but few studies have been carried out on the BAp c-axis orientation; so the adaptation of BAp crystal orientation to stress distribution was examined in rat dentulous mandible during bone growth and mastication. Female SD rats 4 to 14 weeks old were prepared, and the bone mineral density (BMD) and BAp crystal orientation were analyzed in a cross-section of mandible across the first molar focusing on two positions: separated from and just under the tooth root on the same cross-section perpendicular to the mesiodistal axis. The degree of BAp orientation was analyzed by a microbeam X-ray diffractometer using Cu-Kα radiation equipped with a detector of curved one-dimensional PSPC and two-dimensional PSPC in the reflection and transmission optics, respectively. BMD quickly increased during bone growth up to 14 weeks, although it was independent of the position from the tooth root. In contrast, BAp crystal orientation strongly depended on the age and the position from the tooth root, even in the same cross-section and direction, especially along the mesiodistal and the biting axes. With increased biting stress during bone growth, the degree of BAp orientation increased along the mesiodistal axis in a position separated from the tooth root more than that near the tooth root. In contrast, BAp preferential alignment clearly appeared along the biting axis near the tooth root. We conclude that BAp orientation rather than BMD sensitively adapts to local stress distribution, especially from the chewing stress in vivo in the mandible.

  10. Simultaneous changes in the function and expression of beta 1 integrins during the growth arrest of poorly differentiated colorectal cells (LISP-1

    R.A. Roela

    2003-08-01

    Full Text Available Cells usually lose adhesion and increase proliferation and migration during malignant transformation. Here, we studied how proliferation can affect the other two characteristics, which ultimately lead to invasion and metastasis. We determined the expression of ß1 integrins, as well as adhesion and migration towards laminin-1, fibronectin, collagens type I and type IV presented by LISP-1 colorectal cancer cells exposed to 2.5% dimethyl sulfoxide (DMSO, an agent capable of decreasing proliferation in this poorly differentiated colorectal cell line. Untreated cells (control, as shown by flow cytometry and monoclonal antibodies, expressed alpha2 (63.8 ± 11.3% positive cells, alpha3 (93.3 ± 7.0%, alpha5 (50.4 ± 12.0% and alpha6 (34.1 ± 4.9% integrins but not alpha1, alpha4, alphav or ß4. Cells adhered well to laminin-1 (73.4 ± 6.0% and fibronectin (40.0 ± 2.0% substrates but very little to collagens. By using blocking monoclonal antibodies, we showed that alpha2, alpha3 and alpha6 mediated laminin-1 adhesion, but neither alpha3 nor alpha5 contributed to fibronectin adherence. DMSO arrested cells at G0/G1 (control: 55.0 ± 2.4% vs DMSO: 70.7 ± 2.5% while simultaneously reducing alpha5 (24.2 ± 19% and alpha6 (14.3 ± 10.8% expression as well as c-myc mRNA (7-fold, the latter shown by Northern blotting. Although the adhesion rate did not change after exposure to DMSO, alpha3 and alpha5 played a major role in laminin-1 and fibronectin adhesion, respectively. Migration towards laminin-1, which was clearly increased upon exposure to DMSO (control: 6 ± 2 cells vs DMSO: 64 ± 6 cells, was blocked by an antibody against alpha6. We conclude that the effects of DMSO on LISP-1 proliferation were accompanied by concurrent changes in the expression and function of integrins, consequently modulating adhesion/migration, and revealing a complex interplay between function/expression and the proliferative state of cells.

  11. Transcriptome adaptation of group B Streptococcus to growth in human amniotic fluid.

    Izabela Sitkiewicz

    Full Text Available BACKGROUND: Streptococcus agalactiae (group B Streptococcus is a bacterial pathogen that causes severe intrauterine infections leading to fetal morbidity and mortality. The pathogenesis of GBS infection in this environment is poorly understood, in part because we lack a detailed understanding of the adaptation of this pathogen to growth in amniotic fluid. To address this knowledge deficit, we characterized the transcriptome of GBS grown in human amniotic fluid (AF and compared it with the transcriptome in rich laboratory medium. METHODS: GBS was grown in Todd Hewitt-yeast extract medium and human AF. Bacteria were collected at mid-logarithmic, late-logarithmic and stationary growth phase. We performed global expression microarray analysis using a custom-made Affymetrix GeneChip. The normalized hybridization values derived from three biological replicates at each growth point were obtained. AF/THY transcript ratios representing greater than a 2-fold change and P-value exceeding 0.05 were considered to be statistically significant. PRINCIPAL FINDINGS: We have discovered that GBS significantly remodels its transcriptome in response to exposure to human amniotic fluid. GBS grew rapidly in human AF and did not exhibit a global stress response. The majority of changes in GBS transcripts in AF compared to THY medium were related to genes mediating metabolism of amino acids, carbohydrates, and nucleotides. The majority of the observed changes in transcripts affects genes involved in basic bacterial metabolism and is connected to AF composition and nutritional requirements of the bacterium. Importantly, the response to growth in human AF included significant changes in transcripts of multiple virulence genes such as adhesins, capsule, and hemolysin and IL-8 proteinase what might have consequences for the outcome of host-pathogen interactions. CONCLUSIONS/SIGNIFICANCE: Our work provides extensive new information about how the transcriptome of GBS responds

  12. A Novel Muscarinic Antagonist R2HBJJ Inhibits Non-Small Cell Lung Cancer Cell Growth and Arrests the Cell Cycle in G0/G1

    Hua, Nan; Wei, Xiaoli; Liu, Xiaoyan; Ma, Xiaoyun; He, Xinhua; Zhuo, Rengong; Zhao, Zhe; Wang, Liyun; Yan, Haitao; Zhong, Bohua; Zheng, Jianquan

    2012-01-01

    Lung cancers express the cholinergic autocrine loop, which facilitates the progression of cancer cells. The antagonists of mAChRs have been demonstrated to depress the growth of small cell lung cancers (SCLCs). In this study we intended to investigate the growth inhibitory effect of R2HBJJ, a novel muscarinic antagonist, on non-small cell lung cancer (NSCLC) cells and the possible mechanisms. The competitive binding assay revealed that R2HBJJ had a high affinity to M3 and M1 AChRs. R2HBJJ pre...

  13. E. coli 6S RNA: a universal transcriptional regulator within the centre of growth adaptation.

    Geissen, René; Steuten, Benedikt; Polen, Tino; Wagner, Rolf

    2010-01-01

    Bacterial 6S RNA has been shown to bind with high affinity to σ(70)-containing RNA polymerase, suppressing σ(70)-dependent transcription during stationary phase, when 6S RNA concentrations are highest. We recently reported a genome-wide transcriptional comparison of wild-type and 6S RNA deficient E. coli strains. Contrary to the expected σ(70)- and stationary phase-specific regulatory effect of 6S RNA it turned out that mRNA levels derived from many alternative sigma factors, including σ(38) or σ(32), were affected during exponential and stationary growth. Among the most noticeably down-regulated genes at stationary growth are ribosomal proteins and factors involved in translation. In addition, a striking number of mRNA levels coding for enzymes involved in the purine metabolism, for transporters and stress regulators are altered both during log- and stationary phase. During the study we discovered a link between 6S RNA and the general stress alarmone ppGpp, which has a higher basal level in cells deficient in 6S RNA. This finding points to a functional interrelation of 6S RNA and the global network of stress and growth adaptation. PMID:20930516

  14. WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition ofhuman invasive urinary bladder cancer cells

    Tang, Yaxiong; Simoneau, Anne R; Liao, Wu-Xiang; Yi, Guo; Hope, Christopher; Liu, Feng; Li, Shunqiang; Xie, Jun; Holcombe, Randall F; Jurnak, Frances A.; Mercola, Dan; Hoang, Bang H.; Zi, Xiaolin

    2009-01-01

    Epigenetic silencing of secreted wingless-type (Wnt) antagonists through hypermethylation is associated with tobacco smoking and with invasive bladder cancer. The secreted Wnt inhibitory factor-1 (WIF1) has shown consistent growth-inhibitory effect on various cancer cell lines. Therefore,we assessed the mechanisms of action of WIF1 by either restoring WIF1 expression in invasive bladder cancer cell lines (T24 and TSU-PR1) or using a recombinant protein containing functional WIF1 domain. Both ...

  15. The stringent response and cell cycle arrest in Escherichia coli.

    Daniel J Ferullo; Lovett, Susan T.

    2008-01-01

    The bacterial stringent response, triggered by nutritional deprivation, causes an accumulation of the signaling nucleotides pppGpp and ppGpp. We characterize the replication arrest that occurs during the stringent response in Escherichia coli. Wild type cells undergo a RelA-dependent arrest after treatment with serine hydroxamate to contain an integer number of chromosomes and a replication origin-to-terminus ratio of 1. The growth rate prior to starvation determines the number of chromosomes...

  16. The Stringent Response and Cell Cycle Arrest in Escherichia coli

    Daniel J Ferullo; Lovett, Susan T.

    2008-01-01

    The bacterial stringent response, triggered by nutritional deprivation, causes an accumulation of the signaling nucleotides pppGpp and ppGpp. We characterize the replication arrest that occurs during the stringent response in Escherichia coli. Wild type cells undergo a RelA-dependent arrest after treatment with serine hydroxamate to contain an integer number of chromosomes and a replication origin-to-terminus ratio of 1. The growth rate prior to starvation determines the number of chromosomes...

  17. Antibodies to Placental Immunoregulatory Ferritin with Transfer of Polyclonal Lymphocytes Arrest MCF-7 Human Breast Cancer Growth in a Nude Mouse Model

    Marisa Halpern

    2007-06-01

    Full Text Available The recently cloned human gene named “placental immunoregulatory ferritin” (PLIF is a pregnancyrelated immunomodulator. Recombinant PLIF and its bioactive domain C48 are immune-suppressive and induce pronounced IL-10 production by immune cells. PLIF is expressed in the placenta and breast cancer cells. Blocking PLIF in pregnant mice by anti-C48 antibodies inhibited placental and fetal growth and modulated the cytokine network. It has been revealed that anti-C48 treatment inhibited MCF-7 tumor growth in nude mice. However, this significant effect was observed only in those transfused with human peripheral blood mononuclear cells. Blocking PLIF in tumor-engrafted human immune cell transfused mice resulted in massive infiltration of human CD45+ cells (mainly CD8+ T cells, both intratumorally and in the tumor periphery, and a significant number of caspase-3+ cells. In vitro, antiC48 treatment of MCF-7 tumor cells cocultured with human lymphocytes induced a significant increase in interferon-γ secretion. We conclude that blocking PLIF inhibits breast cancer growth, possibly by an effect on the cytokine network in immune cells and on breakdown of immunosuppression.

  18. Brain serotonergic activation in growth-stunted farmed salmon: adaption versus pathology

    Vindas, Marco A.; Johansen, Ida B.; Folkedal, Ole;

    2016-01-01

    Signalling systems activated under stress are highly conserved, suggesting adaptive effects of their function. Pathologies arising from continued activation of such systems may represent a mismatch between evolutionary programming and current environments. Here, we use Atlantic salmon (Salmo salar......) in aquaculture as a model to explore this stance of evolutionary-based medicine, for which empirical evidence has been lacking. Growth-stunted (GS) farmed fish were characterized by elevated brain serotonergic activation, increased cortisol production and behavioural inhibition. We make the novel...... observation that the serotonergic system in GS fish is unresponsive to additional stressors, yet a cortisol response is maintained. The inability of the serotonergic system to respond to additional stress, while a cortisol response is present, probably leads to both imbalance in energy metabolism and...

  19. Adaptive mutations in sugar metabolism restore growth on glucose in a pyruvate decarboxylase negative yeast strain

    Zhang, Yiming; Liu, Guodong; Engqvist, Martin K. M.;

    2015-01-01

    carbon source, and requires supplementation of C2 compounds to the medium in order to meet the requirement for cytosolic acetyl-CoA for biosynthesis of fatty acids and ergosterol. Results: In this study, a Pdc negative strain was adaptively evolved for improved growth in glucose medium via serial......Background: A Saccharomyces cerevisiae strain carrying deletions in all three pyruvate decarboxylase (PDC) genes (also called Pdc negative yeast) represents a non-ethanol producing platform strain for the production of pyruvate derived biochemicals. However, it cannot grow on glucose as the sole...... transfer, resulting in three independently evolved strains, which were able to grow in minimal medium containing glucose as the sole carbon source at the maximum specific rates of 0.138, 0.148, 0.141 h-1, respectively. Several genetic changes were identified in the evolved Pdc negative strains by genomic...

  20. Universal approximation of extreme learning machine with adaptive growth of hidden nodes.

    Zhang, Rui; Lan, Yuan; Huang, Guang-Bin; Xu, Zong-Ben

    2012-02-01

    Extreme learning machines (ELMs) have been proposed for generalized single-hidden-layer feedforward networks which need not be neuron-like and perform well in both regression and classification applications. In this brief, we propose an ELM with adaptive growth of hidden nodes (AG-ELM), which provides a new approach for the automated design of networks. Different from other incremental ELMs (I-ELMs) whose existing hidden nodes are frozen when the new hidden nodes are added one by one, in AG-ELM the number of hidden nodes is determined in an adaptive way in the sense that the existing networks may be replaced by newly generated networks which have fewer hidden nodes and better generalization performance. We then prove that such an AG-ELM using Lebesgue p-integrable hidden activation functions can approximate any Lebesgue p-integrable function on a compact input set. Simulation results demonstrate and verify that this new approach can achieve a more compact network architecture than the I-ELM. PMID:24808516

  1. Force-induced bone growth and adaptation: A system theoretical approach to understanding bone mechanotransduction

    The modeling, analysis, and design of treatment therapies for bone disorders based on the paradigm of force-induced bone growth and adaptation is a challenging task. Mathematical models provide, in comparison to clinical, medical and biological approaches an structured alternative framework to understand the concurrent effects of the multiple factors involved in bone remodeling. By now, there are few mathematical models describing the appearing complex interactions. However, the resulting models are complex and difficult to analyze, due to the strong nonlinearities appearing in the equations, the wide range of variability of the states, and the uncertainties in parameters. In this work, we focus on analyzing the effects of changes in model structure and parameters/inputs variations on the overall steady state behavior using systems theoretical methods. Based on an briefly reviewed existing model that describes force-induced bone adaptation, the main objective of this work is to analyze the stationary behavior and to identify plausible treatment targets for remodeling related bone disorders. Identifying plausible targets can help in the development of optimal treatments combining both physical activity and drug-medication. Such treatments help to improve/maintain/restore bone strength, which deteriorates under bone disorder conditions, such as estrogen deficiency.

