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Sample records for affect tumour growth

  1. Abcc10 status affects mammary tumour growth, metastasis, and docetaxel treatment response

    PubMed Central

    Domanitskaya, N; Wangari-Talbot, J; Jacobs, J; Peiffer, E; Mahdaviyeh, Y; Paulose, C; Malofeeva, E; Foster, K; Cai, K Q; Zhou, Y; Egleston, B; Hopper-Borge, E

    2014-01-01

    Background: Resistance to chemotherapeutic agents is a major obstacle to cancer treatment. A group of ABC efflux pumps, the Multidrug Resistance Proteins, is a source of resistance. Herein, we investigated the role of ABCC10 in mammary tumours, given the important role we have defined for ABCC10 in transporting taxanes, and the recognition that some ABCC proteins have roles in tumour growth. Methods: ABCC10 expression was correlated to human breast cancer subtype using breast tissue microarrays. Real-time quantitative PCR and western blot analysis were used to examine ABCC10 expression in human breast cancer lines. Abcc10−/− mice were crossed to MMTV-PyVmT mice to produce Abcc10−/− vs Abcc10+/+ mammary tumours and derivative cell lines. We used allograft and cellular assays to perform baseline and drug sensitization analysis of tumours and cell lines. Results: Clinical sample analyses indicated that ABCC10 was more highly expressed in Her2+ and ER+ than in Her2−, ER−, and triple-negative breast cancer. Unexpectedly, PyVmT; Abcc10−/− tumours grew more rapidly than PyVmT; Abcc10+/+ tumours and were associated with significantly reduced apoptosis and metastasis. PyVmT; Abcc10−/− lines were less migratory than PyVmT; Abcc10+/+ lines. Finally, we showed increased survival of docetaxel-treated MMTV-PyVmT; Abcc10−/− mice compared with wild-type mice. Conclusions: These data identify roles for Abcc10 in breast cancer pathogenesis and in vivo docetaxel resistance. PMID:24937672

  2. Biophysical models of tumour growth

    NASA Astrophysics Data System (ADS)

    Tracqui, P.

    2009-05-01

    Tumour growth is a multifactorial process, which has stimulated in recent decades the development of numerous models trying to figure out the mechanisms controlling solid tumours morphogenesis. While the earliest models were focusing on cell proliferation kinetics, modulated by the availability of supplied nutrients, new modelling approaches emphasize the crucial role of several biophysical processes, including local matrix remodelling, active cell migration and traction, and reshaping of host tissue vasculature. After a brief presentation of this experimental background, this review will outline a number of representative models describing, at different scales, the growth of avascular and vascularized tumours. Special attention will be paid to the formulation of tumour-host tissue interactions that selectively drive changes in tumour size and morphology, and which are notably mediated by the mechanical status and elasticity of the tumour microenvironment. Emergence of invasive behaviour through growth instabilities at the tumour-host interface will be presented considering both reaction-diffusion and mechano-cellular models. In the latter part of the review, patient-oriented implications of tumour growth modelling are outlined in the context of brain tumours. Some conceptual views of the adaptive strategies and selective barriers that govern tumour evolution are presented in conclusion as potential guidelines for the development of future models.

  3. An Evolutionary Hybrid Cellular Automaton Model of Solid Tumour Growth

    PubMed Central

    Gerlee, P.; Anderson, A.R.A.

    2007-01-01

    We propose a cellular automaton model of solid tumour growth, in which each cell is equipped with a micro-environment response network. This network is modelled using a feed-forward artificial neural network, that takes environmental variables as an input and from these determines the cellular behaviour as the output. The response of the network is determined by connection weights and thresholds in the network, which are subject to mutations when the cells divide. As both available space and nutrients are limited resources for the tumour this gives rise to clonal evolution where only the fittest cells survive. Using this approach we have investigated the impact of the tissue oxygen concentration on the growth and evolutionary dynamics of the tumour. The results show that the oxygen concentration affects the selection pressure, cell population diversity and morphology of the tumour. A low oxygen concentration in the tissue gives rise to a tumour with a fingered morphology that contains aggressive phenotypes with a small apoptotic potential, while a high oxygen concentration in the tissue gives rise to a tumour with a round morphology containing less evolved phenotypes. The tissue oxygen concentration thus affects the tumour at both the morphological level and on the phenotype level. PMID:17374383

  4. The distribution of saponins in vivo affects their synergy with chimeric toxins against tumours expressing human epidermal growth factor receptors in mice

    PubMed Central

    Bachran, C; Weng, A; Bachran, D; Riese, SB; Schellmann, N; Melzig, MF; Fuchs, H

    2010-01-01

    Background and purpose: Certain saponins synergize with antitumour drugs to enhance their efficacy, but the mechanisms underlying this synergy in vivo are not well studied. Here, we describe the distribution of Saponinum album (Spn) from Gypsophila paniculata L. in mice after subcutaneous injection. Experimental approach: The [3H]-labelled Spn used for in vivo experiments was biologically active, as it still increased the cytotoxicity of a chimeric toxin in vitro. Distribution of [3H]-Spn was measured in BALB/c mice, with or without subcutaneous tumours in the flank. Labelled Spn was subcutaneously injected in the neck, and samples of organs, blood, urine and tumour tissue were analysed for radioactivity, 5–240 min after the injection. Key results: The majority of [3H]-Spn distributed within 10 min throughout the entire animal, with high levels of radioactivity in the urine by 30 min. No preferential accumulation in tumour tissue or other organs was observed. In tumour-bearing mice, using a sequential combination of Spn (given first) and a chimeric toxin against the epidermal growth factor receptor, ErbB1, we tested two different pretreatment times for Spn. There was high antitumour efficacy (66% inhibition of tumour growth) after 60 min pre treatment with Spn, but no significant inhibition after 10 min pre treatment with Spn. Conclusions and implications: [3H]-Spn was rapidly cleared from the mice after s.c. injection, and antitumour synergy with chimeric toxins was correlated with the removal of excess Spn from tissues. Disposition of Spn in vivo may critically determine antitumour synergy with chimeric toxins. PMID:20015087

  5. Tumour-induced neoneurogenesis and perineural tumour growth: a mathematical approach

    NASA Astrophysics Data System (ADS)

    Lolas, Georgios; Bianchi, Arianna; Syrigos, Konstantinos N.

    2016-02-01

    It is well-known that tumours induce the formation of a lymphatic and a blood vasculature around themselves. A similar but far less studied process occurs in relation to the nervous system and is referred to as neoneurogenesis. The relationship between tumour progression and the nervous system is still poorly understood and is likely to involve a multitude of factors. It is therefore relevant to study tumour-nerve interactions through mathematical modelling: this may reveal the most significant factors of the plethora of interacting elements regulating neoneurogenesis. The present work is a first attempt to model the neurobiological aspect of cancer development through a system of differential equations. The model confirms the experimental observations that a tumour is able to promote nerve formation/elongation around itself, and that high levels of nerve growth factor and axon guidance molecules are recorded in the presence of a tumour. Our results also reflect the observation that high stress levels (represented by higher norepinephrine release by sympathetic nerves) contribute to tumour development and spread, indicating a mutually beneficial relationship between tumour cells and neurons. The model predictions suggest novel therapeutic strategies, aimed at blocking the stress effects on tumour growth and dissemination.

  6. Tumour-induced neoneurogenesis and perineural tumour growth: a mathematical approach

    PubMed Central

    Lolas, Georgios; Bianchi, Arianna; Syrigos, Konstantinos N.

    2016-01-01

    It is well-known that tumours induce the formation of a lymphatic and a blood vasculature around themselves. A similar but far less studied process occurs in relation to the nervous system and is referred to as neoneurogenesis. The relationship between tumour progression and the nervous system is still poorly understood and is likely to involve a multitude of factors. It is therefore relevant to study tumour-nerve interactions through mathematical modelling: this may reveal the most significant factors of the plethora of interacting elements regulating neoneurogenesis. The present work is a first attempt to model the neurobiological aspect of cancer development through a system of differential equations. The model confirms the experimental observations that a tumour is able to promote nerve formation/elongation around itself, and that high levels of nerve growth factor and axon guidance molecules are recorded in the presence of a tumour. Our results also reflect the observation that high stress levels (represented by higher norepinephrine release by sympathetic nerves) contribute to tumour development and spread, indicating a mutually beneficial relationship between tumour cells and neurons. The model predictions suggest novel therapeutic strategies, aimed at blocking the stress effects on tumour growth and dissemination. PMID:26861829

  7. Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis

    PubMed Central

    Kostourou, V; Robinson, S P; Cartwright, J E; Whitley, G St J

    2002-01-01

    Angiogenesis is a prerequisite for tumour progression and is highly regulated by growth factors and cytokines a number of which also stimulate the production of nitric oxide. Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthesis. Asymmetric dimethylarginine is metabolised by dimethylarginine dimethylaminohydrolase. To study the effect of dimethylarginine dimethylaminohydrolase on tumour growth and vascular development, the rat C6 glioma cell line was manipulated to overexpress the rat gene for dimethylarginine dimethylaminohydrolase I. Enhanced expression of dimethylarginine dimethylaminohydrolase I increased nitric oxide synthesis (as indicated by a two-fold increase in the production of cGMP), expression and secretion of vascular endothelial cell growth factor, and induced angiogenesis in vitro. Tumours derived from these cells grew more rapidly in vivo than cells with normal dimethylarginine dimethylaminohydrolase I expression. Immunohistochemical and magnetic resonance imaging measurements were consistent with increased tumour vascular development. Furthermore, dimethylarginine dimethylaminohydrolase activity was detected in a series of human tumours. This data demonstrates that dimethylarginine dimethylaminohydrolase plays a pivotal role in tumour growth and the development of the tumour vasculature by regulating the concentration of nitric oxide and altering vascular endothelial cell growth factor production. British Journal of Cancer (2002) 87, 673–680. doi:10.1038/sj.bjc.6600518 www.bjcancer.com © 2002 Cancer Research UK PMID:12237779

  8. Adaptation to statins restricts human tumour growth in Nude mice

    PubMed Central

    2011-01-01

    Background Statins have long been used as anti-hypercholesterolemia drugs, but numerous lines of evidence suggest that they may also bear anti-tumour potential. We have recently demonstrated that it was possible to isolate cancer cells adapted to growth in the continuous presence of lovastatin. These cells grew more slowly than the statin-sensitive cells of origin. In the present study, we compared the ability of both statin-sensitive and statin-resistant cells to give rise to tumours in Nude mice. Methods HGT-1 human gastric cancer cells and L50 statin-resistant derivatives were injected subcutaneously into Nude mice and tumour growth was recorded. At the end of the experiment, tumours were recovered and marker proteins were analyzed by western blotting, RT-PCR and immunohistochemistry. Results L50 tumours grew more slowly, showed a strong decrease in cyclin B1, over-expressed collagen IV, and had reduced laminin 332, VEGF and CD34 levels, which, collectively, may have restricted cell division, cell adhesion and neoangiogenesis. Conclusions Taken together, these results showed that statin-resistant cells developed into smaller tumours than statin-sensitive cells. This may be reflective of the cancer restricting activity of statins in humans, as suggested from several retrospective studies with subjects undergoing statin therapy for several years. PMID:22107808

  9. [Cerebellar cognitive affective syndrome secondary to a cerebellar tumour].

    PubMed

    Domínguez-Carral, J; Carreras-Sáez, I; García-Peñas, J J; Fournier-Del Castillo, C; Villalobos-Reales, J

    2015-01-01

    Cerebellar cognitive affective syndrome is characterized by disturbances of executive function, impaired spatial cognition, linguistic difficulties, and personality change. The case of an 11 year old boy is presented, with behavior problems, learning difficulties and social interaction problems. In the physical examination he had poor visual contact, immature behavior, reduced expressive language and global motor disability with gait dyspraxia, with no defined cerebellar motor signs. In the neuropsychological evaluation he has a full scale overall intellectual quotient of 84, with signs of cerebellar cognitive affective syndrome. A tumour affecting inferior cerebellar vermis was observed in the magnetic resonance imaging, which had not significantly grown during 5 years of follow up. The cerebellum participates in controlling cognitive and affective functions. Cerebellar pathology must be considered in the differential diagnosis of children with cognitive or learning disorder with associated behavioral and emotional components. PMID:24954915

  10. Inhibition of angiogenesis and murine tumour growth by laminarin sulphate.

    PubMed Central

    Hoffman, R.; Paper, D. H.; Donaldson, J.; Vogl, H.

    1996-01-01

    LAM S5 is a polysulphated derivative of the glucan laminarian that inhibits basic fibroblast growth factor (bFGF) binding and the bFGF-stimulated proliferation of fetal bovine heart endothelial (FBHE) cells. This report demonstrates that LAM S5 has anti-angiogenic activity, as shown by inhibition of tubule formation by endothelial cells cultured on Matrigel and inhibition of vascularisation of the chick chorioallantoic membrane. In addition, LAM S5 caused a tumour growth delay of the murine RIF-1 tumour of 2.6 days (P = 0.01). Images Figure 2 PMID:8630276

  11. Investigation of various growth mechanisms of solid tumour growth within the linear-quadratic model for radiotherapy

    NASA Astrophysics Data System (ADS)

    McAneney, H.; O'Rourke, S. F. C.

    2007-02-01

    The standard linear-quadratic survival model for radiotherapy is used to investigate different schedules of radiation treatment planning to study how these may be affected by different tumour repopulation kinetics between treatments. The laws for tumour cell repopulation include the logistic and Gompertz models and this extends the work of Wheldon et al (1977 Br. J. Radiol. 50 681), which was concerned with the case of exponential re-growth between treatments. Here we also consider the restricted exponential model. This has been successfully used by Panetta and Adam (1995 Math. Comput. Modelling 22 67) in the case of chemotherapy treatment planning.Treatment schedules investigated include standard fractionation of daily treatments, weekday treatments, accelerated fractionation, optimized uniform schedules and variation of the dosage and α/β ratio, where α and β are radiobiological parameters for the tumour tissue concerned. Parameters for these treatment strategies are extracted from the literature on advanced head and neck cancer, prostate cancer, as well as radiosensitive parameters. Standardized treatment protocols are also considered. Calculations based on the present analysis indicate that even with growth laws scaled to mimic initial growth, such that growth mechanisms are comparable, variation in survival fraction to orders of magnitude emerged. Calculations show that the logistic and exponential models yield similar results in tumour eradication. By comparison the Gompertz model calculations indicate that tumours described by this law result in a significantly poorer prognosis for tumour eradication than either the exponential or logistic models. The present study also shows that the faster the tumour growth rate and the higher the repair capacity of the cell line, the greater the variation in outcome of the survival fraction. Gaps in treatment, planned or unplanned, also accentuate the differences of the survival fraction given alternative growth

  12. Time course of ovarian tumour growth in soft agar culture.

    PubMed Central

    Verheijen, R. H.; Feitz, W. F.; Kenemans, P.; Vooys, G. P.; Herman, C. J.

    1985-01-01

    Single time point assessment is usually employed in the Human Tumour Cloning System as the only parameter for in vitro growth. This does not seem to give a fair expression of the dynamic biological properties of tumour growth and time dependent effects, e.g. of cytotoxic drugs. We studied the time course of colony formation in temporal growth patterns (TGPs) and compared this method of growth evaluation with conventional single time point assessment in 57 samples of ovarian tumour cultures in the HTCS. A first advantage of the use of TGPs is that more cultures become evaluable, as this assessment over time can detect a rise in the number of colonies in dishes where colony-like clumps have initially been seeded. Thus only 28 of the cultures were evaluable for single time point assessment, whereas 57 were available for TGP evaluation. Growth was more often seen at TGP evaluation (14/57) than at single day assessment (8/57). Evaluation of growth over the course of time potentially allows detection of sensitivity to drugs. Furthermore TGPs reflect the dynamics of biological growth. These features cannot be studied in single time point assessment. PMID:4063146

  13. Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages

    PubMed Central

    Huber, Roman; Meier, Barbara; Otsuka, Atsushi; Fenini, Gabriele; Satoh, Takashi; Gehrke, Samuel; Widmer, Daniel; Levesque, Mitchell P.; Mangana, Joanna; Kerl, Katrin; Gebhardt, Christoffer; Fujii, Hiroko; Nakashima, Chisa; Nonomura, Yumi; Kabashima, Kenji; Dummer, Reinhard; Contassot, Emmanuel; French, Lars E.

    2016-01-01

    Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target. PMID:27426915

  14. Targeting the erythropoietin receptor on glioma cells reduces tumour growth

    SciTech Connect

    Peres, Elodie A.; Valable, Samuel; Guillamo, Jean-Sebastien; Marteau, Lena; Bernaudin, Jean-Francois; Roussel, Simon; Lechapt-Zalcman, Emmanuele; Bernaudin, Myriam; Petit, Edwige

    2011-10-01

    Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cells leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.

  15. Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin.

    PubMed Central

    Stewart, D. J.; Molepo, J. M.; Green, R. M.; Montpetit, V. A.; Hugenholtz, H.; Lamothe, A.; Mikhael, N. Z.; Redmond, M. D.; Gadia, M.; Goel, R.

    1995-01-01

    We assessed factors which affect cisplatin concentrations in human surgical tumour specimens. Cisplatin 10 mg m-2 was given i.v. to 45 consenting patients undergoing surgical resection of neoplasms, and platinum was assayed in resected tumour and in deproteinated plasma by flameless atomic absorption spectrophotometry. By multiple stepwise regression analysis of normalised data, patient characteristics that emerged as being most closely associated (P < 0.05) with tumour platinum concentrations (after correcting for associations with other variables) were tumour 'source' [primary brain lymphomas, medulloblastomas and meningiomas ('type LMM') > 'others' > lung cancer > head/neck cancer > gliomas) or tumour 'type' (LMM > brain metastases > extracerebral tumours > gliomas), serum calcium and chloride (positive correlations) and bilirubin (negative). Tumour location (intracranial vs extracranial) did not correlate with platinum concentrations. If values for a single outlier were omitted, high-grade gliomas had significantly higher platinum concentrations (P < 0.003) than low-grade gliomas. For intracranial tumours, the computerised tomographic scan feature that correlated most closely with platinum concentrations in multivariate analysis was the darkness of peritumoral oedema. Tumour source or type is a much more important correlate of human tumour cisplatin concentrations than is intracranial vs extracranial location. Serum calcium, chloride and bilirubin levels may affect tumour cisplatin uptake or retention. CT scan characteristics may help predict cisplatin concentrations in intracranial tumours. PMID:7880744

  16. Emergent properties of a computational model of tumour growth

    PubMed Central

    2016-01-01

    While there have been enormous advances in our understanding of the genetic drivers and molecular pathways involved in cancer in recent decades, there also remain key areas of dispute with respect to fundamental theories of cancer. The accumulation of vast new datasets from genomics and other fields, in addition to detailed descriptions of molecular pathways, cloud the issues and lead to ever greater complexity. One strategy in dealing with such complexity is to develop models to replicate salient features of the system and therefore to generate hypotheses which reflect on the real system. A simple tumour growth model is outlined which displays emergent behaviours that correspond to a number of clinically relevant phenomena including tumour growth, intra-tumour heterogeneity, growth arrest and accelerated repopulation following cytotoxic insult. Analysis of model data suggests that the processes of cell competition and apoptosis are key drivers of these emergent behaviours. Questions are raised as to the role of cell competition and cell death in physical cancer growth and the relevance that these have to cancer research in general is discussed. PMID:27413638

  17. Inhibition of tumour-induced lipolysis in vitro and cachexia and tumour growth in vivo by eicosapentaenoic acid.

    PubMed

    Tisdale, M J; Beck, S A

    1991-01-01

    Stimulation of lipolysis in murine adipocytes in response to a lipid-mobilizing factor produced by a cachexia-inducing murine adenocarcinoma was inhibited by eicosapentaenoic acid (EPA) with a Ki value of 104 microM. The inhibitory effect was strictly structurally specific, since other related fatty acids of both the (n-3) and (n-6) series were ineffective as inhibitors of the lipolytic process. Induction of lipolysis by both salbutamol and ACTH was also inhibited by EPA, suggesting that the effect is exerted on a step central to the process of lipolysis. Lipolysis induced with the tumour lipid-mobilizing factor was associated with a prolonged elevation of the intracellular level of cyclic AMP in adipocytes, in contrast with ACTH and salbutamol. The elevation of adipocyte cyclic AMP in response to the tumour lipid-mobilizing factor and lipolytic hormones was inhibited by EPA. In vivo, administration of pure EPA to weight losing mice bearing the MAC16 adenocarcinoma completely prevented weight loss and tumour growth rate. In contrast both the other (n-3) fatty acid present in fish oil, docosahexaenoic acid (DHA), and linoleic acid were ineffective in inhibiting weight loss or the growth of the MAC16 tumour. This suggests that inhibition of tumour lipolytic activity accounts for the anticachectic effect of EPA, and that a correlation may exist between the inhibition of cachexia and the inhibition of tumour growth. PMID:1846070

  18. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo

    NASA Astrophysics Data System (ADS)

    Plate, Karl H.; Breier, Georg; Weich, Herbert A.; Risau, Werner

    1992-10-01

    CLINICAL and experimental studies suggest that angiogenesis is a prerequisite for solid tumour growth1,2. Several growth factors with mitogenic or chemotactic activity for endothelial cells in vitro have been described, but it is not known whether these mediate tumour vascularization in vivo3,4. Glioblastoma, the most common and most malignant brain tumour in humans, is distinguished from astrocytoma by the presence of necroses and vascular prolifer-ations5'6. Here we show that expression of an endothelial cell-specific mitogen, vascular endothelial growth factor (VEGF), is induced in astrocytoma cells but is dramatically upregulated in two apparently different subsets of glioblastoma cells. The high-affinity tyrosine kinase receptor for VEGF, flt, although not expressed in normal brain endothelium, is upregulated in tumour endothelial cells in vivo. These observations strongly support the concept that tumour angiogenesis is regulated by paracrine mechanisms and identify VEGF as a potential tumour angiogenesis factor in vivo.

  19. MEK inhibition prevents tumour-shed transforming growth factor-β-induced T-regulatory cell augmentation in tumour milieu.

    PubMed

    Hossain, Dewan M S; Panda, Abir K; Chakrabarty, Sreeparna; Bhattacharjee, Pushpak; Kajal, Kirti; Mohanty, Suchismita; Sarkar, Irene; Sarkar, Diptendra K; Kar, Santosh K; Sa, Gaurisankar

    2015-04-01

    Tumour progression is associated with immune-suppressive conditions that facilitate the escape of tumour cells from the regimen of immune cells, subsequently paralysing the host defence mechanisms. Induction of CD4(+)  CD25(+)  FoxP3(+) T regulatory (Treg) cells has been implicated in the tumour immune escape mechanism, although the novel anti-cancer treatment strategies targeting Treg cells remain unknown. The focus of this study is to define the interaction between tumour and immune system, i.e. how immune tolerance starts and gradually leads to the induction of adaptive Treg cells in the tumour microenvironment. Our study identified hyperactivated mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -signalling as a potential target for reversing Treg cell augmentation in breast cancer patients. In more mechanistic detail, pharmacological inhibitors of MEK/ERK signalling inhibited transforming growth factor-β (TGF-β) production in tumour cells that essentially blocked TGF-β-SMAD3/SMAD4-mediated induction of CD25/interleukin-2 receptor α on CD4(+) T-cell surface. As a result high-affinity binding of interleukin-2 on those cells was prohibited, causing lack of Janus kinase 1 (JAK1)/JAK3-mediated signal transducer and activator of transcription 3 (STAT3)/STAT5 activation required for FoxP3 expression. Finally, for a more radical approach towards a safe MEK inhibitor, we validate the potential of multi-kinase inhibitor curcumin, especially the nano-curcumin made out of pure curcumin with greater bioavailability; in repealing tumour-shed TGF-β-induced Treg cell augmentation. PMID:25284464

  20. Goshajinkigan reduces oxaliplatin-induced peripheral neuropathy without affecting anti-tumour efficacy in rodents.

    PubMed

    Ushio, Soichiro; Egashira, Nobuaki; Sada, Hikaru; Kawashiri, Takehiro; Shirahama, Masafumi; Masuguchi, Ken; Oishi, Ryozo

    2012-06-01

    Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. Goshajinkigan (GJG) is a Kampo medicine that is used for the treatments of several neurological symptoms including pain and numbness. More recently, GJG has been reported to prevent the oxaliplatin-induced peripheral neuropathy in clinical studies. No experimental study, however, has been conducted to date to determine the effect of GJG on pain behaviour in a rat model of oxaliplatin-induced neuropathy. Moreover, the impact on the anti-tumour effect of oxaliplatin remains unknown. In the present study, we examined the effects of GJG on the peripheral neuropathy and anti-tumour activity of oxaliplatin in rodents. Repeated administration of oxaliplatin caused cold hyperalgesia from days 3 to 37 and mechanical allodynia from days 21 to 28. Repeated administration of GJG prevented the oxaliplatin-induced cold hyperalgesia but not mechanical allodynia and axonal degeneration in rat sciatic nerve. Single administration of GJG reduced both cold hyperalgesia and mechanical allodynia after the development of neuropathy. In addition, GJG did not affect the anti-tumour effect of oxaliplatin in the tumour cells or tumour cells-implanted mice. These results suggest that GJG relieves the oxaliplatin-induced cold hyperalgesia and mechanical allodynia without affecting anti-tumour activity of oxaliplatin, and, therefore, may be useful for the oxaliplatin-induced neuropathy in clinical practice. PMID:21907570

  1. Canine pancreatic islet cell tumours secreting insulin-like growth factor type 2: a rare entity.

    PubMed

    Finotello, R; Ressel, L; Arvigo, M; Baroni, G; Marchetti, V; Romanelli, G; Burrow, R; Mignacca, D; Blackwood, L

    2016-06-01

    Insulin-like growth factor type II (IGF-II) is the main cause of non-islet cell tumour hypoglycaemia (NICTH) and insulin is thought to be the only factor causing hypoglycaemia in insulinomas. However, two case reports of pancreatic neuroendocrine tumours (PNETs) producing IGF-II have been previously published: a human and a canine patient. In this study, we investigated clinical, histopathological, immunohistochemical and ultrastructural features, and biological behaviour of canine pancreatic IGF-II-omas, a subgroup of PNETs that has not been previously characterized. Case records of 58 dogs with confirmed PNETs and hypoglycaemia were reviewed: six patients were affected by IGF-II-omas. Surgery was performed in all cases and two dogs had metastases. Four patients remained alive and in remission at 370, 440, 560 and 890 days post-diagnosis; two died of non-tumour-related causes. IGF-II-omas can be differentiated from insulinomas through hypoinsulinaemia, IGF-II positive and insulin negative immunostaining. The prevalence of this neoplasia is low, accounting for just 6% of PNETs. PMID:24428588

  2. Oral administration of Aloe vera and honey reduces Walker tumour growth by decreasing cell proliferation and increasing apoptosis in tumour tissue.

    PubMed

    Tomasin, Rebeka; Gomes-Marcondes, Maria Cristina Cintra

    2011-04-01

    Cancer is diagnosed in approximately 11 million people and is responsible for almost 8 million deaths worldwide every year. Research in cancer control has shown the importance of co-adjuvant therapies. Aloe vera may reduce tumour mass and metastasis rates, while honey may inhibit tumour growth. This study verified the influence of Aloe vera and honey on tumour growth and in the apoptosis process by assessing tumour size, the cell proliferation rate (Ki67-LI) and Bax/Bcl-2 expression at 7, 14 and 20 days after Walker 256 carcinoma implant in Wistar rats distributed into two groups: the WA group - tumour-bearing rats that received a gavage with a 670 µL/kg dose of Aloe vera and honey solution daily, and the CW group - tumour-bearing rats which received only a 0.9% NaCl solution. The effect of Aloe vera and honey against tumour growth was observed through a decrease in relative weight (%) and Ki67-LI in tumours from the WA group compared with those from the CW group. The Bax/Bcl-2 ratio increased in tumours from the WA group at all tested timepoints. These data suggest Aloe vera and honey can modulate tumour growth by reducing cell proliferation and increasing apoptosis susceptibility. PMID:20839215

  3. An imaging-based tumour growth and treatment response model: investigating the effect of tumour oxygenation on radiation therapy response

    NASA Astrophysics Data System (ADS)

    Titz, Benjamin; Jeraj, Robert

    2008-09-01

    A multiscale tumour simulation model employing cell-line-specific biological parameters and functional information derived from pre-therapy PET/CT imaging data was developed to investigate effects of different oxygenation levels on the response to radiation therapy. For each tumour voxel, stochastic simulations were performed to model cellular growth and therapeutic response. Model parameters were fitted to published preclinical experiments of head and neck squamous cell carcinoma (HNSCC). Using the obtained parameters, the model was applied to a human HNSCC case to investigate effects of different uniform and non-uniform oxygenation levels and results were compared for treatment efficacy. Simulations of the preclinical studies showed excellent agreement with published data and underlined the model's ability to quantitatively reproduce tumour behaviour within experimental uncertainties. When using a simplified transformation to derive non-uniform oxygenation levels from molecular imaging data, simulations of the clinical case showed heterogeneous tumour response and variability in radioresistance with decreasing oxygen levels. Once clinically validated, this model could be used to transform patient-specific data into voxel-based biological objectives for treatment planning and to investigate biologically optimized dose prescriptions.