  2. Cause–effect relationship among morphological adaptations, growth, and gas exchange response of pedunculate oak seedlings to waterlogging

    Tatin Froux, Fabienne; Capelli, Nicolas; Parelle, Julien

    2014-01-01

    & Context In response to waterlogging, pedunculate oak is known to develop adventitious roots and hypertrophied lenti-cels. However, to date, a link between these adaptations and the ability to maintain net CO 2 assimilation rates and growth has not been demonstrated. & Aims The aim of this study was to explore the cause–effect relationship between the ability to form morphological adap-tations (hypertrophied lenticels and adventitious roots) and the capacity to maintain high assimilation rat...

  3. Survival and growth patterns of white spruce (Picea glauca [Moench] Voss) rangewide provenances and their implications for climate change adaptation

    Lu, Pengxin; Parker, William H.; Cherry, Marilyn; Colombo, Steve; Parker, William C.; Man, Rongzhou; Roubal, Ngaire

    2014-01-01

    Intraspecific assisted migration (ISAM) through seed transfer during artificial forest regeneration has been suggested as an adaptation strategy to enhance forest resilience and productivity under future climate. In this study, we assessed the risks and benefits of ISAM in white spruce based on long-term and multilocation, rangewide provenance test data. Our results indicate that the adaptive capacity and growth potential of white spruce varied considerably among 245 range-wide provenances sa...

  4. Thyroid hormone is required for growth adaptation to pressure load in the ovine fetal heart.

    Segar, Jeffrey L; Volk, Ken A; Lipman, Michael H B; Scholz, Thomas D

    2013-03-01

    Thyroid hormone exerts broad effects on the adult heart, but little is known regarding the role of thyroid hormone in the regulation of cardiac growth early in development and in response to pathophysiological conditions. To address this issue, we determined the effects of fetal thyroidectomy on cardiac growth and growth-related gene expression in control and pulmonary-artery-banded fetal sheep. Fetal thyroidectomy (THX) and/or placement of a restrictive pulmonary artery band (PAB) were performed at 126 ± 1 days of gestation (term, 145 days). Four groups of animals [n = 5-6 in each group; (i) control; (ii) fetal THX; (iii) fetal PAB; and (iv) fetal PAB + THX] were monitored for 1 week prior to being killed. Fetal heart rate was significantly lower in the two THX groups compared with the non-THX groups, while mean arterial blood pressure was similar among groups. Combined left and right ventricle free wall + septum weight, expressed per kilogram of fetal weight, was significantly increased in PAB (6.27 ± 0.85 g kg(-1)) compared with control animals (4.72 ± 0.12 g kg(-1)). Thyroidectomy significantly attenuated the increase in cardiac mass associated with PAB (4.94 ± 0.13 g kg(-1)), while THX alone had no detectable effect on heart mass (4.95 ± 0.27 g kg(-1)). The percentage of binucleated cardiomyocytes was significantly decreased in THX and PAB +THX groups (∼16%) compared with the non-THX groups (∼27%). No differences in levels of activated Akt, extracellular signal-regulated kinase or c-Jun N-terminal kinase were detected among the groups. Markers of cellular proliferation but not apoptosis or expression of growth-related genes were lower in the THX and THX+ PAB groups relative to thyroid-intact animals. These findings suggest that in the late-gestation fetal heart, thyroid hormone has important cellular growth functions in both physiological and pathophysiological states. Specifically, thyroid hormone is required for adaptive fetal cardiac growth in

  5. ADAPTATION TO UNFAVORABLE CONDITIONS OF GROWTH: PATHOGENICITY OF ACHOLEPLASMA LAIDLAWII PG8

    Maxim V. Trushin

    2006-11-01

    Full Text Available ABSTRACT:As a result of cultivation of A. laidlawii PG8 cells on the deficient medium during 480 days, the mycoplasma culture adapted in vitro to unfavorable growth conditions was obtained. The culture consisted of cells with sizes less than 0.2 µm and features of A. laidlawii PG8 ultramicroforms, nanocells. A. laidlawii PG8 culture adapted in vitro to unfavorable growth conditions shows more evident phytopathogenicity than the unadapted one. Infecting plants V. minor L. by A. laidlawii PG8 culture adapted in vitro to UGC resulted in the appearance of chloroses in 75%, necrosis – 50%, leaves marcescence – 50% and abnormalities of bine development in 30% of plants through 12 days, while infecting plants by A. laidlawii PG8 culture unadapted to UGC led to respective signs in 40%, 25%, 25% and 0% of samples, respectively, through 30 days. The ability of A. laidlawii PG8 to form UMF resistant to stress factors in UGC with high phytopathogenic potential seems to demand a new approach to investigate the precise mechanisms of interacting the mycoplasma with host organisms.RESUMENComo resultado del cultivo de células de A. laidlawii PG8 en medio deficiente durante 480 días, fue obtenido un cultivo de mycoplasma adaptado in vitro a las condiciones desfavorables del crecimiento. El cultivo consistió en células con tamaño menor de 0.2 µm y características PG8 ultramicroformas de A. laidlawii nanocélulas. El cultivo de A. laidlawii PG8 adaptado in vitro a condiciones desfavorables del crecimiento muestra más evidente fitopatogenicidad que el inadaptado. Plantas infectadas V. minor L. por el cultivo del A. laidlawii PG8 adaptado in vitro a UGC dio como resultado la aparición de clorosis en el 75%, necrosis en el 50%, marcescencia de las hojas en el 50% y anormalidades del desarrollo del bine en el 30% de plantas a los 12 días, mientras que las plantas infectadas por el cultivo del A. laidlawii PG8 inadaptado a UGC, condujo a dichos signos en

  6. Posttraumatic growth measures: translation and adaptation of three self-report instruments to Brazilian Portuguese

    Thiago Loreto Garcia da Silva

    2016-06-01

    Full Text Available Abstract Background Posttraumatic growth is one of the most commonly used concepts to evaluate positive changes after trauma. The principal scales used internationally to evaluate this phenomenon have not yet a Brazilian Portuguese version. Objectives This study aimed to translate and adapt to the Brazilian context the Posttraumatic Growth Inventory (PTGI, the Core Beliefs Inventory (CBI, and the Event Related Rumination Inventory (ERRI. Methods The procedures included translation, back translation, expert committee’s evaluation, and pilot testing in the target population. Results All items of all three instruments had a good content validity index after evaluation by four experts and three reformulations. The back translation of the final version also demonstrated that all Brazilian Portuguese versions convey the same meaning as the original English version. The final version was pilot tested with 30 undergraduate students, and all the items were above the cut-off point. Discussion This study was able to produce Brazilian versions of the PTGI, CBI, and ERRI. Further studies are underway to determine the reliability, factorial validity, and convergent validity of the subscales of the instruments.

  7. Adaptation of Lactococcus lactis to high growth temperature leads to a dramatic increase in acidification rate.

    Chen, Jun; Shen, Jing; Ingvar Hellgren, Lars; Ruhdal Jensen, Peter; Solem, Christian

    2015-01-01

    Lactococcus lactis is essential for most cheese making, and this mesophilic bacterium has its growth optimum around 30 °C. We have, through adaptive evolution, isolated a mutant TM29 that grows well up to 39 °C, and continuous growth at 40 °C is possible if pre-incubated at a slightly lower temperature. At the maximal permissive temperature for the wild-type, 38 °C, TM29 grows 33% faster and has a 12% higher specific lactate production rate than its parent MG1363, which results in fast lactate accumulation. Genome sequencing was used to reveal the mutations accumulated, most of which were shown to affect thermal tolerance. Of the mutations with more pronounced effects, two affected expression of single proteins (chaperone; riboflavin transporter), two had pleiotropic effects (RNA polymerase) which changed the gene expression profile, and one resulted in a change in the coding sequence of CDP-diglyceride synthase. A large deletion containing 10 genes was also found to affect thermal tolerance significantly. With this study we demonstrate a simple approach to obtain non-GMO derivatives of the important L. lactis that possess properties desirable by the industry, e.g. thermal robustness and increased rate of acidification. The mutations we have identified provide a genetic basis for further investigation of thermal tolerance. PMID:26388459

  8. Adaptive Use of Information during Growth Can Explain Long-Term Effects of Early Life Experiences.

    English, Sinead; Fawcett, Tim W; Higginson, Andrew D; Trimmer, Pete C; Uller, Tobias

    2016-05-01

    Development is a continuous process during which individuals gain information about their environment and adjust their phenotype accordingly. In many natural systems, individuals are particularly sensitive to early life experiences, even in the absence of later constraints on plasticity. Recent models have highlighted how the adaptive use of information can explain age-dependent plasticity. These models assume that information gain and phenotypic adjustments either cannot occur simultaneously or are completely independent. This assumption is not valid in the context of growth, where finding food results both in a size increase and learning about food availability. Here, we describe a simple model of growth to provide proof of principle that long-term effects of early life experiences can arise through the coupled dynamics of information acquisition and phenotypic change in the absence of direct constraints on plasticity. The increase in reproductive value from gaining information and sensitivity of behavior to experiences declines across development. Early life experiences have long-term impacts on age of maturity, yet-due to compensatory changes in behavior-our model predicts no substantial effects on reproductive success. We discuss how the evolution of sensitive windows can be explained by experiences having short-term effects on informational and phenotypic states, which generate long-term effects on life-history decisions. PMID:27104994

  9. Cardiac arrest – cardiopulmonary resuscitation

    Basri Lenjani

    2014-01-01

    Conclusions: All survivors from cardiac arrest have received appropriate medical assistance within 10 min from attack, which implies that if cardiac arrest occurs near an institution health care (with an opportunity to provide the emergent health care the rate of survival is higher.

  10. Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells

    McNaughton, Melissa; Pitman, Melissa; Pitson, Stuart M.; Pyne, Nigel J.; Pyne, Susan

    2016-01-01

    Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest. PMID:26934645

  11. Mangrove dolabrane-type of diterpenes tagalsins suppresses tumor growth via ROS-mediated apoptosis and ATM/ATR-Chk1/Chk2-regulated cell cycle arrest.

    Neumann, Jennifer; Yang, Yi; Köhler, Rebecca; Giaisi, Marco; Witzens-Harig, Mathias; Liu, Dong; Krammer, Peter H; Lin, Wenhan; Li-Weber, Min

    2015-12-01

    Natural compounds are an important source for drug development. With an increasing cancer rate worldwide there is an urgent quest for new anti-cancer drugs. In this study, we show that a group of dolabrane-type of diterpenes, collectively named tagalsins, isolated from the Chinese mangrove genus Ceriops has potent cytotoxicity on a panel of hematologic cancer cells. Investigation of the molecular mechanisms by which tagalsins kill malignant cells revealed that it induces a ROS-mediated damage of DNA. This event leads to apoptosis induction and blockage of cell cycle progression at S-G2 phase via activation of the ATM/ATR-Chk1/Chk2 check point pathway. We further show that tagalsins suppress growth of human T-cell leukemia xenografts in vivo. Tagalsins show only minor toxicity on healthy cells and are well tolerated by mice. Our study shows a therapeutic potential of tagalsins for the treatment of hematologic malignancies and a new source of anticancer drugs. PMID:26061604

  12. The Pseudomonas aeruginosa antimetabolite L-2-amino-4-methoxy-trans-3-butenoic acid inhibits growth of Erwinia amylovora and acts as a seed germination-arrest factor.

    Lee, Xiaoyun; Azevedo, Mark D; Armstrong, Donald J; Banowetz, Gary M; Reimmann, Cornelia

    2013-02-01

    The Pseudomonas aeruginosa antimetabolite L-2-amino-4-methoxy-trans-3-butenoic acid (AMB) shares biological activities with 4-formylaminooxyvinylglycine, a related molecule produced by Pseudomonas fluorescens WH6. We found that culture filtrates of a P. aeruginosa strain overproducing AMB weakly interfered with seed germination of the grassy weed Poa annua and strongly inhibited growth of Erwinia amylovora, the causal agent of the devastating orchard crop disease known as fire blight. AMB was active against a 4-formylaminooxyvinylglycine-resistant isolate of E. amylovora, suggesting that the molecular targets of the two oxyvinylglycines in Erwinia do not, or not entirely, overlap. The AMB biosynthesis and transport genes were shown to be organized in two separate transcriptional units, ambA and ambBCDE, which were successfully expressed from IPTG-inducible tac promoters in the heterologous host P. fluorescens CHA0. Engineered AMB production enabled this model biocontrol strain to become inhibitory against E. amylovora and to weakly interfere with the germination of several graminaceous seeds. We conclude that AMB production requires no additional genes besides ambABCDE and we speculate that their expression in marketed fire blight biocontrol strains could potentially contribute to disease control. PMID:23757135

  13. Inhibition of in vitro growth and arrest in the G0/G1 phase of HCT8 line human colon cancer cells by kaempferide triglycoside from Dianthus caryophyllus.

    Martineti, Valentina; Tognarini, Isabella; Azzari, Chiara; Carbonell Sala, Silvia; Clematis, Francesca; Dolci, Marcello; Lanzotti, Virginia; Tonelli, Francesco; Brandi, Maria Luisa; Curir, Paolo

    2010-09-01

    The effects of phytoestrogens have been studied in the hypothalamic-pituitary-gonadal axis and in various non-gonadal targets. Epidemiologic and experimental evidence indicates a protective effect of phytoestrogens also in colorectal cancer. The mechanism through which estrogenic molecules control colorectal cancer tumorigenesis could possibly involve estrogen receptor beta, the predominantly expressed estrogen receptor subtype in colon mucosa.To validate this hypothesis, we therefore used an engineered human colon cancer cell line induced to overexpress estrogen receptor beta, beside its native cell line, expressing very low levels of ERbeta and not expressing ERalpha; as a phytoestrogenic molecule, we used kaempferide triglycoside, a glycosylated flavonol from a Dianthus caryophyllus cultivar. The inhibitory properties of this molecule toward vegetal cell growth have been previously demonstrated: however, no data on its activity on animal cell or information about the mechanism of this activity are available. Kaempferide triglycoside proved to inhibit the proliferation of native and estrogen receptor beta overexpressing colon cancer cells through a mechanism not mediated by ligand binding dependent estrogen receptor activation. It affected HCT8 cell cycle progression by increasing the G(0)/G(1) cell fraction and in estrogen receptor beta overexpressing cells increased two antioxidant enzymes. Interestingly, the biological effects of this kaempferide triglycoside were strengthened by the presence of high levels of estrogen receptor beta.Pleiotropic molecular effects of phytoestrogens may explain their protective activity against colorectal cancer and may represent an interesting area for future investigation with potential clinical applications. PMID:20104502

  14. Seedling growth dynamic of Haloxylon ammodendron and its adaptation strategy to habitat condition in hinterland of desert

    WEI Jiang; ZHANG XiMing; SHAN LiShan; YAN HaiLong; LIANG ShaoMing

    2007-01-01

    Through measuring the above/below-ground growth data of Haloxylon ammodendron seedlings at different stages in hinterland of the desert the results show that the H. ammodendron seedling growth has demonstrated different adaptation characteristics in the continued arid environment with time and space. In May, July, September and October, the growth speed of vertical root is 0.607 cm/d, 0.809 cm/d, 0.155 cm/d and 0.394 cm/d, respectively; the growth speed of height is 0.093 cm/d, 0.076 cm/d,0.408 cm/d and 136 cm/d, respectively. It is explained that seedlings root system has the growth superiority in space. The maximum growth speed of below-ground (vertical root and horizontal root) of seedling is earlier than that of above-ground (height and horizontal of shoot). In the different periods,the vertical growth speed and the horizontal growth speed of below-ground is 2-10 times and 3-5 times than the height increase speed and the shoot growth speed, respectively. In the whole season,the growth speed of above/below-ground of seedlings shows the alternation growth tendency. At the different periods, the root/shoot ratio of H. ammodendron seedlings is 0.41, 0.3, 0.39 and 0.88. All these characteristics are the comprehensive performance of seedlings' strategy selection to adapt to the continued arid environment.