  4. Tetrandrine suppresses human glioma growth by inhibiting cell survival, proliferation and tumour angiogenesis through attenuating STAT3 phosphorylation.

    PubMed

    Ma, Ji-wei; Zhang, Yong; Li, Ru; Ye, Jie-cheng; Li, Hai-ying; Zhang, Yi-kai; Ma, Zheng-lai; Li, Jin-ying; Zhong, Xue-yun; Yang, Xuesong

    2015-10-01

    Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, has been reported to possess anti-tumour activity. However, its effects on human glioma remain unknown. In this study, we demonstrated that Tet inhibited human glioma cell growth in vitro and in vivo. It has been hypothesised that Tet inhibits glioma growth by affecting glioma cell survival, proliferation and vasculature in and around the xenograft tumour in the chick CAM model and signal transducer and activator of transcription 3 (STAT3) mediated these activities. Therefore, we conducted a detailed analysis of the inhibitory effects of Tet on cell survival using a TUNEL assay and flow cytometric analysis; on cell proliferation based on the expression of proliferating cell nuclear antigen; and on angiogenesis using a CAM anti-angiogenesis assay. We used western blotting to investigate the role of STAT3 on the anti-glioma activities of Tet. The results revealed that Tet inhibited survival and proliferation in human glioma cells, impaired tumour angiogenesis and decreased the expression of phosphorylated STAT3 and its downstream proteins. In sum, our data indicate that STAT3 is involved in Tet-induced the regression of glioma growth by activating tumour cell apoptosis, inhibiting glioma cell proliferation and inhibiting angiogenesis. PMID:26086859

  5. Loss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR

    PubMed Central

    Henze, Anne-Theres; Garvalov, Boyan K.; Seidel, Sascha; Cuesta, Angel M.; Ritter, Mathias; Filatova, Alina; Foss, Franziska; Dopeso, Higinio; Essmann, Clara L.; Maxwell, Patrick H.; Reifenberger, Guido; Carmeliet, Peter; Acker-Palmer, Amparo; Acker, Till

    2014-01-01

    Solid tumours are exposed to microenvironmental factors such as hypoxia that normally inhibit cell growth. However, tumour cells are capable of counteracting these signals through mechanisms that are largely unknown. Here we show that the prolyl hydroxylase PHD3 restrains tumour growth in response to microenvironmental cues through the control of EGFR. PHD3 silencing in human gliomas or genetic deletion in a murine high-grade astrocytoma model markedly promotes tumour growth and the ability of tumours to continue growing under unfavourable conditions. The growth-suppressive function of PHD3 is independent of the established PHD3 targets HIF and NF-κB and its hydroxylase activity. Instead, loss of PHD3 results in hyperphosphorylation of epidermal growth factor receptor (EGFR). Importantly, epigenetic/genetic silencing of PHD3 preferentially occurs in gliomas without EGFR amplification. Our findings reveal that PHD3 inactivation provides an alternative route of EGFR activation through which tumour cells sustain proliferative signalling even under conditions of limited oxygen availability. PMID:25420773

  6. Platelet-cytokine Complex Suppresses Tumour Growth by Exploiting Intratumoural Thrombin-dependent Platelet Aggregation

    PubMed Central

    Li, Yu-Tung; Nishikawa, Tomoyuki; Kaneda, Yasufumi

    2016-01-01

    Tumours constitute unique microenvironments where various blood cells and factors are exposed as a result of leaky vasculature. In the present study, we report that thrombin enrichment in B16F10 melanoma led to platelet aggregation, and this property was exploited to administer an anticancer cytokine, interferon-gamma induced protein 10 (IP10), through the formation of a platelet-IP10 complex. When intravenously infused, the complex reached platelet microaggregates in the tumour. The responses induced by the complex were solely immune-mediated, and tumour cytotoxicity was not observed. The complex suppressed the growth of mouse melanoma in vivo, while both platelets and the complex suppressed the accumulation of FoxP3+ regulatory T cells in the tumour. These results demonstrated that thrombin-dependent platelet aggregation in B16F10 tumours defines platelets as a vector to deliver anticancer cytokines and provide specific treatment benefits. PMID:27117228

  7. Remodelling of extracellular matrix due to solid stress accumulation during tumour growth

    PubMed Central

    Pirentis, Athanassios P.; Polydorou, Christiana; Papageorgis, Panagiotis; Voutouri, Chrysovalantis; Mpekris, Fotios; Stylianopoulos, Triantafyllos

    2015-01-01

    Solid stresses emerge as the expanding tumour displaces and deforms the surrounding normal tissue, and also as a result of intratumoural component interplay. Among other things, solid stresses are known to induce extensive extracellular matrix synthesis and reorganization. In the present study, we developed a mathematical model of tumour growth that distinguishes the contribution to stress generation by collagenous and non-collagenous tumour structural components, and also investigates collagen fibre remodelling exclusively due to solid stress. To this end, we initially conducted in vivo experiments using an orthotopic mouse model for breast cancer to monitor primary tumour growth and derive the mechanical properties of the tumour. Subsequently, we fitted the mathematical model to experimental data to determine values of the model parameters. According to the model, intratumoural solid stress is compressive, whereas extratumoural stress in the tumour vicinity is compressive in the radial direction and tensile in the periphery. Furthermore, collagen fibres engaged in stress generation only in the peritumoural region, and not in the interior where they were slackened due to the compressive stress state. Peritumoural fibres were driven away from the radial direction, tended to realign tangent to the tumour-host interface, and were also significantly stretched by tensile circumferential stresses. By means of this remodelling, the model predicts that the tumour is enveloped by a progressively thickening capsule of collagen fibres. This prediction is consistent with long-standing observations of tumour encapsulation and histologic sections that we performed, and it further corroborates the expansive growth hypothesis for the capsule formation. PMID:26194953

  8. A single dividing cell population with imbalanced fate drives oesophageal tumour growth.

    PubMed

    Frede, Julia; Greulich, Philip; Nagy, Tibor; Simons, Benjamin D; Jones, Philip H

    2016-09-01

    Understanding the cellular mechanisms of tumour growth is key for designing rational anticancer treatment. Here we used genetic lineage tracing to quantify cell behaviour during neoplastic transformation in a model of oesophageal carcinogenesis. We found that cell behaviour was convergent across premalignant tumours, which contained a single proliferating cell population. The rate of cell division was not significantly different in the lesions and the surrounding epithelium. However, dividing tumour cells had a uniform, small bias in cell fate so that, on average, slightly more dividing than non-dividing daughter cells were generated at each round of cell division. In invasive cancers induced by Kras(G12D) expression, dividing cell fate became more strongly biased towards producing dividing over non-dividing cells in a subset of clones. These observations argue that agents that restore the balance of cell fate may prove effective in checking tumour growth, whereas those targeting cycling cells may show little selectivity. PMID:27548914

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

    PubMed Central

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

    1998-01-01

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

  10. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth

    PubMed Central

    Grivennikov, Sergei I.; Wang, Kepeng; Mucida, Daniel; Stewart, C. Andrew; Schnabl, Bernd; Jauch, Dominik; Taniguchi, Koji; Yu, Guann-Yi; Osterreicher, Christoph H.; Hung, Kenneth E.; Datz, Christian; Feng, Ying; Fearon, Eric R.; Oukka, Mohamed; Tessarollo, Lino; Coppola, Vincenzo; Yarovinsky, Felix; Cheroutre, Hilde; Eckmann, Lars; Trinchieri, Giorgio; Karin, Michael

    2013-01-01

    Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of β-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses1,2. Curiously, however, ‘inflammatory signature’ genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer3,4. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates5, referred to as ‘tumour elicited inflammation’6. Although infiltrating CD4+ TH1 cells and CD8+ cytotoxic T cells constitute a positive prognostic sign in colorectal cancer7,8, myeloid cells and T-helper interleukin (IL)-17-producing (TH17) cells promote tumorigenesis5,6, and a ‘TH17 expression signature’ in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival9. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier10. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by

  11. Nitric Oxide Up-Regulates RUNX2 in LNCaP Prostate Tumours: Implications for Tumour Growth In Vitro and In Vivo.

    PubMed

    Nesbitt, Heather; Browne, Gillian; O'Donovan, Katie M; Byrne, Niall M; Worthington, Jenny; McKeown, Stephanie R; McKenna, Declan J

    2016-02-01

    Aberrant expression of the transcription factor RUNX2 in prostate cancer has a number of important consequences including increased resistance to apoptosis, invasion and metastasis to bone. We previously demonstrated that hypoxia up-regulated RUNX2 in tumour cells, which in turn up-regulated the anti-apoptotic factor Bcl-2. Here, we investigate the impact of nitric oxide (NO) on RUNX2 and Bcl-2 expression in prostate cancer and further, how RUNX2 over-expression can impact tumour growth, angiogenesis and oxygenation in vivo. The effect of NO levels on RUNX2 and thus Bcl-2 expression was examined in prostate cancer cells in vitro using methods including gene and protein expression analyses, nitrite quantitation, protein-DNA interaction assays (ChIP) and viability assays (XTT). The effect of RUNX2 over-expression on tumour physiology (growth, oxygenation and angiogenesis) was also assessed in vivo using LNCaP xenografts. A low (but not high) concentration of NO (10 μM) induced expression of RUNX2 and Bcl-2, conferring resistance to docetaxel. These effects were induced via the ERK and PI3K pathways and were dependent on intact AP-1 binding sites in the RUNX2 promoter. RUNX2 over-expression in LNCaP tumours in vivo decreased the time to tumour presentation and increased tumour growth. Moreover, these tumours exhibited improved tumour angiogenesis and oxygenation. Low levels of NO increase expression of RUNX2 and Bcl-2 in LNCaP prostate tumour cells, and in vivo up-regulation of RUNX2 created tumours with a more malignant phenotype. Collectively, our data reveals the importance of NO-regulation of key factors in prostate cancer disease progression. PMID:26189652

  12. Perfluorocarbon nanoparticles enhance reactive oxygen levels and tumour growth inhibition in photodynamic therapy.

    PubMed

    Cheng, Yuhao; Cheng, Hao; Jiang, Chenxiao; Qiu, Xuefeng; Wang, Kaikai; Huan, Wei; Yuan, Ahu; Wu, Jinhui; Hu, Yiqiao

    2015-01-01

    Photodynamic therapy (PDT) kills cancer cells by converting tumour oxygen into reactive singlet oxygen ((1)O2) using a photosensitizer. However, pre-existing hypoxia in tumours and oxygen consumption during PDT can result in an inadequate oxygen supply, which in turn hampers photodynamic efficacy. Here to overcome this problem, we create oxygen self-enriching photodynamic therapy (Oxy-PDT) by loading a photosensitizer into perfluorocarbon nanodroplets. Because of the higher oxygen capacity and longer (1)O2 lifetime of perfluorocarbon, the photodynamic effect of the loaded photosensitizer is significantly enhanced, as demonstrated by the accelerated generation of (1)O2 and elevated cytotoxicity. Following direct injection into tumours, in vivo studies reveal tumour growth inhibition in the Oxy-PDT-treated mice. In addition, a single-dose intravenous injection of Oxy-PDT into tumour-bearing mice significantly inhibits tumour growth, whereas traditional PDT has no effect. Oxy-PDT may enable the enhancement of existing clinical PDT and future PDT design. PMID:26525216

  13. Perfluorocarbon nanoparticles enhance reactive oxygen levels and tumour growth inhibition in photodynamic therapy

    PubMed Central

    Cheng, Yuhao; Cheng, Hao; Jiang, Chenxiao; Qiu, Xuefeng; Wang, Kaikai; Huan, Wei; Yuan, Ahu; Wu, Jinhui; Hu, Yiqiao

    2015-01-01

    Photodynamic therapy (PDT) kills cancer cells by converting tumour oxygen into reactive singlet oxygen (1O2) using a photosensitizer. However, pre-existing hypoxia in tumours and oxygen consumption during PDT can result in an inadequate oxygen supply, which in turn hampers photodynamic efficacy. Here to overcome this problem, we create oxygen self-enriching photodynamic therapy (Oxy-PDT) by loading a photosensitizer into perfluorocarbon nanodroplets. Because of the higher oxygen capacity and longer 1O2 lifetime of perfluorocarbon, the photodynamic effect of the loaded photosensitizer is significantly enhanced, as demonstrated by the accelerated generation of 1O2 and elevated cytotoxicity. Following direct injection into tumours, in vivo studies reveal tumour growth inhibition in the Oxy-PDT-treated mice. In addition, a single-dose intravenous injection of Oxy-PDT into tumour-bearing mice significantly inhibits tumour growth, whereas traditional PDT has no effect. Oxy-PDT may enable the enhancement of existing clinical PDT and future PDT design. PMID:26525216

  14. Investigating the effect of longitudinal micro-CT imaging on tumour growth in mice

    NASA Astrophysics Data System (ADS)

    Foster, W. Kyle; Ford, Nancy L.

    2011-01-01

    The aim of this study is to determine the impact of longitudinal micro-CT imaging on the growth of B16F1 tumours in C57BL/6 mice. Sixty mice received 2 × 105 B16F1 cells subcutaneously in the hind flank and were divided into control (no scan), 'low-dose' (80 kVp, 70 mA, 8 s, 0.07 Gy), 'medium-dose' (80 kVp, 50 mA, 30 s, 0.18 Gy) and 'high-dose' (80 kVp, 50 mA, 50 s, 0.30 Gy) groups. All imaging was performed on a fast volumetric micro-CT scanner (GE Locus Ultra, London, Canada). Each mouse was imaged on days 4, 8, 12 and 16. After the final imaging session, each tumour was excised, weighed on an electronic balance, imaged to obtain the final tumour volume and processed for histology. Final tumour volume was used to evaluate the impact of longitudinal micro-CT imaging on the tumour growth. An ANOVA indicated no statistically significant difference in tumour volume (p = 0.331, α = β = 0.1) when discriminating against a treatment-sized effect. Histological samples revealed no observable differences in apoptosis or cell proliferation. We conclude that four imaging sessions, using standard protocols, over the course of 16 days did not cause significant changes in final tumour volume for B16F1 tumours in female C57BL/6 mice (ANOVA, α = β = 0.1, p = 0.331).

  15. On the importance of the submicrovascular network in a computational model of tumour growth.

    PubMed

    Lesart, Anne-Cécile; van der Sanden, Boudewijn; Hamard, Lauriane; Estève, François; Stéphanou, Angélique

    2012-09-01

    A computational model is potentially a powerful tool to apprehend complex phenomena like solid tumour growth and to predict the outcome of therapies. To that end, the confrontation of the model with experiments is essential to validate this tool. In this study, we develop a computational model specifically dedicated to the interpretation of tumour growth as observed in a mouse model with a dorsal skinfold chamber. Observation of the skin vasculature at the dorsal window scale shows a sparse network of a few main vessels of several hundreds micrometers in diameter. However observation at a smaller scale reveals the presence of a dense and regular interconnected network of capillaries about ten times smaller. We conveniently designate this structure as the submicrovascular network (SMVN).(1) The question that we wish to answer concerns the necessity of explicitly taking into account the SMVN in the computational model to describe the tumour evolution observed in the dorsal chamber. For that, simulations of tumour growth realised with and without the SMVN are compared and lead to two distinct scenarios. Parameters that are known to strongly influence the tumour evolution are then tested in the two cases to determine to which extent those parameters can be used to compensate the observed differences between these scenarios. Explicit modelling of the smallest vessels appears mandatory although not necessarily under the form of a regular grid. A compromise between the two investigated cases can thus be reached. PMID:22705361

  16. Physical Modelling and Simulations of Tumour Growth and Angiogenesis: Predictions and New Hypotheses

    NASA Astrophysics Data System (ADS)

    Scalerandi, M.; Griffa, M.

    2005-01-01

    The initial stages of tumour growth (avascular phase) are characterised by a low nutrient availability, which soon become a limiting factor for the progression of the neoplasm. Normally a transition to a vascular phase occurs, during which cancer cells stimulate the proliferation of endothelial cells belonging to vessels, hence the formation of new capillaries. The newly formed vascular system rapidly approaches the tumour surface and even infiltrates it, providing additional nutrients which allow further growth (angiogenesis). Blocking the process, might induce tumour to latency, with the consequent implications from therapeutical point of view. In the present contribution we will consider angiogenesis as a case study to show how mathematical models help in the interpretation and quantification of the experimental results.

  17. Microencapsulation of human cells: its effects on growth of normal and tumour cells in vitro.

    PubMed Central

    Shimi, S. M.; Hopwood, D.; Newman, E. L.; Cuschieri, A.

    1991-01-01

    The growth kinetics of established human colorectal tumour cell lines (HT29, HT115 and COLO 320DM) and human diploid fibroblasts (Flow 2002) were studied in conventional culture and in microcapsules formed from alginate-poly(L-lysine)-alginate membranes. The tumour lines grew rapidly in microcapsules but, in the case of the substrate-adherent lines HT29 and HT115, only after a prolonged lag phase. This phase was reduced by serial passage in microcapsules. The anchorage-independent line COLO 320DM showed no lengthening in lag phase. Microencapsulated fibroblasts underwent negligible growth but remained viable. Some evidence for functional differentiation (microvilli, cell-cell junctions) of the tumour line HT115 within the microcapsules was observed. We conclude that the use of microcapsules provides an alternative system with some advantages for the study of human cancer and its metastases in vitro. Images Figure 4 Figure 6 PMID:2039691

  18. Combretastatin A-4 inhibits cell growth and metastasis in bladder cancer cells and retards tumour growth in a murine orthotopic bladder tumour model

    PubMed Central

    Shen, Cheng-Huang; Shee, Jia-Jen; Wu, Jin-Yi; Lin, Yi-Wen; Wu, Jiann-Der; Liu, Yi-Wen

    2010-01-01

    BACKGROUND AND PURPOSE Bladder cancer is a highly recurrent cancer after intravesical therapy, so new drugs are needed to treat this cancer. Hence, we investigated the anti-cancer activity of combretastatin A-4 (CA-4), an anti-tubulin agent, in human bladder cancer cells and in a murine orthotopic bladder tumour model. EXPERIMENTAL APPROACH Cytotoxicity of CA-4 was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, propidium iodide (PI) staining assay and clonogenic survival assay. In vivo microtubule assembly assay, cell cycle analyses, Western blot and cell migration assay were used to study the mechanism of CA-4. The effect of intravesical CA-4 therapy on the development of tumours was studied in the murine orthotopic bladder tumour model. KEY RESULTS CA-4 inhibited microtubule polymerization in vivo. Cytotoxic IC50 values of CA-4 in human bladder cancer cells were below 4 nM. Analyses of cell-cycle distribution showed CA-4 obviously induced G2-M phase arrest with sub-G1 formation. The analyses of apoptosis showed that CA-4 induced caspase-3 activation and decreased BubR1 and Bub3 in cancer cells. In addition to apoptosis, CA-4 was also found to induce the formation of multinucleated cells. CA-4 had a significantly reduced cell migration in vitro. Importantly, the in vivo study revealed that intravesical CA-4 therapy retarded the development of murine bladder tumours. CONCLUSIONS AND IMPLICATIONS These data demonstrate that CA-4 kills bladder cancer cells by inducing apoptosis and mitotic catastrophe. It inhibited cell migration in vitro and tumour growth in vivo. Hence, CA-4 intravesical therapy could provide another strategy for treating superficial bladder cancers. PMID:20649598

  19. Tumour cell–derived extracellular vesicles interact with mesenchymal stem cells to modulate the microenvironment and enhance cholangiocarcinoma growth

    PubMed Central

    Haga, Hiroaki; Yan, Irene K.; Takahashi, Kenji; Wood, Joseph; Zubair, Abba; Patel, Tushar

    2015-01-01

    The contributions of mesenchymal stem cells (MSCs) to tumour growth and stroma formation are poorly understood. Tumour cells can transfer genetic information and modulate cell signalling in other cells through the release of extracellular vesicles (EVs). We examined the contribution of EV-mediated inter-cellular signalling between bone marrow MSCs and tumour cells in human cholangiocarcinoma, highly desmoplastic cancers that are characterized by tumour cells closely intertwined within a dense fibrous stroma. Exposure of MSCs to tumour cell–derived EVs enhanced MSC migratory capability and expression of alpha-smooth muscle actin mRNA, in addition to mRNA expression and release of CXCL-1, CCL2 and IL-6. Conditioned media from MSCs exposed to tumour cell–derived EVs increased STAT-3 phosphorylation and proliferation in tumour cells. These effects were completely blocked by anti-IL-6R antibody. In conclusion, tumour cell–derived EVs can contribute to the generation of tumour stroma through fibroblastic differentiation of MSCs, and can also selectively modulate the cellular release of soluble factors such as IL-6 by MSCs that can, in turn, alter tumour cell proliferation. Thus, malignant cells can “educate” MSCs to induce local microenvironmental changes that enhance tumour cell growth. PMID:25557794

  20. Oxygen-Driven Tumour Growth Model: A Pathology-Relevant Mathematical Approach

    PubMed Central

    Delgado-SanMartin, Juan A.; Hare, Jennifer I.; de Moura, Alessandro P. S.; Yates, James W. T.

    2015-01-01

    Xenografts -as simplified animal models of cancer- differ substantially in vasculature and stromal architecture when compared to clinical tumours. This makes mathematical model-based predictions of clinical outcome challenging. Our objective is to further understand differences in tumour progression and physiology between animal models and the clinic. To achieve that, we propose a mathematical model based upon tumour pathophysiology, where oxygen -as a surrogate for endocrine delivery- is our main focus. The Oxygen-Driven Model (ODM), using oxygen diffusion equations, describes tumour growth, hypoxia and necrosis. The ODM describes two key physiological parameters. Apparent oxygen uptake rate (kR′) represents the amount of oxygen cells seem to need to proliferate. The more oxygen they appear to need, the more the oxygen transport. kR′ gathers variability from the vasculature, stroma and tumour morphology. Proliferating rate (k p) deals with cell line specific factors to promote growth. The K H,K N describe the switch of hypoxia and necrosis. Retrospectively, using archived data, we looked at longitudinal tumour volume datasets for 38 xenografted cell lines and 5 patient-derived xenograft-like models. Exploration of the parameter space allows us to distinguish 2 groups of parameters. Group 1 of cell lines shows a spread in values of kR′ and lower k p, indicating that tumours are poorly perfused and slow growing. Group 2 share the value of the oxygen uptake rate (kR′) and vary greatly in k p, which we interpret as having similar oxygen transport, but more tumour intrinsic variability in growth. However, the ODM has some limitations when tested in explant-like animal models, whose complex tumour-stromal morphology may not be captured in the current version of the model. Incorporation of stroma in the ODM will help explain these discrepancies. We have provided an example. The ODM is a very simple -and versatile- model suitable for the design of preclinical

  1. Canine Mammary Tumours Are Affected by Frequent Copy Number Aberrations, including Amplification of MYC and Loss of PTEN

    PubMed Central

    Borge, Kaja S.; Nord, Silje; Van Loo, Peter; Lingjærde, Ole C.; Gunnes, Gjermund; Alnæs, Grethe I. G.; Solvang, Hiroko K.; Lüders, Torben; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Lingaas, Frode

    2015-01-01

    Background Copy number aberrations frequently occur during the development of many cancers. Such events affect dosage of involved genes and may cause further genomic instability and progression of cancer. In this survey, canine SNP microarrays were used to study 117 canine mammary tumours from 69 dogs. Results We found a high occurrence of copy number aberrations in canine mammary tumours, losses being more frequent than gains. Increased frequency of aberrations and loss of heterozygosity were positively correlated with increased malignancy in terms of histopathological diagnosis. One of the most highly recurrently amplified regions harbored the MYC gene. PTEN was located to a frequently lost region and also homozygously deleted in five tumours. Thus, deregulation of these genes due to copy number aberrations appears to be an important event in canine mammary tumour development. Other potential contributors to canine mammary tumour pathogenesis are COL9A3, INPP5A, CYP2E1 and RB1. The present study also shows that a more detailed analysis of chromosomal aberrations associated with histopathological parameters may aid in identifying specific genes associated with canine mammary tumour progression. Conclusions The high frequency of copy number aberrations is a prominent feature of canine mammary tumours as seen in other canine and human cancers. Our findings share several features with corresponding studies in human breast tumours and strengthen the dog as a suitable model organism for this disease. PMID:25955013

  2. Blocking CLEC14A-MMRN2 binding inhibits sprouting angiogenesis and tumour growth

    PubMed Central

    PJ, Noy; P, Lodhia; K, Khan; X, Zhuang; DG, Ward; AR, Verissimo; A, Bacon; R, Bicknell

    2015-01-01

    We previously identified CLEC14A as a tumour endothelial marker. Here we show CLEC14A is a regulator of sprouting angiogenesis in vitro and in vivo. Using a HUVEC spheroid sprouting assay we found CLEC14A to be a regulator of sprout initiation. Analysis of endothelial sprouting in aortic ring and in vivo subcutaneous sponge assays from clec14a+/+ and clec14a−/− mice revealed defects in sprouting angiogenesis in CLEC14A deficient animals. Tumour growth was retarded and vascularity reduced in clec14a−/− mice. Pulldown and co-immunoprecipitation experiments confirmed MMRN2 binds to the extracellular region of CLEC14A. The CLEC14A-MMRN2 interaction was interrogated using mouse monoclonal antibodies. Monoclonal antibodies were screened for their ability to block this interaction. Clone C4 but not C2 blocked CLEC14A-MMRN2 binding. C4 antibody perturbed tube formation and endothelial sprouting in vitro and in vivo, with a similar phenotype to loss of CLEC14A. Significantly, tumour growth was impaired in C4 treated animals and vascular density was also reduced in the C4 treated group. We conclude that CLEC14A-MMRN2 binding has a role in inducing sprouting angiogenesis during tumour growth, that has the potential to be manipulated in future anti-angiogenic therapy design. PMID:25745997

  3. Blocking CLEC14A-MMRN2 binding inhibits sprouting angiogenesis and tumour growth.

    PubMed

    Noy, P J; Lodhia, P; Khan, K; Zhuang, X; Ward, D G; Verissimo, A R; Bacon, A; Bicknell, R

    2015-11-19

    We previously identified CLEC14A as a tumour endothelial marker. Here we show that CLEC14A is a regulator of sprouting angiogenesis in vitro and in vivo. Using a human umbilical vein endothelial cell spheroid-sprouting assay, we found CLEC14A to be a regulator of sprout initiation. Analysis of endothelial sprouting in aortic ring and in vivo subcutaneous sponge assays from clec14a(+/+) and clec14a(-/-) mice revealed defects in sprouting angiogenesis in CLEC14A-deficient animals. Tumour growth was retarded and vascularity reduced in clec14a(-/-) mice. Pull-down and co-immunoprecipitation experiments confirmed that MMRN2 binds to the extracellular region of CLEC14A. The CLEC14A-MMRN2 interaction was interrogated using mouse monoclonal antibodies. Monoclonal antibodies were screened for their ability to block this interaction. Clone C4, but not C2, blocked CLEC14A-MMRN2 binding. C4 antibody perturbed tube formation and endothelial sprouting in vitro and in vivo, with a similar phenotype to loss of CLEC14A. Significantly, tumour growth was impaired in C4-treated animals and vascular density was also reduced in the C4-treated group. We conclude that CLEC14A-MMRN2 binding has a role in inducing sprouting angiogenesis during tumour growth, which has the potential to be manipulated in future antiangiogenic therapy design. PMID:25745997

  4. Aerosolised 5-azacytidine suppresses tumour growth and reprogrammes the epigenome in an orthotopic lung cancer model

    PubMed Central

    Reed, M D; Tellez, C S; Grimes, M J; Picchi, M A; Tessema, M; Cheng, Y S; March, T H; Kuehl, P J; Belinsky, S A

    2013-01-01

    Background: Epigenetic silencing by promoter methylation and chromatin remodelling affects hundreds of genes and is a causal event for lung cancer. Treatment of patients with low doses of the demethylating agent 5-azacytidine in combination with the histone deacetylase inhibitor entinostat has yielded clinical responses. The subcutaneous dosing route for consecutive days and reduced bioavailability of 5-azacytidine because of inactivation by cytidine deaminase may limit the expansion of epigenetic therapy into Phase III trials. To mitigate these barriers, an aerosol of 5-azacytidine was generated and characterised. Methods: The effect of aerosol vs systemic delivery of 5-azacytidine on tumour burden and molecular response of engrafted lung tumours in the nude rat was compared. Results: Pharmacokinetics revealed major improvement in the half-life of 5-azacytidine in lung tissue with aerosol delivery. Aerosolised 5-azacytidine significantly reduced lung tumour burden and induced global demethylation of the epigenome at one-third of the comparable effective systemic dose. High commonality for demethylation of genes was seen in tumours sampled throughout lung lobes and across treated animals receiving the aerosolised drug. Conclusion: Collectively, these findings show that aerosolised 5-azacytidine targets the lung, effectively reprogrammes the epigenome of tumours, and is a promising approach to combine with other drugs for treating lung cancer. PMID:24045660

  5. The status of epidermal growth factor receptor in borderline ovarian tumours

    PubMed Central

    Showeil, Rania; Romano, Claudia; Valganon, Mikel; Lambros, Maryou; Trivedi, Pritesh; Van Noorden, Susan; Sriraksa, Ruethairat; El-Kaffash, Dalal; El-Etreby, Nour; Natrajan, Rachael; Foroni, Letizia; Osborne, Richard; El-Bahrawy, Mona

    2016-01-01

    The majority of borderline ovarian tumours (BOTs) behave in a benign fashion, but some may show aggressive behavior. The reason behind this has not been elucidated. The epidermal growth factor receptor (EGFR) is known to contribute to cell survival signals as well as metastatic potential of some tumours. EGFR expression and gene status have not been thoroughly investigated in BOTs as it has in ovarian carcinomas. In this study we explore protein expression as well as gene mutations and amplifications of EGFR in BOTs in comparison to a subset of other epithelial ovarian tumours. We studied 85 tumours, including 61 BOTs, 10 low grade serous carcinomas (LGSCs), 9 high grade serous carcinomas (HGSCs) and 5 benign epithelial tumours. EGFR protein expression was studied using immunohistochemistry. Mutations were investigated by Sanger sequencing exons 18-21 of the tyrosine kinase domain of EGFR. Cases with comparatively higher protein expression were examined for gene amplification by chromogenic in situ hybridization. We also studied the tumours for KRAS and BRAF mutations. Immunohistochemistry results revealed both cytoplasmic and nuclear EGFR expression with variable degrees between tumours. The level of nuclear localization was relatively higher in BOTs and LGSCs as compared to HGSCs or benign tumours. The degree of nuclear expression of BOTs showed no significant difference from that in LGSCs (mean ranks 36.48, 33.05, respectively, p=0.625), but was significantly higher than in HGSCs (mean ranks: 38.88, 12.61 respectively, p< 0.001) and benign tumours (mean ranks: 35.18, 13.00 respectively, p= 0.010). Cytoplasmic expression level was higher in LGSCs. No EGFR gene mutations or amplification were identified, yet different polymorphisms were detected. Five different types of point mutations in the KRAS gene and the V600E BRAF mutation were detected exclusively in BOTs and LGSCs. Our study reports for the first time nuclear localization of EGFR in BOTs. The nuclear

  6. ELL targets c-Myc for proteasomal degradation and suppresses tumour growth

    PubMed Central

    Chen, Yu; Zhou, Chi; Ji, Wei; Mei, Zhichao; Hu, Bo; Zhang, Wei; Zhang, Dawei; Wang, Jing; Liu, Xing; Ouyang, Gang; Zhou, Jiangang; Xiao, Wuhan

    2016-01-01

    Increasing evidence supports that ELL (eleven–nineteen lysine-rich leukaemia) is a key regulator of transcriptional elongation, but the physiological function of Ell in mammals remains elusive. Here we show that ELL functions as an E3 ubiquitin ligase and targets c-Myc for proteasomal degradation. In addition, we identify that UbcH8 serves as a ubiquitin-conjugating enzyme in this pathway. Cysteine 595 of ELL is an active site of the enzyme; its mutation to alanine (C595A) renders the protein unable to promote the ubiquitination and degradation of c-Myc. ELL-mediated c-Myc degradation inhibits c-Myc-dependent transcriptional activity and cell proliferation, and also suppresses c-Myc-dependent xenograft tumour growth. In contrast, the ELL(C595A) mutant not only loses the ability to inhibit cell proliferation and xenograft tumour growth, but also promotes tumour metastasis. Thus, our work reveals a previously unrecognized function for ELL as an E3 ubiquitin ligase for c-Myc and a potential tumour suppressor. PMID:27009366

  7. Plasmid Transfer of Plasminogen K1-5 Reduces Subcutaneous Hepatoma Growth by Affecting Inflammatory Factors

    PubMed Central

    Koch, Lea A.; Strassburg, Christian P.; Raskopf, Esther

    2014-01-01

    There is evidence that plasminogen K1-5 (PlgK1-5) directly affects tumour cells and inflammation. Therefore, we analysed if PlgK1-5 has immediate effects on hepatoma cells and inflammatory factors in vitro and in vivo. In vitro, effects of plasmid encoding PlgK1-5 (pK1-5) on Hepa129, Hepa1-6, and HuH7 cell viability, apoptosis, and proliferation as well as VEGF and TNF-alpha expression and STAT3-phosphorylation were investigated. In vivo, tumour growth, proliferation, vessel density, and effects on vascular endothelial growth factor (VEGF) and tumour necrosis factor alpha (TNF-alpha) expression were examined following treatment with pK1-5. In vivo, pK1-5 halved cell viability; cell death was increased by up to 15% compared to the corresponding controls. Proliferation was not affected. VEGF, TNF-alpha, and STAT3-phosphorylation were affected following treatment with pK1-5. In vivo, ten days after treatment initiation, pK1-5 reduced subcutaneous tumour growth by 32% and mitosis by up to 77% compared to the controls. Vessel density was reduced by 50%. TNF-alpha levels in tumour and liver tissue were increased, whereas VEGF levels in tumours and livers were reduced after pK1-5 treatment. Taken together, plasmid gene transfer of PlgK1-5 inhibits hepatoma (cell) growth not only by reducing vessel density but also by inducing apoptosis, inhibiting proliferation, and triggering inflammation. PMID:24895598

  8. RA-XII inhibits tumour growth and metastasis in breast tumour-bearing mice via reducing cell adhesion and invasion and promoting matrix degradation

    PubMed Central

    Leung, Hoi-Wing; Zhao, Si-Meng; Yue, Grace Gar-Lee; Lee, Julia Kin-Ming; Fung, Kwok-Pui; Leung, Ping-Chung; Tan, Ning-Hua; Lau, Clara Bik-San

    2015-01-01

    Cancer cells acquire invasive ability to degrade and adhere to extracellular matrix (ECM) and migrate to adjacent tissues. This ultimately results metastasis. Hence, the present study investigated the in vitro effects of cyclopeptide glycoside, RA-XII on cell adhesion, invasion, proliferation and matrix degradation, and its underlying mechanism in murine breast tumour cells, 4T1. The effect of RA-XII on tumour growth and metastasis in 4T1-bearing mice was also investigated. Our results showed that RA-XII inhibited tumour cell adhesion to collagen, fibronectin and laminin, RA-XII also reduced the expressions of vascular cell adhesion molecule, intracellular adhesion molecule and integrins, and integrin binding. In addition, RA-XII significantly inhibited breast tumour cell migration via interfering cofilin signaling and chemokine receptors. The activities of matrix metalloproteinase-9 and urokinase-type of plasminogen activator, and the expressions of ECM-associated proteinases were attenuated significantly by RA-XII. Furthermore, RA-XII induced G1 phase arrest and inhibited the expressions of cyclins and cyclin-dependent kinases. RA-XII inhibited the expressions of molecules in PI3K/AKT, NF-kappaB, FAK/pSRC, MAPK and EGFR signaling. RA-XII was also shown to have anti-tumour, anti-angiogenic and anti-metastatic activities in metastatic breast tumour-bearing mice. These findings strongly suggested that RA-XII is a potential anti-metastatic agent for breast cancer. PMID:26592552

  9. Matrix metalloproteinase-1 is induced by epidermal growth factor in human bladder tumour cell lines and is detectable in urine of patients with bladder tumours.

    PubMed Central

    Nutt, J. E.; Mellon, J. K.; Qureshi, K.; Lunec, J.

    1998-01-01

    The matrix metalloproteinases are a family of enzymes that degrade the extracellular matrix and are considered to be important in tumour invasion and metastasis. The effect of epidermal growth factor (EGF) on matrix metalloproteinase-1 (MMP1) production in two human bladder tumour cell lines, RT112 and RT4, has been investigated. In the RT112 cell line, an increase in MMP1 mRNA levels was found after a 6-h incubation with EGF, and this further increased to 20-fold that of control levels at 24- and 48-h treatment with 50 ng ml(-1) of EGF. MMP2 mRNA levels remained constant over this time period, whereas in the RT4 cells no MMP2 transcripts were detectable, but MMP1 transcripts again increased with 24- and 48-h treatment with 50 ng ml(-1) of EGF. MMP1 protein concentration in the conditioned medium from both cell lines increased with 24- and 48-h treatment of the cells and the total MMP1 was higher in the medium than the cells, demonstrating that the bladder tumour cell lines synthesize and secrete MMP1 protein after continuous stimulation with EGF. MMP1 protein was detected in urine from patients with bladder tumours, with a significant increase in concentration with increased stage and grade of tumour. MMP1 urine concentrations may therefore be a useful prognostic indicator for bladder tumour progression. Images Figure 1 Figure 2 PMID:9683296

  10. NPM1 Silencing Reduces Tumour Growth and MAPK Signalling in Prostate Cancer Cells

    PubMed Central

    Loubeau, Gaëlle; Boudra, Rafik; Maquaire, Sabrina; Lours-Calet, Corinne; Beaudoin, Claude; Verrelle, Pierre; Morel, Laurent

    2014-01-01

    The chaperone nucleophosmin (NPM1) is over-expressed in the epithelial compartment of prostate tumours compared to adjacent healthy epithelium and may represent one of the key actors that support the neoplastic phenotype of prostate adenocarcinoma cells. Yet, the mechanisms that underlie NPM1 mediated phenotype remain elusive in the prostate. To better understand NPM1 functions in prostate cancer cells, we sought to characterize its impact on prostate cancer cells behaviour and decipher the mechanisms by which it may act. Here we show that NPM1 favors prostate tumour cell migration, invasion and colony forming. Furthermore, knockdown of NPM1 leads to a decrease in the growth of LNCaP-derived tumours grafted in Nude mice in vivo. Such oncogenic-like properties are found in conjunction with a positive regulation of NPM1 on the ERK1/2 (Extracellular signal-Regulated Kinases 1/2) kinase phosphorylation in response to EGF (Epidermal Growth Factor) stimulus, which is critical for prostate cancer progression following the setting of an autonomous production of the growth factor. NPM1 could then be a target to switch off specifically ERK1/2 pathway activation in order to decrease or inhibit cancer cell growth and migration. PMID:24796332

  11. Intralymphatic mRNA vaccine induces CD8 T-cell responses that inhibit the growth of mucosally located tumours

    PubMed Central

    Bialkowski, Lukasz; van Weijnen, Alexia; Van der Jeught, Kevin; Renmans, Dries; Daszkiewicz, Lidia; Heirman, Carlo; Stangé, Geert; Breckpot, Karine; Aerts, Joeri L.; Thielemans, Kris

    2016-01-01

    The lack of appropriate mouse models is likely one of the reasons of a limited translational success rate of therapeutic vaccines against cervical cancer, as rapidly growing ectopic tumours are commonly used for preclinical studies. In this work, we demonstrate that the tumour microenvironment of TC-1 tumours differs significantly depending on the anatomical location of tumour lesions (i.e. subcutaneously, in the lungs and in the genital tract). Our data demonstrate that E7-TriMix mRNA vaccine-induced CD8+ T lymphocytes migrate into the tumour nest and control tumour growth, although they do not express mucosa-associated markers such as CD103 or CD49a. We additionally show that despite the presence of the antigen-specific T cells in the tumour lesions, the therapeutic outcomes in the genital tract model remain limited. Here, we report that such a hostile tumour microenvironment can be reversed by cisplatin treatment, leading to a complete regression of clinically relevant tumours when combined with mRNA immunization. We thereby demonstrate the necessity of utilizing clinically relevant models for preclinical evaluation of anticancer therapies and the importance of a simultaneous combination of anticancer immune response induction with targeting of tumour environment. PMID:26931556

  12. Intralymphatic mRNA vaccine induces CD8 T-cell responses that inhibit the growth of mucosally located tumours.

    PubMed

    Bialkowski, Lukasz; van Weijnen, Alexia; Van der Jeught, Kevin; Renmans, Dries; Daszkiewicz, Lidia; Heirman, Carlo; Stangé, Geert; Breckpot, Karine; Aerts, Joeri L; Thielemans, Kris

    2016-01-01

    The lack of appropriate mouse models is likely one of the reasons of a limited translational success rate of therapeutic vaccines against cervical cancer, as rapidly growing ectopic tumours are commonly used for preclinical studies. In this work, we demonstrate that the tumour microenvironment of TC-1 tumours differs significantly depending on the anatomical location of tumour lesions (i.e. subcutaneously, in the lungs and in the genital tract). Our data demonstrate that E7-TriMix mRNA vaccine-induced CD8(+) T lymphocytes migrate into the tumour nest and control tumour growth, although they do not express mucosa-associated markers such as CD103 or CD49a. We additionally show that despite the presence of the antigen-specific T cells in the tumour lesions, the therapeutic outcomes in the genital tract model remain limited. Here, we report that such a hostile tumour microenvironment can be reversed by cisplatin treatment, leading to a complete regression of clinically relevant tumours when combined with mRNA immunization. We thereby demonstrate the necessity of utilizing clinically relevant models for preclinical evaluation of anticancer therapies and the importance of a simultaneous combination of anticancer immune response induction with targeting of tumour environment. PMID:26931556

  13. XRP44X, an Inhibitor of Ras/Erk Activation of the Transcription Factor Elk3, Inhibits Tumour Growth and Metastasis in Mice.

    PubMed

    Semenchenko, Kostyantyn; Wasylyk, Christine; Cheung, Henry; Tourrette, Yves; Maas, Peter; Schalken, Jack A; van der Pluijm, Gabri; Wasylyk, Bohdan

    2016-01-01

    Transcription factors have an important role in cancer but are difficult targets for the development of tumour therapies. These factors include the Ets family, and in this study Elk3 that is activated by Ras oncogene /Erk signalling, and is involved in angiogenesis, malignant progression and epithelial-mesenchymal type processes. We previously described the identification and in-vitro characterisation of an inhibitor of Ras / Erk activation of Elk3 that also affects microtubules, XRP44X. We now report an initial characterisation of the effects of XRP44X in-vivo on tumour growth and metastasis in three preclinical models mouse models, subcutaneous xenografts, intra-cardiac injection-bone metastasis and the TRAMP transgenic mouse model of prostate cancer progression. XRP44X inhibits tumour growth and metastasis, with limited toxicity. Tumours from XRP44X-treated animals have decreased expression of genes containing Elk3-like binding motifs in their promoters, Elk3 protein and phosphorylated Elk3, suggesting that perhaps XRP44X acts in part by inhibiting the activity of Elk3. Further studies are now warranted to develop XRP44X for tumour therapy. PMID:27427904

  14. XRP44X, an Inhibitor of Ras/Erk Activation of the Transcription Factor Elk3, Inhibits Tumour Growth and Metastasis in Mice

    PubMed Central

    Cheung, Henry; Tourrette, Yves; Maas, Peter; Schalken, Jack A; van der Pluijm, Gabri

    2016-01-01

    Transcription factors have an important role in cancer but are difficult targets for the development of tumour therapies. These factors include the Ets family, and in this study Elk3 that is activated by Ras oncogene /Erk signalling, and is involved in angiogenesis, malignant progression and epithelial-mesenchymal type processes. We previously described the identification and in-vitro characterisation of an inhibitor of Ras / Erk activation of Elk3 that also affects microtubules, XRP44X. We now report an initial characterisation of the effects of XRP44X in-vivo on tumour growth and metastasis in three preclinical models mouse models, subcutaneous xenografts, intra-cardiac injection-bone metastasis and the TRAMP transgenic mouse model of prostate cancer progression. XRP44X inhibits tumour growth and metastasis, with limited toxicity. Tumours from XRP44X-treated animals have decreased expression of genes containing Elk3-like binding motifs in their promoters, Elk3 protein and phosphorylated Elk3, suggesting that perhaps XRP44X acts in part by inhibiting the activity of Elk3. Further studies are now warranted to develop XRP44X for tumour therapy. PMID:27427904

  15. Growth hormone receptor antagonism suppresses tumour regrowth after radiotherapy in an endometrial cancer xenograft model.

    PubMed

    Evans, Angharad; Jamieson, Stephen M F; Liu, Dong-Xu; Wilson, William R; Perry, Jo K

    2016-08-28

    Human GH expression is associated with poor survival outcomes for endometrial cancer patients, enhanced oncogenicity of endometrial cancer cells and reduced sensitivity to ionising radiation in vitro, suggesting that GH is a potential target for anticancer therapy. However, whether GH receptor inhibition sensitises to radiotherapy in vivo has not been tested. In the current study, we evaluated whether the GH receptor antagonist, pegvisomant (Pfizer), sensitises to radiotherapy in vivo in an endometrial tumour xenograft model. Subcutaneous administration of pegvisomant (20 or 100 mg/kg/day, s.c.) reduced serum IGF1 levels by 23% and 68%, respectively, compared to vehicle treated controls. RL95-2 xenografts grown in immunodeficient NIH-III mice were treated with vehicle or pegvisomant (100 mg/kg/day), with or without fractionated gamma radiation (10 × 2.5 Gy over 5 days). When combined with radiation, pegvisomant significantly increased the median time tumours took to reach 3× the pre-radiation treatment volume (49 days versus 72 days; p = 0.001). Immunohistochemistry studies demonstrated that 100 mg/kg pegvisomant every second day was sufficient to abrogate MAP Kinase signalling throughout the tumour. In addition, treatment with pegvisomant increased hypoxic regions in irradiated tumours, as determined by immunohistochemical detection of pimonidazole adducts, and decreased the area of CD31 labelling in unirradiated tumours, suggesting an anti-vascular effect. Pegvisomant did not affect intratumoral staining for HIF1α, VEGF-A, CD11b, or phospho-EGFR. Our results suggest that blockade of the human GH receptor may improve the response of GH and/or IGF1-responsive endometrial tumours to radiation. PMID:27241667

  16. Hypoxia optimises tumour growth by controlling nutrient import and acidic metabolite export.

    PubMed

    Parks, Scott K; Cormerais, Yann; Marchiq, Ibtissam; Pouyssegur, Jacques

    2016-01-01

    In their quest for survival and successful growth, cancer cells optimise their cellular processes to enable them to outcompete normal cells in their microenvironment. In essence cancer cells: (i) enhance uptake of nutrients/metabolites, (ii) utilise nutrients more efficiently via metabolic alterations and (iii) deal with the metabolic waste products in a way that furthers their progression while hampering the survival of normal tissue. Hypoxia Inducible Factors (HIFs) act as essential drivers of these adaptations via the promotion of numerous membrane proteins including glucose transporters (GLUTs), monocarboxylate transporters (MCTs), amino-acid transporters (LAT1, xCT), and acid-base regulating carbonic anhydrases (CAs). In addition to a competitive growth advantage for tumour cells, these HIF-regulated proteins are implicated in metastasis, cancer 'stemness' and the immune response. Current research indicates that combined targeting of these HIF-regulated membrane proteins in tumour cells will provide promising therapeutic strategies in the future. PMID:26724171

  17. Incompressible limit of a mechanical model of tumour growth with viscosity.

    PubMed

    Perthame, Benoît; Vauchelet, Nicolas

    2015-09-13

    Various models of tumour growth are available in the literature. The first type describe the evolution of the cell number density when considered as a continuous visco-elastic material with growth. The second type describe the tumour as a set, and rules for the free boundary are given related to the classical Hele-Shaw model of fluid dynamics. Following previous papers where the material is described by a purely elastic material, or when active cell motion is included, we make the link between the two types of description considering the 'stiff pressure law' limit. Even though viscosity is a regularizing effect, new mathematical difficulties arise in the visco-elastic case because estimates on the pressure field are weaker and do not immediately imply compactness. For instance, travelling wave solutions and numerical simulations show that the pressure is discontinuous in space, which is not the case for an elastic material. PMID:26261366

  18. The food processing contaminant glyoxal promotes tumour growth in the multiple intestinal neoplasia (Min) mouse model.

    PubMed

    Svendsen, Camilla; Høie, Anja Hortemo; Alexander, Jan; Murkovic, Michael; Husøy, Trine

    2016-08-01

    Glyoxal is formed endogenously and at a higher rate in the case of hyperglycemia. Glyoxal is also a food processing contaminant and has been shown to be mutagenic and genotoxic in vitro. The tumourigenic potential of glyoxal was investigated using the multiple intestinal neoplasia (Min) mouse model, which spontaneously develops intestinal tumours and is susceptible to intestinal carcinogens. C57BL/6J females were mated with Min males. Four days after mating and throughout gestation and lactation, the pregnant dams were exposed to glyoxal through drinking water (0.0125%, 0.025%, 0.05%, 0.1%) or regular tap water. Female and male offspring were housed separately from PND21 and continued with the same treatment. One group were only exposed to 0.1% glyoxal from postnatal day (PND) 21. There was no difference in the number of intestinal tumours between control and treatment groups. However, exposure to 0.1% glyoxal starting in utero and at PND21 caused a significant increase in tumour size in the small intestine for male and female mice in comparison with respective control groups. This study suggests that glyoxal has tumour growth promoting properties in the small intestine in Min mice. PMID:27288931

  19. Prognostic markers and tumour growth kinetics in melanoma patients progressing on vemurafenib.

    PubMed

    Seifert, Heike; Fisher, Rosalie; Martin-Liberal, Juan; Edmonds, Kim; Hughes, Peta; Khabra, Komel; Gore, Martin; Larkin, James

    2016-04-01

    The BRAF inhibitor vemurafenib is an effective drug in patients with BRAF mutant metastatic melanoma, but resistance occurs after a median of 6 months. The anti-CTLA4-antibody, ipilimumab, is a standard first-line and second-line treatment option in Europe, with a median time to response of 2-3 months, but some patients show rapid clinical deterioration before that. The aim of this analysis was to identify prognostic markers for survival after failure of vemurafenib treatment to identify patients who have a sufficient life expectancy to respond to new immunotherapy treatments. We retrospectively analysed 101 consecutive unselected patients treated with vemurafenib for metastatic melanoma at a single institution. The association between clinical parameters and death within 3 months after cessation of vemurafenib (n=69) was assessed by binary logistic and Cox regression. Of the patients, 45% died within 3 months of progression on vemurafenib. Elevated baseline serum lactate dehydrogenase, absence of normalization of serum lactate dehydrogenase on vemurafenib therapy, performance status of at least 2 at progression and time from primary tumour to metastatic disease less than 5 years were identified as poor prognostic markers. In an exploratory tumour growth kinetics analysis (n=16), we found that following cessation of vemurafenib, approximately a third each showed a stable, decelerated or accelerated rate of tumour growth. Patients with these poor prognostic markers are unlikely to have sufficient life expectancy to complete ipilimumab treatment after failure with vemurafenib. Consideration needs to be given to the elective use of immunotherapy before patients become resistant to vemurafenib. This requires prospective randomized evaluation. Our tumour growth kinetics analysis requires confirmation; however, it may suggest that intermittent vemurafenib treatment should be investigated in clinical trials. PMID:26684061

  20. Investigating the role of tumour cell derived iNOS on tumour growth and vasculature in vivo using a tetracycline regulated expression system.

    PubMed

    Papaevangelou, Efthymia; Whitley, Guy S; Johnstone, Alan P; Robinson, Simon P; Howe, Franklyn A

    2016-06-01

    Nitric oxide (NO) is a free radical signalling molecule involved in various physiological and pathological processes, including cancer. Both tumouricidal and tumour promoting effects have been attributed to NO, making its role in cancer biology controversial and unclear. To investigate the specific role of tumour-derived NO in vascular development, C6 glioma cells were genetically modified to include a doxycycline regulated gene expression system that controls the expression of an antisense RNA to inducible nitric oxide synthase (iNOS) to manipulate endogenous iNOS expression. Xenografts of these cells were propagated in the presence or absence of doxycycline. Susceptibility magnetic resonance imaging (MRI), initially with a carbogen (95% O2 /5% CO2 ) breathing challenge and subsequently an intravascular blood pool contrast agent, was used to assess haemodynamic vasculature (ΔR2 *) and fractional blood volume (fBV), and correlated with histopathological assessment of tumour vascular density, maturation and function. Inhibition of NO production in C6 gliomas led to significant growth delay and inhibition of vessel maturation. Parametric fBV maps were used to identify vascularised regions from which the carbogen-induced ΔR2 * was measured and found to be positively correlated with vessel maturation, quantified ex vivo using fluorescence microscopy for endothelial and perivascular cell staining. These data suggest that tumour-derived iNOS is an important mediator of tumour growth and vessel maturation, hence a promising target for anti-vascular cancer therapies. The combination of ΔR2 * response to carbogen and fBV MRI can provide a marker of tumour vessel maturation that could be applied to non-invasively monitor treatment response to iNOS inhibitors. PMID:26756734

  1. Low Dose, Low Cost Estradiol Pellets Can Support MCF-7 Tumour Growth in Nude Mice without Bladder Symptoms

    PubMed Central

    Dall, Genevieve; Vieusseux, Jessica; Unsworth, Ashleigh; Anderson, Robin; Britt, Kara

    2015-01-01

    MCF-7 cells are a slow growing estrogen receptor (ER) positive human breast cancer cell line that is commonly used to model estrogen responsive breast cancer cell growth in-vitro and tumour growth in-vivo. These tumours require estrogen supplementation, and in-vivo doses of between 0.72mg and 2mg estradiol pellets are commonly implanted in the dorsal flank of ovariectomised, immunocompromised mice. We wanted to grow MCF-7 tumours in immunocompromised mice without the need to be ovariectomised. When we treated immunocompromised mice with 0.72mg pellets to induce MCF7 tumour growth, the mice developed urosepsis. We have now shown that lower doses of estradiol pellets, 0.3mg and 0.5mg, induce elevated serum estrogen levels and maintain tumour growth, without causing urosepsis. Supplementation for only one week did not support sustained MCF7 tumour growth. In conclusion, 0.3mg and 0.5mg silastic pellets can be used to stimulate ER+ breast cancer growth in ovary-intact, immune compromised mice. PMID:26640593

  2. Hypoxic repression of pyruvate dehydrogenase activity is necessary for metabolic reprogramming and growth of model tumours

    PubMed Central

    Golias, Tereza; Papandreou, Ioanna; Sun, Ramon; Kumar, Bhavna; Brown, Nicole V.; Swanson, Benjamin J.; Pai, Reetesh; Jaitin, Diego; Le, Quynh-Thu; Teknos, Theodoros N.; Denko, Nicholas C.

    2016-01-01

    Tumour cells fulfil the bioenergetic and biosynthetic needs of proliferation using the available environmental metabolites. Metabolic adaptation to hypoxia causes decreased mitochondrial function and increased lactate production. This work examines the biological importance of the hypoxia-inducible inhibitory phosphorylations on the pyruvate dehydrogenase E1α subunit. Pancreatic cancer cell lines were genetically manipulated to alter the net phosphorylation of PDH E1α through reduced kinase expression or enhanced phosphatase expression. The modified cells were tested for hypoxic changes in phosphorylated E1α, mitochondrial metabolism and growth as xenografted tumours. Even though there are four PDHK genes, PDHK1 is essential for inhibitory PDH phosphorylation of E1α at serine 232, is partially responsible for modification of serines 293 and 300, and these phosphorylations are necessary for model tumour growth. In order to determine the clinical relevance, a cohort of head and neck cancer patient biopsies was examined for phosphorylated E1α and expression of PDHK1. Patients with detectable 232 phosphorylation or expression of PDHK1 tend to have worse clinical outcome. These data show that PDHK1 activity is unique and non-redundant in the family of PHDK enzymes and a PDHK1 specific inhibitor would therefore have anti-cancer activity with reduced chance of side effects from inhibition of other PDHKs. PMID:27498883

  3. Hypoxic repression of pyruvate dehydrogenase activity is necessary for metabolic reprogramming and growth of model tumours.