  15. Control of growth and adaptation to nutritional shifts for bacteria exposed to amino acid-limiting environments

    Mateescu, Eduard M.; Hwa, Terence

    2007-03-01

    In order to grow at the highest rate sustainable by the environment, bacteria turn on different metabolic pathways and utilize a myriad of adaptive strategies. The macromolecular composition (RNA, DNA, protein) and overall cell size (mass) can be very different in different environments. Surprisingly however, these differences appear to depend only on the growth rate and not on the growth medium itself. As the nutritional environment changes in time, the cells quickly adapt their composition to the one corresponding to the new conditions. Here, we propose a phenomenological model of growth and adaptation control for the bacterial cell, based on a simplified formulation of the central dogma and a simplified implementation of the stringent response. The core model contains no free parameters and provides a simple intuitive understanding of cell growth control. The results generated by the model, physiological state of the cell as well as the characteristics of the transition between optimized states of growth, are in qualitative and semi-quantitative agreement (i.e. within a factor of 2) with the experimental observations.

  16. Metoclopramide-induced cardiac arrest

    Martha M. Rumore

    2011-11-01

    Full Text Available The authors report a case of cardiac arrest in a patient receiving intravenous (IV metoclopramide and review the pertinent literature. A 62-year-old morbidly obese female admitted for a gastric sleeve procedure, developed cardiac arrest within one minute of receiving metoclopramide 10 mg via slow intravenous (IV injection. Bradycardia at 4 beats/min immediately appeared, progressing rapidly to asystole. Chest compressions restored vital function. Electrocardiogram (ECG revealed ST depression indicative of myocardial injury. Following intubation, the patient was transferred to the intensive care unit. Various cardiac dysrrhythmias including supraventricular tachycardia (SVT associated with hypertension and atrial fibrillation occurred. Following IV esmolol and metoprolol, the patient reverted to normal sinus rhythm. Repeat ECGs revealed ST depression resolution without pre-admission changes. Metoclopramide is a non-specific dopamine receptor antagonist. Seven cases of cardiac arrest and one of sinus arrest with metoclopramide were found in the literature. The metoclopramide prescribing information does not list precautions or adverse drug reactions (ADRs related to cardiac arrest. The reaction is not dose related but may relate to the IV administration route. Coronary artery disease was the sole risk factor identified. According to Naranjo, the association was possible. Other reports of cardiac arrest, severe bradycardia, and SVT were reviewed. In one case, five separate IV doses of 10 mg metoclopramide were immediately followed by asystole repeatedly. The mechanism(s underlying metoclopramide’s cardiac arrest-inducing effects is unknown. Structural similarities to procainamide may play a role. In view of eight previous cases of cardiac arrest from metoclopramide having been reported, further elucidation of this ADR and patient monitoring is needed. Our report should alert clinicians to monitor patients and remain diligent in surveillance and

  17. ADAPTATION OF CRACK GROWTH DETECTION TECHNIQUES TO US MATERIAL TEST REACTORS

    A. Joseph Palmer; Sebastien P. Teysseyre; Kurt L. Davis; Gordon Kohse; Yakov Ostrovsky; David M. Carpenter; Joy L. Rempe

    2015-04-01

    A key component in evaluating the ability of Light Water Reactors to operate beyond 60 years is characterizing the degradation of materials exposed to radiation and various water chemistries. Of particular concern is the response of reactor materials to Irradiation Assisted Stress Corrosion Cracking (IASCC). Some test reactors outside the United States, such as the Halden Boiling Water Reactor (HBWR), have developed techniques to measure crack growth propagation during irradiation. The basic approach is to use a custom-designed compact loading mechanism to stress the specimen during irradiation, while the crack in the specimen is monitored in-situ using the Direct Current Potential Drop (DCPD) method. In 2012 the US Department of Energy commissioned the Idaho National Laboratory and the MIT Nuclear Reactor Laboratory (MIT NRL) to take the basic concepts developed at the HBWR and adapt them to a test rig capable of conducting in-pile IASCC tests in US Material Test Reactors. The first two and half years of the project consisted of designing and testing the loader mechanism, testing individual components of the in-pile rig and electronic support equipment, and autoclave testing of the rig design prior to insertion in the MIT Reactor. The load was applied to the specimen by means of a scissor like mechanism, actuated by a miniature metal bellows driven by pneumatic pressure and sized to fit within the small in-core irradiation volume. In addition to the loader design, technical challenges included developing robust connections to the specimen for the applied current and voltage measurements, appropriate ceramic insulating materials that can endure the LWR environment, dealing with the high electromagnetic noise environment of a reactor core at full power, and accommodating material property changes in the specimen, due primarily to fast neutron damage, which change the specimen resistance without additional crack growth. The project culminated with an in

  18. Ethyl-2-amino-pyrrole-3-carboxylates are novel potent anticancer agents that affect tubulin polymerization, induce G2/M cell-cycle arrest, and effectively inhibit soft tissue cancer cell growth in vitro.

    Boichuk, Sergei; Galembikova, Aigul; Zykova, Svetlana; Ramazanov, Bulat; Khusnutdinov, Ramil; Dunaev, Pavel; Khaibullina, Svetlana; Lombardi, Vincent

    2016-08-01

    Microtubules are known to be one of the most attractive and validated targets in cancer therapy. However, the clinical use of drugs that affect the dynamic state of microtubules has been hindered by chemoresistance and toxicity issues. Accordingly, the development of novel agents that target microtubules is needed. Here, we report the identification of novel compounds with pirrole and carboxylate structures: ethyl-2-amino-pyrrole-3-carboxylates (EAPCs) that provide potent cytotoxic activities against multiple soft tissue cancer cell lines in vitro. Using the MTS cell proliferation assay, we assessed the activity of EAPCs on various cancer cell lines including leiomyosarcoma SK-LMS-1, rhabdomyosarcoma RD, gastrointestinal stromal tumor GIST-T1, A-673 Ewing's sarcoma, and U-2 OS osteosarcoma. We found that in the majority of cases, two EAPC compounds (EAPC-20 and EAPC-24) considerably inhibited cancer cell proliferation in vitro. The growth-inhibitory effects of EAPC-20 and EAPC-24 were time and dose dependent. The molecular mechanisms of action of these compounds were because of the inhibition of tubulin polymerization and induction of a robust G2/M cell-cycle arrest, leading to considerable accumulation of tumor cells in the M-phase. Finally, EAPCs induced tumor cell death by apoptotic pathways. The above-mentioned effects were also observed in most soft tissue tumor cell lines and the gastrointestinal stromal tumor cell line investigated. Taken together, our data identify potent antitumor activity of EAPCs in vitro, thus providing a novel scaffold with which to develop potent chemotherapeutic agents for cancer therapy. PMID:27129079

  19. Juvenile Arrests, 1998. Juvenile Justice Bulletin.

    Snyder, Howard N.

    This report provides a summary and analysis of national and state juvenile arrest data in the United States. In 1998, law enforcement agencies made an estimated 2.6 million arrests of persons under age 18. Federal Bureau of Investigations statistics indicate that juveniles account for 18% of all arrests, and 17% of all violent crime arrests in…

  20. Comparison of two bacterial azoreductases acquired during adaptation to growth on azo dyes.

    Zimmermann, T; Gasser, F; Kulla, H G; Leisinger, T

    1984-05-01

    Selection for utilization of carboxy-Orange I [1-(4'-carboxyphenylazo)-4-naphthol] in the chemostat yielded Pseudomonas strain K24 which was unable to grow on carboxy-Orange II [1-(4'-carboxyphenylazo)-2-naphthol] while selection for growth on carboxy-Orange II had previously led to strain KF46 which did not utilize carboxy-Orange I. Orange I azoreductase of strain K24, the key enzyme of dye degradation, was purified 80-fold with 17% yield to electrophoretic homogeneity and compared to the previously purified Orange II azoreductase of strain KF46. Common properties of the two enzymes were their monomeric structure, their specificity for NADPH and NADH as cosubstrates, the range of their Km values for substrates and cosubstrates as well as their reactivity towards a series of substrate analogs. They differed from each other with respect to molecular weight (21,000 and 30,000) and in the absolute requirement of Orange I azoreductase for a hydroxy group in the 4'position of the naphthol ring of the substrate molecule as compared to the requirement for substrates with a 2-naphthol moiety by Orange II azoreductase. The pure enzymes did not exhibit immunological cross-reaction with each other. Crude extracts of strains K24 and KF46 and of azoreductase-negative strains isolated at different stages of the adaptation experiments, however, contained material which cross-reacted (CRM) with both anti Orange I azoreductase serum and anti Orange II azoreductase serum. The CRM may represent a common precursor protein of the azoreductases in strains K24 and KF46. PMID:6742955

  1. Intestinal growth adaptation and glucagon-like peptide 2 in rats with ileal--jejunal transposition or small bowel resection

    Thulesen, J; Hartmann, B; Kissow, Hannelouise; Jeppesen, P B; Orskov, C; Holst, J J; Poulsen, S S

    2001-01-01

    twofold in the distally resected group. Tissue GLP-2 levels were unchanged in resected rats. The data indicate that transposition of a distal part of the small intestine, and thereby exposure of L cells to a more nutrient-rich chyme, leads to intestinal growth. The adaptive intestinal growth is associated......Glucagon-like peptide 2 (GLP-2), produced by enteroendocrine L-cells, regulates intestinal growth. This study investigates circulating and intestinal GLP-2 levels in conditions with altered L-cell exposure to nutrients. Rats were allocated to the following experimental groups: ileal......-jejunal transposition, resection of the proximal or distal half of the small intestine, and appropriate sham-operated controls. After two weeks, ileal-jejunal transposition led to pronounced growth of the transposed segment and also of the remaining intestinal segments. Plasma GLP-2 levels increased twofold, whereas...

  2. 33 CFR 154.822 - Detonation arresters, flame arresters, and flame screens.

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Detonation arresters, flame... BULK Vapor Control Systems § 154.822 Detonation arresters, flame arresters, and flame screens. (a) Each detonation arrester required by this part must: (1) Be capable of arresting a detonation from either side...

  3. Chondroitinase ABC promotes recovery of adaptive limb movements and enhances axonal growth caudal to a spinal hemisection

    Jefferson, Stephanie C.; Tester, Nicole J.; Howland, Dena R.

    2011-01-01

    A number of studies have shown that Chondroitinase ABC (Ch’ase ABC) digestion of inhibitory chondroitin sulfate glycosaminoglycans significantly enhances axonal growth and recovery in rodents following spinal cord injury (SCI). Further, our group has shown improved recovery following SCI in the larger cat model. The purpose of the current study was to determine if intraspinal delivery of Ch’ase ABC, following T10 hemisections in adult cats, enhances adaptive movement features during a skilled...

  4. Between feast and famine: endogenous inducer synthesis in the adaptation of Escherichia coli to growth with limiting carbohydrates.

    Death, A; Ferenci, T

    1994-01-01

    Escherichia coli adapted to growth with low carbohydrate concentrations bypassed the requirement for exogenous inducer with at least three well-studied sugar regulons. Induction of mgl and gal genes became independent of added galactose in bacteria approaching stationary phase or during continuous culture with micromolar glucose in the medium. Bacteria became independent of exogenous induction because endogenous galactose and cyclic AMP (cAMP) pools were sufficient for high expression of mgl ...

  5. Sculpting Pickering Emulsion Droplets by Arrest and Jamming

    Burke, Christopher; Wei, Zengyi; Caggioni, Marco; Spicer, Patrick; Atherton, Tim

    Pickering emulsion droplets can be arrested into non-spherical shapes--useful for applications such as active delivery--through a general mechanism of deformation followed by absorption of additional colloidal particles onto the interface, relaxation of the droplet caused by surface tension and arrest at some point due to crowding of the particles. We perform simulations of the arrest process to clarify the relative importance of diffusive rearrangement of particles and collective forcing due to surface evolution. Experiment and theory are compared, giving insight into the stability of the resulting capsules and the robustness of the production process for higher-throughput production in, for example, microfluidic systems. We adapt theoretical tools from the jamming literature to better understand the arrested configurations and long timescale evolution of the system: using linear programming and a penalty function approach, we identify unjamming motions in kinetically arrested states. We propose a paradigm of ``metric jamming'' to describe the limiting behavior of this class of system: a structure is metric-jammed if it is stable with respect to collective motion of the particles as well as evolution of the hypersurface on which the packing is embedded. Supported by a Cottrell Award from the Research Corporation for Science Advancement.

  6. Adaptation to low pH and lignocellulosic inhibitors resulting in ethanolic fermentation and growth of Saccharomyces cerevisiae.