    PubMed

    Golias, Tereza; Papandreou, Ioanna; Sun, Ramon; Kumar, Bhavna; Brown, Nicole V; Swanson, Benjamin J; Pai, Reetesh; Jaitin, Diego; Le, Quynh-Thu; Teknos, Theodoros N; Denko, Nicholas C

    2016-01-01

    Tumour cells fulfil the bioenergetic and biosynthetic needs of proliferation using the available environmental metabolites. Metabolic adaptation to hypoxia causes decreased mitochondrial function and increased lactate production. This work examines the biological importance of the hypoxia-inducible inhibitory phosphorylations on the pyruvate dehydrogenase E1α subunit. Pancreatic cancer cell lines were genetically manipulated to alter the net phosphorylation of PDH E1α through reduced kinase expression or enhanced phosphatase expression. The modified cells were tested for hypoxic changes in phosphorylated E1α, mitochondrial metabolism and growth as xenografted tumours. Even though there are four PDHK genes, PDHK1 is essential for inhibitory PDH phosphorylation of E1α at serine 232, is partially responsible for modification of serines 293 and 300, and these phosphorylations are necessary for model tumour growth. In order to determine the clinical relevance, a cohort of head and neck cancer patient biopsies was examined for phosphorylated E1α and expression of PDHK1. Patients with detectable 232 phosphorylation or expression of PDHK1 tend to have worse clinical outcome. These data show that PDHK1 activity is unique and non-redundant in the family of PHDK enzymes and a PDHK1 specific inhibitor would therefore have anti-cancer activity with reduced chance of side effects from inhibition of other PDHKs. PMID:27498883

  4. Effect of VEGF receptor inhibitor PTK787/ZK222548 combined with ionizing radiation on endothelial cells and tumour growth

    PubMed Central

    Hess, C; Vuong, V; Hegyi, I; Riesterer, O; Wood, J; Fabbro, D; Glanzmann, C; Bodis, S; Pruschy, M

    2001-01-01

    The vascular endothelial growth factor (VEGF) receptor is a major target for anti-angiogenesis-based cancer treatment. Here we report the treatment effect of ionizing radiation in combination with the novel orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on endothelial cell proliferation in vitro and with tumour xenografts in vivo. Combined treatment of human umbilical vein endothelial cells with increasing doses of PTK787/ZK222584 and ionizing radiation abrogated VEGF-dependent proliferation in a dose-dependent way, but inhibition of endothelial cell proliferation was not due to apoptosis induction. In vivo, a combined treatment regimen of PTK787/ZK222584 (4 × 100 mg/kg) during 4 consecutive days in combination with ionizing radiation (4 × 3 Gy) exerted a substantial tumour growth delay for radiation-resistant p53-disfunctional tumour xenografts derived from SW480 colon adenocarcinoma cells while each treatment modality alone had only a minimal effect on tumour size and neovascularization. SW480 tumours from animals that received a combined treatment regimen, displayed not only an extended tumour growth delay but also a significant decrease in the number of microvessels in the tumour xenograft. These results support the model of a cooperative antitumoural effect of angiogenesis inhibitor and irradiation and show that the orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 is suitable for combination therapy with irradiation. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11747347

  5. Tumour growth stimulation following partial hepatectomy in mice is associated with increased upregulation of c-Met.

    PubMed

    Harun, Nadia; Costa, Patricia; Christophi, C

    2014-01-01

    Hepatic resection is the preferred option for curative treatment of colorectal liver metastasis (CLM). However, this is associated with significant recurrence rates in both hepatic and extrahepatic sites. The upregulation of growth factors required for liver regeneration after resection is thought to stimulate the growth of micrometastases. The current study describes temporal changes in the expression of hepatocyte growth factor receptor (c-Met), epidermal growth factor receptor (EGFR) and insulin growth factor I receptor (IGF-IR) in an orthotopic mouse model of liver resection and tumour induction. Mice underwent 70% hepatectomy and induction of liver metastases through intrasplenic injection of colorectal cancer cells. Control groups included sham-operated mice and 70% hepatectomy alone. The expression levels of liver and tumour c-Met, EGFR and IGF-IR were quantified by quantitative RT-PCR at different time points. 70% liver resection stimulates tumour growth; increases the expression of c-Met within established tumours and surrounding liver parenchyma; downregulates EGFR expression and increases IGF-IR expression within the liver parenchyma. In conclusion, we demonstrate in our mouse model that major hepatectomy stimulates engraftment and growth of CLM and that this effect is probably due to the upregulation of c-Met as a result of the liver regeneration process. Liver IGF-IR may also contribute to this phenomenon through a paracrine effect on tumour growth. This study provides support for the role of c-Met in the stimulation of tumour growth after resection possibly through the promotion of tumour cell proliferation. PMID:23900501

  6. NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces tumour growth in adenocarcinoma-bearing mice.

    PubMed Central

    Orucevic, A.; Lala, P. K.

    1996-01-01

    We tested whether NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, can prevent interleukin 2 (IL-2)-induced capillary leakage in tumour-bearing mice without compromising the therapeutic benefits of IL-2. C3H/HeJ female mice transplanted s.c. with 2.5 x 10(5) C3-L5 mammary carcinoma cells were treated with: nothing, IL-2 (ten injections of 15,000 Cetus units i.p. every 8 h), L-NAME (0.1, 0.5, or 1 mg ml-1 drinking water), IL-2 + L-NAME (0.1 or 0.5 or 1 mg ml-1 drinking water). Therapies were given in one round (IL-2, days 10-13; L-NAME, days 9-13) or in two rounds (IL-2, days 10-13 and 20-23; L-NAME, days 9-13 and days 19-23) after tumour transplantation. Capillary leakage was measured from the water contents of the pleural cavities, lungs, spleen and kidneys. Effects of the therapies on the primary tumour size and the number of spontaneous lung metastases were also recorded. NO production was measured as the nitrite + nitrate levels in the serum and in the pleural effusion. After the first round of therapies, addition of L-NAME significantly reduced IL-2-induced pulmonary oedema and water retention in the spleen in a dose-dependent manner. It also significantly reduced the IL-2-induced rise in NO levels in the serum and pleural fluid, but did not affect IL-2-induced pleural effusion or water retention in the kidney. At later stages of tumour growth (day 23), tumours themselves induced significant fluid retention in the lungs and the kidney, which was not aggravated further with the second round of IL-2 therapy. At this time, L-NAME therapy alone ameliorated tumour-induced pulmonary oedema. During both rounds of therapy different doses of L-NAME alone caused a reduction of primary tumour growth as well as spontaneous lung metastases, which improved further with the addition of IL-2. The combination therapy was at least as effective as IL-2 therapy. In summary, L-NAME had anti-tumour effects in vivo, reduced the severity of IL-2

  7. Investigation of patient, tumour and treatment variables affecting residual motion for respiratory-gated radiotherapy

    NASA Astrophysics Data System (ADS)

    George, R.; Ramakrishnan, V.; Siebers, J. V.; Chung, T. D.; Keall, P. J.

    2006-10-01

    Respiratory gating can reduce the apparent respiratory motion during imaging and treatment; however, residual motion within the gating window remains. Respiratory training can improve respiratory reproducibility and, therefore, the efficacy of respiratory-gated radiotherapy. This study was conducted to determine whether residual motion during respiratory gating is affected by patient, tumour or treatment characteristics. The specific aims of this study were to: (1) identify significant characteristics affecting residual motion, (2) investigate time trends of residual motion over a period of days (inter-session) and (3) investigate time trends of residual motion within the same day (intra-session). Twenty-four lung cancer patients were enrolled in an Institutional Review Board (IRB)-approved protocol. For approximately five sessions, 331 four-minute, respiratory motion traces were acquired with free breathing, audio instructions and audio-visual biofeedback for each patient. The residual motion was quantified by the standard deviation of the displacement within the gating window. The generalized linear model was used to obtain coefficients for each variable within the model and to evaluate the clinical and statistical significance. The statistical significance was determined by a p-value <0.05, while effect sizes of >=0.1 cm (one standard deviation) were considered clinically significant. This data analysis was applied to patient, tumour and treatment variables. Inter- and intra-session variations were also investigated. The only variable that was significant for both inhale- and exhale-based gating was disease type. In addition, visual-training displacement, breathing type and Karnofsky performance status (KPS) values were significant for inhale-based gating, and dose-per-fraction was significant for exhale-based gating. Temporal respiratory variations within and between sessions were observed for individual patients. However inter- and intra-session analyses did

  8. Growth of cultured human glioma tumour cells can be regulated with histamine and histamine antagonists.

    PubMed Central

    Van der Ven, L. T.; Prinsen, I. M.; Jansen, G. H.; Roholl, P. J.; Defferrari, R.; Slater, R.; Den Otter, W.

    1993-01-01

    The 50% survival time for low grade astrocytomas is 50 months and for high grade astrocytomas it is 13 months, underlining the need for new therapies. Several reports show that in vivo histamine antagonists cause retardation of tumour growth in some animal models and prolonged survival in cancer patients. Therefore we have tested the growth modulating effects of histamine and histamine antagonists on human glioma cultures. Twelve freshly excised human gliomas were cultured and tested for their in vitro sensitivity to histamine and histamine antagonists. Four continuous glioma cell lines were used to confirm the glioma-specificity of the effects observed in the primary cell lines. In low serum concentration (0 or 1%) the growth of 5/9 primary glioma-derived cultures could be stimulated with 0.2 mM histamine, and in 4/5 cases with 0.2 microM histamine. One mM of the histamine H2-receptor antagonist cimetidine could inhibit the growth of 4/5 primary glioma cultures when tested in 1% human AB serum, and of 6/13 cases when tested in 1% FCS. Lower concentrations (down to 1 microM) were less effective. The histamine H1-receptor antagonist pyrilamine gave variable results. The specificity of the effects is indicated by the absence of a generalised toxic effect, by the observation that the antagonist-induced inhibition could be reversed with histamine, and by the correlation of the obtained cimetidine-induced growth inhibition with the maximal growth rate of the primary cell lines in 10% FCS. The observed cimetidine-induced inhibition of the in vitro proliferation of gliomas suggests that cimetidine is a relevant candidate for the in vivo growth inhibition of these tumours. Images Figure 1 Figure 2 PMID:8353038

  9. Correlation of adverse effects of cisplatin administration in patients affected by solid tumours: A retrospective evaluation

    PubMed Central

    ASTOLFI, LAURA; GHISELLI, SARA; GUARAN, VALERIA; CHICCA, MILVIA; SIMONI, EDI; OLIVETTO, ELENA; LELLI, GIORGIO; MARTINI, ALESSANDRO

    2013-01-01

    Cisplatin is the most common antineoplastic drug used for the therapy of solid tumours. To date, researchers have focused on the dosage to be administered for each specific tumour, mainly considering the local adverse effects. The aim of this study was to correlate the severity of the adverse effects with: i) the dosage of cisplatin; ii) the specific site of the tumour; iii) the association with other drugs; and iv) the symptoms. We analysed data from 123 patients with 11 different tumour classes undergoing therapy from 2007 to 2008 at St. Anna Hospital (Ferrara, Italy), using the Spearman non-parametric correlation index. Even though significant correlations were found among the variables, the overall results showed that the main factor influencing the severity of the adverse effects was the dosage of cisplatin administered. PMID:23404427

  10. Combined effect of levan and cytotoxic agents on the growth of experimental tumours in mice.

    PubMed Central

    Leibovici, J.; Stark, Y.; Wolman, M.

    1983-01-01

    The combined effect of the polysaccharide levan (previously shown to exert a host-dependent as well as direct antitumoural activity) and the cytotoxic agents cyclophosphamide (CY), methotrexate (MTX), vincristine (VINC) and 5-fluoro-uracil (SFU) was studied in Lewis lung carcinoma and AKR lymphoma. Combined chemo- and immunotherapy was applied beginning on the day of tumour cell inoculation. Additive effects were obtained with the combined treatments, compared to single treatments, with all the combinations except MTX-levan in Lewis lung carcinoma, where the combined effect was synergistic. The additive effect was obtained with different doses and routes of chemotherapy, whether local or intraperitoneal. A 2 mg dose of CY combined with levan administered at daily doses of 10 mg, resulted in a 100% prevention of Lewis lung carcinoma growth. It is suggested that the levan may have two beneficial effects: it can exert an inhibitory effect on tumour growth and diminish the deleterious effect of cytotoxic agents on the immune system. PMID:6882675

  11. SARI inhibits angiogenesis and tumour growth of human colon cancer through directly targeting ceruloplasmin.

    PubMed

    Dai, Lei; Cui, Xueliang; Zhang, Xin; Cheng, Lin; Liu, Yi; Yang, Yang; Fan, Ping; Wang, Qingnan; Lin, Yi; Zhang, Junfeng; Li, Chunlei; Mao, Ying; Wang, Qin; Su, Xiaolan; Zhang, Shuang; Peng, Yong; Yang, Hanshuo; Hu, Xun; Yang, Jinliang; Huang, Meijuan; Xiang, Rong; Yu, Dechao; Zhou, Zongguang; Wei, Yuquan; Deng, Hongxin

    2016-01-01

    SARI, also called as BATF2, belongs to the BATF family and has been implicated in cancer cell growth inhibition. However, the role and mechanism of SARI in tumour angiogenesis are elusive. Here we demonstrate that SARI deficiency facilitates AOM/DSS-induced colonic tumorigenesis in mice. We show that SARI is a novel inhibitor of colon tumour growth and angiogenesis in mice. Antibody array and HUVEC-related assays indicate that VEGF has an essential role in SARI-controlled inhibition of angiogenesis. Furthermore, Co-IP/PAGE/mass spectrometry indicates that SARI directly targets ceruloplasmin (Cp), and induces protease degradation of Cp, thereby inhibiting the activity of the HIF-1α/VEGF axis. Tissue microarray results indicate that SARI expression inversely correlates with poor clinical outcomes in colon cancer patients. Collectively, our results indicate that SARI is a potential target for therapy by inhibiting angiogenesis through the reduction of VEGF expression and is a prognostic indicator for patients with colon cancer. PMID:27353863

  12. Postoperative intrapleural BCG in lung cancer: lack of efficacy and possible enhancement of tumour growth.

    PubMed Central

    Bakker, W; Nijhuis-Heddes, J M; Wever, A M; Brutel de la Rivière, A; van der Velde, E A; Dijkman, J H

    1981-01-01

    Fifty-six patients out of a group of 99 with lung cancer received postoperative intrapleural BCG (Pasteur strain) in three different dosages (16 X 10(6) culturable particles (cp), 32 X 10(6) cp, and 64 X 10(6) cp). When comparing the whole group of 99 patients with a historical control group of 126 patients no statistically significant differences were found in survival and disease-free interval. The two groups were well matched in respect of age, sex, histology, stage of disease, and type of operation. Patients with epidermoid carcinoma stage I receiving BCG, however, did significantly worse than those who had not received BCG in terms of disease-free interval. This unfavourable trend was caused by earlier local recurrences rather than metastases. The possible phenomenon of enhanced tumour growth noted in or patients with epidermoid carcinoma stage I might be related to the dosages used in this study, but the different BCG strain used hinders comparison with other studies. We conclude that BCG has no beneficial effect on survival or on disease-free interval; possible enhancement of tumour growth in stage I epidermoid carcinoma was found. PMID:7330812

  13. SARI inhibits angiogenesis and tumour growth of human colon cancer through directly targeting ceruloplasmin

    PubMed Central

    Dai, Lei; Cui, Xueliang; Zhang, Xin; Cheng, Lin; Liu, Yi; Yang, Yang; Fan, Ping; Wang, Qingnan; Lin, Yi; Zhang, Junfeng; Li, Chunlei; Mao, Ying; Wang, Qin; Su, Xiaolan; Zhang, Shuang; Peng, Yong; Yang, Hanshuo; Hu, Xun; Yang, Jinliang; Huang, Meijuan; Xiang, Rong; Yu, Dechao; Zhou, Zongguang; Wei, Yuquan; Deng, Hongxin

    2016-01-01

    SARI, also called as BATF2, belongs to the BATF family and has been implicated in cancer cell growth inhibition. However, the role and mechanism of SARI in tumour angiogenesis are elusive. Here we demonstrate that SARI deficiency facilitates AOM/DSS-induced colonic tumorigenesis in mice. We show that SARI is a novel inhibitor of colon tumour growth and angiogenesis in mice. Antibody array and HUVEC-related assays indicate that VEGF has an essential role in SARI-controlled inhibition of angiogenesis. Furthermore, Co-IP/PAGE/mass spectrometry indicates that SARI directly targets ceruloplasmin (Cp), and induces protease degradation of Cp, thereby inhibiting the activity of the HIF-1α/VEGF axis. Tissue microarray results indicate that SARI expression inversely correlates with poor clinical outcomes in colon cancer patients. Collectively, our results indicate that SARI is a potential target for therapy by inhibiting angiogenesis through the reduction of VEGF expression and is a prognostic indicator for patients with colon cancer. PMID:27353863

  14. N-terminus-modified Hec1 suppresses tumour growth by interfering with kinetochore-microtubule dynamics.

    PubMed

    Orticello, M; Fiore, M; Totta, P; Desideri, M; Barisic, M; Passeri, D; Lenzi, J; Rosa, A; Orlandi, A; Maiato, H; Del Bufalo, D; Degrassi, F

    2015-06-01

    Mitotic proteins are attractive targets to develop molecular cancer therapeutics due to the intimate interdependence between cell proliferation and mitosis. In this work, we have explored the therapeutic potential of the kinetochore (KT) protein Hec1 (Highly Expressed in Cancer protein 1) as a molecular target to produce massive chromosome missegregation and cell death in cancer cells. Hec1 is a constituent of the Ndc80 complex, which mediates KT-microtubule (MT) attachments at mitosis and is upregulated in various cancer types. We expressed Hec1 fused with enhanced green fluorescent protein (EGFP) at its N-terminus MT-interaction domain in HeLa cells and showed that expression of this modified Hec1, which localized at KTs, blocked cell proliferation and promoted apoptosis in tumour cells. EGFP-Hec1 was extremely potent in tumour cell killing and more efficient than siRNA-induced Hec1 depletion. In striking contrast, normal cells showed no apparent cell proliferation defects or cell death following EGFP-Hec1 expression. Live-cell imaging demonstrated that cancer cell death was associated with massive chromosome missegregation within multipolar spindles after a prolonged mitotic arrest. Moreover, EGFP-Hec1 expression was found to increase KT-MT attachment stability, providing a molecular explanation for the abnormal spindle architecture and the cytotoxic activity of this modified protein. Consistent with cell culture data, EGFP-Hec1 expression was found to strongly inhibit tumour growth in a mouse xenograft model by disrupting mitosis and inducing multipolar spindles. Taken together, these findings demonstrate that stimulation of massive chromosome segregation defects can be used as an anti-cancer strategy through the activation of mitotic catastrophe after a multipolar mitosis. Importantly, this study represents a clear proof of concept that targeting KT proteins required for proper KT-MT attachment dynamics constitutes a powerful approach in cancer therapy. PMID

  15. Addition of vasopressin synthetic analogue [V(4)Q(5)]dDAVP to standard chemotherapy enhances tumour growth inhibition and impairs metastatic spread in aggressive breast tumour models.

    PubMed

    Garona, Juan; Pifano, Marina; Pastrian, Maria B; Gomez, Daniel E; Ripoll, Giselle V; Alonso, Daniel F

    2016-08-01

    [V(4)Q(5)]dDAVP is a novel 2nd generation vasopressin analogue with robust antitumour activity against metastatic breast cancer. We recently reported that, by acting on vasopressin V2r membrane receptor present in tumour cells and microvascular endothelium, [V(4)Q(5)]dDAVP inhibits angiogenesis and metastatic progression of the disease without overt toxicity. Despite chemotherapy remaining as a primary therapeutic option for aggressive breast cancer, its use is limited by low selectivity and associated adverse effects. In this regard, we evaluated potential combinational benefits by adding [V(4)Q(5)]dDAVP to standard-of-care chemotherapy. In vitro, combination of [V(4)Q(5)]dDAVP with sub-IC50 concentrations of paclitaxel or carmustine resulted in a cooperative inhibition of breast cancer cell growth in comparison to single-agent therapy. In vivo antitumour efficacy of [V(4)Q(5)]dDAVP addition to chemotherapy was first evaluated using the triple-negative MDA-MB-231 breast cancer xenograft model. Tumour-bearing mice were treated with i.v. injections of [V(4)Q(5)]dDAVP (0.3 μg/kg, thrice weekly) in combination with weekly cycles of paclitaxel (10 mg/kg i.p.). After 6 weeks of treatment, combination regimen resulted in greater tumour growth inhibition compared to monotherapy. [V(4)Q(5)]dDAVP addition was also associated with reduction of local aggressiveness, and impairment of tumour invasion and infiltration of the skin. Benefits of combined therapy were confirmed in the hormone-independent and metastatic F3II breast cancer model by combining [V(4)Q(5)]dDAVP with carmustine (25 mg/kg i.p.). Interestingly, [V(4)Q(5)]dDAVP plus cytotoxic agents severely impaired colony forming ability of tumour cells and inhibited breast cancer metastasis to lung. The present study shows that [V(4)Q(5)]dDAVP may complement conventional chemotherapy by modulating metastatic progression and early stages of microtumour establishment, and thus supports further preclinical testing of

  16. IGF-II dependent autocrine growth in cell lines derived from renal tumours of childhood

    PubMed Central

    Zumkeller, W; Mahmood, A; Dellow, R; Schofield, P N

    1995-01-01

    Aims—To determine the role of insulin-like growth factors (IGF) in the proliferation of tumour cells, by studying the mitogenic response to IGFs of three cell lines of differing phenotype established from both malignant rhabdoid and Wilms tumour, representing a range of cell types (GOS 4, G401, and T3/73). Methods—Production of IGF-II and IGF-I was measured by radioimmunoassay, and the presence of IGF binding protein complexes was observed by gel exclusion chromatography. Following growth analyses in serum-free media to ascertain the dependence of the cell lines on exogenous IGFs, the generation of autocrine growth was measured by a density dependence assay of proliferation in culture. Receptors were measured by radioligand cross linking and autocrine growth through these receptors assayed by the use of blocking antibodies. Results—While GOS 4 and G401 were able to proliferate in serum-free medium over a period of 5 d, T3/73 showed an absolute dependence on IGFs added daily at 1-10 ng/ml. Plating at clonal density showed that cell growth was directly density dependent in serum-free medium. The serum independent proliferation of G401 and GOS 4 was blocked by the addition of an antibody to the type 1 IGF receptor (α-IR3) suggesting that the effects of autocrine factors are mediated through type 1 IGF receptors. S1 nuclease protection analysis indicated that all three cell lines produced significant amounts of mRNA derived mainly from the P3 IGF-II promoter, but transcripts for IGF-I were undetectable. Radioimmunoassay of IGFs from conditioned media showed that all the lines made assayable IGF-II (8·6, 8·4, and 6·1 ng/ml/24 h/106 cells for GOS 4, G401, and T3/73 respectively). The presence of species consistent with both type 1 and type II IGF receptors was demonstrated using radioligand binding to cell membranes followed by cross linking. Conclusions—Autocrine IGF-II may contribute to the serum independence of GOS 4 and G401 cells, whereas T3/73 may

  17. Inhibitory effect of STAT3 gene combined with CDDP on growth of human Wilms tumour SK-NEP-1 cells.

    PubMed

    Wang, Junrong; Zhang, Nina; Qu, Haijiang; You, Guangxian; Yuan, Junhui; Chen, Caie; Li, Wenyi; Pan, Feng

    2016-07-01

    To investigate the effects of signal transducer and activator of transcription 3 (STAT3) combined with cisplatin (CDDP) on the growth of human Wilms tumour (WT) SK-NEP-1 cell subcutaneous xenografts in nude mice and the possible mechanisms. Human WT SK-NEP-1 cells were subcutaneously transplanted to establish the BALB/c nude mice xenograft model. Mice were randomly divided into five groups: blank control group, adenovirus control group (NC group), STAT3 group, CDDP group and STAT3 plus CDDP group (combination group). Tumour volume and tumour weight were observed during the therapeutic process. The expression levels of STAT3, glucose regulatory protein 78 (GRP78) and BCL2-associated X protein (BAX) were evaluated by immunohistochemical analysis. Compared with the STAT3 group or CDDP group, the tumour weight and volume was significantly reduced in the combination group (P<0.05). No statistical significance was found in NC group compared with the blank control group (P > 0.05). Immunohistochemical analysis showed that STAT3, GRP78 and BAX protein levels in the combination group were significantly higher than those in STAT3 group and CDDP group (P<0.05). Exogenous STAT3 and CDDP may synergistically inhibit the xenograft tumour growth through up-regulation of BAX protein via GRP78. PMID:27129294

  18. Visual electrophysiology in children with tumours affecting the visual pathway. Case reports.

    PubMed

    Brecelj, J; Stirn-Kranjc, B; Skrbec, M

    2000-09-01

    In 9 children (8-14 years of age) with orbital, suprasellar or postchiasmal tumours, visual loss was studied by visual electrophysiology in relation to ophthalmologic and neuroimaging findings. Pattern electroretinography (PERG) and pattern visual evoked potentials (PVEP) to full and half-field pattern-reversal stimulation were recorded and PERG and PVEP changes were related to the tumour location. PERG wave P50 attenuation was found associated with the central retinal dysfunction in the child with orbital rhabdomyosarcoma; PVEP wave P100 delay was associated with the optic nerve dysfunction in a child with retrobulbar chondrosarcoma and in a child with optic nerve glioma; PVEP wave P100 asymmetry was associated with the crossed fibers dysfunction in a child with hypothalamic germinoma, and PVEP wave P100 uncrossed asymmetry was associated with postchiasmal dysfunction in children with postchiasmal tumours (one with pilocytic astrocytoma and two with angioma). On the other hand, normal PERG suggested that there was no central retinal dysfunction in a child with pleomorphic adenoma of the lacrimal gland, and normal PVEP to full and half-field stimulation excluded visual pathway dysfunction at the chiasm in a child with suprasellar arachnoidal cyst. Follow-up was useful in indicating whether visual dysfunction was progressive or not. We conclude that PERG and PVEP findings contributed to understanding whether the dysfunction originated was at the retina, in the optic nerve, chiasm or postchiasmal pathway. PMID:11200546

  19. A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α.

    PubMed

    Begley, Ulrike; Sosa, Maria Soledad; Avivar-Valderas, Alvaro; Patil, Ashish; Endres, Lauren; Estrada, Yeriel; Chan, Clement T Y; Su, Dan; Dedon, Peter C; Aguirre-Ghiso, Julio A; Begley, Thomas

    2013-03-01

    Emerging evidence points to aberrant regulation of translation as a driver of cell transformation in cancer. Given the direct control of translation by tRNA modifications, tRNA modifying enzymes may function as regulators of cancer progression. Here, we show that a tRNA methyltransferase 9-like (hTRM9L/KIAA1456) mRNA is down-regulated in breast, bladder, colorectal, cervix and testicular carcinomas. In the aggressive SW620 and HCT116 colon carcinoma cell lines, hTRM9L is silenced and its re-expression and methyltransferase activity dramatically suppressed tumour growth in vivo. This growth inhibition was linked to decreased proliferation, senescence-like G0/G1-arrest and up-regulation of the RB interacting protein LIN9. Additionally, SW620 cells re-expressing hTRM9L did not respond to hypoxia via HIF1-α-dependent induction of GLUT1. Importantly, hTRM9L-negative tumours were highly sensitive to aminoglycoside antibiotics and this was associated with altered tRNA modification levels compared to antibiotic resistant hTRM9L-expressing SW620 cells. Our study links hTRM9L and tRNA modifications to inhibition of tumour growth via LIN9 and HIF1-α-dependent mechanisms. It also suggests that aminoglycoside antibiotics may be useful to treat hTRM9L-deficient tumours. PMID:23381944

  20. Effects of nandrolone decanoate on the toxicity and anti-tumour action of CCNU and FU in murine tumours.

    PubMed Central

    Bibby, M. C.; Double, J. A.; Mughal, M. A.

    1981-01-01

    Pre-treatment with the anabolic steroid nandrolone decanoate (ND) increases the LD50 of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 5-Fluorouracil (FU) in NMRI mice. Administration of ND did not affect the anti-tumour action of CCNU against a transplantable mouse adenocarcinoma of the colon (MAC 13) or the anti-tumour action of FU against MAC 26. In both tumour lines ND had no significant effect on tumour growth. These data suggest that an increase in the anti-tumour selectivity of these agents may be produced by pre-treatment with ND. PMID:7295514

  1. A monoclonal antibody against KCNK9 K+ channel extracellular domain inhibits tumour growth and metastasis

    PubMed Central

    Sun, Han; Luo, Liqun; Lal, Bachchu; Ma, Xinrong; Chen, Lieping; Hann, Christine L.; Fulton, Amy M.; Leahy, Daniel J.; Laterra, John

    2016-01-01

    Two-pore domain potassium (K2P) channels act to maintain cell resting membrane potential—a prerequisite for many biological processes. KCNK9, a member of K2P family, is implicated in cancer, owing to its overexpression in human tumours and its ability to promote neoplastic cell survival and growth. However, KCNK9's underlying contributions to malignancy remain elusive due to the absence of specific modulators. Here we describe the development of monoclonal antibodies against the KCNK9 extracellular domain and their functional effects. We show that one antibody (Y4) with the highest affinity binding induces channel internalization. The addition of Y4 to KCNK9-expressing carcinoma cells reduces cell viability and increases cell death. Systemic administration of Y4 effectively inhibits growth of human lung cancer xenografts and murine breast cancer metastasis in mice. Evidence for Y4-mediated carcinoma cell autonomous and immune-dependent cytotoxicity is presented. Our study reveals that antibody-based KCNK9 targeting is a promising therapeutic strategy in KCNK9-expressing malignancies. PMID:26842342

  2. Nanodiamond modified copolymer scaffolds affects tumour progression of early neoplastic oral keratinocytes.

    PubMed

    Suliman, Salwa; Mustafa, Kamal; Krueger, Anke; Steinmüller-Nethl, Doris; Finne-Wistrand, Anna; Osdal, Tereza; Hamza, Amani O; Sun, Yang; Parajuli, Himalaya; Waag, Thilo; Nickel, Joachim; Johannessen, Anne Christine; McCormack, Emmet; Costea, Daniela Elena

    2016-07-01

    This study aimed to evaluate the tumorigenic potential of functionalising poly(LLA-co-CL) scaffolds. The copolymer scaffolds were functionalised with nanodiamonds (nDP) or with nDP and physisorbed BMP-2 (nDP-PHY) to enhance osteoinductivity. Culturing early neoplastic dysplastic keratinocytes (DOK(Luc)) on nDP modified scaffolds reduced significantly their subsequent sphere formation ability and decreased significantly the cells' proliferation in the supra-basal layers of in vitro 3D oral neoplastic mucosa (3D-OT) when compared to DOK(Luc) previously cultured on nDP-PHY scaffolds. Using an in vivo non-invasive environmentally-induced oral carcinogenesis model, nDP scaffolds were observed to reduce bioluminescence intensity of tumours formed by DOK(Luc) + carcinoma associated fibroblasts (CAF). nDP modification was also found to promote differentiation of DOK(Luc) both in vitro in 3D-OT and in vivo in xenografts formed by DOK(Luc) alone. The nDP-PHY scaffold had the highest number of invasive tumours formed by DOK(Luc) + CAF outside the scaffold area compared to the nDP and control scaffolds. In conclusion, in vitro and in vivo results presented here demonstrate that nDP modified copolymer scaffolds are able to decrease the tumorigenic potential of DOK(Luc), while confirming concerns for the therapeutic use of BMP-2 for reconstruction of bone defects in oral cancer patients due to its tumour promoting capabilities. PMID:27108402

  3. Depletion of tumour glutathione in vivo by buthionine sulphoximine: modulation by the rate of cellular proliferation and inhibition of cancer growth.

    PubMed Central

    Terradez, P; Asensi, M; Lasso de la Vega, M C; Puertes, I R; Viña, J; Estrela, J M

    1993-01-01

    We have investigated in Ehrlich-ascites-tumour-bearing mice the effect of buthionine sulphoximine (BSO), a selective inhibitor of GSH synthesis, on the rate of GSH depletion of tumour versus normal tissues and its relation to tumour cell proliferation. In normal tissues, GSH and GSSG remain unchanged or close to normal values during tumour growth, even at the last stage of growth when the animal is close to death. After administration of a single dose of BSO (4 mmol/kg), the rates of GSH depletion and recovery in the tumour and in several normal tissues are very different. BSO depletes GSH in cancer cells to a level of 0.3-0.4 mumol/g. The fall in GSH levels is faster when tumour cells do not proliferate actively. Four treatments of 4 mmol of BSO/kg at 48 h intervals induce a significant decrease (about 44%) in tumour growth. Our data show that the rate of BSO-induced GSH depletion in cancer cells depends on the stage of tumour growth, and that BSO administration also inhibits cancer-cell proliferation. A mechanism involving changes in protein kinase C activity and intracellular pH is proposed to explain the inhibition of cancer growth elicited by BSO. PMID:8503882

  4. Melphalan sensitivity as a function of progressive metastatic growth in two subpopulations of a mouse mammary tumour.

    PubMed Central

    Miller, B. E.; Miller, F. R.; Machemer, T.; Heppner, G. H.

    1993-01-01

    In order to examine in detail the sensitivity to chemotherapy of tumour cells at various organ sites and at various stages of metastasis, we have used a series of cell lines, all selected from sister subpopulations derived from a single mouse mammary tumour, which can be distinguished and quantitated from normal cells and from each other through growth in selective medium. For the studies described here, we used two lines, 4T07 and 66FAR, which will form colonies in vitro in medium containing 60 microM 6-thioguanine or 330 microM 2,6-diaminopurine, respectively. Both cell lines have similar sensitivity to the test chemotherapeutic agent, melphalan, in vitro. These two tumour cell lines were treated with melphalan in vivo, when growing either in lungs as experimental metastases at various times after cell injection or as palpable tumours growing subcutaneously. Responses to various doses of melphalan were measured by removing lungs or subcutaneous tumours and performing colony-forming assays in selective medium. The data indicate marked shifts in sensitivity as a function of metastatic stage. Analyses of dose-response curves show that both cell lines were similarly sensitive to melphalan at early times (45 min) after cell injection i.v. but became less sensitive at an intermediate time after injection (3 days). Differences between the two lines became apparent at later times after i.v. injection (by day 8 or 9) and in subcutaneous tumours, where a marked reduction in the shoulder of the dose response curve was seen in line 4T07, resulting in sensitivity equal to or greater than the of early times, whereas the dose response parameters of 66FAR remained at those of the intermediate time point. These results show that, in heterogeneous tumours, individual subpopulations of tumour cells may respond differently to chemotherapeutic agents at various disease stages. In vitro measures of tumour sensitivity do not predict these changes in in vivo sensitivity. Model systems

  5. Deoxyelephantopin, a novel multifunctional agent, suppresses mammary tumour growth and lung metastasis and doubles survival time in mice

    PubMed Central

    Huang, Chi-Chang; Lo, Chiu-Ping; Chiu, Chih-Yang; Shyur, Lie-Fen

    2010-01-01

    Background and purpose: Elephantopus scaber L. (Asteraceae) is a traditional herbal medicine with anti-cancer effects. We evaluated the in vitro and in vivo efficacy of a major sesquiterpene lactone constituent of E. scaber, deoxyelephantopin (DET), against mammary adenocarcinoma and the underlying molecular mechanism. Experimental approach: A variety of cellular assays, immunoblotting and immunohistochemistry, as well as both orthotopic and metastatic TS/A tumour models in BALB/c mice, were used. Test mice were pretreated and post-treated with DET or paclitaxel and mammary tumour growth evaluated. Key results: DET (≤2 µg·mL−1) significantly inhibited colony formation, cell proliferation, migration and invasion of TS/A cells and induced G2/M arrest and apoptosis in TS/A cells. c-Jun N-terminal kinase-mediated p21Waf1/Cip1 expression and caspase activation cascades were up-regulated by DET, effects suppressed by N-acetyl-L-cysteine. Moreover, tumour necrosis factor α-induced matrix metalloproteinase-9 enzyme activity and expression and nuclear factor-kappa B activation were abolished by DET. Pretreatment with DET was more effective than paclitaxel, for profound suppression of orthotopic tumour growth (99% vs. 68% reduction in tumour size) and lung metastasis of TS/A cells (82% vs. 63% reduction in metastatic pulmonary foci) and prolonged median survival time (56 vs. 37 days, P < 0.01) in mice. The levels of cyclooxygenase-2 and vascular endothelial growth factor in metastatic lung tissues of TS/A-bearing mice were attenuated by DET. Conclusions and implications: Our data provide evidence for the suppression of mammary adenocarcinoma by DET with several mechanisms and suggest that DET has potential as a chemopreventive agent for breast cancer. PMID:20105176

  6. Para-Phenylenediamine Induces Apoptotic Death of Melanoma Cells and Reduces Melanoma Tumour Growth in Mice.

    PubMed

    Bhowmick, Debajit; Bhar, Kaushik; Mallick, Sanjaya K; Das, Subhadip; Chatterjee, Nabanita; Sarkar, Tuhin Subhra; Chakrabarti, Rajarshi; Das Saha, Krishna; Siddhanta, Anirban

    2016-01-01

    Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD) in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cells in vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS), and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be a potential less expensive candidate to be developed as a chemotherapeutic agent for melanoma. PMID:27293892

  7. TAp63 regulates oncogenic miR-155 to mediate migration and tumour growth

    PubMed Central

    Mattiske, Sam; Ho, Kristen; Noll, Jacqueline E.; Neilsen, Paul M.; Callen, David F.; Suetani, Rachel J.

    2013-01-01

    miR-155 is an oncogenic microRNA which is upregulated in many solid cancers. The targets of miR-155 are well established, with over 100 confirmed mRNA targets. However, the regulation of miR-155 and the basis of its upregulation in cancer is not well understood. We have previously shown that miR-155 is regulated by p63, and here we investigate the role of the major p63 isoforms TAp63 and ΔNp63 in this regulation. When the TAp63 isoform was knocked down, or exogenously overexpressed, miR-155 levels were elevated in response to TAp63 knockdown or reduced in response to TAp63 overexpression. The ΔNp63 isoform is shown to directly bind to the p63 response element on the miR-155 host gene, and this binding is enriched when TAp63 is knocked down. This could indicate that TAp63 prevents ΔNp63 from binding to the miR-155 host gene. The knockdown of TAp63, and the subsequent elevation of miR-155, enhances migration and tumour growth similar to that seen when directly overexpressing miR-155. The migratory phenotype is abrogated when miR-155 is inhibited, indicating that miR-155 is responsible for the phenotypic effect of TAp63 knockdown. PMID:24177167

  8. Para-Phenylenediamine Induces Apoptotic Death of Melanoma Cells and Reduces Melanoma Tumour Growth in Mice

    PubMed Central

    Bhowmick, Debajit; Bhar, Kaushik; Mallick, Sanjaya K.; Das, Subhadip; Chatterjee, Nabanita; Sarkar, Tuhin Subhra; Chakrabarti, Rajarshi; Das Saha, Krishna; Siddhanta, Anirban

    2016-01-01

    Melanoma is one of the most aggressive forms of cancer, usually resistant to standard chemotherapeutics. Despite a huge number of clinical trials, any success to find a chemotherapeutic agent that can effectively destroy melanoma is yet to be achieved. Para-phenylenediamine (p-PD) in the hair dyes is reported to purely serve as an external dyeing agent. Very little is known about whether p-PD has any effect on the melanin producing cells. We have demonstrated p-PD mediated apoptotic death of both human and mouse melanoma cells in vitro. Mouse melanoma tumour growth was also arrested by the apoptotic activity of intraperitoneal administration of p-PD with almost no side effects. This apoptosis is shown to occur primarily via loss of mitochondrial membrane potential (MMP), generation of reactive oxygen species (ROS), and caspase 8 activation. p-PD mediated apoptosis was also confirmed by the increase in sub-G0/G1 cell number. Thus, our experimental observation suggests that p-PD can be a potential less expensive candidate to be developed as a chemotherapeutic agent for melanoma. PMID:27293892

  9. Cellular and molecular mechanisms affecting tumour radiosensitivity : An in vitro study

    NASA Astrophysics Data System (ADS)

    Power, Olive Mary

    The response of tumour cells in vitro to ionising radiation can, to a certain extent, predict the response of tumours to various radiotherapy treatment modalities. This thesis considers some of the factors known to be involved in the radiation response of human tumour cells in vitro. These parameters include radiation-induced cell-cycle perturbations, apoptosis and DNA damage repair. A panel of eight human tumour cell lines with markedly differing radiosensitivities were assessed in order to determine the key factors governing their radiation response. A wide range of doses spanning both the low dose region (0-2 Gy and 0-5 Gy) and the clinically relevant region (1-4 Gy) were used to determine whether differences in responses could distinguish cells which were radiosensitive or resistant. Ionising radiation produced a cell cycle delay in all cell lines in one or both of the cellular checkpoints. A Gl/S delay was detected in those cell lines that expressed wild-type p53, and the duration of this delay appeared to be directly related to the level of constitutive protein. p53 protein stabilisation was observed after 4 h, even at doses of 0-2 Gy, although a Gl/S delay was only detectable at higher doses. There was no direct relationship between p53 status and survival although wild-type p53 expression was more prevalent in the radiosensitive cell lines (3/4 sensitives are wild-type versus 2/4 resistants). A G2/M delay could only be detected at doses of > 1 Gy. This delay appeared to be dose independent in the resistant cell lines, suggesting a threshold dose of IGy, above which no further effect is observed. A radiation-induced reduction of cyclin B1 protein was observed in all cell lines implicating this protein in the induction of a G2/M delay. The duration of G2/M delay was significantly longer in the radiosensitive cell lines at 4 Gy (7-20 h versus 4-6 h at 4 Gy). The proportion of cells that exited the G2/M block and re-entered GO/G1 phase was also significantly

  10. Antagonists of growth hormone-releasing hormone (GH-RH) enhance tumour growth inhibition induced by androgen deprivation in human MDA-Pca-2b prostate cancers.

    PubMed

    Letsch, M; Schally, A V; Stangelberger, A; Groot, K; Varga, J L

    2004-02-01

    In the present study, we investigated whether the growth hormone-releasing hormone (GH-RH) antagonist JV-1-38 could enhance the effects of androgen deprivation produced by the anti-androgen Flutamide and luteinising hormone-releasing hormone (LH-RH) agonist Decapeptyl in an experimental model of human androgen-sensitive MDA PCa 2b prostate carcinoma implanted subcutaneously (s.c.) into nude mice. We also evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) the effects of combined treatment on the mRNA expression for prostate-specific antigen (PSA) and measured serum PSA levels. In experiment 1, GH-RH antagonist JV-1-38 greatly inhibited tumour growth in combination with Decapeptyl, but was ineffective when given alone. Thus, combined therapy with JV-1-38 at 20 microg/day and Decapeptyl microcapsules releasing 12.5 microg/day for 29 days inhibited significantly (P<0.01) MDA PCa 2b tumour growth by 65%, compared with controls. Combined treatment also significantly (P<0.05) decreased serum PSA levels by 52% and reduced tumour weight by 54% vs. controls. In experiment 2, GH-RH antagonist JV-1-38 at 20 microg/day likewise showed powerful growth inhibitory effects when combined with Flutamide (25 mg/kg/day) for 21 days. Combined treatment with JV-1-38 and slow-release pellets of Flutamide significantly (P<0.001) inhibited tumour growth by 61% versus controls, and was significantly (P<0.05) more effective than Flutamide or JV-1-38 alone. Combination therapy also reduced significantly (P<0.001) tumour weight and serum PSA levels by 59 and 47%, respectively. The mRNA expression for PSA in MDA PCa 2b tumours was not changed by JV-1-38, Decapeptyl and Flutamide alone or in their respective combinations. Our findings suggest that GH-RH antagonists could enhance the tumour inhibitory effects of androgen deprivation for the primary therapy of patients with advanced prostate carcinoma. PMID:14746863

  11. Gradient Infiltration of Neutrophil Extracellular Traps in Colon Cancer and Evidence for Their Involvement in Tumour Growth

    PubMed Central

    Kambas, Konstantinos; Papagoras, Charalampos; Miltiades, Paraskevi; Angelidou, Iliana; Mitsios, Alexandros; Kotsianidis, Ioannis; Skendros, Panagiotis; Sivridis, Efthimios; Maroulakou, Ioanna; Giatromanolaki, Alexandra; Ritis, Konstantinos

    2016-01-01

    Background The role of neutrophils in tumour biology is largely unresolved. Recently, independent studies indicated either neutrophil extracellular traps (NETs) or Tissue Factor (TF) involvement in cancer biology and associated thrombosis. However, their individual or combined role in colonic adenocarcinoma is still unexplored. Methods Colectomy tissue specimens and variable number of draining lymph nodes were obtained from ten patients with adenocarcinoma of the colon. NETs deposition and neutrophil presence as well as TF expression were examined by immunostaining. The effect of NETs on cancer cell growth was studied in in vitro co-cultures of Caco-2 cell line and acute myeloid leukemia primary cells. Proliferation and apoptosis/necrosis of cancer cells were analyzed by flow cytometry. Results TF-bearing NETs and neutrophil localization were prominent in tumour sections and the respective metastatic lymph nodes. Interestingly, neutrophil infiltration and NETs concentration were gradually reduced from the tumour mass to the distal margin. The in vitro-generated NETs impeded growth of cancer cell cultures by inducing apoptosis and/or inhibiting proliferation. Conclusions These data support further the role of neutrophils and NETs in cancer biology. We also suggest their involvement on cancer cell growth. PMID:27136460

  12. Fractal scaling of microbial colonies affects growth

    NASA Astrophysics Data System (ADS)

    Károlyi, György

    2005-03-01

    The growth dynamics of filamentary microbial colonies is investigated. Fractality of the fungal or actinomycetes colonies is shown both theoretically and in numerical experiments to play an important role. The growth observed in real colonies is described by the assumption of time-dependent fractality related to the different ages of various parts of the colony. The theoretical results are compared to a simulation based on branching random walks.

  13. Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform

    PubMed Central

    Casazza, Andrea; Kigel, Boaz; Maione, Federica; Capparuccia, Lorena; Kessler, Ofra; Giraudo, Enrico; Mazzone, Massimiliano; Neufeld, Gera; Tamagnone, Luca

    2012-01-01

    Secreted Semaphorin 3E (Sema3E) promotes cancer cell invasiveness and metastatic spreading. The pro-metastatic activity of Sema3E is due to its proteolytic fragment p61, capable of transactivating the oncogenic tyrosine kinase ErbB2 that associates with the Sema3E receptor PlexinD1 in cancer cells. Here, we show that a mutated, uncleavable variant of Sema3E (Uncl-Sema3E) binds to PlexinD1 like p61-Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signalling cascade leading to metastatic spreading. Furthermore, Uncl-Sema3E competes with endogenous p61-Sema3E produced by tumour cells, thereby hampering their metastatic ability. Uncl-Sema3E also acts independently as a potent anti-angiogenic factor. It activates a PlexinD1-mediated signalling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival. The putative therapeutic potential of Uncl-Sema3E was validated in multiple orthotopic or spontaneous tumour models in vivo, where either local or systemic delivery of Uncl-Sema3E-reduced angiogenesis, growth and metastasis, even in the case of tumours refractory to treatment with a soluble vascular endothelial growth factor trap. In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading. PMID:22247010

  14. PET imaging of epidermal growth factor receptor expression in tumours using 89Zr-labelled ZEGFR:2377 affibody molecules

    PubMed Central

    GAROUSI, JAVAD; ANDERSSON, KEN G.; MITRAN, BOGDAN; PICHL, MARIE-LOUISE; STÅHL, STEFAN; ORLOVA, ANNA; LÖFBLOM, JOHN; TOLMACHEV, VLADIMIR

    2016-01-01

    Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor, which is overexpressed in many types of cancer. The use of EGFR-targeting monoclonal antibodies and tyrosine-kinase inhibitors improves significantly survival of patients with colorectal, non-small cell lung cancer and head and neck squamous cell carcinoma. Detection of EGFR overexpression provides important prognostic and predictive information influencing management of the patients. The use of radionuclide molecular imaging would enable non-invasive repeatable determination of EGFR expression in disseminated cancer. Moreover, positron emission tomography (PET) would provide superior sensitivity and quantitation accuracy in EGFR expression imaging. Affibody molecules are a new type of imaging probes, providing high contrast in molecular imaging. In the present study, an EGFR-binding affibody molecule (ZEGFR:2377) was site-specifically conjugated with a deferoxamine (DFO) chelator and labelled under mild conditions (room temperature and neutral pH) with a positron-emitting radionuclide 89Zr. The 89Zr-DFO-ZEGFR:2377 tracer demonstrated specific high affinity (160±60 pM) binding to EGFR-expressing A431 epidermoid carcinoma cell line. In mice bearing A431 xenografts, 89Zr-DFO-ZEGFR:2377 demonstrated specific uptake in tumours and EGFR-expressing tissues. The tracer provided tumour uptake of 2.6±0.5% ID/g and tumour-to-blood ratio of 3.7±0.6 at 24 h after injection. 89Zr-DFO-ZEGFR:2377 provides higher tumour-to-organ ratios than anti-EGFR antibody 89Zr-DFO-cetuximab at 48 h after injection. EGFR-expressing tumours were clearly visualized by microPET using 89Zr-DFO-ZEGFR:2377 at both 3 and 24 h after injection. In conclusion, 89Zr-DFO-ZEGFR:2377 is a potential probe for PET imaging of EGFR-expression in vivo. PMID:26847636

  15. PET imaging of epidermal growth factor receptor expression in tumours using 89Zr-labelled ZEGFR:2377 affibody molecules.

    PubMed

    Garousi, Javad; Andersson, Ken G; Mitran, Bogdan; Pichl, Marie-Louise; Ståhl, Stefan; Orlova, Anna; Löfblom, John; Tolmachev, Vladimir

    2016-04-01

    Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor, which is overexpressed in many types of cancer. The use of EGFR-targeting monoclonal antibodies and tyrosine-kinase inhibitors improves significantly survival of patients with colorectal, non-small cell lung cancer and head and neck squamous cell carcinoma. Detection of EGFR overexpression provides important prognostic and predictive information influencing management of the patients. The use of radionuclide molecular imaging would enable non-invasive repeatable determination of EGFR expression in disseminated cancer. Moreover, positron emission tomography (PET) would provide superior sensitivity and quantitation accuracy in EGFR expression imaging. Affibody molecules are a new type of imaging probes, providing high contrast in molecular imaging. In the present study, an EGFR-binding affibody molecule (ZEGFR:2377) was site-specifically conjugated with a deferoxamine (DFO) chelator and labelled under mild conditions (room temperature and neutral pH) with a positron-emitting radionuclide (89)Zr. The (89)Zr-DFO-ZEGFR:2377 tracer demonstrated specific high affinity (160 ± 60 pM) binding to EGFR-expressing A431 epidermoid carcinoma cell line. In mice bearing A431 xenografts, (89)Zr-DFO-ZEGFR:2377 demonstrated specific uptake in tumours and EGFR-expressing tissues. The tracer provided tumour uptake of 2.6 ± 0.5% ID/g and tumour-to-blood ratio of 3.7 ± 0.6 at 24 h after injection. (89)Zr-DFO-ZEGFR:2377 provides higher tumour-to-organ ratios than anti-EGFR antibody (89)Zr-DFO-cetuximab at 48 h after injection. EGFR‑expressing tumours were clearly visualized by microPET using (89)Zr-DFO-ZEGFR:2377 at both 3 and 24 h after injection. In conclusion, 8(9)Zr-DFO-ZEGFR:2377 is a potential probe for PET imaging of EGFR-expression in vivo. PMID:26847636

  16. Inhibitors of Glioma Growth that Reveal the Tumour to the Immune System

    PubMed Central

    Nieto-Sampedro, Manuel; Valle-Argos, Beatriz; Gómez-Nicola, Diego; Fernández-Mayoralas, Alfonso; Nieto-Díaz, Manuel

    2011-01-01

    Treated glioblastoma patients survive from 6 to 14 months. In the first part of this review, we describe glioma origins, cancer stem cells and the genomic alterations that generate dysregulated cell division, with enhanced proliferation and diverse response to radiation and chemotherapy. We review the pathways that mediate tumour cell proliferation, neo-angiogenesis, tumor cell invasion, as well as necrotic and apoptotic cell death. Then, we examine the ability of gliomas to evade and suppress the host immune system, exhibited at the levels of antigen recognition and immune activation, limiting the effective signaling between glioma and host immune cells. The second part of the review presents current therapies and their drawbacks. This is followed by a summary of the work of our laboratory during the past 20 years, on oligosaccharide and glycosphingolipid inhibitors of astroblast and astrocytoma division. Neurostatins, the O-acetylated forms of gangliosides GD1b and GT1b naturally present in mammalian brain, are cytostatic for normal astroblasts, but cytotoxic for rat C6 glioma cells and human astrocytoma grades III and IV, with ID50 values ranging from 200 to 450 nM. The inhibitors do not affect neurons or fibroblasts up to concentrations of 4 μM or higher. At least four different neurostatin-activated, cell-mediated antitumoral processes, lead to tumor destruction: (i) inhibition of tumor neovascularization; (ii) activation of microglia; (iii) activation of natural killer (NK) cells; (iv) activation of cytotoxic lymphocytes (CTL). The enhanced antigenicity of neurostatin-treated glioma cells, could be related to their increased expression of connexin 43. Because neurostatins and their analogues show specific activity and no toxicity for normal cells, a clinical trial would be the logical next step. PMID:22084619

  17. Aberrant Promoter Methylation of the Tumour Suppressor RASSF10 and Its Growth Inhibitory Function in Breast Cancer

    PubMed Central

    Richter, Antje M.; Walesch, Sara K.; Dammann, Reinhard H.

    2016-01-01

    Breast cancer is the most common cancer in women, with 1.7 million new cases each year. As early diagnosis and prognosis are crucial factors in cancer treatment, we investigated potential DNA methylation biomarkers of the tumour suppressor family Ras-association domain family (RASSF). Promoter hypermethylation of tumour suppressors leads to their inactivation and thereby promotes cancer development and progression. In this study we analysed the tumour suppressors RASSF1A and RASSF10. Our study shows that RASSF10 is expressed in normal breast but inactivated by methylation in breast cancer. We observed a significant inactivating promoter methylation of RASSF10 in primary breast tumours. RASSF10 is inactivated in 63% of primary breast cancer samples but only 4% of normal control breast tissue is methylated (p < 0.005). RASSF1A also shows high promoter methylation levels in breast cancer of 56% vs. 8% of normal tissue (p < 0.005). Interestingly more than 80% of breast cancer samples harboured a hypermethylation of RASSF10 and/or RASSF1A promoter. Matching samples exhibited a strong tumour specific promoter methylation of RASSF10 in comparison to the normal control breast tissue. Demethylation treatment of breast cancer cell lines MCF7 and T47D reversed RASSF10 promoter hypermethylation and re-established RASSF10 expression. In addition, we could show the growth inhibitory potential of RASSF10 in breast cancer cell lines MCF7 and T47D upon exogenous expression of RASSF10 by colony formation. We could further show, that RASSF10 induced apoptotic changes in MCF7 and T47D cells, which was verified by a significant increase in the apoptotic sub G1 fraction by 50% using flow cytometry for MCF7 cells. In summary, our study shows the breast tumour specific inactivation of RASSF10 and RASSF1A due to DNA methylation of their CpG island promoters. Furthermore RASSF10 was characterised by the ability to block growth of breast cancer cell lines by apoptosis induction. PMID

  18. Combined inhibition of MAP kinase and KIT signaling synergistically destabilizes ETV1 and suppresses GIST tumour growth

    PubMed Central

    Ran, Leili; Sirota, Inna; Cao, Zhen; Murphy, Devan; Chen, Yuedan; Shukla, Shipra; Xie, Yuanyuan; Kaufmann, Michael C.; Gao, Dong; Zhu, Sinan; Rossi, Ferdinando; Wongvipat, John; Taguchi, Takahiro; Tap, William D.; Mellinghoff, Ingo K.; Besmer, Peter; Antonescu, Cristina R.; Chen, Yu; Chi, Ping

    2015-01-01

    Gastrointestinal stromal tumour (GIST), originating from the interstitial cells of Cajal (ICCs), is characterized by frequent activating mutations of the KIT receptor tyrosine kinase. Despite the clinical success of imatinib that targets KIT, most advanced GIST patients develop resistance and eventually die of the disease. The ETS family transcription factor, ETV1, is a master regulator of the ICC lineage. Using mouse models of Kit activation and Etv1 ablation, we demonstrate that Etv1 is required for GIST initiation and proliferation in vivo, validating it as a therapeutic target. We further uncover a positive feedback circuit where MAP kinase activation downstream of KIT stabilizes the ETV1 protein and ETV1 positively regulates KIT expression. Combined targeting of ETV1 stability by imatinib and MEK162 resulted in increased growth suppression in vitro and complete tumour regression in vivo. The combination strategy to target ETV1 may provide an effective therapeutic strategy in GIST clinical management. PMID:25572173

  19. Application of boronated anti-CEA immunoliposome to tumour cell growth inhibition in in vitro boron neutron capture therapy model.

    PubMed Central

    Yanagië, H.; Tomita, T.; Kobayashi, H.; Fujii, Y.; Takahashi, T.; Hasumi, K.; Nariuchi, H.; Sekiguchi, M.

    1991-01-01

    An immunoliposome containing a 10B-compound has been examined as a selective drug delivery system in boron neutron-capture therapy. Liposomes, conjugated with monoclonal antibodies specific for carcinoembryonic antigen (CEA) were shown to bind selectively to cells bearing CEA on their surface. The immunoliposomes attached to tumour cells suppressed growth in vitro upon thermal neutron irradiation and suppression was dependent upon the concentration of the 10B-compound in the liposomes and on the density of antibody conjugated to the liposomes. The results suggest that immunoliposomes containing the 10B-compound could act as a selective and efficient carrier of 10B atoms to target tumour cells in boron neutron-capture therapy. Images Figure 1 PMID:2021537

  20. Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth.

    PubMed

    Gerling, Marco; Büller, Nikè V J A; Kirn, Leonard M; Joost, Simon; Frings, Oliver; Englert, Benjamin; Bergström, Åsa; Kuiper, Raoul V; Blaas, Leander; Wielenga, Mattheus C B; Almer, Sven; Kühl, Anja A; Fredlund, Erik; van den Brink, Gijs R; Toftgård, Rune

    2016-01-01

    A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma-specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor. PMID:27492255

  1. Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth

    PubMed Central

    Gerling, Marco; Büller, Nikè V. J. A.; Kirn, Leonard M.; Joost, Simon; Frings, Oliver; Englert, Benjamin; Bergström, Åsa; Kuiper, Raoul V.; Blaas, Leander; Wielenga, Mattheus C. B.; Almer, Sven; Kühl, Anja A.; Fredlund, Erik; van den Brink, Gijs R.; Toftgård, Rune

    2016-01-01

    A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma-specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor. PMID:27492255

  2. Clinical and methodological confounders in assessing the cerebellar cognitive affective syndrome in adult patients with posterior fossa tumours.