    Narayanan, Venkatachalam; Sànchez I Nogué, Violeta; van Niel, Ed W J; Gorwa-Grauslund, Marie F

    2016-12-01

    Lignocellulosic bioethanol from renewable feedstocks using Saccharomyces cerevisiae is a promising alternative to fossil fuels owing to environmental challenges. S. cerevisiae is frequently challenged by bacterial contamination and a combination of lignocellulosic inhibitors formed during the pre-treatment, in terms of growth, ethanol yield and productivity. We investigated the phenotypic robustness of a brewing yeast strain TMB3500 and its ability to adapt to low pH thereby preventing bacterial contamination along with lignocellulosic inhibitors by short-term adaptation and adaptive lab evolution (ALE). The short-term adaptation strategy was used to investigate the inherent ability of strain TMB3500 to activate a robust phenotype involving pre-culturing yeast cells in defined medium with lignocellulosic inhibitors at pH 5.0 until late exponential phase prior to inoculating them in defined media with the same inhibitor cocktail at pH 3.7. Adapted cells were able to grow aerobically, ferment anaerobically (glucose exhaustion by 19 ± 5 h to yield 0.45 ± 0.01 g ethanol g glucose(-1)) and portray significant detoxification of inhibitors at pH 3.7, when compared to non-adapted cells. ALE was performed to investigate whether a stable strain could be developed to grow and ferment at low pH with lignocellulosic inhibitors in a continuous suspension culture. Though a robust population was obtained after 3600 h with an ability to grow and ferment at pH 3.7 with inhibitors, inhibitor robustness was not stable as indicated by the characterisation of the evolved culture possibly due to phenotypic plasticity. With further research, this short-term adaptation and low pH strategy could be successfully applied in lignocellulosic ethanol plants to prevent bacterial contamination. PMID:27566648

  7. Diabetic intestinal growth adaptation and glucagon-like peptide 2 in the rat

    Thulesen, J; Hartmann, B; Nielsen, C;

    1999-01-01

    Dietary fibre influence growth and function of the upper gastrointestinal tract. This study investigates the importance of dietary fibre in intestinal growth in experimental diabetes, and correlates intestinal growth with plasma levels of the intestinotrophic factor, glucagon-like peptide 2 (GLP-2)....

  8. Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1

    Collado, M.; Medema, R.H.; Garcia-Cao, I.; Dubuisson, M.L.N.; Barradas, M.; Glassford, J.; Rivas, C.; Burgering, B.M.T.; Serrano, M.; Lam, E.W.-F.

    2000-01-01

    A senescence-like growth arrest is induced in mouse primary embryo fibroblasts by inhibitors of phosphoinositide 3-kinase (PI3K). We observed that senescence-like growth arrest is correlated with an increase in p27Kip1 but that down-regulation of other cyclin-dependent kinase (CDK) inhibitors, inclu

  9. The stringent response and cell cycle arrest in Escherichia coli.

    Ferullo, Daniel J; Lovett, Susan T

    2008-12-01

    The bacterial stringent response, triggered by nutritional deprivation, causes an accumulation of the signaling nucleotides pppGpp and ppGpp. We characterize the replication arrest that occurs during the stringent response in Escherichia coli. Wild type cells undergo a RelA-dependent arrest after treatment with serine hydroxamate to contain an integer number of chromosomes and a replication origin-to-terminus ratio of 1. The growth rate prior to starvation determines the number of chromosomes upon arrest. Nucleoids of these cells are decondensed; in the absence of the ability to synthesize ppGpp, nucleoids become highly condensed, similar to that seen after treatment with the translational inhibitor chloramphenicol. After induction of the stringent response, while regions corresponding to the origins of replication segregate, the termini remain colocalized in wild-type cells. In contrast, cells arrested by rifampicin and cephalexin do not show colocalized termini, suggesting that the stringent response arrests chromosome segregation at a specific point. Release from starvation causes rapid nucleoid reorganization, chromosome segregation, and resumption of replication. Arrest of replication and inhibition of colony formation by ppGpp accumulation is relieved in seqA and dam mutants, although other aspects of the stringent response appear to be intact. We propose that DNA methylation and SeqA binding to non-origin loci is necessary to enforce a full stringent arrest, affecting both initiation of replication and chromosome segregation. This is the first indication that bacterial chromosome segregation, whose mechanism is not understood, is a step that may be regulated in response to environmental conditions. PMID:19079575

  10. The stringent response and cell cycle arrest in Escherichia coli.

    Daniel J Ferullo

    2008-12-01

    Full Text Available The bacterial stringent response, triggered by nutritional deprivation, causes an accumulation of the signaling nucleotides pppGpp and ppGpp. We characterize the replication arrest that occurs during the stringent response in Escherichia coli. Wild type cells undergo a RelA-dependent arrest after treatment with serine hydroxamate to contain an integer number of chromosomes and a replication origin-to-terminus ratio of 1. The growth rate prior to starvation determines the number of chromosomes upon arrest. Nucleoids of these cells are decondensed; in the absence of the ability to synthesize ppGpp, nucleoids become highly condensed, similar to that seen after treatment with the translational inhibitor chloramphenicol. After induction of the stringent response, while regions corresponding to the origins of replication segregate, the termini remain colocalized in wild-type cells. In contrast, cells arrested by rifampicin and cephalexin do not show colocalized termini, suggesting that the stringent response arrests chromosome segregation at a specific point. Release from starvation causes rapid nucleoid reorganization, chromosome segregation, and resumption of replication. Arrest of replication and inhibition of colony formation by ppGpp accumulation is relieved in seqA and dam mutants, although other aspects of the stringent response appear to be intact. We propose that DNA methylation and SeqA binding to non-origin loci is necessary to enforce a full stringent arrest, affecting both initiation of replication and chromosome segregation. This is the first indication that bacterial chromosome segregation, whose mechanism is not understood, is a step that may be regulated in response to environmental conditions.

  11. Recovering from a bad start: rapid adaptation and tradeoffs to growth below a threshold density

    Marx Christopher J

    2012-01-01

    Abstract Background Bacterial growth in well-mixed culture is often assumed to be an autonomous process only depending upon the external conditions under control of the investigator. However, increasingly there is awareness that interactions between cells in culture can lead to surprising phenomena such as density-dependence in the initiation of growth. Results Here I report the unexpected discovery of a density threshold for growth of a strain of Methylobacterium extorquens AM1 used to inocu...

  12. Optimal regeneration planning for old-growth forest: addressing scientific uncertainty in endangered species recovery through adaptive management

    Moore, C.T.; Conroy, M.J.

    2006-01-01

    Stochastic and structural uncertainties about forest dynamics present challenges in the management of ephemeral habitat conditions for endangered forest species. Maintaining critical foraging and breeding habitat for the endangered red-cockaded woodpecker (Picoides borealis) requires an uninterrupted supply of old-growth forest. We constructed and optimized a dynamic forest growth model for the Piedmont National Wildlife Refuge (Georgia, USA) with the objective of perpetuating a maximum stream of old-growth forest habitat. Our model accommodates stochastic disturbances and hardwood succession rates, and uncertainty about model structure. We produced a regeneration policy that was indexed by current forest state and by current weight of evidence among alternative model forms. We used adaptive stochastic dynamic programming, which anticipates that model probabilities, as well as forest states, may change through time, with consequent evolution of the optimal decision for any given forest state. In light of considerable uncertainty about forest dynamics, we analyzed a set of competing models incorporating extreme, but plausible, parameter values. Under any of these models, forest silviculture practices currently recommended for the creation of woodpecker habitat are suboptimal. We endorse fully adaptive approaches to the management of endangered species habitats in which predictive modeling, monitoring, and assessment are tightly linked.

  13. Different Transcriptional Responses from Slow and Fast Growth Rate Strains of Listeria monocytogenes Adapted to Low Temperature

    Cordero, Ninoska; Maza, Felipe; Navea-Perez, Helen; Aravena, Andrés; Marquez-Fontt, Bárbara; Navarrete, Paola; Figueroa, Guillermo; González, Mauricio; Latorre, Mauricio; Reyes-Jara, Angélica

    2016-01-01

    Listeria monocytogenes has become one of the principal foodborne pathogens worldwide. The capacity of this bacterium to grow at low temperatures has opened an interesting field of study in terms of the identification and classification of new strains of L. monocytogenes with different growth capacities at low temperatures. We determined the growth rate at 8°C of 110 strains of L. monocytogenes isolated from different food matrices. We identified a group of slow and fast strains according to their growth rate at 8°C and performed a global transcriptomic assay in strains previously adapted to low temperature. We then identified shared and specific transcriptional mechanisms, metabolic and cellular processes of both groups; bacterial motility was the principal process capable of differentiating the adaptation capacity of L. monocytogenes strains with different ranges of tolerance to low temperatures. Strains belonging to the fast group were less motile, which may allow these strains to achieve a greater rate of proliferation at low temperature. PMID:26973610

  14. Wide plate crack arrest testing

    To predict the behavior of a nuclear pressure vessel undergoing pressurized thermal shock, certain information on dynamic crack propagation and arrest is required. The purpose of the work described is to provide such data on wide plates fracturing at temperatures up to the upper shelf region. Four tests have been completed on the 26 MN Universal Testing Machine at NBS. The specimens are to be fractured in a thermal gradient that, in the most extreme case, might extend from -1000C to 2000 across the 1 meter specimen width. This is done so that the crack will initiate in a cold, brittle region and arrest in a hot, tough region. An important part of this study is data acquisition from the numerous strain gages, thermocouples, timing wires, crack mouth opening displacement gages, and acoustic emission transducers that are mounted on the specimen. Each test has been different with respect to conditions of testing, specimen configuration, and instrumentation used. The progressive changes in test procedure represent attempts to obtain the desired crack run and arrest behavior and to improve upon the quality of the data collected. In particular, efforts were made to initiate crack propagation at lower stress intensity factors. Also, strain gage combinations and locations were optimized to better deduce the crack position as a function of time. Another result of great interest that can be deduced from these tests is the initiation of fracture toughness and the arrest toughness

  15. Sudden Cardiac Arrest (SCA) Risk Assessment

    ... Find a Specialist Share Twitter Facebook SCA Risk Assessment Sudden Cardiac Arrest (SCA) occurs abruptly and without ... of all ages and health conditions. Start Risk Assessment The Sudden Cardiac Arrest (SCA) Risk Assessment Tool ...

  16. Crack propagation and arrest in CFRP materials with strain softening regions

    Dilligan, Matthew Anthony

    Understanding the growth and arrest of cracks in composite materials is critical for their effective utilization in fatigue-sensitive and damage susceptible applications such as primary aircraft structures. Local tailoring of the laminate stack to provide crack arrest capacity intermediate to major structural components has been investigated and demonstrated since some of the earliest efforts in composite aerostructural design, but to date no rigorous model of the crack arrest mechanism has been developed to allow effective sizing of these features. To address this shortcoming, the previous work in the field is reviewed, with particular attention to the analysis methodologies proposed for similar arrest features. The damage and arrest processes active in such features are investigated, and various models of these processes are discussed and evaluated. Governing equations are derived based on a proposed mechanistic model of the crack arrest process. The derived governing equations are implemented in a numerical model, and a series of simulations are performed to ascertain the general characteristics of the proposed model and allow qualitative comparison to existing experimental results. The sensitivity of the model and the arrest process to various parameters is investigated, and preliminary conclusions regarding the optimal feature configuration are developed. To address deficiencies in the available material and experimental data, a series of coupon tests are developed and conducted covering a range of arrest zone configurations. Test results are discussed and analyzed, with a particular focus on identification of the proposed failure and arrest mechanisms. Utilizing the experimentally derived material properties, the tests are reproduced with both the developed numerical tool as well as a FEA-based implementation of the arrest model. Correlation between the simulated and experimental results is analyzed, and future avenues of investigation are identified

  17. Cardiac arrest: resuscitation and reperfusion.

    Patil, Kaustubha D; Halperin, Henry R; Becker, Lance B

    2015-06-01

    The modern treatment of cardiac arrest is an increasingly complex medical procedure with a rapidly changing array of therapeutic approaches designed to restore life to victims of sudden death. The 2 primary goals of providing artificial circulation and defibrillation to halt ventricular fibrillation remain of paramount importance for saving lives. They have undergone significant improvements in technology and dissemination into the community subsequent to their establishment 60 years ago. The evolution of artificial circulation includes efforts to optimize manual cardiopulmonary resuscitation, external mechanical cardiopulmonary resuscitation devices designed to augment circulation, and may soon advance further into the rapid deployment of specially designed internal emergency cardiopulmonary bypass devices. The development of defibrillation technologies has progressed from bulky internal defibrillators paddles applied directly to the heart, to manually controlled external defibrillators, to automatic external defibrillators that can now be obtained over-the-counter for widespread use in the community or home. But the modern treatment of cardiac arrest now involves more than merely providing circulation and defibrillation. As suggested by a 3-phase model of treatment, newer approaches targeting patients who have had a more prolonged cardiac arrest include treatment of the metabolic phase of cardiac arrest with therapeutic hypothermia, agents to treat or prevent reperfusion injury, new strategies specifically focused on pulseless electric activity, which is the presenting rhythm in at least one third of cardiac arrests, and aggressive post resuscitation care. There are discoveries at the cellular and molecular level about ischemia and reperfusion pathobiology that may be translated into future new therapies. On the near horizon is the combination of advanced cardiopulmonary bypass plus a cocktail of multiple agents targeted at restoration of normal metabolism and

  18. Growth rate regulates membrane fluidity and membrane cold adaptation in .i.Bacillus subtilis./i

    Beranová, J.; Jemiola-Rzeminska, M.; Elhottová, Dana; Strzalka, K.; Konopásek, I.

    2007-01-01

    Roč. 274, Suppl. 1 (2007), s. 362. ISSN 1742-464X. [Congress of the Federation-of-European-Biochemical-Societies /32./. 07.07.2007-12.07.2007, Vienna] Institutional research plan: CEZ:AV0Z60660521 Keywords : membrane fluidity * membrane cold adaptation * Bacillus subtilis Subject RIV: EH - Ecology, Behaviour

  19. Interindividual Variation in Functionally Adapted Trait Sets Is Established During Postnatal Growth and Predictable Based on Bone Robustness

    Pandey, Nirnimesh; Bhola, Siddharth; Goldstone, Andrew; Chen, Fred; Chrzanowski, Jessica; Terranova, Carl J.; Ghillani, Richard

    2009-01-01

    Adults acquire unique sets of morphological and tissue-quality bone traits that are predictable based on robustness and deterministic of strength and fragility. How and when individual trait sets arise during growth has not been established. Longitudinal structural changes of the metacarpal diaphysis were measured for boys and girls from 3 mo to 8 yr of age using hand radiographs obtained from the Bolton-Brush collection. Robustness varied ∼2-fold among boys and girls, and individual values were established by 2 yr of age, indicating that genetic and environmental factors controlling the relationship between growth in width and growth in length were established early during postnatal growth. Significant negative correlations between robustness and relative cortical area and a significant positive correlation between robustness and a novel measure capturing the efficiency of growth indicated that coordination of the subperiosteal and endocortical surfaces was responsible for this population acquiring a narrow range of trait sets that was predictable based on robustness. Boys and girls with robust diaphyses had proportionally thinner cortices to minimize mass, whereas children with slender diaphyses had proportionally thicker cortices to maximize stiffness. Girls had more slender metacarpals with proportionally thicker cortices compared with boys at all prepubertal ages. Although postnatal growth patterns varied in fundamentally different ways with sex and robustness, the dependence of trait sets on robustness indicated that children sustained variants affecting subperiosteal growth because they shared a common biological factor regulating functional adaptation. Considering the natural variation in acquired trait sets may help identify determinants of fracture risk, because age-related bone loss and gain will affect slender and robust structures differently. PMID:20001599

  20. Staphylococcus aureus Alters Growth Activity, Autolysis, and Antibiotic Tolerance in a Human Host-Adapted Pseudomonas aeruginosa Lineage

    Frydenlund Michelsen, Charlotte; Christensen, Anne-Mette; Bojer, Martin Saxtorph;

    2014-01-01

    Interactions among members of polymicrobial infections or between pathogens and the commensal flora may determine disease outcomes. Pseudomonas aeruginosa and Staphylococcus aureus are important opportunistic human pathogens and are both part of the polymicrobial infection communities in human...... hosts. In this study, we analyzed the in vitro interaction between S. aureus and a collection of P. aeruginosa isolates representing different evolutionary steps of a dominant lineage, DK2, that have evolved through decades of growth in chronically infected patients. While the early adapted P....... aeruginosa DK2 strains outcompeted S. aureus during coculture on agar plates, we found that later P. aeruginosa DK2 strains showed a commensal-like interaction, where S. aureus was not inhibited by P. aeruginosa and the growth activity of P. aeruginosa was enhanced in the presence of S. aureus. This effect...