    PubMed

    Omar, Dashne; Ryan, Tracy; Carson, Alan; Bak, Thomas H; Torrens, Lorna; Whittle, Ian

    2014-12-01

    The cerebellar cognitive affective syndrome (CCAS) was first described by Schmahmann and Sherman as a constellation of symptoms including dysexecutive syndrome, spatial cognitive deficit, linguistic deficits and behavioural abnormalities in patients with a lesion in the cerebellum with otherwise normal brain. Neurosurgical patients with cerebellar tumours constitute one of the cohorts in which the CCAS has been described. In this paper, we present a critical review of the literature of this syndrome in neurosurgical patients. Thereafter, we present a prospective clinical study of 10 patients who underwent posterior fossa tumour resection and had a detailed post-operative neuropsychological, neuropsychiatric and neuroradiological assessment. Because our findings revealed a large number of perioperative neuroradiological confounding variables, we reviewed the neuroimaging of a further 20 patients to determine their prevalence. Our literature review revealed that study design, methodological quality and sometimes both diagnostic criteria and findings were inconsistent. The neuroimaging study (pre-operative, n = 10; post-operative, n = 10) showed very frequent neuroradiological confounding complications (e.g. hydrocephalus; brainstem compression; supratentorial lesions and post-operative subdural hygroma); the impact of such features had largely been ignored in the literature. Findings from our clinical study showed various degree of deficits in neuropsychological testing (n = 1, memory; n = 3, verbal fluency; n = 3, attention; n = 2, spatial cognition deficits; and n = 1, behavioural changes), but no patient had full-blown features of CCAS. Our study, although limited, finds no robust evidence of the CCAS following surgery. This and our literature review highlight a need for guidelines regarding study design and methodology when attempting to evaluate neurosurgical cases with regard to the potential CCAS. PMID:24881640

  3. In vivo detection of small tumour lesions by multi-pinhole SPECT applying a 99mTc-labelled nanobody targeting the Epidermal Growth Factor Receptor

    PubMed Central

    Krüwel, Thomas; Nevoltris, Damien; Bode, Julia; Dullin, Christian; Baty, Daniel; Chames, Patrick; Alves, Frauke

    2016-01-01

    The detection of tumours in an early phase of tumour development in combination with the knowledge of expression of tumour markers such as epidermal growth factor receptor (EGFR) is an important prerequisite for clinical decisions. In this study we applied the anti-EGFR nanobody 99mTc-D10 for visualizing small tumour lesions with volumes below 100 mm3 by targeting EGFR in orthotopic human mammary MDA-MB-468 and MDA-MB-231 and subcutaneous human epidermoid A431 carcinoma mouse models. Use of nanobody 99mTc-D10 of a size as small as 15.5 kDa enables detection of tumours by single photon emission computed tomography (SPECT) imaging already 45 min post intravenous administration with high tumour uptake (>3% ID/g) in small MDA-MB-468 and A431 tumours, with tumour volumes of 52.5 mm3 ± 21.2 and 26.6 mm3 ± 16.7, respectively. Fast blood clearance with a serum half-life of 4.9 min resulted in high in vivo contrast and ex vivo tumour to blood and tissue ratios. In contrast, no accumulation of 99mTc-D10 in MDA-MB-231 tumours characterized by a very low expression of EGFR was observed. Here we present specific and high contrast in vivo visualization of small human tumours overexpressing EGFR by preclinical multi-pinhole SPECT shortly after administration of anti-EGFR nanobody 99mTc-D10. PMID:26912069

  4. In vivo detection of small tumour lesions by multi-pinhole SPECT applying a (99m)Tc-labelled nanobody targeting the Epidermal Growth Factor Receptor.

    PubMed

    Krüwel, Thomas; Nevoltris, Damien; Bode, Julia; Dullin, Christian; Baty, Daniel; Chames, Patrick; Alves, Frauke

    2016-01-01

    The detection of tumours in an early phase of tumour development in combination with the knowledge of expression of tumour markers such as epidermal growth factor receptor (EGFR) is an important prerequisite for clinical decisions. In this study we applied the anti-EGFR nanobody (99m)Tc-D10 for visualizing small tumour lesions with volumes below 100 mm(3) by targeting EGFR in orthotopic human mammary MDA-MB-468 and MDA-MB-231 and subcutaneous human epidermoid A431 carcinoma mouse models. Use of nanobody (99m)Tc-D10 of a size as small as 15.5 kDa enables detection of tumours by single photon emission computed tomography (SPECT) imaging already 45 min post intravenous administration with high tumour uptake (>3% ID/g) in small MDA-MB-468 and A431 tumours, with tumour volumes of 52.5 mm(3) ± 21.2 and 26.6 mm(3) ± 16.7, respectively. Fast blood clearance with a serum half-life of 4.9 min resulted in high in vivo contrast and ex vivo tumour to blood and tissue ratios. In contrast, no accumulation of (99m)Tc-D10 in MDA-MB-231 tumours characterized by a very low expression of EGFR was observed. Here we present specific and high contrast in vivo visualization of small human tumours overexpressing EGFR by preclinical multi-pinhole SPECT shortly after administration of anti-EGFR nanobody (99m)Tc-D10. PMID:26912069

  5. Malignant Extra Renal Rhabdoid Tumour Presenting as Central Airway Obstruction

    PubMed Central

    Bal, Amanjit; Agarwal, Ritesh; Das, Ashim

    2014-01-01

    Rhabdoid tumours are one of the most aggressive childhood neoplasms associated with high mortality. The commonest age group affected is children less than five years of age. Rhabdoid tumour presenting as an endoluminal tracheal mass leading to central airway obstruction has not been previously reported. We describe the case of a 17-year-old male patient where malignant rhabdoid tumour masqueraded as bronchial asthma leading to a delayed diagnosis of upper airway obstruction by tracheal growth. Histopathological examination and immunohistochemistry confirmed the diagnosis of malignant rhabdoid tumour. PMID:25243090

  6. How Population Growth Affects Linkage Disequilibrium

    PubMed Central

    Rogers, Alan R.

    2014-01-01

    The “LD curve” relates the linkage disequilibrium (LD) between pairs of nucleotide sites to the distance that separates them along the chromosome. The shape of this curve reflects natural selection, admixture between populations, and the history of population size. This article derives new results about the last of these effects. When a population expands in size, the LD curve grows steeper, and this effect is especially pronounced following a bottleneck in population size. When a population shrinks, the LD curve rises but remains relatively flat. As LD converges toward a new equilibrium, its time path may not be monotonic. Following an episode of growth, for example, it declines to a low value before rising toward the new equilibrium. These changes happen at different rates for different LD statistics. They are especially slow for estimates of σd2, which therefore allow inferences about ancient population history. For the human population of Europe, these results suggest a history of population growth. PMID:24907258

  7. Tumour progression and metastasis.

    PubMed

    Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

    2016-01-01

    The two biological mechanisms that determine types of malignancy are infiltration and metastasis, for which tumour microenvironment plays a key role in developing and establishing the morphology, growth and invasiveness of a malignancy. The microenvironment is formed by complex tissue containing the extracellular matrix, tumour and non-tumour cells, a signalling network of cytokines, chemokines, growth factors, and proteases that control autocrine and paracrine communication among individual cells, facilitating tumour progression. During the development of the primary tumour, the tumour stroma and continuous genetic changes within the cells makes it possible for them to migrate, having to count on a pre-metastatic niche receptor that allows the tumour's survival and distant growth. These niches are induced by factors produced by the primary tumour; if it is eradicated, the active niches become responsible for activating the latent disseminated cells. Due to the importance of these mechanisms, the strategies that develop tumour cells during tumour progression and the way in which the microenvironment influences the formation of metastasis are reviewed. It also suggests that the metastatic niche can be an ideal target for new treatments that make controlling metastasis possible. PMID:26913068

  8. Fractionated Radiotherapy with 3 x 8 Gy Induces Systemic Anti-Tumour Responses and Abscopal Tumour Inhibition without Modulating the Humoral Anti-Tumour Response

    PubMed Central

    Habets, Thomas H. P. M.; Oth, Tammy; Houben, Ans W.; Huijskens, Mirelle J. A. J.; Senden-Gijsbers, Birgit L. M. G.; Schnijderberg, Melanie C. A.; Brans, Boudewijn; Dubois, Ludwig J.; Lambin, Philippe; De Saint-Hubert, Marijke; Germeraad, Wilfred T. V.; Tilanus, Marcel G. J.; Mottaghy, Felix M.

    2016-01-01

    Accumulating evidence indicates that fractionated radiotherapy (RT) can result in distant non-irradiated (abscopal) tumour regression. Although preclinical studies indicate the importance of T cells in this infrequent phenomenon, these studies do not preclude that other immune mechanisms exhibit an addition role in the abscopal effect. We therefore addressed the question whether in addition to T cell mediated responses also humoral anti-tumour responses are modulated after fractionated RT and whether systemic dendritic cell (DC) stimulation can enhance tumour-specific antibody production. We selected the 67NR mammary carcinoma model since this tumour showed spontaneous antibody production in all tumour-bearing mice. Fractionated RT to the primary tumour was associated with a survival benefit and a delayed growth of a non-irradiated (contralateral) secondary tumour. Notably, fractionated RT did not affect anti-tumour antibody titers and the composition of the immunoglobulin (Ig) isotypes. Likewise, we demonstrated that treatment of tumour-bearing Balb/C mice with DC stimulating growth factor Flt3-L did neither modulate the magnitude nor the composition of the humoral immune response. Finally, we evaluated the immune infiltrate and Ig isotype content of the tumour tissue using flow cytometry and found no differences between treatment groups that were indicative for local antibody production. In conclusion, we demonstrate that the 67NR mammary carcinoma in Balb/C mice is associated with a pre-existing antibody response. And, we show that in tumour-bearing Balb/C mice with abscopal tumour regression such pre-existing antibody responses are not altered upon fractionated RT and/or DC stimulation with Flt3-L. Our research indicates that evaluating the humoral immune response in the setting of abscopal tumour regression is not invariably associated with therapeutic effects. PMID:27427766

  9. Efficient Monte Carlo modelling of individual tumour cell propagation for hypoxic head and neck cancer

    NASA Astrophysics Data System (ADS)

    Tuckwell, W.; Bezak, E.; Yeoh, E.; Marcu, L.

    2008-09-01

    A Monte Carlo tumour model has been developed to simulate tumour cell propagation for head and neck squamous cell carcinoma. The model aims to eventually provide a radiobiological tool for radiation oncology clinicians to plan patient treatment schedules based on properties of the individual tumour. The inclusion of an oxygen distribution amongst the tumour cells enables the model to incorporate hypoxia and other associated parameters, which affect tumour growth. The object oriented program FORTRAN 95 has been used to create the model algorithm, with Monte Carlo methods being employed to randomly assign many of the cell parameters from probability distributions. Hypoxia has been implemented through random assignment of partial oxygen pressure values to individual cells during tumour growth, based on in vivo Eppendorf probe experimental data. The accumulation of up to 10 million virtual tumour cells in 15 min of computer running time has been achieved. The stem cell percentage and the degree of hypoxia are the parameters which most influence the final tumour growth rate. For a tumour with a doubling time of 40 days, the final stem cell percentage is approximately 1% of the total cell population. The effect of hypoxia on the tumour growth rate is significant. Using a hypoxia induced cell quiescence limit which affects 50% of cells with and oxygen levels less than 1 mm Hg, the tumour doubling time increases to over 200 days and the time of tumour growth for a clinically detectable tumour (109 cells) increases from 3 to 8 years. A biologically plausible Monte Carlo model of hypoxic head and neck squamous cell carcinoma tumour growth has been developed for real time assessment of the effects of multiple biological parameters which impact upon the response of the individual patient to fractionated radiotherapy.

  10. Efficient Monte Carlo modelling of individual tumour cell propagation for hypoxic head and neck cancer.

    PubMed

    Tuckwell, W; Bezak, E; Yeoh, E; Marcu, L

    2008-09-01

    A Monte Carlo tumour model has been developed to simulate tumour cell propagation for head and neck squamous cell carcinoma. The model aims to eventually provide a radiobiological tool for radiation oncology clinicians to plan patient treatment schedules based on properties of the individual tumour. The inclusion of an oxygen distribution amongst the tumour cells enables the model to incorporate hypoxia and other associated parameters, which affect tumour growth. The object oriented program FORTRAN 95 has been used to create the model algorithm, with Monte Carlo methods being employed to randomly assign many of the cell parameters from probability distributions. Hypoxia has been implemented through random assignment of partial oxygen pressure values to individual cells during tumour growth, based on in vivo Eppendorf probe experimental data. The accumulation of up to 10 million virtual tumour cells in 15 min of computer running time has been achieved. The stem cell percentage and the degree of hypoxia are the parameters which most influence the final tumour growth rate. For a tumour with a doubling time of 40 days, the final stem cell percentage is approximately 1% of the total cell population. The effect of hypoxia on the tumour growth rate is significant. Using a hypoxia induced cell quiescence limit which affects 50% of cells with and oxygen levels less than 1 mm Hg, the tumour doubling time increases to over 200 days and the time of tumour growth for a clinically detectable tumour (10(9) cells) increases from 3 to 8 years. A biologically plausible Monte Carlo model of hypoxic head and neck squamous cell carcinoma tumour growth has been developed for real time assessment of the effects of multiple biological parameters which impact upon the response of the individual patient to fractionated radiotherapy. PMID:18677039

  11. An imaging-based computational model for simulating angiogenesis and tumour oxygenation dynamics

    NASA Astrophysics Data System (ADS)

    Adhikarla, Vikram; Jeraj, Robert

    2016-05-01

    Tumour growth, angiogenesis and oxygenation vary substantially among tumours and significantly impact their treatment outcome. Imaging provides a unique means of investigating these tumour-specific characteristics. Here we propose a computational model to simulate tumour-specific oxygenation changes based on the molecular imaging data. Tumour oxygenation in the model is reflected by the perfused vessel density. Tumour growth depends on its doubling time (T d) and the imaged proliferation. Perfused vessel density recruitment rate depends on the perfused vessel density around the tumour (sMVDtissue) and the maximum VEGF concentration for complete vessel dysfunctionality (VEGFmax). The model parameters were benchmarked to reproduce the dynamics of tumour oxygenation over its entire lifecycle, which is the most challenging test. Tumour oxygenation dynamics were quantified using the peak pO2 (pO2peak) and the time to peak pO2 (t peak). Sensitivity of tumour oxygenation to model parameters was assessed by changing each parameter by 20%. t peak was found to be more sensitive to tumour cell line related doubling time (~30%) as compared to tissue vasculature density (~10%). On the other hand, pO2peak was found to be similarly influenced by the above tumour- and vasculature-associated parameters (~30–40%). Interestingly, both pO2peak and t peak were only marginally affected by VEGFmax (~5%). The development of a poorly oxygenated (hypoxic) core with tumour growth increased VEGF accumulation, thus disrupting the vessel perfusion as well as further increasing hypoxia with time. The model with its benchmarked parameters, is applied to hypoxia imaging data obtained using a [64Cu]Cu-ATSM PET scan of a mouse tumour and the temporal development of the vasculature and hypoxia maps are shown. The work underscores the importance of using tumour-specific input for analysing tumour evolution. An extended model incorporating therapeutic effects can serve as a powerful tool for

  12. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression.

    PubMed

    Keith, Brian; Johnson, Randall S; Simon, M Celeste

    2012-01-01

    Hypoxia-inducible factors (HIFs) are broadly expressed in human cancers, and HIF1α and HIF2α were previously suspected to promote tumour progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from various approaches that reveal unique and sometimes opposing activities of these HIFα isoforms in both normal physiology and disease. These effects are mediated in part through the regulation of unique target genes, as well as through direct and indirect interactions with important oncoproteins and tumour suppressors, including MYC and p53. As HIF inhibitors are currently undergoing clinical evaluation as cancer therapeutics, a more thorough understanding of the unique roles performed by HIF1α and HIF2α in human neoplasia is warranted. PMID:22169972

  13. Tumour growth inhibition and anti-angiogenic effects using curcumin correspond to combined PDE2 and PDE4 inhibition.

    PubMed

    Abusnina, Abdurazzag; Keravis, Thérèse; Zhou, Qingwei; Justiniano, Hélène; Lobstein, Annelise; Lugnier, Claire

    2015-02-01

    Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis by stimulating endothelial cells. Increase in cyclic AMP (cAMP) level inhibits VEGF-induced endothelial cell proliferation and migration. Cyclic nucleotide phosphodiesterases (PDEs), which specifically hydrolyse cyclic nucleotides, are critical in the regulation of this signal transduction. We have previously reported that PDE2 and PDE4 up-regulations in human umbilical vein endothelial cells (HUVECs) are implicated in VEGF-induced angiogenesis and that inhibition of PDE2 and PDE4 activities prevents the development of the in vitro angiogenesis by increasing cAMP level, as well as the in vivo chicken embryo angiogenesis. We have also shown that polyphenols are able to inhibit PDEs. The curcumin having anti-cancer properties, the present study investigated whether PDE2 and PDE4 inhibitors and curcumin could have similar in vivo anti-tumour properties and whether the anti-angiogenic effects of curcumin are mediated by PDEs. Both PDE2/PDE4 inhibitor association and curcumin significantly inhibited in vivo tumour growth in C57BL/6N mice. In vitro, curcumin inhibited basal and VEGF-stimulated HUVEC proliferation and migration and delayed cell cycle progression at G0/G1, similarly to the combination of selective PDE2 and PDE4 inhibitors. cAMP levels in HUVECs were significantly increased by curcumin, similarly to rolipram (PDE4 inhibitor) and BAY-60-550 (PDE2 inhibitor) association, indicating cAMP-PDE inhibitions. Moreover, curcumin was able to inhibit VEGF-induced cAMP-PDE activity without acting on cGMP-PDE activity and to modulate PDE2 and PDE4 expressions in HUVECs. The present results suggest that curcumin exerts its in vitro anti-angiogenic and in vivo anti-tumour properties through combined PDE2 and PDE4 inhibition. PMID:25230992

  14. Immunological fluctuations during intrathecal immunotherapy in three patients affected by CNS tumours disseminating via CSF.

    PubMed

    Salmaggi, A; Dufour, A; Silvani, A; Ciusani, E; Nespolo, A; Boiardi, A

    1994-07-01

    The immunological therapy of cancer has been proposed in a number of neoplasms (Borden, Sondel, 1989; Foon, 1989; Rosenberg, 1992) and has recently been adopted in the treatment of Central Nervous System (CNS) tumors in combination with conventional surgical and radiotherapeutical approach. In this context, loco-regional administration of immunomodulating agents (for instance in post-surgical cavity) allows to achieve much higher in situ concentrations than by systemic route. Since these treatments have potential adverse effects, careful assessment of clinical and immunological parameters in phase I trials is needed. CNS tumors disseminating via Cerebrospinal Fluid (CSF) pathways offer a stimulating opportunity for intrathecal immunotherapy. In this context, alpha-IFN and IL2 (alone or in combination with LAK cells) have been employed either loco-regionally or intrathecally (Merchant, Mc Vicar, Merchant & Young, 1992; Schiller, Hank, Storer, Borchert, Moore, Albertini, Bechhofer, Wesley, Brown, Bastin & Sondel, 1993). The rationale for the use of both these substances includes the known anti-tumor action of alpha-IFN (Mahaley, Urso, Whaley, Blue, Williams, Guaspari & Selker, 1985; Nagai, 1988) and the ability of r-IL2 to generate activated cells effective in lysing tumor cell targets (Hayes, Moore, Pierz, Chen, Da Rosso, Nirenberg & Allen, 1993). We treated 3 patients (2 affected by disseminating cerebellar medulloblastoma, 1 by disseminating thalamic glioblastoma) by intrathecal r-IL2 via recervoir. In the first 2 patients, this treatment was preceded by alpha-IFN (also intrathecally). Monitoring of immunological effects of the treatment schedule involved kinetics of CSF and serum TNF-alpha, IL2s and IL2R during the first day of r-IL2 treatment, as well as on day +2 and +4 of both r-IL2 cycles, and assessment of CSF cells, protein and CSF and PB NK cell activity and CD3-CD56+ cells during the course of all treatment cycles. We also assessed clinical and

  15. Oral inoculation of probiotics Lactobacillus acidophilus NCFM suppresses tumour growth both in segmental orthotopic colon cancer and extra-intestinal tissue.

    PubMed

    Chen, Chien-Chang; Lin, Wei-Chuan; Kong, Man-Shan; Shi, Hai Ning; Walker, W Allan; Lin, Chun-Yen; Huang, Ching-Tai; Lin, Yung-Chang; Jung, Shih-Ming; Lin, Tzou-Yien

    2012-06-01

    Modulation of the cellular response by the administration of probiotic bacteria may be an effective strategy for preventing or inhibiting tumour growth. We orally pre-inoculated mice with probiotics Lactobacillus acidophilus NCFM (La) for 14 d. Subcutaneous dorsal-flank tumours and segmental orthotopic colon cancers were implanted into mice using CT-26 murine colon adenocarcinoma cells. On day 28 after tumour initiation, the lamina propria of the colon, mesenteric lymph nodes (MLN) and spleen were harvested and purified for flow cytometry and mRNA analyses. We demonstrated that La pre-inoculation reduced tumour volume growth by 50·3 %, compared with untreated mice at 28 d after tumour implants (2465·5 (SEM 1290·4) v. 4950·9 (SEM 1689·3) mm³, P<0·001). Inoculation with La reduced the severity of colonic carcinogenesis caused by CT-26 cells, such as level of colonic involvement and structural abnormality of epithelial/crypt damage. Moreover, La enhanced apoptosis of CT-26 cells both in dorsal-flank tumour and segmental orthotopic colon cancer, and the mean counts of apoptotic body were higher in mice pre-inoculated with La (P<0·05) compared with untreated mice. La pre-inoculation down-regulated the CXCR4 mRNA expressions in the colon, MLN and extra-intestinal tissue, compared with untreated mice (P<0·05). In addition, La pre-inoculation reduced the mean fluorescence index of MHC class I (H-2Dd, -Kd and -Ld) in flow cytometry analysis. Taken together, these findings suggest that probiotics La may play a role in attenuating tumour growth during CT-26 cell carcinogenesis. The down-regulated expression of CXCR4 mRNA and MHC class I, as well as increasing apoptosis in tumour tissue, indicated that La may be associated with modulating the cellular response triggered by colon carcinogenesis. PMID:21992995

  16. Tumour progression and metastasis

    PubMed Central

    Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

    2016-01-01

    The two biological mechanisms that determine types of malignancy are infiltration and metastasis, for which tumour microenvironment plays a key role in developing and establishing the morphology, growth and invasiveness of a malignancy. The microenvironment is formed by complex tissue containing the extracellular matrix, tumour and non-tumour cells, a signalling network of cytokines, chemokines, growth factors, and proteases that control autocrine and paracrine communication among individual cells, facilitating tumour progression. During the development of the primary tumour, the tumour stroma and continuous genetic changes within the cells makes it possible for them to migrate, having to count on a pre-metastatic niche receptor that allows the tumour’s survival and distant growth. These niches are induced by factors produced by the primary tumour; if it is eradicated, the active niches become responsible for activating the latent disseminated cells. Due to the importance of these mechanisms, the strategies that develop tumour cells during tumour progression and the way in which the microenvironment influences the formation of metastasis are reviewed. It also suggests that the metastatic niche can be an ideal target for new treatments that make controlling metastasis possible. PMID:26913068

  17. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo

    PubMed Central

    Yasuda, S; Sho, M; Yamato, I; Yoshiji, H; Wakatsuki, K; Nishiwada, S; Yagita, H; Nakajima, Y

    2013-01-01

    Recent basic and clinical studies have shown that the programmed death ligand (PD-L)/PD-1 pathway has a significant role in tumour immunity, and its blockade has a therapeutic potential against several human cancers. We hypothesized that anti-angiogeneic treatment might augment the efficacy of PD-1 blockade. To this end, we evaluated combining the blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2) in a murine cancer model using Colon-26 adenocarcinoma. Interestingly, simultaneous treatment with anti-PD-1 and anti-VEGFR2 monoclonal antibodies (mAbs) inhibited tumour growth synergistically in vivo without overt toxicity. Blocking VEGFR2 inhibited tumour neovascularization significantly, as demonstrated by the reduced number of microvessels, while PD-1 blockade had no impact on tumour angiogenesis. PD-1 blockade might promote T cell infiltration into tumours and significantly enhanced local immune activation, as shown by the up-regulation of several proinflammatory cytokine expressions. Importantly, VEGFR2 blockade did not interfere with T cell infiltration and immunological activation induced by PD-1 blockade. In conclusion, simultaneous blockade of PD-1 and VEGFR2 induced a synergistic in-vivo anti-tumour effect, possibly through different mechanisms that might not be mutually exclusive. This unique therapeutic strategy may hold significant promise for future clinical application. PMID:23600839

  18. miR‐490‐5p suppresses tumour growth in renal cell carcinoma through targeting PIK3CA

    PubMed Central

    Chen, Ke; Zeng, Jin; Tang, Kun; Xiao, Haibing; Hu, Junhui; Huang, Chunhua; Yao, Weimin; Yu, Gan; Xiao, Wei; Guan, Wei; Guo, Xiaolin; Xu, Hua

    2015-01-01

    Background Information Dysregulated micro‐RNAs have been reported in many human cancers, including renal cell carcinoma. Recent studies indicated that miR‐490 is involved in tumour development and progression. However, the expression profile and function in renal cell carcinoma remains unknown. Results Herein, we showed that miR‐490‐5p was down‐regulated in renal cell carcinoma tissues and cells compared with the adjacent normal tissues and normal cells. We also provided evidence that miR‐490‐5p acts as a tumour suppressor in renal carcinoma in a variety of in vitro and in vivo assays. Mechanistically, miR‐490‐5p was verified to directly bind to 3′ UTR of the PIK3CA mRNA and reduce the expression of PIK3CA at both mRNA and protein levels, which further inhibits phosphatidylinositol 3‐kinase/Akt signalling pathway. We further showed that knockdown of PIK3CA can block the growth inhibitory effect of miR‐490‐5p, and over‐expression of PIK3CA can reverse the inhibitory effect of miR‐490‐5p on renal cancer cell tumourigenicity. Conclusions Taken together, our results indicated for the first time that miR‐490‐5p functions as a tumour suppressor in renal carcinoma by targeting PIK3CA. Significance Our findings suggest that miR‐490‐5p may be a potential gene therapy target for the treatment of renal cell carcinoma. PMID:26559013

  19. Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer.

    PubMed

    Hornsveld, M; Tenhagen, M; van de Ven, R A; Smits, A M M; van Triest, M H; van Amersfoort, M; Kloet, D E A; Dansen, T B; Burgering, B M; Derksen, P W B

    2016-09-01

    Loss of cellular adhesion leads to the progression of breast cancer through acquisition of anchorage independence, also known as resistance to anoikis. Although inactivation of E-cadherin is essential for acquisition of anoikis resistance, it has remained unclear how metastatic breast cancer cells counterbalance the induction of apoptosis without E-cadherin-dependent cellular adhesion. We report here that E-cadherin inactivation in breast cancer cells induces PI3K/AKT-dependent FOXO3 inhibition and identify FOXO3 as a novel and direct transcriptional activator of the pro-apoptotic protein BMF. As a result, E-cadherin-negative breast fail to upregulate BMF upon transfer to anchorage independence, leading to anoikis resistance. Conversely, expression of BMF in E-cadherin-negative metastatic breast cancer cells is sufficient to inhibit tumour growth and dissemination in mice. In conclusion, we have identified repression of BMF as a major cue that underpins anoikis resistance and tumour dissemination in E-cadherin-deficient metastatic breast cancer. PMID:27035620

  20. The Viscum album preparation Isorel inhibits the growth of melanoma B16F10 by influencing the tumour-host relationship.

    PubMed

    Zarkovic, N; Zarkovic, K; Grainca, S; Kissel, D; Jurin, M

    1997-04-01

    The aim of this study was to analyse whether Viscum album (mistletoe; Isorel) modulates the tumour-host relationship and whether this might be a basic mechanism of the antitumorous activity of the drug. The effects of a single intraperitoneal injection of the drug (100 mg/kg single 'planta tota' dose) were analysed for mice-bearing melanoma B16F10 growing in the hind limb. Injection of Isorel reduced the size of the tumour and caused abundant tumour necrosis with inflammatory response, oedema and destruction of the malignant tissue. Furthermore, the lymphocytes of saline-treated tumorous mice were not able to respond to the mitogenic lectin concanavalin A in vitro, while those of mistletoe extract-treated mice showed high reactivity too the mitogen, but only if cultured in the medium supplemented with the plasma of the mistletoe extract-treated mice. Moreover, melanoma cells exposed to the mistletoe extract were more sensitive to the cytotoxic activity of the lymphocytes than the control tumour cells, particularly in the presence of the plasma of mistletoe extract-treated mice. The plasma itself, however, did not show any cytotoxic activity. These results indicate that the antitumour activity of the mistletoe drug is due to a modulation of the tumour-host relationship, mediated by direct cytotoxicity of the drug to tumour cells and/or through a potentiation of immune response by certain, as yet unidentified, growth modifying humoral factors of the host. PMID:9179362

  1. Expression of vascular endothelial growth factor in human oral squamous cell carcinoma: its association with tumour progression and p53 gene status.