  1. Adaptation of model genetically engineered microorganisms to lake water: growth rate enhancements and plasmid loss.

    Sobecky, P A; Schell, M A; Moran, M. A.; Hodson, R. E.

    1992-01-01

    When a genetically engineered microorganism (GEM) is released into a natural ecosystem, its survival, and hence its potential environmental impact, depends on its genetic stability and potential for growth under highly oligotrophic conditions. In this study, we compared plasmid stability and potential for growth on low concentrations of organic nutrients of strains of Pseudomonas putida serving as model GEMs. Plasmid-free and plasmid-bearing (NAH7) prototrophic isogenic strains and two amino-...

  2. Rapid Evolution of Culture-Impaired Bacteria During Adaptation to Biofilm Growth

    Jon Penterman; Dao Nguyen; Erin Anderson; Benjamin J. Staudinger; Everett P. Greenberg; Joseph S. Lam; Pradeep K. Singh

    2014-01-01

    Biofilm growth increases the fitness of bacteria in harsh conditions. However, bacteria from clinical and environmental biofilms can exhibit impaired growth in culture, even when the species involved are readily culturable and permissive conditions are used. Here, we show that culture-impaired variants of Pseudomonas aeruginosa arise rapidly and become abundant in laboratory biofilms. The culture-impaired phenotype is caused by mutations that alter the outer-membrane lipopolysaccharide struct...

  3. Geography, environmental efficiency and Italian economic growth: a spatially-adapted Environmental Kuznets Curve

    Ciriaci, Daria; Palma, Daniela

    2010-01-01

    The present paper tests the hypothesis that environmental degradation and per capita income follow an inverted-U-shaped relationship (the so-called Environmental Kuznets Curve) at the Italian Nut3 level over the period 1990-2005. We adopt a spatial econometric approach to account for the localised nature of environmental damage. In this spatially-adapted EKC, we explicitly introduced the role of energy intensive sectors to control for local industrial structure. The experiment brought to ligh...

  4. Effect of a biofield treatment on plant growth and adaptation (Benth.)

    Trivedi, Mahendra Kumar

    2015-01-01

    Quantum mechanics was developed when human energies of consciousness were found to influence observations at the scale of elementary particles, here referred as non-contact biofield treatment or biofield energies . Quantum mechanics has also proved efficacious in biological processes. The present experiments found an enhanced and significant impact of the biofield treatment on adaptive micropropagation response and callus induction of two plant species, Withania somnifera and Amaranthus dubiu...

  5. Long-term warming of a subarctic heath decreases soil bacterial community growth but has no effects on its temperature adaptation

    Rinnan, Riikka; Michelsen, Anders; Bååth, E

    2011-01-01

    , respectively. The decrease was most likely due to decreased availability of labile substrate under warming. However, we found no evidence for temperature adaptation of soil bacterial communities. The optimum temperature for bacterial growth was on average 25 °C, and the apparent minimum temperature for growth......We tested whether bacterial communities of subarctic heath soil are adapted to elevated temperature after experimental warming by open-top greenhouses for 7 or 17 years. The long-term warming by 1–2 °C significantly decreased bacterial community growth, by 28% and 73% after 7 and 17 years...

  6. Adaptation of the QoL-AGHDA scale for adults with growth hormone deficiency in four Slavic languages

    McKenna Stephen P

    2011-08-01

    Full Text Available Abstract Purpose The Quality of Life in Adult Growth Hormone Deficiency Assessment (QoL-AGHDA is a disease-specific quality of life measure specific to individuals who are growth hormone deficient. The present study describes the adaptation of the QoL-AGHDA for use in the following four Slavic languages; Czech, Polish, Serbian and Slovakian. Methods The study involved three stages in each language; translation, cognitive debriefing and validation. The validation stage assessed internal consistency (Cronbach's alpha, reproducibility (test-retest reliability using Spearman's rank correlations, convergent and divergent validity (Correlations with the NHP and known group validity. Results The QoL-AGHDA was successfully translated into the target languages with minimal problems. Cognitive debriefing interviewees (n = 15-18 found the measures easy to complete and identified few problems with the content. Internal consistency (Czech Republic = 0.91, Poland = 0.91, Serbia = 0.91 and Slovakia = 0.89 and reproducibility (Czech Republic = 0.91, Poland = 0.91, Serbia = 0.88 and Slovakia = 0.93 were good in all adaptations. Convergent and divergent validity and known group validity data were not available for Slovakia. The QoL-AGHDA correlated as expected with the NHP scales most relevant to GHD. The QoL-AGHDA was able to distinguish between participants based on a range of variables. Conclusions The QoL-AGHDA was successfully adapted for use in the Czech Republic, Poland, Serbia and Slovakia. Further validation of the Slovakian version would be beneficial. The addition of these new lanaguage versions will prove valuable to multinational clinical trials and to clinical practice in the respective countries.

  7. Adaptation to metal-contaminated soils in populations of the moss, Ceratodon purpureus: Vegetative growth and reproductive expression

    Jules, E.S.; Shaw, A.J. (Univ. of Michigan, Ann Arbor, MI (United States))

    1994-06-01

    Many observations suggest that morphological evolution occurs slowly in bryophytes, and this has been suggested to reflect low genetic diversity within species. Isozyme studies, however, stand in apparent contrast and have shown that bryophytes can contain high levels of genetic variability within and among populations. In light of this conflict, we tested the potential of the moss, Ceratodon purpureus, to undergo adaptive change (i.e., ecotypic differentiation) in response to soils that have been contaminated with high levels of metals for 90 years by measuring gametophytic growth and reproductive expression under experimental conditions. Variation in protonemal growth in sterile culture indicates that plants from one population growing on contaminated soil near a smelter are significantly more tolerant of zinc, cadmium, and lead than plants from uncontaminated sites. Results from a common garden experiment, in which plants were grown on soil from the smelter site, indicate that plants from near the smelter are significantly more tolerant of contaminated soils than plants from uncontaminated sites for vegetative growth. The same experiment suggests that plants from the smelter site are also more tolerant in terms of gametangial production (although we could not test this statistically). Our results demonstrate that C. purpureus has been able to undergo relatively rapid evolution in response to strong selective pressures. 29 refs., 4 figs., 5 tabs.

  8. Adaptation of high-growth influenza H5N1 vaccine virus in Vero cells: implications for pandemic preparedness.

    Tseng, Yu-Fen; Hu, Alan Yung-Chih; Huang, Mei-Liang; Yeh, Wei-Zhou; Weng, Tsai-Chuan; Chen, Yu-Shuan; Chong, Pele; Lee, Min-Shi

    2011-01-01

    Current egg-based influenza vaccine production technology can't promptly meet the global demand during an influenza pandemic as shown in the 2009 H1N1 pandemic. Moreover, its manufacturing capacity would be vulnerable during pandemics caused by highly pathogenic avian influenza viruses. Therefore, vaccine production using mammalian cell technology is becoming attractive. Current influenza H5N1 vaccine strain (NIBRG-14), a reassortant virus between A/Vietnam/1194/2004 (H5N1) virus and egg-adapted high-growth A/PR/8/1934 virus, could grow efficiently in eggs and MDCK cells but not Vero cells which is the most popular cell line for manufacturing human vaccines. After serial passages and plaque purifications of the NIBRG-14 vaccine virus in Vero cells, one high-growth virus strain (Vero-15) was generated and can grow over 10(8) TCID(50)/ml. In conclusion, one high-growth H5N1 vaccine virus was generated in Vero cells, which can be used to manufacture influenza H5N1 vaccines and prepare reassortant vaccine viruses for other influenza A subtypes. PMID:22022351

  9. Adaptation and growth of Serratia marcescens in contact lens disinfectant solutions containing chlorhexidine gluconate.

    Gandhi, P A; Sawant, A D; Wilson, L.A.; Ahearn, D G

    1993-01-01

    Serratia marcescens (11 of 12 strains) demonstrated an ability to grow in certain chlorhexidine-based disinfecting solutions recommended for rigid gas-permeable contact lenses. For a representative strain, cells that were grown in nutrient-rich medium, washed, and inoculated into disinfecting solution went into a nonrecoverable phase within 24 h. However, after 4 days, cells that had the ability to grow in the disinfectant (doubling time, g = 5.7 h) emerged. Solutions supporting growth of S. ...

  10. Evaluation of Spring Wheat (20 Varieties Adaptation to Soil Drought during Seedlings Growth Stage

    Jolanta Biesaga-Kościelniak

    2014-04-01

    Full Text Available The effect of soil drought (10 days on the growth of plants, the accumulation of water and leakage of electrolytes, gas exchange, the contents of chl a + b and carotenoids in leaves and photochemical activity of photosystem II was studied at the seedling stage by transient fluorescent analysis in 20 of the popular varieties of polish spring wheat. Drought caused a particularly strong reduction in vigor of growth of seedlings, net photosynthesis rate and triggered an increase in electrolyte leakage from the leaves. Certain varieties during the drought demonstrated relatively intense CO2 assimilation at low water loss through transpiration. The varieties tested were significantly different in terms of tolerance to drought of the processes of gas exchange and seedlings development. Photochemical processes in PSII showed high tolerance to drought and at the same time low differentiation among varieties. The results obtained suggested that tolerance of growth parameters to drought and CO2 assimilation at the seedling stage may alleviate consequent depression of final yield of the grain.

  11. Carbamazepine induces mitotic arrest in mammalian Vero cells

    Perez Martin, J.M.; Fernandez Freire, P.; Labrador, V. [Departamento de Biologia, Facultad de Ciencias, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid (Spain); Hazen, M.J. [Departamento de Biologia, Facultad de Ciencias, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid (Spain)], E-mail: mariajose.hazen@uam.es

    2008-01-01

    We reported recently that the anticonvulsant drug carbamazepine, at supratherapeutic concentrations, exerts antiproliferative effects in mammalian Vero cells, but the underlying mechanism has not been elucidated. This motivates us to examine rigorously whether growth arrest was associated with structural changes in cellular organization during mitosis. In the present work, we found that exposure of the cells to carbamazepine led to an increase in mitotic index, mainly due to the sustained block at the metaphase/anaphase boundary, with the consequent inhibition of cell proliferation. Indirect immunofluorescence, using antibodies directed against spindle apparatus proteins, revealed that mitotic arrest was associated with formation of monopolar spindles, caused by impairment of centrosome separation. The final consequence of the spindle defects induced by carbamazepine, depended on the duration of cell cycle arrest. Following the time course of accumulation of metaphase and apoptotic cells during carbamazepine treatments, we observed a causative relationship between mitotic arrest and induction of cell death. Conversely, cells released from the block of metaphase by removal of the drug, continued to progress through mitosis and resume normal proliferation. Our results show that carbamazepine shares a common antiproliferative mechanism with spindle-targeted drugs and contribute to a better understanding of the cytostatic activity previously described in Vero cells. Additional studies are in progress to extend these initial findings that define a novel mode of action of carbamazepine in cultured mammalian cells.

  12. Carbamazepine induces mitotic arrest in mammalian Vero cells

    We reported recently that the anticonvulsant drug carbamazepine, at supratherapeutic concentrations, exerts antiproliferative effects in mammalian Vero cells, but the underlying mechanism has not been elucidated. This motivates us to examine rigorously whether growth arrest was associated with structural changes in cellular organization during mitosis. In the present work, we found that exposure of the cells to carbamazepine led to an increase in mitotic index, mainly due to the sustained block at the metaphase/anaphase boundary, with the consequent inhibition of cell proliferation. Indirect immunofluorescence, using antibodies directed against spindle apparatus proteins, revealed that mitotic arrest was associated with formation of monopolar spindles, caused by impairment of centrosome separation. The final consequence of the spindle defects induced by carbamazepine, depended on the duration of cell cycle arrest. Following the time course of accumulation of metaphase and apoptotic cells during carbamazepine treatments, we observed a causative relationship between mitotic arrest and induction of cell death. Conversely, cells released from the block of metaphase by removal of the drug, continued to progress through mitosis and resume normal proliferation. Our results show that carbamazepine shares a common antiproliferative mechanism with spindle-targeted drugs and contribute to a better understanding of the cytostatic activity previously described in Vero cells. Additional studies are in progress to extend these initial findings that define a novel mode of action of carbamazepine in cultured mammalian cells

  13. Retinoids arrest breast cancer cell proliferation: retinoic acid selectively reduces the duration of receptor tyrosine kinase signaling

    Tighe, Ann P.; Talmage, David A

    2004-01-01

    Retinoic acid (RA) induces cell cycle arrest of hormone-dependent human breast cancer (HBC) cells. Previously, we demonstrated that RA-induced growth arrest of T-47D HBC cells required the activity of the RA-induced protein kinase, protein kinase Cα (PKCα) [J. Cell Physiol. 172 (1997) 306]. Here, we demonstrate that RA treatment of T-47D cells interfered with growth factor signaling to downstream, cytoplasmic and nuclear targets. RA treatment did not inhibit epidermal growth factor (EGF) rece...

  14. An Adaptive Multigrid Algorithm for Simulating Solid Tumor Growth Using Mixture Models

    Wise, S.M.; Lowengrub, J.S.; Cristini, V

    2011-01-01

    In this paper we give the details of the numerical solution of a three-dimensional multispecies diffuse interface model of tumor growth, which was derived in (Wise et al., J. Theor. Biol. 253 (2008)) and used to study the development of glioma in (Frieboes et al., NeuroImage 37 (2007) and tumor invasion in (Bearer et al., Cancer Research, 69 (2009)) and (Frieboes et al., J. Theor. Biol. 264 (2010)). The model has a thermodynamic basis, is related to recently developed mixture models, and is c...

  15. Effects of submergence on growth and survival of saplings of three wetland trees differing in adaptive mechanisms for flood tolerance

    Fumiko Iwanaga

    2015-04-01

    Full Text Available Aim of study: Withstanding total submergence and reaeration following submergence is essential for the survival and establishment of wetland species. We focused on “LOES–low oxygen escape syndrome” and “LOQS–low oxygen quiescence syndrome” and compared tolerances to total submergence among wetland woody species differing in morphological adaptation to soil flooding. Area of study, materials and methods: This study examined the survival of 2-year-old saplings of Taxodium distichum and Metasequioia glyptostroboides (LOQS species, and Alnus japonica (LOES species, during and after total submergence. Saplings were completely submerged, then de-submerged to determine trends in survival and growth Main results: The M. glyptostroboides and A. japonica saplings could not survive prolonged submergence for more than 8 weeks, whereas saplings of T. distichum survived for over 2 years. Submerged saplings of all species showed no significant growth or modifications in morphology and anatomy under water, such as shoot elongation, adventitious root formation, and/or aerenchyma development. All T. distichum saplings that were de-submerged in the second year had the same pattern of shoot growth regardless of differences in timing and seasonality of de-submergence. Wood formation in T. distichum saplings ceased during submergence and resumed after de-submergence in spring and summer, but not in autumn. Research highlights: T. distichum saplings, which survived longer submergence periods than A. japonica and M. glyptostroboides, had physiological characteristics, such as suspension of growth and metabolism, which allowed survival of protracted total submergence (at least 2 years when saplings were immersed during the dormant stage before leaf flushing.

  16. Simultaneous Radial Lengthening and Ulnar Shortening for a Delayed Presentation of Radius Distal Physeal Arrest: A Case Report

    Erdal Uzun

    2014-12-01

    Full Text Available Distal radius fractures are common injuries in both children and in the elderly (25%; 18%. Distal radius physeal fractures have a high incidence, but physeal growth arrest occurs at a low rate. As a main deformity, radial shortening occurs with relative ulnar overgrowth leading to significant complaints of pain and functional limitations after distal radial growth arrest. In this paper we aim to report on the restoration of the wrist mechanics attained by performing a surgical technique of simultaneous radial lengthening and ulnar shortening procedures in an adolescent with a significant ulnar overgrowth deformity due to a posttraumatic growth arrest of distal radius.

  17. Survival and growth patterns of white spruce (Picea glauca [Moench] Voss) rangewide provenances and their implications for climate change adaptation.

    Lu, Pengxin; Parker, William H; Cherry, Marilyn; Colombo, Steve; Parker, William C; Man, Rongzhou; Roubal, Ngaire

    2014-06-01

    Intraspecific assisted migration (ISAM) through seed transfer during artificial forest regeneration has been suggested as an adaptation strategy to enhance forest resilience and productivity under future climate. In this study, we assessed the risks and benefits of ISAM in white spruce based on long-term and multilocation, rangewide provenance test data. Our results indicate that the adaptive capacity and growth potential of white spruce varied considerably among 245 range-wide provenances sampled across North America; however, the results revealed that local populations could be outperformed by nonlocal ones. Provenances originating from south-central Ontario and southwestern Québec, Canada, close to the southern edge of the species' natural distribution, demonstrated superior growth in more northerly environments compared with local populations and performed much better than populations from western Canada and Alaska, United States. During the 19-28 years between planting and measurement, the southern provenances have not been more susceptible to freezing damage compared with local populations, indicating they have the potential to be used now for the reforestation of more northerly planting sites; based on changing temperature, these seed sources potentially could maintain or increase white spruce productivity at or above historical levels at northern sites. A universal response function (URF), which uses climatic variables to predict provenance performance across field trials, indicated a relatively weak relationship between provenance performance and the climate at provenance origin. Consequently, the URF from this study did not provide information useful to ISAM. The ecological and economic importance of conserving white spruce genetic resources in south-central Ontario and southwestern Québec for use in ISAM is discussed. PMID:25360273

  18. Cognitive and Functional Consequence of Cardiac Arrest.

    Perez, Claudia A; Samudra, Niyatee; Aiyagari, Venkatesh

    2016-08-01

    Cardiac arrest is associated with high morbidity and mortality. Better-quality bystander cardiopulmonary resuscitation training, cardiocerebral resuscitation principles, and intensive post-resuscitation hospital care have improved survival. However, cognitive and functional impairment after cardiac arrest remain areas of concern. Research focus has shifted beyond prognostication in the immediate post-arrest period to identification of mechanisms for long-term brain injury and implementation of promising protocols to reduce neuronal injury. These include therapeutic temperature management (TTM), as well as pharmacologic and psychological interventions which also improve overall neurological function. Comprehensive assessment of cognitive function post-arrest is hampered by heterogeneous measures among studies. However, the domains of attention, long-term memory, spatial memory, and executive function appear to be affected. As more patients survive cardiac arrest for longer periods of time, there needs to be a greater focus on interventions that can enhance cognitive and psychosocial function post-arrest. PMID:27311306

  19. Global optimization, local adaptation and the role of growth in distribution networks

    Ronellenfitsch, Henrik

    2016-01-01

    Highly-optimized complex transport networks serve crucial functions in many man-made and natural systems such as power grids and plant or animal vasculature. Often, the relevant optimization functional is non-convex and characterized by many local extrema. In general, finding the global, or nearly global optimum is difficult. In biological systems, it is believed that natural selection slowly guides the network towards an optimized state. However, general coarse grained models for flow networks with local positive feedback rules for the vessel conductivity typically get trapped in low efficiency, local minima. In this work we show how the growth of the underlying tissue, coupled to the dynamical equations for network development, can drive the system to a dramatically improved optimal state. This general model provides a surprisingly simple explanation for the appearance of highly optimized transport networks in biology such as leaf and animal vasculature.

  20. [Out-of-hospital cardiac arrest].

    Virkkunen, Ilkka; Hoppu, Sanna; Kämäräinen, Antti

    2011-01-01

    Cardiac arrest as the first symptom of coronary artery disease is not uncommon. Some of previously healthy people with sudden cardiac arrest may be saved by effective resuscitation and post-resuscitative therapy. The majority of cardiac arrest patients experience the cardiac arrest outside of the hospital, in which case early recognition of lifelessness, commencement of basic life support and entry to professional care without delay are the prerequisites for recovery. After the heart has started beating again, the clinical picture of post-resuscitation syndrome must be recognized and appropriate treatment utilized. PMID:22204143

  1. Simulated Cardiopulmonary Arrests in a Hospital Setting.

    Mishkin, Barbara H.; And Others

    1982-01-01

    Describes a simulated interdisciplinary role rehearsal for cardiopulmonary arrest to prepare nurses to function effectively. Includes needs analysis, program components, and responses of program participants. (Author)

  2. Ent-11α-Hydroxy-15-oxo-kaur-16-en-19-oic-acid Inhibits Growth of Human Lung Cancer A549 Cells by Arresting Cell Cycle and Triggering Apoptosis

    Li Li; George G Chen; Ying-nian Lu; Yi Liu; Ke-feng Wu; Xian-ling Gong; Zhan-ping Gou; Ming-yue Li; Nian-ci Liang

    2012-01-01

    Objective:To examine the apoptotic effect of ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F),a compound isolated from Pteris semipinnata L(PsL),in human lung cancer A549 cells.Methods:A549 cells were treated with 5F (0-80 μg/ml) for different time periods.Cytotoxicity was examined using a MTT method.Cell cycle was examined using propidium iodide staining.Apoptosis was examined using Hoechst 33258 staining,enzyme-linked immunosorbent assay (ELISA) and caspase-3 activity analysis.Expression of representative apoptosis-related proteins was evaluated by Western blot analysis.Reactive oxygen species (ROS) level was measured using standard protocols.Potential interaction of 5F with cisplatin was also examined.Results:5F inhibited the proliferation of A549 cells in a concentration- and time-dependent manner.5F increased the accumulation of cells in sub-G1 phase and arrested the cells in the G2 phase.Exposure to 5F induced morphological changes and DNA fragmentation that are characteristic of apoptosis.The expression of p21 was increased.5F exposure also increased Bax expression,release of cytochrome c and apoptosis inducing factor (AIF),and activation of caspase-3.5F significantly sensitized the cells to cisplatin toxicity Interestingly,treatment with 5F did not increase ROS,but reduced ROS production induced by cisplatin.Conclusion:SF could inhibit the proliferation of A549 cells by arresting the cells in G2 phase and by inducing mitochondrial-mediated apoptosis.

  3. Adaptation of Trichoderma Species to Pesticide Confidor and Evaluation of their Growth Ability in the Media Containing Confidor

    Farnaz Ershadfath

    2015-12-01

    Full Text Available Introduction: Contamination caused by pesticides is considered as one of the environmental problems. Bioremediation is exploiting the ability of microorganisms to remove pollutants. Trichoderma species are free-living fungi that exist naturally in the environment. These fungi have the ability to uptake some contaminants biologically. The aim of this study is to evaluate the effect of Confidor, as an environmental contaminant, on the growth ability of Trichoderma sp. as a contaminant absorber. Materials and methods: Five species of Trichoderma fungi were cultured in PDA media. Then the fungi were adapted with 3 different concentrations of Confidor gradually (5, 10 and 20 mg/l. The diameter of the fungal colonies growing in different concentrations of the toxin, were measured after 24 hr and were compared with the control samples (medium without toxin. Results: Results showed that in all species of fungi the colony diameters increased significantly with increasing toxin concentrations. The largest colony diameter was related to T.tomentosum, T.asperellum and T.harzianum (88.88, 87.5 and 86.95%, respectively at the concentration of 20 mg of toxic. Also, in all studied fungal species, in the medium containing 20 (mg/ l of toxic, the aerial hyphae expanded much thicker and faster than other concentrations. Discussion and conclusion: The results indicate a significant increase in the growth ability of Trichoderma strains with increasing Confidor concentration. Therefore it could be concluded that Trichoderma fungi have a high potentiality for biodegradation of Confidor.

  4. A novel parameter estimation method for metal oxide surge arrester models

    Mehdi Nafar; Gevork B Gharehpetian; Taher Niknam

    2011-12-01

    Accurate modelling and exact determination of Metal Oxide (MO) surge arrester parameters are very important for arrester allocation, insulation coordination studies and systems reliability calculations. In this paper, a new technique, which is the combination of Adaptive Particle Swarm Optimization (APSO) and Ant Colony Optimization (ACO) algorithms and linking the MATLAB and EMTP, is proposed to estimate the parameters of MO surge arrester models. The proposed algorithm is named Modified Adaptive Particle Swarm Optimization (MAPSO). In the proposed algorithm, to overcome the drawback of the PSO algorithm (convergence to local optima), the inertia weight is tuned by using fuzzy rules and the cognitive and the social parameters are self-adaptively adjusted. Also, to improve the global search capability and prevent the convergence to local minima, ACO algorithm is combined to the proposed APSO algorithm. The transient models of MO surge arrester have been simulated by using ATP-EMTP. The results of simulations have been applied to the program, which is based on MAPSO algorithm and can determine the fitness and parameters of different models. The validity and the accuracy of estimated parameters of surge arrester models are assessed by comparing the predicted residual voltage with experimental results.

  5. Why Be a Shrub? A Basic Model and Hypotheses for the Adaptive Values of a Common Growth Form.

    Götmark, Frank; Götmark, Elin; Jensen, Anna M

    2016-01-01

    Shrubs are multi-stemmed short woody plants, more widespread than trees, important in many ecosystems, neglected in ecology compared to herbs and trees, but currently in focus due to their global expansion. We present a novel model based on scaling relationships and four hypotheses to explain the adaptive significance of shrubs, including a review of the literature with a test of one hypothesis. Our model describes advantages for a small shrub compared to a small tree with the same above-ground woody volume, based on larger cross-sectional stem area, larger area of photosynthetic tissue in bark and stem, larger vascular cambium area, larger epidermis (bark) area, and larger area for sprouting, and faster production of twigs and canopy. These components form our Hypothesis 1 that predicts higher growth rate for a small shrub than a small tree. This prediction was supported by available relevant empirical studies (14 publications). Further, a shrub will produce seeds faster than a tree (Hypothesis 2), multiple stems in shrubs insure future survival and growth if one or more stems die (Hypothesis 3), and three structural traits of short shrub stems improve survival compared to tall tree stems (Hypothesis 4)-all hypotheses have some empirical support. Multi-stemmed trees may be distinguished from shrubs by more upright stems, reducing bending moment. Improved understanding of shrubs can clarify their recent expansion on savannas, grasslands, and alpine heaths. More experiments and other empirical studies, followed by more elaborate models, are needed to understand why the shrub growth form is successful in many habitats. PMID:27507981

  6. Why Be a Shrub? A Basic Model and Hypotheses for the Adaptive Values of a Common Growth Form

    Götmark, Frank; Götmark, Elin; Jensen, Anna M.

    2016-01-01

    Shrubs are multi-stemmed short woody plants, more widespread than trees, important in many ecosystems, neglected in ecology compared to herbs and trees, but currently in focus due to their global expansion. We present a novel model based on scaling relationships and four hypotheses to explain the adaptive significance of shrubs, including a review of the literature with a test of one hypothesis. Our model describes advantages for a small shrub compared to a small tree with the same above-ground woody volume, based on larger cross-sectional stem area, larger area of photosynthetic tissue in bark and stem, larger vascular cambium area, larger epidermis (bark) area, and larger area for sprouting, and faster production of twigs and canopy. These components form our Hypothesis 1 that predicts higher growth rate for a small shrub than a small tree. This prediction was supported by available relevant empirical studies (14 publications). Further, a shrub will produce seeds faster than a tree (Hypothesis 2), multiple stems in shrubs insure future survival and growth if one or more stems die (Hypothesis 3), and three structural traits of short shrub stems improve survival compared to tall tree stems (Hypothesis 4)—all hypotheses have some empirical support. Multi-stemmed trees may be distinguished from shrubs by more upright stems, reducing bending moment. Improved understanding of shrubs can clarify their recent expansion on savannas, grasslands, and alpine heaths. More experiments and other empirical studies, followed by more elaborate models, are needed to understand why the shrub growth form is successful in many habitats. PMID:27507981

  7. Psychopathology in Women Arrested for Domestic Violence

    Stuart, Gregory L.; Moore, Todd M.; Gordon, Kristina Coop; Ramsey, Susan E.; Kahler, Christopher W.