    PubMed Central

    Maeda, T; Matsumura, S; Hiranuma, H; Jikko, A; Furukawa, S; Ishida, T; Fuchihata, H

    1998-01-01

    AIMS: To correlate vascular endothelial growth factor (VEGF) expression in oral squamous cell carcinoma with the clinicopathological characteristics and prognosis; and to assess whether p53 gene status is associated with VEGF expression in human cancers. METHODS: Tumour specimens from 45 patients with oral squamous cell carcinomas were examined. Expression of VEGF was determined using an immunohistochemical method, and a tumour was considered positive when more than 5% of the neoplastic cells showed VEGF immunoreactivity. The p53 gene status was screened using a polymerase chain reaction--single strand conformation polymorphism analysis. RESULTS: VEGF positive staining was detected in 19 (42.2%) of the 45 cases. VEGF immunoreactivity did not correlate with the histological degree of tumour differentiation, clinical stages, or lymph node metastasis. The patients with VEGF positive tumours had a significantly worse prognosis than those with VEGF negative tumours. The five year overall survival rate of the VEGF negative patients was 76.5%, as compared with 48.8% for the VEGF positive patients. No significant association between VEGF expression and the p53 gene status of the tumours was found. CONCLUSIONS: VEGF is a good prognostic indicator of the survival of patients with oral squamous cell carcinoma. The p53 gene status does not seem to be associated with VEGF expression in these cancers. Images PMID:10023341

  2. Immunology of naturally transmissible tumours.

    PubMed

    Siddle, Hannah V; Kaufman, Jim

    2015-01-01

    Naturally transmissible tumours can emerge when a tumour cell gains the ability to pass as an infectious allograft between individuals. The ability of these tumours to colonize a new host and to cross histocompatibility barriers contradicts our understanding of the vertebrate immune response to allografts. Two naturally occurring contagious cancers are currently active in the animal kingdom, canine transmissible venereal tumour (CTVT), which spreads among dogs, and devil facial tumour disease (DFTD), among Tasmanian devils. CTVT are generally not fatal as a tumour-specific host immune response controls or clears the tumours after transmission and a period of growth. In contrast, the growth of DFTD tumours is not controlled by the Tasmanian devil's immune system and the disease causes close to 100% mortality, severely impacting the devil population. To avoid the immune response of the host both DFTD and CTVT use a variety of immune escape strategies that have similarities to many single organism tumours, including MHC loss and the expression of immunosuppressive cytokines. However, both tumours appear to have a complex interaction with the immune system of their respective host, which has evolved over the relatively long life of these tumours. The Tasmanian devil is struggling to survive with the burden of this disease and it is only with an understanding of how DFTD passes between individuals that a vaccine might be developed. Further, an understanding of how these tumours achieve natural transmissibility should provide insights into general mechanisms of immune escape that emerge during tumour evolution. PMID:25187312

  3. Immunology of naturally transmissible tumours

    PubMed Central

    Siddle, Hannah V; Kaufman, Jim

    2015-01-01

    Naturally transmissible tumours can emerge when a tumour cell gains the ability to pass as an infectious allograft between individuals. The ability of these tumours to colonize a new host and to cross histocompatibility barriers contradicts our understanding of the vertebrate immune response to allografts. Two naturally occurring contagious cancers are currently active in the animal kingdom, canine transmissible venereal tumour (CTVT), which spreads among dogs, and devil facial tumour disease (DFTD), among Tasmanian devils. CTVT are generally not fatal as a tumour-specific host immune response controls or clears the tumours after transmission and a period of growth. In contrast, the growth of DFTD tumours is not controlled by the Tasmanian devil's immune system and the disease causes close to 100% mortality, severely impacting the devil population. To avoid the immune response of the host both DFTD and CTVT use a variety of immune escape strategies that have similarities to many single organism tumours, including MHC loss and the expression of immunosuppressive cytokines. However, both tumours appear to have a complex interaction with the immune system of their respective host, which has evolved over the relatively long life of these tumours. The Tasmanian devil is struggling to survive with the burden of this disease and it is only with an understanding of how DFTD passes between individuals that a vaccine might be developed. Further, an understanding of how these tumours achieve natural transmissibility should provide insights into general mechanisms of immune escape that emerge during tumour evolution. PMID:25187312

  4. Impact of CYP24A1 overexpression on growth of colorectal tumour xenografts in mice fed with vitamin D and soy

    PubMed Central

    Höbaus, Julia; Tennakoon, Samawansha; Heffeter, Petra; Groeschel, Charlotte; Aggarwal, Abhishek; Hummel, Doris M.; Thiem, Ursula; Marculescu, Rodrig; Berger, Walter

    2015-01-01

    Our previous studies showed that the 1,25‐dihydroxyvitamin D (1,25‐D3) catabolizing enzyme, 1,25‐dihydoxyvitamin D 24 hydroxylase (CYP24A1) was overexpressed in colorectal tumours and its level correlated with increased proliferation. We hypothesised that cells overexpressing CYP24A1 have growth advantage and a diet rich in vitamin D and soy would restore sensitivity to the anti‐tumourigenic effects of vitamin D. Soy contains genistein, a natural CYP24A1 inhibitor. To determine causality between CYP24A1 and tumour growth, we established xenografts in male SCID mice with HT29 cells stably overexpressing either GFP‐tagged CYP24A1 or GFP. Mice were fed with either high (2500 IU D3/kg) or low vitamin D (100 IU D3/kg) diet in the presence or absence of soy (20% diet). In vitro, cells overexpressing CYP24A1 grew faster than controls. 1,25‐D3, the active vitamin D metabolite, reduced cell number only in the presence of the CYP24A1 inhibitor VID400. Regardless of the amount of vitamin D in the diet, xenografts overexpressing CYP24A1 grew faster, were heavier and more aggressive. Soy reduced tumour volume only in the control xenografts, while the tumours overexpressing CYP24A1 were larger in the presence of dietary soy. In conclusion, we demonstrate that CYP24A1 overexpression results in increased aggressiveness and proliferative potential of colorectal tumours. Irrespective of the dietary vitamin D3, dietary soy is able to increase tumour volume when tumours overexpress CYP24A1, suggesting that combination of vitamin D3 and soy could have an anti‐tumourigenic effect only if CYP24A1 levels are normal. PMID:26238339

  5. Impact of CYP24A1 overexpression on growth of colorectal tumour xenografts in mice fed with vitamin D and soy.

    PubMed

    Höbaus, Julia; Tennakoon, Samawansha; Heffeter, Petra; Groeschel, Charlotte; Aggarwal, Abhishek; Hummel, Doris M; Thiem, Ursula; Marculescu, Rodrig; Berger, Walter; Kállay, Enikö

    2016-01-15

    Our previous studies showed that the 1,25-dihydroxyvitamin D (1,25-D3) catabolizing enzyme, 1,25-dihydoxyvitamin D 24 hydroxylase (CYP24A1) was overexpressed in colorectal tumours and its level correlated with increased proliferation. We hypothesised that cells overexpressing CYP24A1 have growth advantage and a diet rich in vitamin D and soy would restore sensitivity to the anti-tumourigenic effects of vitamin D. Soy contains genistein, a natural CYP24A1 inhibitor. To determine causality between CYP24A1 and tumour growth, we established xenografts in male SCID mice with HT29 cells stably overexpressing either GFP-tagged CYP24A1 or GFP. Mice were fed with either high (2500 IU D3/kg) or low vitamin D (100 IU D3/kg) diet in the presence or absence of soy (20% diet). In vitro, cells overexpressing CYP24A1 grew faster than controls. 1,25-D3, the active vitamin D metabolite, reduced cell number only in the presence of the CYP24A1 inhibitor VID400. Regardless of the amount of vitamin D in the diet, xenografts overexpressing CYP24A1 grew faster, were heavier and more aggressive. Soy reduced tumour volume only in the control xenografts, while the tumours overexpressing CYP24A1 were larger in the presence of dietary soy. In conclusion, we demonstrate that CYP24A1 overexpression results in increased aggressiveness and proliferative potential of colorectal tumours. Irrespective of the dietary vitamin D3, dietary soy is able to increase tumour volume when tumours overexpress CYP24A1, suggesting that combination of vitamin D3 and soy could have an anti-tumourigenic effect only if CYP24A1 levels are normal. PMID:26238339

  6. Surgical implications of tumour immunology.

    PubMed Central

    Somers, S. S.

    1996-01-01

    The presence of immune infiltration of tumour deposits and the existence of effective in vitro anti-tumour immune responses would suggest the possibility of therapeutic manipulation against tumour cells. However, clinical immunotherapy has shown little promise as a cancer treatment. Numerous explanations for this inefficacy have been proposed, one of which involves the elaboration of immunosuppressive moieties from tumour cells. The results of studies presented below show that serum from patients with gastrointestinal and other tumours have immunosuppressive influences on normal lymphocytes. The degree of this in vitro inhibition is related to tumour 'bulk' and may reflect a systemic immunosuppressive influence of the tumour. Isolation and culture of lymphocytes from gastrointestinal tumour deposits demonstrated that these immune cells are functionally inert, suggesting the existence of an immunosuppressive tumour microenvironment. The isolation and partial purification of an immunosuppressive moiety from conditioned culture medium of a variety of human tumour cell lines further supports the hypothesis of tumour-mediated immunosuppression. A number of protein tumour cell products have been described with potent immunosuppressive properties. These include transforming growth factor-beta, interleukin-10, and the retroviral envelope protein p15E. The surgical implications of the proposed tumour-host immune relationship includes the hypothesis that clinically apparent disease may not be amenable to immune attack owing to tumour-mediated immune suppression. The use of immunostimulatory strategies as adjuvant perioperative therapy would seem a more effective environment for the activation of antitumour immune responses in the surgical patient. PMID:8678441

  7. Could single-nucleotide polymorphisms (SNPs) affecting the tumour necrosis factor promoter be considered as part of rheumatoid arthritis evolution?

    PubMed

    Aguillón, Juan C; Cruzat, Andrea; Aravena, Octavio; Salazar, Lorena; Llanos, Carolina; Cuchacovich, Miguel

    2006-01-01

    Tumour necrosis factor (TNF), a cytokine mainly produced by macrophages, is associated with a broad spectrum of biological effects, mainly associated with the host defense against microbes. The TNF gene is located on chromosome six within the major histocompatibility complex (MHC). Rheumatoid arthritis (RA) is a systemic autoimmune disease where TNF plays a central role in its etiology and pathogenesis. Written medical evidence of RA can be traced at least as far back as the 17th century, while human paleopathological studies appear to show the presence of RA prior to this period. The fact that RA has experienced an increment both in severity and mortality could be explained by many causes, particularly the crucial role of the immune system. Single-nucleotide polymorphisms (SNPs) are the most common genetic variations and occur at a frequency of approximately 1 in 1000 bp throughout the genome. The -308 TNF SNP is a mutation that affects the promoter region of the TNF gene. It defines the TNF1 and TNF2 alleles, determining low and high levels of TNF expression, respectively. The presence of the TNF2 allele has also been linked to increased susceptibility to and severity in a variety of autoimmune and inflammatory disorders, including RA, systemic lupus erythematosus, and ankylosing spondylitis. Studies on the functional significance of -308 SNP have detected higher levels of TNF production by cells from TNF2-carrying individuals than cells from TNF1 individuals. This difference does not appear to be due to other genes lying within the MHC region. Since the presence of the TNF2 allele may increase the host's resistance to local infection, by increasing local production of TNF at the infection site, we may suggest that such a mutation has emerged as a selective advantage to carriers of the TNF2 allele. This hypothesis may prove itself by observing the high incidence of tuberculosis and other infectious processes in those patients treated with anti-TNF therapy. Since

  8. Tumour growth inhibition in mice by glycosylated recombinant human lymphotoxin: analysis of tumour-regional mononuclear cells involved with its action.

    PubMed Central

    Funahashi, I.; Watanabe, H.; Abo, T.; Indo, K.; Miyaji, H.

    1993-01-01

    We compared the antitumour effects of glycosylated LT (gLT), nonglycosylated LT and TNF against a solid tumour in mice. We found that: (a) The systemic administration of gLT showed significant antitumour activity. These effects were, however, quite small in nude mice. Nonglycosylated LT and TNF attained the same degree of effectiveness as gLT, but at a 5-times higher dose. The serum half-life of gLT was 3-fold longer than that of nonglycosylated LT and 22-fold longer than that of TNF. (b) The effect of gLT was significantly blocked by pretreatment with anti-asialo GM1 antibody. Treatment with gLT produced a significant reduction in numbers of tumour-regional mononuclear cells, which in turn, produced increases intensive necrosis. (c) Mononuclear cells in the tumour tissues before gLT-injection were predominantly IL-2 receptor +/CD3- cells and CD3+ cells. Pretreatment with the anti-asialo GM1 antibody produced a drastic reduction of IL-2 receptor +/CD3- cells. These findings suggest that the efficient antitumour effect of gLT is due to a longer serum half-life than that of nonglycosylated LT or TNF in vivo, and its function is largely mediated by IL-2 receptor +/CD3- cells. Images Figure 6 Figure 7 PMID:8439496

  9. Alternative splicing of TIA-1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance.

    PubMed

    Hamdollah Zadeh, Maryam A; Amin, Elianna M; Hoareau-Aveilla, Coralie; Domingo, Enric; Symonds, Kirsty E; Ye, Xi; Heesom, Katherine J; Salmon, Andrew; D'Silva, Olivia; Betteridge, Kai B; Williams, Ann C; Kerr, David J; Salmon, Andrew H J; Oltean, Sebastian; Midgley, Rachel S; Ladomery, Michael R; Harper, Steven J; Varey, Alexander H R; Bates, David O

    2015-01-01

    The angiogenic capability of colorectal carcinomas (CRC), and their susceptibility to anti-angiogenic therapy, is determined by expression of vascular endothelial growth factor (VEGF) isoforms. The intracellular protein T-cell Intracellular Antigen (TIA-1) alters post-transcriptional RNA processing and binds VEGF-A mRNA. We therefore tested the hypothesis that TIA-1 could regulate VEGF-A isoform expression in colorectal cancers. TIA-1 and VEGF-A isoform expression was measured in colorectal cancers and cell lines. We discovered that an endogenous splice variant of TIA-1 encoding a truncated protein, short TIA-1 (sTIA-1) was expressed in CRC tissues and invasive K-Ras mutant colon cancer cells and tissues but not in adenoma cell lines. sTIA-1 was more highly expressed in CRC than in normal tissues and increased with tumour stage. Knockdown of sTIA-1 or over-expression of full length TIA-1 (flTIA-1) induced expression of the anti-angiogenic VEGF isoform VEGF-A165b. Whereas flTIA-1 selectively bound VEGF-A165 mRNA and increased translation of VEGF-A165b, sTIA-1 prevented this binding. In nude mice, xenografted colon cancer cells over-expressing flTIA-1 formed smaller, less vascular tumours than those expressing sTIA-1, but flTIA-1 expression inhibited the effect of anti-VEGF antibodies. These results indicate that alternative splicing of an RNA binding protein can regulate isoform specific expression of VEGF providing an added layer of complexity to the angiogenic profile of colorectal cancer and their resistance to anti-angiogenic therapy. PMID:25224594

  10. Alternative splicing of TIA-1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance

    PubMed Central

    Hamdollah Zadeh, Maryam A.; Amin, Elianna M.; Hoareau-Aveilla, Coralie; Domingo, Enric; Symonds, Kirsty E.; Ye, Xi; Heesom, Katherine J.; Salmon, Andrew; D'Silva, Olivia; Betteridge, Kai B.; Williams, Ann C.; Kerr, David J.; Salmon, Andrew H.J.; Oltean, Sebastian; Midgley, Rachel S.; Ladomery, Michael R.; Harper, Steven J.; Varey, Alexander H.R.; Bates, David O.

    2015-01-01

    The angiogenic capability of colorectal carcinomas (CRC), and their susceptibility to anti-angiogenic therapy, is determined by expression of vascular endothelial growth factor (VEGF) isoforms. The intracellular protein T-cell Intracellular Antigen (TIA-1) alters post-transcriptional RNA processing and binds VEGF-A mRNA. We therefore tested the hypothesis that TIA-1 could regulate VEGF-A isoform expression in colorectal cancers. TIA-1 and VEGF-A isoform expression was measured in colorectal cancers and cell lines. We discovered that an endogenous splice variant of TIA-1 encoding a truncated protein, short TIA-1 (sTIA-1) was expressed in CRC tissues and invasive K-Ras mutant colon cancer cells and tissues but not in adenoma cell lines. sTIA-1 was more highly expressed in CRC than in normal tissues and increased with tumour stage. Knockdown of sTIA-1 or over-expression of full length TIA-1 (flTIA-1) induced expression of the anti-angiogenic VEGF isoform VEGF-A165b. Whereas flTIA-1 selectively bound VEGF-A165 mRNA and increased translation of VEGF-A165b, sTIA-1 prevented this binding. In nude mice, xenografted colon cancer cells over-expressing flTIA-1 formed smaller, less vascular tumours than those expressing sTIA-1, but flTIA-1 expression inhibited the effect of anti-VEGF antibodies. These results indicate that alternative splicing of an RNA binding protein can regulate isoform specific expression of VEGF providing an added layer of complexity to the angiogenic profile of colorectal cancer and their resistance to anti-angiogenic therapy. PMID:25224594

  11. Insulin-like growth factor I and risk of epithelial invasive ovarian cancer by tumour characteristics: results from the EPIC cohort

    PubMed Central

    Ose, J; Fortner, R T; Schock, H; Peeters, P H; Onland-Moret, N C; Bueno-de-Mesquita, H B; Weiderpass, E; Gram, I T; Overvad, K; Tjonneland, A; Dossus, L; Fournier, A; Baglietto, L; Trichopoulou, A; Benetou, V; Trichopoulos, D; Boeing, H; Masala, G; Krogh, V; Matiello, A; Tumino, R; Popovic, M; Obón-Santacana, M; Larrañaga, N; Ardanaz, E; Sánchez, M-J; Menéndez, V; Chirlaque, M-D; Travis, R C; Khaw, K-T; Brändstedt, J; Idahl, A; Lundin, E; Rinaldi, S; Kuhn, E; Romieu, I; Gunter, M J; Merritt, M A; Riboli, E; Kaaks, R

    2015-01-01

    Background: Prospective studies on insulin-like growth factor I (IGF-I) and epithelial ovarian cancer (EOC) risk are inconclusive. Data suggest risk associations vary by tumour characteristics. Methods: We conducted a nested case–control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate IGF-I concentrations and EOC risk by tumour characteristics (n=565 cases). Multivariable conditional logistic regression models were used to estimate associations. Results: We observed no association between IGF-I and EOC overall or by tumour characteristics. Conclusions: In the largest prospective study to date was no association between IGF-I and EOC risk. Pre-diagnostic serum IGF-I concentrations may not influence EOC risk. PMID:25349976

  12. The cell proliferation kinetics of the EMT6/M/AC mouse tumour at four volumes during unperturbed growth in vivo.

    PubMed

    Watson, J V

    1976-03-01

    The cell proliferation kinetics of the EMT6/M/AC mouse tumour were determined at four different volumes between 1-5 mm3 and 175 mm3. The decrease in the growth rate between these volumes are mainly due to a decrease in the rate constant for cell production. A small increase in the rate constant for cell loss occurred, but this was thought to be insignificant. The cell loss factor increased from 40% at 1-5 mm3 to over 70% in the 175 mm3 tumours. An increase in the median cell cycle time, from 14-1 hr to 18-5 hr was also found between these same volumes. Results obtained for the NCTC fibrosarcoma and the R-1 rhabdo-myosarcoms indicate that there may be a threshold volume in these sarcomas below which little or no cell loss takes place. This was not found in the EMT6/M/AC tumour. PMID:1260835

  13. HAdV-2-suppressed growth of SV40 T antigen-transformed mouse mammary epithelial cell-induced tumours in SCID mice.

    PubMed

    Wu, Chengjun; Cao, Xiaofang; Yu, Di; Huijbers, Elisabeth J M; Essand, Magnus; Akusjärvi, Göran; Johansson, Staffan; Svensson, Catharina

    2016-02-01

    Human adenovirus (HAdV) vectors are promising tools for cancer therapy, but the shortage of efficient animal models for productive HAdV infections has restricted the evaluation of systemic effects to mainly immunodeficient mice. Previously, we reported a highly efficient replication of HAdV-2 in a non-tumorigenic mouse mammary epithelial cell line, NMuMG. Here we show that HAdV-2 gene expression and progeny formation in NMuMG cells transformed with the SV40 T antigen (NMuMG-T cells) were as efficient as in the parental NMuMG cells. Injection of HAdV-2 into tumours established by NMuMG-T in SCID mice caused reduced tumour growth and signs of intratumoural lesions. HAdV-2 replicated within the NMuMG-T-established tumours, but not in interspersed host-derived tissues within the tumours. The specific infection of NMuMG-T-derived tumours was verified by the lack of viral DNA in kidney, lung or spleen although low levels of viral DNA was occasionally found in liver. PMID:26707269

  14. Acute vascular response to cediranib treatment in human non-small-cell lung cancer xenografts with different tumour stromal architecture

    PubMed Central

    Jiang, Yanyan; Allen, Danny; Kersemans, Veerle; Devery, Aoife M.; Bokobza, Sivan M.; Smart, Sean; Ryan, Anderson J.

    2015-01-01

    Objectives Tumours can be categorised based on their stromal architecture into tumour vessel and stromal vessel phenotypes, and the phenotypes have been suggested to define tumour response to chronic treatment with a VEGFR2 antibody. However, it is unclear whether the vascular phenotypes of tumours associate with acute vascular response to VEGFR tyrosine kinase inhibitors (TKI), or whether the early changes in vascular function are associated with subsequent changes in tumour size. This study was sought to address these questions by using xenograft models of human non-small cell lung cancer (NSCLC) representing stromal vessel phenotype (Calu-3) and tumour vessel phenotype (Calu-6), respectively. Methods For dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), nude mice bearing established Calu-3 or Calu-6 xenografts were treated with a potent pan-VEGFR TKI, cediranib (6 mg/kg), at 0 h and 22 h. DCE-MRI was performed 2 h before the first dose and 2 h after the second dose of cediranib to examine acute changes in tumour vessel perfusion. Tumours were harvested for hypoxia detection by CA9 immunohistochemistry. For tumour growth study, mice carrying established Calu-3 or Calu-6 tumours were treated with cediranib once daily for 5 days. Results Twenty-four hours after cediranib administration, the perfusion of Calu-3 tumours was markedly reduced, with a significant increase in hypoxia. In contrast, neither perfusion nor hypoxia was significantly affected in Calu-6 tumours. Tumour regressions were induced in Calu-3 xenografts, but not in Calu-6 xenografts, although there was a trend towards tumour growth inhibition after 5 days of cediranib treatment. Conclusion These findings suggest that tumour stromal architecture may associate with acute tumour vascular response to VEGFR TKI, and this acute tumour vascular response may be a promising early predictive marker of response to VEGFR TKI in NSCLC. PMID:26323213

  15. Spaceflight and age affect tibial epiphyseal growth plate histomorphometry

    NASA Technical Reports Server (NTRS)

    Montufar-Solis, Dina; Duke, Pauline J.; Durnova, G.

    1992-01-01

    Growth plate histomorphometry of rats flown aboard the Soviet biosatellite Cosmos 2044, a 14-day spaceflight, was compared with that of control groups. In growth plates of flight animals, there was a significant increase in cell number per column and height of the proliferative zone and a reduction in height and cell number in the hypertrophy/calcification zone. No significant differences were found in matrix organization at the ultrastructural level of flight animals, indicating that although spacefligfht continues to affect bone growth of 15-wk-old rats, extracellular matrix is not altered in the same manner as seen previously in younger animals. All groups showed growth plate characteristics attributed to aging: lack of calcification zone, reduced hypertrophy zone, and unraveling of collagen fibrils. Tail-suspended controls did not differ from other controls in any of the parameters measured. The results suggest that growth plates of older rats are less responsive to unloading by spaceflight or suspension than those of younger rats and provide new evidence about the modifying effect of spaceflight on the growth plate.

  16. Reduced tumour growth of the human colonic cancer cell lines COLO-320 and HT-29 in vivo by dietary n-3 lipids.

    PubMed Central

    Sakaguchi, M.; Rowley, S.; Kane, N.; Imray, C.; Davies, A.; Jones, C.; Newbold, M.; Keighley, M. R.; Baker, P.; Neoptolemos, J. P.

    1990-01-01

    Seventy-five nude mice received subcutaneous inoculation with 1 X 10(7) cells of the human colonic cancer cell lines COLO-320 or HT-29. Tumour growth was assessed over 4 weeks in animals given one of three iso-caloric diets; standard diet, high saturated fat (20% coconut) diet and high n-3 fat (20% Maxepa fish oil) diet. The n-3 diet produced significant tumour growth reduction compared to the other diets for COLO-320 at 3 to 4 weeks (P less than 0.05 at least) and similarly for HT-29 at 4 weeks (P less than 0.05). Significant incorporation of n-3 fatty acids occurred in red cell membranes, adipose tissue and both neutral lipid and phospholipid fractions of tumour lipids in animals fed Maxepa (P less than 0.01 at least). This was accompanied by reduction of linoleic acid and arachidonic acid in these tissues (P less than 0.01 at least) but was most marked in the metabolically labile phospholipid fraction. There was high mitotic activity in the tumours from all the groups but there was no difference according to diet. PMID:2245166

  17. The sodium channel β1 subunit mediates outgrowth of neurite-like processes on breast cancer cells and promotes tumour growth and metastasis

    PubMed Central

    Nelson, Michaela; Millican-Slater, Rebecca; Forrest, Lorna C; Brackenbury, William J

    2014-01-01

    Voltage-gated Na+ channels (VGSCs) are heteromeric proteins composed of pore-forming α subunits and smaller β subunits. The β subunits are multifunctional channel modulators and are members of the immunoglobulin superfamily of cell adhesion molecules (CAMs). β1, encoded by SCN1B, is best characterized in the central nervous system (CNS), where it plays a critical role in regulating electrical excitability, neurite outgrowth and migration during development. β1 is also expressed in breast cancer (BCa) cell lines, where it regulates adhesion and migration in vitro. In the present study, we found that SCN1B mRNA/β1 protein were up-regulated in BCa specimens, compared with normal breast tissue. β1 upregulation substantially increased tumour growth and metastasis in a xenograft model of BCa. β1 over-expression also increased vascularization and reduced apoptosis in the primary tumours, and β1 over-expressing tumour cells had an elongate morphology. In vitro, β1 potentiated outgrowth of processes from BCa cells co-cultured with fibroblasts, via trans-homophilic adhesion. β1-mediated process outgrowth in BCa cells required the presence and activity of fyn kinase, and Na+ current, thus replicating the mechanism by which β1 regulates neurite outgrowth in CNS neurons. We conclude that when present in breast tumours, β1 enhances pathological growth and cellular dissemination. This study is the first demonstration of a functional role for β1 in tumour growth and metastasis in vivo. We propose that β1 warrants further study as a potential biomarker and targeting β1-mediated adhesion interactions may have value as a novel anti-cancer therapy. PMID:24729314

  18. Mathematical Modelling of a Brain Tumour Initiation and Early Development: A Coupled Model of Glioblastoma Growth, Pre-Existing Vessel Co-Option, Angiogenesis and Blood Perfusion

    PubMed Central

    Cai, Yan; Wu, Jie; Li, Zhiyong; Long, Quan

    2016-01-01

    We propose a coupled mathematical modelling system to investigate glioblastoma growth in response to dynamic changes in chemical and haemodynamic microenvironments caused by pre-existing vessel co-option, remodelling, collapse and angiogenesis. A typical tree-like architecture network with different orders for vessel diameter is designed to model pre-existing vasculature in host tissue. The chemical substances including oxygen, vascular endothelial growth factor, extra-cellular matrix and matrix degradation enzymes are calculated based on the haemodynamic environment which is obtained by coupled modelling of intravascular blood flow with interstitial fluid flow. The haemodynamic changes, including vessel diameter and permeability, are introduced to reflect a series of pathological characteristics of abnormal tumour vessels including vessel dilation, leakage, angiogenesis, regression and collapse. Migrating cells are included as a new phenotype to describe the migration behaviour of malignant tumour cells. The simulation focuses on the avascular phase of tumour development and stops at an early phase of angiogenesis. The model is able to demonstrate the main features of glioblastoma growth in this phase such as the formation of pseudopalisades, cell migration along the host vessels, the pre-existing vasculature co-option, angiogenesis and remodelling. The model also enables us to examine the influence of initial conditions and local environment on the early phase of glioblastoma growth. PMID:26934465

  19. Identification of the major fibroblast growth factors released spontaneously in inflammatory arthritis as platelet derived growth factor and tumour necrosis factor-alpha.

    PubMed Central

    Thornton, S C; Por, S B; Penny, R; Richter, M; Shelley, L; Breit, S N

    1991-01-01

    Rheumatoid arthritis is characterized by chronic inflammation and proliferation of a number of important elements within the joint including the synovial fibroblasts. Elevated levels of a number of cytokines such as Il-1, IL-2, IL-6, interferon-gamma (IFN-gamma), transforming growth factor-beta and tumour necrosis factor-alpha (TNF-alpha) have been detected in the synovial fluid of patients with rheumatoid arthritis and other inflammatory arthritides. It seems likely that local release of such mediators may be responsible for the proliferation and overgrowth of connective tissue elements in these disorders. In order to ascertain whether there was evidence to suggest local production or release of fibroblast growth factors in the joint in inflammatory arthritis, and to determine their identity, cells were obtained from the synovial fluid of 15 patients with chronic inflammatory arthritides. All subjects' synovial fluid cells spontaneously released growth factor activity for fibroblasts. This was present in large amounts, being detectable in culture supernatants diluted to a titre of at least 1/625. By a series of depletion experiments using solid-phase bound antibodies to cytokines, it was possible to demonstrate that this activity was due to TNF-alpha and platelet-derived growth factor (PDGF). Thus, this study showed for the first time that functionally active PDGF was released from synovial fluid cells. Both PDGF and TNF-alpha appeared to contribute in approximately equal amounts to this fibroblast growth factor activity, and were synergistic in effect. Thus this study provides evidence for the local production and release of these two cytokines and suggests that together they are the dominant factors in fibroblast proliferation within the synovial cavity. PMID:1914237

  20. Analysis of genomic mutation and immunohistochemistry of platelet-derived growth factor receptors in canine vascular tumours.