    2006-01-01

    This study examined the prevalence of psychopathology among women arrested for violence and whether the experience of intimate partner violence (IPV) was associated with Axis I psychopathology. Women who were arrested for domestic violence perpetration and court referred to violence intervention programs (N=103) completed measures of IPV…

  8. The course of circulatory and cerebral recovery after circulatory arrest: influence of pre-arrest, arrest and post-arrest factors.

    Jørgensen, E O; Holm, S

    1999-11-01

    We evaluated the influence of pre-arrest, arrest and post-arrest factors on circulatory and neurological recovery for up to 1 year following circulatory arrest of cardio-pulmonary aetiology in 231 patients. Initially, all patients were unconscious and 106 had some cortical activity recorded in the immediate post-resuscitation EEG (Group I), while 125 had no such activity initially (Group II). The following variables were explored: age, sex, medical history, cause and location of arrest, initial cardiac dysrhythmia, duration of life support, metabolic acidosis, pulse-pressure product and heart pump function capacity early after resuscitation. Outcome measures were duration and quality of circulatory survival, cause of death, neurological recovery and ultimate outcome. First year survival was 33% in Group I and 16% in Group II. Severe heart failure and brain death occurred mainly in Group II. Circulatory recovery was negatively influenced by out-of-hospital arrest, metabolic acidosis and pulse-pressure products below 150. Neurological recovery was negatively influenced by initial dysrhythmias other than ventricular fibrillation, pulse-pressure products below 150, post-arrest heart failure and/or pulmonary complications. It seems that circulatory and cerebral outcomes are mainly determined by the global ischaemic insults sustained during the circulatory arrest period. PMID:10625157

  9. Quick adaptation of Ralstonia Solanacearum to copper stress to recover culturability and growth in water and soil

    Sergio Daniel Moreira Ascarrunz

    2011-06-01

    Full Text Available Cells of Ralstonia solanacearum were exposed to Cu in distilled water, and the resulting Cu-stressed non-culturable cells were inoculated to natural (non-pasteurized and pasteurized soils in order to examine their culturability and recovery. Exposing the cells to 20 µM CuSO4 produced transitory non-culturable cells, which exhibited a remarkable recovery in culturability after incubation in the solution for 36 h, reaching a density near the initial level by 108 h. To determine whether such non-culturable cells actually "resuscitated" or multiplied after adapting to Cu toxicity, growth curves were constructed in order to contrast the rates of increase in culturable cell numbers between Cu-stressed or non-stressed inocula. Additionally, fresh non-stressed cells were exposed to CuSO4 in the presence of nalidixic acid by adding the antibiotic at different times after the onset of Cu stress to verify any cell multiplication during the population increase. The results revealed that the non-culturable cells surviving Cu toxicity adapted very quickly to Cu and began multiplying within 12 h, because only the Cu-stressed cells that were increasing in the exponential growth phase, but not those in the stationary phase, were killed by the antibiotic. Such cells exhibited an apparent tolerance to this metal when inoculated to a freshly prepared solution of CuSO4, and also detoxified the ion in the solution in which they grew. The presence of nutrients greatly counteracted the effect of Cu in water microcosms, since culturable cells were detected and increased in number even when exposed to 40 µM CuSO4. In contrast, when inoculated to non-pasteurized soil, Cu-stressed cells showed no such recoveries. However, when the soil was pasteurized before inoculation or added with nutrients, culturable cells were recovered and increased in number. This indicates that increased nutrient availability in soil allows Cu-stressed cells to quickly overcome the stress and

  10. Quick adaptation of Ralstonia Solanacearum to copper stress to recover culturability and growth in water and soil.

    Ascarrunz, Sergio Daniel Moreira; Natsuaki, Tomohide; Honjo, Hitoshi; Fukui, Ryo

    2011-04-01

    Cells of Ralstonia solanacearum were exposed to Cu in distilled water, and the resulting Cu-stressed non-culturable cells were inoculated to natural (non-pasteurized) and pasteurized soils in order to examine their culturability and recovery. Exposing the cells to 20 μM CuSO4 produced transitory non-culturable cells, which exhibited a remarkable recovery in culturability after incubation in the solution for 36 h, reaching a density near the initial level by 108 h. To determine whether such non-culturable cells actually "resuscitated" or multiplied after adapting to Cu toxicity, growth curves were constructed in order to contrast the rates of increase in culturable cell numbers between Cu-stressed or non-stressed inocula. Additionally, fresh non-stressed cells were exposed to CuSO4 in the presence of nalidixic acid by adding the antibiotic at different times after the onset of Cu stress to verify any cell multiplication during the population increase. The results revealed that the non-culturable cells surviving Cu toxicity adapted very quickly to Cu and began multiplying within 12 h, because only the Cu-stressed cells that were increasing in the exponential growth phase, but not those in the stationary phase, were killed by the antibiotic. Such cells exhibited an apparent tolerance to this metal when inoculated to a freshly prepared solution of CuSO4, and also detoxified the ion in the solution in which they grew. The presence of nutrients greatly counteracted the effect of Cu in water microcosms, since culturable cells were detected and increased in number even when exposed to 40 μM CuSO4. In contrast, when inoculated to non-pasteurized soil, Cu-stressed cells showed no such recoveries. However, when the soil was pasteurized before inoculation or added with nutrients, culturable cells were recovered and increased in number. This indicates that increased nutrient availability in soil allows Cu-stressed cells to quickly overcome the stress and increase in

  11. 2-D gel electrophoresis-based proteomic analysis reveals that ormeloxifen induces G0-G1 growth arrest and ERK-mediated apoptosis in chronic myeloid leukemia cells K562.

    Pal, Pooja; Kanaujiya, Jitendra K; Lochab, Savita; Tripathi, Shashi B; Bhatt, Madan L B; Singh, Pradhyumna K; Sanyal, Sabyasachi; Trivedi, Arun K

    2011-04-01

    Ormeloxifen is a nonsteroidal selective estrogen receptor modulator (SERM) and has been shown to possess anticancer activities in breast and uterine cancer. Here, we show that ormeloxifen induces apoptosis in dose-dependent manner in a variety of leukemia cells, more strikingly in K562. 2-DE-gel electrophoresis of K562 cells induced with ormeloxifen showed that 57 and 30% of proteins belong to apoptosis and cell-cycle pathways, respectively. Our data demonstrate that ormeloxifen-induced apoptosis in K562 cells involves activation of extracellular signal-regulated kinases (ERKs) and subsequent cytochrome c release, leading to mitochondria-mediated caspase-3 activation. Ormeloxifen-induced apoptosis via ERK activation was drastically inhibited by prior treatment of K562 cells with ERK inhibitor PD98059. Ormeloxifen also inhibits proliferation of K562 cells by blocking them in G0-G1 phase by inhibiting c-myc promoter via ormeloxifen-induced MBP-1 (c-myc promoter-binding protein) and upregulation of p21 expression. We further show that ormeloxifen-induced apoptosis in K562 is translatable to mononuclear cells isolated from chronic myeloid leukemia (CML) patients. Thus, ormeloxifen induces apoptosis in K562 cells via phosphorylation of ERK and arrests them in G0-G1 phase by reciprocal regulation of p21 and c-myc. Therefore, inclusion of ormeloxifen in the therapy of chronic myeloid leukemia can be of potential utility. PMID:21360677

  12. Carnosol, a dietary diterpene, displays growth inhibitory effects in human prostate cancer PC3 cells leading to G2-phase cell cycle arrest and targets the 5'-AMP-activated protein kinase (AMPK) pathway

    Johnson, Jeremy J.; Syed, Deeba N.; Heren, Chenelle R.; Suh, Yewseok; Adhami, Vaqar M.; Mukhtar, Hasan

    2010-01-01

    Purpose The anti-cancer effect of carnosol was investigated in human prostate cancer PC3 cells. Methods Biochemical analysis and protein array data of carnosol treated PC3 cells were analyzed. Results We evaluated carnosol for its potential anti-cancer properties in the PC3 cells. Using an MTT assay we found that carnosol (10 – 70 µM) decreases cell viability in a time and dose dependent manner. Next, we evaluated the effect of carnosol (20–60 uM) effect using flow cytometry as well as biochemical analysis and found induction of G2-phase cell cycle arrest. To establish a more precise mechanism, we performed a protein array that evaluated 638 proteins involved in cell signaling pathways. The protein array identified 5'-AMP-activated protein kinase (AMPK), a serine/threonine protein kinase involved in the regulation of cellular energy balance as a potential target. Further downstream effects consistent with cancer inhibition included the modulation of the mTOR/HSP70S6k/4E-BP1 pathway. Additionally, we found that carnosol targeted the PI3K/Akt pathway in a dose dependent manner. Conclusions These results suggest that carnosol targets multiple signaling pathways that include the AMPK pathway. The ability of carnosol to inhibit prostate cancer in vitro suggests carnosol may be a novel agent for the management of PCa. PMID:18286356

  13. Soft Semicrystalline Thermoplastic Elastomers by Arrested Crystallization

    Burns, Adam; Register, Richard

    2014-03-01

    Thermoplastic elastomers (TPEs) marry the solid-state behavior of vulcanized rubbers with the melt processability of thermoplastics. Archetypal soft TPEs consist of triblock copolymers comprising a rubbery mid-block flanked by two identical glassy end-blocks. Incorporating crystalline blocks into TPEs can confer solvent resistance as well as reduce the processing costs by giving access to single-phase melts. However, simply substituting crystalline for glassy end-blocks dramatically degrades the solid-state mechanical properties, particularly at large strains. We seek to integrate the benefits of crystallinity into TPEs, while maintaining the desired mechanical properties, using the block architecture: crystalline-glassy-rubbery-glassy-crystalline. Methods have been developed to synthesize highly symmetric, narrow-distribution block copolymers with this architecture using anionic polymerization of butadiene, styrene, and isoprene followed by hydrogenation. Judicious choices of block molecular weights indeed yield homogeneous melts above the melting point of the crystalline component. Upon cooling, crystallization--rather than interblock repulsion--establishes the solid-state microstructure which physically crosslinks the rubbery mid-block, ultimately conferring elasticity. Subsequent vitrification of the adjacent glassy blocks arrests the growth of the crystallites, and protects them from yielding under applied load. As a result, our materials show low initial moduli, strain hardening, and high extensibility, typical of commercial TPEs.

  14. Extracellular enzymatic activities of cold-adapted bacteria from polar oceans and effect of temperature and salinity on cell growth

    Zeng Yinxin; Yu Yong; Chen Bo; Li Huirong

    2004-01-01

    The potential of 324 bacteria isolated from different habitats in polar oceans to produce a variety of extracellular enzymatic activities at low temperature was investigated. By plate assay, lipase, protease, amylase, gelatinase, agarase, chitinase or cellulase were detected. Lipases were generally present by bacteria living in polar oceans. Protease-producing bacteria held the second highest proportion in culturable isolates. Strains producing amylase kept a relative stable proportion of around 30% in different polar marine habitats. All 50 Arctic sea-ice bacteria producing proteases were cold-adapted strains, however, only 20% were psychrophilic. 98% of them could grow at 3% NaCl, and 56% could grow without NaCl. On the other hand, 98% of these sea-ice bacteria produced extracellular proteases with optimum temperature at or higher than 35℃, well above the upper temperature limit of cell growth. Extracellular enzymes including amylase, agarase, cellulase and lipase released by bacteria from seawater or sediment in polar oceans, most expressed maximum activities between 25 and 35℃. Among extracellular enzymes released by bacterial strain BSw20308, protease expressed maximum activity at 40℃, higher than 35℃ of polysaccharide hydrolases and 25℃ of lipase.

  15. A Computational Approach to Model Vascular Adaptation During Chronic Hemodialysis: Shape Optimization as a Substitute for Growth Modeling

    Mahmoudzadeh Akherat, S. M. Javid; Boghosian, Michael; Cassel, Kevin; Hammes, Mary

    2015-11-01

    End-stage-renal disease patients depend on successful long-term hemodialysis via vascular access, commonly facilitated via a Brachiocephalic Fistula (BCF). The primary cause of BCF failure is Cephalic Arch Stenosis (CAS). It is believed that low Wall Shear Stress (WSS) regions, which occur because of the high flow rates through the natural bend in the cephalic vein, create hemodynamic circumstances that trigger the onset and development of Intimal Hyperplasia (IH) and subsequent CAS. IH is hypothesized to be a natural effort to reshape the vessel, aiming to bring the WSS values back to a physiologically acceptable range. We seek to explore the correlation between regions of low WSS and subsequent IH and CAS in patient-specific geometries. By utilizing a shape optimization framework, a method is proposed to predict cardiovascular adaptation that could potentially be an alternative to vascular growth and remodeling. Based on an objective functional that seeks to alter the vessel shape in such a way as to readjust the WSS to be within the normal physiological range, CFD and shape optimization are then coupled to investigate whether the optimal shape evolution is correlated with actual patient-specific geometries thereafter. Supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (R01 DK90769).

  16. Chromosomal Aneuploidies and Early Embryonic Developmental Arrest

    Maria Maurer

    2015-07-01

    Full Text Available Background: Selecting the best embryo for transfer, with the highest chance of achieving a vital pregnancy, is a major goal in current in vitro fertilization (IVF technology. The high rate of embryonic developmental arrest during IVF treatment is one of the limitations in achieving this goal. Chromosomal abnormalities are possibly linked with chromosomal arrest and selection against abnormal fertilization products. The objective of this study was to evaluate the frequency and type of chromosomal abnormalities in preimplantation embryos with developmental arrest. Materials and Methods: This cohort study included blastomeres of embryos with early developmental arrest that were biopsied and analyzed by fluorescence in-situ hybridization (FISH with probes for chromosomes 13, 16, 18, 21 and 22. Forty-five couples undergoing IVF treatment were included, and 119 arrested embryos were biopsied. All probes were obtained from the Kinderwunsch Zentrum, Linz, Austria, between August 2009 and August 2011. Results: Of these embryos, 31.6% were normal for all chromosomes tested, and 68.4% were abnormal. Eleven embryos were uniformly aneuploid, 20 were polyploid, 3 were haploid, 11 displayed mosaicism and 22 embryos exhibited chaotic chromosomal complement. Conclusion: Nearly 70% of arrested embryos exhibit chromosomal errors, making chromosomal abnormalities a major cause of embryonic arrest and may be a further explanation for the high developmental failure rates during culture of the embryos in the IVF setting.

  17. Aqueous Extracts of the Edible Gracilaria tenuistipitata are Protective Against H2O2-Induced DNA Damage, Growth Inhibition, and Cell Cycle Arrest

    Chi-Chen Yeh

    2012-06-01

    Full Text Available Potential antioxidant properties of an aqueous extract of the edible red seaweed Gracilaria tenuistipitata (AEGT against oxidative DNA damage were evaluated. The AEGT revealed several antioxidant molecules, including phenolics, flavonoids and ascorbic acid. In a cell-free assay, the extract exhibited 1,1-diphenyl-2-picrylhydrazyl (DPPH radical scavenging activity that significantly reduced H2O2-induced plasmid DNA breaks in a dose-response manner (P < 0.001. The AEGT also suppressed H2O2-induced oxidative DNA damage in H1299 cells by reducing the percentage of damaged DNA in a dose-response manner (P < 0.001 as measured by a modified alkaline comet-nuclear extract (comet-NE assay. The MTT assay results showed that AEGT confers significant protection against H2O2-induced cytotoxicity and that AEGT itself is not cytotoxic (P < 0.001. Moreover, H2O2-induced cell cycle G2/M arrest was significantly released when cells were co-treated with different concentrations of AEGT (P < 0.001. Taken together, these findings suggest that edible red algae Gracilaria water extract can prevent H2O2-induced oxidative DNA damage and its related cellular responses.

  18. Genotypic variation in growth and physiological response to drought stress and re-watering reveals the critical role of recovery in drought adaptation in maize seedlings

    Daoqian eChen

    2016-01-01

    Full Text Available Non-irrigated crops in temperate climates and irrigated crops in arid climates are subjected to continuous cycles of water stress and re-watering. Thus, fast and efficient recovery from water stress may be among the key determinants of plant drought adaptation. The present study was designed to comparatively analyze the roles of drought resistance and drought recovery in drought adaptation and to investigate the physiological basis of genotypic variation in drought adaptation in maize (Zea mays seedlings. As the seedlings behavior in growth associate with yield under drought, it could partly reflect the potential of drought adaptability. Growth and physiological responses to progressive drought stress and recovery were observed in seedlings of ten maize lines. The results showed that drought adaptability is closely related to drought recovery (r = 0.714**, but not to drought resistance (r = 0.332. Drought induced decreases in leaf water content, water potential, osmotic potential, gas exchange parameters, chlorophyll content, Fv/Fm and nitrogen content, and increased H2O2 accumulation and lipid peroxidation. After recovery, most of these physiological parameters rapidly returned to normal levels. The physiological responses varied between lines. Further correlation analysis indicated that the physiological bases of drought resistance and drought recovery are definitely different, and that maintaining higher chlorophyll content (r = 0.874*** and Fv/Fm (r = 0.626* under drought stress contributes to drought recovery. Our results suggest that both drought resistance and recovery are key determinants of plant drought adaptation, and that drought recovery may play a more important role than previously thought. In addition, leaf water potential, chlorophyll content and Fv/Fm could be used as efficient reference indicators in the selection of drought-adaptive genotypes.

  19. Crack arrest saturation model under combined electrical and mechanical loadings

    R.R. Bhargava

    2009-12-01

    Full Text Available Purpose: The investigation aims at proposing a model for cracked piezoelectric strip which is capable to arrest the crack.Design/methodology/approach: Under the combined effect of electrical and mechanical loadings applied at the edges of the strip, the developed saturation zone is produced at each tip of the crack. To arrest further opening of the crack, the rims of the developed saturation zones are subjected to in-plane cohesive, normal uniform constant saturation point electrical displacement. The problem is solved using Fourier integral transform method which reduces the problem to the solution of Fredholm integral equation of the second kind. This integral equation in turn is solved numerically.Findings: The expressions are derived for different intensity factors and energy release rate. A qualitative analysis of the parameters affecting the arrest of opening of the crack and fatigue crack growth with respect to strip thickness and material constants are presented graphically.Research limitations/implications: The investigations are carried out by considering the material electrical brittle. Consequently, the zones protrude along the straight lines ahead of the crack tips. And further, the small scale electrical yielding conditions are used.Practical implications: Piezoelectric materials are widely getting used nowadays, even in day to day life like piezoelectric cigarette lighter, children toys etc. And, its advance used in technology like transducers, actuators has been already in progress. So, the aspect of cracking of piezoelectric materials are of great practical importance.Originality/value: The piezoelectric material under the combined effect of electrical and mechanical loadings gives the assessment of electrical displacement which is required to arrest the crack. The various useful interpretations are also drawn from the graphs.

  20. Composite Pressure Vessel Including Crack Arresting Barrier

    DeLay, Thomas K. (Inventor)

    2013-01-01

    A pressure vessel includes a ported fitting having an annular flange formed on an end thereof and a tank that envelopes the annular flange. A crack arresting barrier is bonded to and forming a lining of the tank within the outer surface thereof. The crack arresting barrier includes a cured resin having a post-curing ductility rating of at least approximately 60% through the cured resin, and further includes randomly-oriented fibers positioned in and throughout the cured resin.

  1. Surviving out-of-hospital cardiac arrest.

    Evans, Nick

    2016-05-01

    Emergency care nurses have been urged to play their part in Scotland's push to revolutionise care for cardiac arrest patients - by teaching others how to save a life. This article discusses the Scottish out-of-hospital cardiac arrest strategy, with particular focus on the drive to increase bystander cardiopulmonary resuscitation (CPR) rates, and on how emergency nurses are being enlisted to help promote the training of members of the public. PMID:27165393

  2. THE RACE/ETHNICITY DISPARITY IN MISDEMEANOR MARIJUANA ARRESTS IN NEW YORK CITY.

    Golub, Andrew; Johnson, Bruce D; Dunlap, Eloise

    2007-01-01

    RESEARCH SUMMARY: This article examines the growth in marijuana misdemeanor arrests in New York City (NYC) from 1980 to 2003 and its differential impact on blacks and Hispanics. Since 1980, the New York City Police Department (NYPD) expanded its use of arrest and detention for minor offenses under its quality-of-life (QOL) policing initiative. Arrest data indicate that during the 1990s the primary focus of QOL policing became smoking marijuana in public view (MPV). By 2000, MPV had become the most common misdemeanor arrest, accounting for 15% of all NYC adult arrests and rivaling controlled substance arrests as the primary focus of drug abuse control. Of note, most MPV arrestees have been black or Hispanic. Furthermore, black and Hispanic MPV arrestees have been more likely to be detained prior to arraignment, convicted, and sentenced to jail than their white counterparts. POLICY IMPLICATIONS: In light of the disparities, we recommend that the NYPD consider scaling back on MPV enforcement and reducing the harshness of treatment by routinely issuing Desk Appearance Tickets when the person is not wanted on other charges, so that most MPV arrestees would not be detained. Furthermore, we recommend that legislators should consider making smoking marijuana in public a violation and not a misdemeanor. Lastly, we suggest ways that NYC could monitor the effectiveness of these policy modifications to assure that the city continues to meet its goals for order maintenance. PMID:18841246

  3. Predicting crack arrest in reactor pressure vessels

    The pressurized thermal shock (PTS) issue has provided increased motivation for the search for a reasonably accurate crack arrest prediction methodology. This issue has assumed greater significance recently as a consequence of the imposition of Regulatory Guide 1.99 Revision 2 procedures for determining the effects of radiation embrittlement in the context of the screening criteria in the PTS rule that is used by the United States Nuclear Regulatory Commission to assess the integrity of reactor pressure vessels. The currently accepted procedure for predicting crack arrest is the so-called KIa procedure, which is based on static linear elastic fracture mechanics principles, with a crack being presumed to arrest when the crack tip stress intensity factor KIST falls below a value KIa. The present paper reviews recent EPRI sponsored research, which shows that the static procedure is overly conservative when it is applied to the first arrest of a deep crack in the thickness of a reactor vessel. This conclusion is clearly important when assessing the consequences of the imposition of the procedures of Regulatory Guide 1.99 Revision 2. A more accurate crack arrest prediction procedure, i.e. the Combustion Engineering constrained static procedure or the reflectionless stress intensity factor procedure which are very similar in concept and their arrest prediction, should be considered to assess the impact of its use in the context of the screening criteria limits in the PTS rule. (orig.)

  4. Sex Disparities in Arrest Outcomes for Domestic Violence

    Hamilton, Melissa; Worthen, Meredith G. F.

    2011-01-01

    Domestic violence arrests have been historically focused on protecting women and children from abusive men. Arrest patterns continue to reflect this bias with more men arrested for domestic violence compared to women. Such potential gender variations in arrest patterns pave the way to the investigation of disparities by sex of the offender in…

  5. Canopy shade causes a rapid and transient arrest in leaf development through auxin-induced cytokinin oxidase activity.

    Carabelli, Monica; Possenti, Marco; Sessa, Giovanna; Ciolfi, Andrea; Sassi, Massimiliano; Morelli, Giorgio; Ruberti, Ida

    2007-08-01

    A plant grown under canopies perceives the reduction in the ratio of red (R) to far-red (FR) light as a warning of competition, and enhances elongation growth in an attempt to overgrow its neighbors. Here, we report that the same low R/FR signal that induces hypocotyl elongation also triggers a rapid arrest of leaf primordium growth, ensuring that plant resources are redirected into extension growth. The growth arrest induced by low R/FR depends on auxin-induced cytokinin breakdown in incipient vein cells of developing primordia, thus demonstrating the existence of a previously unrecognized regulatory circuit underlying plant response to canopy shade. PMID:17671088

  6. Burkholderia pseudomallei transcriptional adaptation in macrophages

    Chieng Sylvia

    2012-07-01

    Full Text Available Abstract Background Burkholderia pseudomallei is a facultative intracellular pathogen of phagocytic and non-phagocytic cells. How the bacterium interacts with host macrophage cells is still not well understood and is critical to appreciate the strategies used by this bacterium to survive and how intracellular survival leads to disease manifestation. Results Here we report the expression profile of intracellular B. pseudomallei following infection of human macrophage-like U937 cells. During intracellular growth over the 6 h infection period, approximately 22 % of the B. pseudomallei genome showed significant transcriptional adaptation. B. pseudomallei adapted rapidly to the intracellular environment by down-regulating numerous genes involved in metabolism, cell envelope, motility, replication, amino acid and ion transport system and regulatory function pathways. Reduced expression in catabolic and housekeeping genes suggested lower energy requirement and growth arrest during macrophage infection, while expression of genes encoding anaerobic metabolism functions were up regulated. However, whilst the type VI secretion system was up regulated, expression of many known virulence factors was not significantly modulated over the 6hours of infection. Conclusions The transcriptome profile described here provides the first comprehensive view of how B. pseudomallei survives within host cells and will help identify potential virulence factors and proteins that are important for the survival and growth of B. pseudomallei within human cells.

  7. Seasonal and altitudinal variations on adaptation, growth and testicular activity of Baladi goats with vertical transhumance in Eastern Mediterranean

    The effects of transhumance on body growth and adaptation parameters in theBaladi goat, and testicular activity in bucks were studied over a period of one year. Thirty two animals were allocated to 4 similar groups according to age (100 days for 8 male and 8 female kids, and 3-4 years for 8 bucks and 8 does) and sex. Goats were raised in a coastal pasture area for the winter period (WP), then transhumed towards a mountainous area in May for the summer period (SP). Every 21 days, animals were weighed and monitored for a whole day to estimate the distance travelled; four does and four bucks were followed for two successive days to evaluate the nature of the plants grazed by direct observation. Four summer and two winter collections of these plants were subjected to proximate analysis; Respiration and heart rates were recorded every two hours between 6:00 a.m. and 6:00 p.m.; Testicular volume and semen quality were also measured. Animals traveled 1 km/h in summer period and 0.8 km/h in winter. Herbaceous plants formed 95% of the plants grazed in SP and ligneous plants formed the majority of the plants ingested (80 to 95%) in WP. Protein percentages decreased from 15.2 to 8.6% between the beginning and the middle of the SP whereas it was around 11% in WP. Weight gain was greater during SP in comparison to WP except for bucks (12, 7.6, 4.2 and -3.3 kg vs. 3.4,1.8, -7.5 and 3.3 kg for male and female goat kids, does and bucks, respectively). Respiration and heart rates showed adaptation of animals to walking long distances in both zones, stabilizing respectively at 47-50 breaths/min and 83-90 beats/min after a 6 km walk. Decrease in semen concentration was observed at the end of the animal's stay in each zone, with values between 3.1 and 3.7 spermatozoa x 109/ml vs. 1.7and 2.7 spermatozoa x 109/ml in SP and WP, respectively. The volume varied between 1.0 ±0.2 and 1.6 ± 0.4 ml in SP, and decreased to 0.6 ± 0.3 ml in WP. Transhumance is thus beneficial for only two

  8. Reversible cryo-arrest for imaging molecules in living cells at high spatial resolution.

    Masip, Martin E; Huebinger, Jan; Christmann, Jens; Sabet, Ola; Wehner, Frank; Konitsiotis, Antonios; Fuhr, Günther R; Bastiaens, Philippe I H

    2016-08-01

    The dynamics of molecules in living cells hampers precise imaging of molecular patterns by functional and super-resolution microscopy. We developed a method that circumvents lethal chemical fixation and allows on-stage cryo-arrest for consecutive imaging of molecular patterns within the same living, but arrested, cells. The reversibility of consecutive cryo-arrests was demonstrated by the high survival rate of different cell lines and by intact growth factor signaling that was not perturbed by stress response. Reversible cryo-arrest was applied to study the evolution of ligand-induced receptor tyrosine kinase activation at different scales. The nanoscale clustering of epidermal growth factor receptor (EGFR) in the plasma membrane was assessed by single-molecule localization microscopy, and endosomal microscale activity patterns of ephrin receptor A2 (EphA2) were assessed by fluorescence lifetime imaging microscopy. Reversible cryo-arrest allows the precise determination of molecular patterns while conserving the dynamic capabilities of living cells. PMID:27400419

  9. Industrial Growth and the Theory of Retardation. Precursors of an Adaptive Evolutionary Theory of EconomicChange

    John Stanley Metcalfe

    2003-01-01

    In the 1930s the idea of industrial growth was explored extensively by many economists in particular by Simon Kuznets and Arthur Burns. In their detailed empirical studies they identified diversity of industry growth rates and retardation of industry growth rates as a central feature of capitalist economic development. Yet the theory of growth rate diversity and retardation has only recently begun to be explored in detail by evolutionary economists. This paper is written in recognition of the...

  10. 4-Formylaminooxyvinylglycine, an Herbicidal Germination-Arrest Factor (GAF) from Pseudomonas Rhizosphere Bacteria

    A new oxyvinylglycine has been identified as a naturally occurring herbicide that irreversibly arrests germination of the seeds of grassy weeds; such as annual bluegrass (Poa annua), without significantly affecting the growth of established grass seedlings and mature plants, or germination of the se...