    PubMed

    Abou Asa, S; Mori, T; Maruo, K; Khater, A; El-Sawak, A; Abd el-Aziz, E; Yanai, T; Sakai, H

    2015-09-01

    We examined whether mutation of the platelet-derived growth factor receptor protein tyrosine kinase (PDGFR)-α and PDGFR-β genes contributes to their overexpression in canine vascular tumours. Genomic sequences of trans- or juxtamembrane regions of PDGFR-α and PDGFR-β were analysed with immunohistochemical staining and polymerase chain reaction-direct sequencing using DNA from paraffin-embedded neoplastic tissues of 27 hemangiosarcomas (HSAs) and 20 hemangiomas (HAs). Immunohistochemically, 75% of the HA cases were positive for PDGFR-α and almost most of the HA cases were negative for PDGFR-β. Of the HSA cases, 55.6% were negative for PDGFR-α and 63% were strongly positive for PDGFR-β. Among the HA cases, 1 missense mutation was detected in PDGFR-α exon 18 and 1 in PDGFR-β exon 17. Two HSA cases had missense mutations in exon 14 and 1 in exon 17 of PDGFR-β. Thus, genomic mutation of trans- or juxtamembrane regions of PDGFRs was not the main mechanism driving the activation of receptors in HSA and HA. PMID:23611531

  1. Silencing of hypoxia inducible factor-1α by RNA interference inhibits growth of SK-NEP-1 Wilms tumour cells in vitro, and suppresses tumourigenesis and angiogenesis in vivo.

    PubMed

    Shi, Bo; Li, Ying; Wang, Xiuli; Yang, Yi; Li, Dan; Liu, Xin; Yang, Xianghong

    2016-06-01

    Wilms tumour is the most common tumour of the pediatric kidney. Elevation of hypoxia-inducible factor 1α (HIF-1α) has been detected in 93% to 100% of human Wilms tumour specimens, suggesting a potential value of HIF-1α as a therapeutic target for Wilms tumour. In the present study, a stable HIF-1α-silenced Wilms tumour cell strain was established by introducing HIF-1α short-hairpin RNA (shRNA) into SK-NEP-1 cells. Silencing of HIF-1α significantly reduced single-cell growth capacity, suppressed proliferation and arrested cell cycle of SK-NEP-1 cells. In addition, reduction of HIF-1α expression induced apoptosis in SK-NEP-1 cells, which was accompanied by increased levels of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP) and Bax as well as downregulation of Bcl-2 in the cells. Furthermore, when inoculated subcutaneously in nude mice, HIF-1α-silenced SK-NEP-1 cells displayed retarded tumour growth and impaired tumour angiogenesis. In summary, the findings of this study suggest that HIF-1α plays a critical role in the development of Wilms tumour, and it may serve as a candidate target of gene therapy for Wilms tumour. PMID:27015631

  2. The effects of delays in radiotherapy treatment on tumour control

    NASA Astrophysics Data System (ADS)

    Wyatt, R. M.; Beddoe, A. H.; Dale, R. G.

    2003-01-01

    There is often a considerable delay from initial tumour diagnosis to the start of radiotherapy treatment, which may be due to factors such as waiting lists and referral delays. This paper uses widely published models and clinical parameters to calculate the effect of delays in treatment on local tumour control for four different types of tumour - squamous cell carcinoma (head and neck), breast, cervix and prostate. The Poisson model for tumour control probability (TCP), an exponential function for tumour growth and the linear quadratic model of cell kill are used to calculate the change in TCP for delays between diagnosis and treatment of up to 100 days. Typical values of the clinical parameters have been taken from the literature; these include α and β, σα, tumour size at diagnosis, pre-treatment doubling time, delay in onset of accelerated repopulation and doubling time during treatment. It is acknowledged that there are limitations in the reliability of these data for predicting absolute values of tumour control, but models are still useful for predicting how changes in treatment parameters are likely to affect the outcome. It is shown that for fast-growing tumours a delay of 1-2 months can have a significant adverse effect on the outcome, whereas for slow-growing tumours such as Ca prostate a delay of a few months does not significantly reduce the probability of tumour control. These calculations show the importance of ensuring that delays from diagnosis through to treatment are minimized, especially for patients with rapidly proliferating tumours.

  3. Tumour macrophages as potential targets of bisphosphonates

    PubMed Central

    2011-01-01

    Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use. Bisphosphonates (BPs), such as zoledronic acid, are anti-resorptive agents approved for treatment of skeletal complication associated with metastatic breast cancer and prostate cancer. These agents act on osteoclasts, key cells in the bone microenvironment, to inhibit bone resorption. Over the past 30 years this has led to a great reduction in skeletal-related events (SRE's) in patients with advanced cancer and improved the morbidity associated with cancer-induced bone disease. However, there is now a growing body of evidence, both from in vitro and in vivo models, showing that zoledronic acid can also target tumour cells to increase apoptotic cell death and decrease proliferation, migration and invasion, and that this effect is significantly enhanced in combination with chemotherapy agents. Whether macrophages in the peripheral tumour microenvironment are exposed to sufficient levels of bisphosphonate to be affected is currently unknown. Macrophages belong to the same cell lineage as osteoclasts, the major target of BPs, and are highly phagocytic cells shown to be sensitive to

  4. Interactions between human monocytes and tumour cells. Monocytes can either enhance or inhibit the growth and survival of K562 cells.

    PubMed Central

    Davies, B.; Edwards, S. W.

    1992-01-01

    Human bloodstream monocytes can kill cultured tumour cells (K562), as assessed by specific release of 51Cr from the targets and by inhibition of 3H-thymidine incorporation. Confluent monolayers of monocytes were required for maximal cytotoxicity, and the density of the K562 cells was also an important factor. For example, when K562 cells were seeded at high cell densities, they were killed during incubation with monocytes, but when seeded at low cell densities their growth and survival was enhanced during culture with monocytes. The factor(s) which promoted the survival and division of low density K562 cultures was endogenously secreted from monocytes as it was present in monocyte-conditioned medium, whereas the cytotoxic factor(s) were only expressed during co-culture of monocytes with K562 cells. Conditioned medium from HL 60, U-937, HeLa and K562 could also enhance the growth and survival of low density K562 cultures, and a similar effect was also observed upon the addition of catalase and superoxide dismutase to such cultures. Thus, the monocyte:target ratio is important in determining whether monocytes exhibit cytotoxic or growth-promoting effects and hence tumour-derived or monocyte-derived reactive oxidant species may play a role in tumour cell cycle regulation. PMID:1520583

  5. Gastrointestinal stromal tumour.

    PubMed

    Joensuu, Heikki; Hohenberger, Peter; Corless, Christopher L

    2013-09-14

    Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms that arise in the gastrointestinal tract, usually in the stomach or the small intestine and rarely elsewhere in the abdomen. They can occur at any age, the median age being 60-65 years, and typically cause bleeding, anaemia, and pain. GISTs have variable malignant potential, ranging from small lesions with a benign behaviour to fatal sarcomas. Most tumours stain positively for the mast/stem cell growth factor receptor KIT and anoctamin 1 and harbour a kinase-activating mutation in either KIT or PDGFRA. Tumours without such mutations could have alterations in genes of the succinate dehydrogenase complex or in BRAF, or rarely RAS family genes. About 60% of patients are cured by surgery. Adjuvant treatment with imatinib is recommended for patients with a substantial risk of recurrence, if the tumour has an imatinib-sensitive mutation. Tyrosine kinase inhibitors substantially improve survival in advanced disease, but secondary drug resistance is common. PMID:23623056

  6. Strength of Rocks Affected by Deformation Enhanced Grain Growth

    NASA Astrophysics Data System (ADS)

    Kellermann Slotemaker, A.; de Bresser, H.; Spiers, C.

    2005-12-01

    One way of looking into the possibility of long-term strength changes in the lithosphere is to study transient effects resulting from modifications of the microstructure of rocks. It is generally accepted that mechanical weakening may occur due to progressive grain size refinement resulting from dynamic recrystallization. A decrease in grain size may induce a switch from creep controlled by grain size insensitive dislocation mechanisms to creep governed by grain size sensitive (GSS) mechanisms involving diffusion and grain boundary sliding processes. This switch forms a well-known scenario to explain localization in the lithosphere. However, fine-grained rocks in localized deformation zones are prone to grain coarsening due to surface energy driven grain boundary migration (SED-GBM). This might harden the rock, affecting its role in localizing strain in the long term. The question has arisen if grain growth by SED-GBM in a rock deforming in the GSS creep field can be significantly affected by strain. The broad aim of this study is to shed more light onto this. We have experimentally investigated the microstructural and strength evolution of fine-grained (~0.6 μm) synthetic forsterite and Fe-bearing olivine aggregates that coarsen in grain size while deforming by GSS creep at elevated pressure (600 MPa) and temperature (850-1000 °C). The materials were prepared by `sol-gel' method and contained 0.3-0.5 wt% water and 5-10 vol% enstatite. We performed i) static heat treatment tests of various time durations involving hot isostatic pressing (HIP), and ii) heat treatment tests starting with HIP and continuing with deformation up to 45% axial strain at strain rates in the range 4x10-7 - 1x10-4 s-1. Microstructures were characterized by analyzing full grain size distributions and textures using SEM/EBSD. In addition to the experiments, we studied microstructural evolution in simple two-dimensional numerical models, combining deformation and SED-GBM by means of the

  7. Factors Affecting Growth of Pinus radiata in Chile

    NASA Astrophysics Data System (ADS)

    Alvarez-Munoz, Jose Santos

    The Chilean forestry industry is based on hundreds of thousands of hectares of Pinus radiata plantations that have been established in a variety of soil and climate conditions. This approach has resulted in highly variable plantation productivity even when the best available technology was used. Little information is known about the ecophysiology basis for this variability. We explored the spatial and temporal variation of stand growth in Chile using a network of permanent sample plots from Modelo Nacional de Simulacion de Pino radiata. We hypothesized that the climate would play an important role in the annual variations in productivity. To answer these questions we developed the following projects: (1) Determination of site resource availability from historical data from automatic weather stations (rainfall, temperatures) and a geophysical model for solar irradiation, (2) Determination of peak annual leaf area index (LAI) for selected permanent sample plots using remote sensing technologies, (3) Analysis of soil, climate, canopy and stand factors affecting the Pinus radiata plantation growth and the use efficiency of site resources. For project 1, we estimated solar irradiation using the r.sun , Hargreaves-Samani (HS), and Bristow-Campbell (BC) models and validated model estimates with observations from weather stations. Estimations from a calibrated r.sun model accounted for 94% of the variance (r2=0.94) in monthly mean measured values. The r.sun model performed quite well for a wide range of Chilean conditions when compared with the HS and BC models. Our estimates of global irradiation may be improved with better estimates of cloudiness as they become available. Our model was able to provide spatial estimates of daily, weekly, monthly and yearly solar irradiation. For project 2, we estimated the inter-annual variation of LAI (Leaf Area Index), using remote sensing technologies. We determined LAI using Landsat Thematic Mapper (TM) data covering a 5 year period

  8. Downregulation of transforming growth factor β (TGFβ) and latent TGFβ binding protein (LTBP)-4 expression in late stage canine mammary tumours.

    PubMed

    Klopfleisch, R; Schütze, M; Gruber, A D

    2010-12-01

    Although canine mammary tumours (CMT) are the most common malignant tumours in bitches the pathogenesis is far from understood. To analyse the role of the transforming growth factor β (TGFβ) family in the carcinogenesis of CMT, relative mRNA and protein expression of TGFβ-1, -2 and -3, TGFβ receptor (TGFβR)-1 and -3, latent TGFβ-binding protein (LTBP)-1, -3 and -4, and oestrogen receptor α in CMT were quantified. mRNA expression concentrations were measured in laser-microdissected tissue samples of mammary adenomas, carcinomas and their lymph node metastases and normalised to the non-neoplastic mammary gland of the same dog. Carcinomas and metastases had significantly decreased expression levels of TGFβ-3, TGFβR-3 and LTBP-4, but increased LTBP-1 expression when compared to non-neoplastic glands or adenomas. Decreased TGFβ and LTBP-4 expression were confirmed immunohistochemically. The data suggested that loss of TGFβ-3 and LTBP-4 may have growth-stimulatory effects in late-stage tumours, and loss of their expression, together with reduced TGFβR-3 expression, may be associated with increased proliferative activity of CMT similar to findings in human breast cancer. PMID:19836277

  9. ERas protein is overexpressed and binds to the activated platelet-derived growth factor β receptor in bovine urothelial tumour cells associated with papillomavirus infection.

    PubMed

    Russo, Valeria; Roperto, Franco; Esposito, Iolanda; Ceccarelli, Dora Maria; Zizzo, Nicola; Leonardi, Leonardo; Capparelli, Rosanna; Borzacchiello, Giuseppe; Roperto, Sante

    2016-06-01

    Embryonic stem cell-expressed Ras (ERas) encodes a constitutively active form of guanosine triphosphatase (GTPase) that binds to and activates phosphatidylinositol 3 kinase (PI3K), which in turn phosphorylates and activates downstream targets such as Akt. The current study evaluated ERas regulation and expression in papillomavirus-associated urothelial tumours in cattle grazing on lands rich in bracken fern. ERas was found upregulated and overexpressed by PCR, real time PCR and Western blot. Furthermore, protein overexpression was also confirmed by immunohistochemistry. ERas was found to interact physically and colocalise with the activated platelet derived growth factor β receptor (PDGFβR) by coimmunoprecipitation and laser scanning confocal investigations. Phosphorylation of Akt, a downstream effector both of ERas and PDGFβR, appeared to be increased in urothelial tumour cells. Altogether, these data indicate that ERas/PDGFβR complex could play a role in the pathogenesis of bovine papillomavirus-associated bladder neoplasia. PMID:27256024

  10. Hepatocyte growth factor-induced up-regulation of Twist drives epithelial-mesenchymal transition in a canine mammary tumour cell line.

    PubMed

    Yoshida, Kota; Choisunirachon, Nan; Saito, Tomochika; Matsumoto, Kaori; Saeki, Kohei; Mochizuki, Manabu; Nishimura, Ryohei; Sasaki, Nobuo; Nakagawa, Takayuki

    2014-12-01

    Epithelial-mesenchymal transition (EMT) is a crucial step in tumour progression. However, the molecular mechanisms underlying EMT in canine tumours remain to be elucidated. In this study, the similarity or difference in the molecular mechanism of EMT in canine cells was evaluated and compared with that reported in human and mouse cells. We used eight cell lines derived from canine mammary cancers. Stimulation with hepatocyte growth factor (HGF) increased cell motility and changed EMT-related markers towards mesenchyme in CHMm cell line. These changes were accompanied by an increase in Twist expression and did not occur in CHMm transfected with Twist siRNA, indicating that Twist plays a key role in this phenomenon in CHMm. However, the down-regulation of E-cadherin was not observed by HGF stimulation. Further studies are required to elucidate the difference between human and canine Twist. PMID:25278141

  11. Do plastic particles affect microalgal photosynthesis and growth?

    PubMed

    Sjollema, Sascha B; Redondo-Hasselerharm, Paula; Leslie, Heather A; Kraak, Michiel H S; Vethaak, A Dick

    2016-01-01

    The unbridled increase in plastic pollution of the world's oceans raises concerns about potential effects these materials may have on microalgae, which are primary producers at the basis of the food chain and a major global source of oxygen. Our current understanding about the potential modes and mechanisms of toxic action that plastic particles exert on microalgae is extremely limited. How effects might vary with particle size and the physico-chemical properties of the specific plastic material in question are equally unelucidated, but may hold clues to how toxicity, if observed, is exerted. In this study we selected polystyrene particles, both negatively charged and uncharged, and three different sizes (0.05, 0.5 and 6μm) for testing the effects of size and material properties. Microalgae were exposed to different polystyrene particle sizes and surface charges for 72h. Effects on microalgal photosynthesis and growth were determined by pulse amplitude modulation fluorometry and flow cytometry, respectively. None of the treatments tested in these experiments had an effect on microalgal photosynthesis. Microalgal growth was negatively affected (up to 45%) by uncharged polystyrene particles, but only at high concentrations (250mg/L). Additionally, these adverse effects were demonstrated to increase with decreasing particle size. PMID:26675372

  12. Artificial Polychromatic Light Affects Growth and Physiology in Chicks

    PubMed Central

    Yang, Bo; Yu, Yonghua

    2014-01-01

    Despite the overwhelming use of artificial light on captive animals, its effect on those animals has rarely been studied experimentally. Housing animals in controlled light conditions is useful for assessing the effects of light. The chicken is one of the best-studied animals in artificial light experiments, and here, we evaluate the effect of polychromatic light with various green and blue components on the growth and physiology in chicks. The results indicate that green-blue dual light has two side-effects on chick body mass, depending on the various green to blue ratios. Green-blue dual light with depleted and medium blue component decreased body mass, whereas enriched blue component promoted body mass in chicks compared with monochromatic green- or blue spectra-treated chicks. Moreover, progressive changes in the green to blue ratios of green-blue dual light could give rise to consistent progressive changes in body mass, as suggested by polychromatic light with higher blue component resulting in higher body mass. Correlation analysis confirmed that food intake was positively correlated with final body mass in chicks (R2 = 0.7664, P = 0.0001), suggesting that increased food intake contributed to the increased body mass in chicks exposed to higher blue component. We also found that chicks exposed to higher blue component exhibited higher blood glucose levels. Furthermore, the glucose level was positively related to the final body mass (R2 = 0.6406, P = 0.0001) and food intake (R2 = 0.784, P = 0.0001). These results demonstrate that spectral composition plays a crucial role in affecting growth and physiology in chicks. Moreover, consistent changes in spectral components might cause the synchronous response of growth and physiology. PMID:25469877

  13. Family Poverty Affects the Rate of Human Infant Brain Growth

    PubMed Central

    Hanson, Jamie L.; Hair, Nicole; Shen, Dinggang G.; Shi, Feng; Gilmore, John H.; Wolfe, Barbara L.; Pollak, Seth D.

    2013-01-01

    Living in poverty places children at very high risk for problems across a variety of domains, including schooling, behavioral regulation, and health. Aspects of cognitive functioning, such as information processing, may underlie these kinds of problems. How might poverty affect the brain functions underlying these cognitive processes? Here, we address this question by observing and analyzing repeated measures of brain development of young children between five months and four years of age from economically diverse backgrounds (n = 77). In doing so, we have the opportunity to observe changes in brain growth as children begin to experience the effects of poverty. These children underwent MRI scanning, with subjects completing between 1 and 7 scans longitudinally. Two hundred and three MRI scans were divided into different tissue types using a novel image processing algorithm specifically designed to analyze brain data from young infants. Total gray, white, and cerebral (summation of total gray and white matter) volumes were examined along with volumes of the frontal, parietal, temporal, and occipital lobes. Infants from low-income families had lower volumes of gray matter, tissue critical for processing of information and execution of actions. These differences were found for both the frontal and parietal lobes. No differences were detected in white matter, temporal lobe volumes, or occipital lobe volumes. In addition, differences in brain growth were found to vary with socioeconomic status (SES), with children from lower-income households having slower trajectories of growth during infancy and early childhood. Volumetric differences were associated with the emergence of disruptive behavioral problems. PMID:24349025

  14. Family poverty affects the rate of human infant brain growth.

    PubMed

    Hanson, Jamie L; Hair, Nicole; Shen, Dinggang G; Shi, Feng; Gilmore, John H; Wolfe, Barbara L; Pollak, Seth D

    2013-01-01

    Living in poverty places children at very high risk for problems across a variety of domains, including schooling, behavioral regulation, and health. Aspects of cognitive functioning, such as information processing, may underlie these kinds of problems. How might poverty affect the brain functions underlying these cognitive processes? Here, we address this question by observing and analyzing repeated measures of brain development of young children between five months and four years of age from economically diverse backgrounds (n = 77). In doing so, we have the opportunity to observe changes in brain growth as children begin to experience the effects of poverty. These children underwent MRI scanning, with subjects completing between 1 and 7 scans longitudinally. Two hundred and three MRI scans were divided into different tissue types using a novel image processing algorithm specifically designed to analyze brain data from young infants. Total gray, white, and cerebral (summation of total gray and white matter) volumes were examined along with volumes of the frontal, parietal, temporal, and occipital lobes. Infants from low-income families had lower volumes of gray matter, tissue critical for processing of information and execution of actions. These differences were found for both the frontal and parietal lobes. No differences were detected in white matter, temporal lobe volumes, or occipital lobe volumes. In addition, differences in brain growth were found to vary with socioeconomic status (SES), with children from lower-income households having slower trajectories of growth during infancy and early childhood. Volumetric differences were associated with the emergence of disruptive behavioral problems. PMID:24349025

  15. Tumour vasculature--a potential therapeutic target.

    PubMed Central

    Baillie, C. T.; Winslet, M. C.; Bradley, N. J.

    1995-01-01

    The tumour vasculature is vital for the establishment, growth and metastasis of solid tumours. Its physiological properties limit the effectiveness of conventional anti-cancer strategies. Therapeutic approaches directed at the tumour vasculature are reviewed, suggesting the potential of anti-angiogenesis and the targeting of vascular proliferation antigens as cancer treatments. PMID:7543770

  16. miR-155 is up-regulated in primary and secondary glioblastoma and promotes tumour growth by inhibiting GABA receptors.

    PubMed

    D'Urso, Pietro I; D'Urso, Oscar F; Storelli, Carlo; Mallardo, Massimo; Gianfreda, Cosimo Damiano; Montinaro, Antonio; Cimmino, Antonia; Pietro, Caliandro; Marsigliante, Santo

    2012-07-01

    An altered expression of microRNAs (miRNAs) contributes both to the development of cancer and to the progression of the disease. Malignant tumours and tumour cell lines have widespread deregulated expressions of miRNAs compared to normal tissues. In this study, we investigated the expression profiles of 340 mammalian miRNAs in 93 cases of multiform glioblastoma (primary and secondary glioblastoma tumours), by means of DNA microarrays. We show that the expression profiles of 10 miRNAs can distinguish primary from secondary glioblastoma types. Moreover, we found elevated miR-155 levels in primary and secondary glioblastoma tissues as well as in glioblastoma primary cultures. We hypothesised that γ-aminobutyric acid A receptor 1 (GABRA1) is a miR-155 target, and studied the correlation between miR-155 up-regulation and the GABRA1 protein in cultured glioblastoma cells by miRNA silencing. We show that a decrease in miR-155 expression to normal levels restores the expression of GABRA1, making glioblastoma cells sensitive to signals that inhibit cell proliferation mediated by GABRA1. In conclusion, the expression patterns of different miRNAs characterise primary and secondary glioblastomas. The aberrant overexpression of miR-155 contributes to the malignant phenotype of glioblastoma cells removing growth inhibition. PMID:22470130

  17. Insulin-like growth factor I is expressed in classical and nodular lymphocyte-predominant Hodgkin's lymphoma tumour and microenvironmental cells.

    PubMed

    Eppler, Elisabeth; Janas, Eva; Link, Karl; Weidmann, Lukas; Bischofberger, Helena; Wenger, Michael; Tinguely, Marianne; Schraml, Peter; Moch, Holger; Fellbaum, Christian

    2015-03-01

    Hodgkin's lymphoma (HL) is among the most frequent nodal lymphomas in the Western world and is classified into two disease entities: nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) and classical Hodgkin's lymphoma (cHL, 95% of all HL). HL lesions are characterised by a minority of clonal neoplastic cells, namely Hodgkin and Reed-Sternberg (HRS) cells and their variants in cHL and lymphocyte-predominant (LP) cells in NLPHL, both occurring within a microenvironment of, for example, reactive T and B cells, macrophages and granulocytes that are assumed to support the proliferation and maintenance of neoplastic cells through cytokines, chemokines and growth factors. Insulin-like growth factor I (IGF-I) is an important growth factor involved in proliferation, differentiation, apoptosis and cell survival of numerous (including immune) tissues and probably has a role in tumour pathogenesis and maintenance. Although HL is characterised by disturbed cell differentiation and apoptosis mechanisms, with the involvement of the IGF-I receptor (IGF-1R), the distinct location of IGF-I in HL has not yet been defined. We localise IGF-I by double-immunofluorescence in frequent neoplastic cells of all cHL and NLPHL cases investigated. Additionally, IGF-I immunoreactivity is detected in high endothelial venules and various immune cells within the surrounding tissue of cHL including neutrophils and macrophages. IGF-1R immunoreactivity of variable intensity is found in HRS cells and high endothelial venules within the microenvironment in cHL. We assume that autocrine and paracrine IGF-I plays an anti-apoptotic role in tumour pathogenesis and in shaping the tumour microenvironment. PMID:25487403

  18. Reproductive Tract Tumours: The Scourge of Woman Reproduction Ails Indian Rhinoceroses

    PubMed Central

    Hermes, Robert; Göritz, Frank; Saragusty, Joseph; Stoops, Monica A.; Hildebrandt, Thomas B.

    2014-01-01

    In Indian rhinoceros, extensive leiomyoma, a benign smooth muscle tumour, was sporadically diagnosed post mortem and commonly thought of as contributing factor for reduced fecundity of this species in captivity. However, to date, the prevalence of reproductive tract tumours and their relevance for fecundity are unknown. Our analysis of the international studbook now reveals that females cease reproducing at the age of 18.1±1.2 years; equivalent to a reproductive lifespan of just 9.5±1.3 years. This short reproductive life is in sharp contrast to their longevity in captivity of over 40 years. Here we show, after examining 42% of the captive female population, that age-related genital tract tumours are highly prevalent in this endangered species. Growth and development of these tumours was found to be age-related, starting from the age of 10 years. All females older than 12 years had developed genital tumours, just 7–9 years past maturity. Tumour sizes ranged from 1.5–10 cm. With age, tumours became more numerous, sometimes merging into one large diffuse tumour mass. These tumours, primarily vaginal and cervical, presumably cause widespread young-age infertility by the age of 18 years. In few cases, tumour necrosis suggested possible malignancy of tumours. Possible consequences of such genital tract tumour infestation are hindered intromission, pain during mating, hampered sperm passage, risk of ascending infection during pregnancy, dystocia, or chronic vaginal bleeding. In humans, leiomyoma affect up to 80% of pre-menopause women. While a leading cause for infertility, pregnancy is known to reduce the risk of tumour development. However, different from human, surgical intervention is not a viable treatment option in rhinoceroses. Thus, in analogy to humans, we suggest early onset and seamless consecutive pregnancies to help reduce prevalence of this disease, better maintain a self-sustained captive population and improve animal welfare. PMID:24671211

  19. Reproductive tract tumours: the scourge of woman reproduction ails Indian rhinoceroses.

    PubMed

    Hermes, Robert; Göritz, Frank; Saragusty, Joseph; Stoops, Monica A; Hildebrandt, Thomas B

    2014-01-01

    In Indian rhinoceros, extensive leiomyoma, a benign smooth muscle tumour, was sporadically diagnosed post mortem and commonly thought of as contributing factor for reduced fecundity of this species in captivity. However, to date, the prevalence of reproductive tract tumours and their relevance for fecundity are unknown. Our analysis of the international studbook now reveals that females cease reproducing at the age of 18.1±1.2 years; equivalent to a reproductive lifespan of just 9.5±1.3 years. This short reproductive life is in sharp contrast to their longevity in captivity of over 40 years. Here we show, after examining 42% of the captive female population, that age-related genital tract tumours are highly prevalent in this endangered species. Growth and development of these tumours was found to be age-related, starting from the age of 10 years. All females older than 12 years had developed genital tumours, just 7-9 years past maturity. Tumour sizes ranged from 1.5-10 cm. With age, tumours became more numerous, sometimes merging into one large diffuse tumour mass. These tumours, primarily vaginal and cervical, presumably cause widespread young-age infertility by the age of 18 years. In few cases, tumour necrosis suggested possible malignancy of tumours. Possible consequences of such genital tract tumour infestation are hindered intromission, pain during mating, hampered sperm passage, risk of ascending infection during pregnancy, dystocia, or chronic vaginal bleeding. In humans, leiomyoma affect up to 80% of pre-menopause women. While a leading cause for infertility, pregnancy is known to reduce the risk of tumour development. However, different from human, surgical intervention is not a viable treatment option in rhinoceroses. Thus, in analogy to humans, we suggest early onset and seamless consecutive pregnancies to help reduce prevalence of this disease, better maintain a self-sustained captive population and improve animal welfare. PMID:24671211

  20. Leydig cell tumours in childhood.

    PubMed

    Mengel, W; Knorr, D

    1983-01-01

    Two cases of Leydig cell tumours in childhood are presented. In one case, delayed diagnosis and operation led to pubertas praecox vera whereas in the other case normal growth and development occurred after early diagnosis and operation. PMID:6878724

  1. The effect of low dose carbidopa/levodopa on prolactin and growth hormone concentrations in patients with breast cancer and in benign breast tumours.

    PubMed Central

    Jones, M K; Ramsay, I D; Jenner, P G

    1978-01-01

    1 Low doses of carbidopa/levodopa (12.5 mg 1-alpha-methyl-dopahydrazine, 125 mg levodopa) were administered orally to 29 patients with tumours of the breast (16 with breast cancer, 13 with benign breast disease). 2 Plasma dopa response curves were similar in all the patients studied. 3 Prolactin and growth hormone showed similar responses to carbidopa/levodopa irrespective of age or diagnosis. 4 Prolactin showed an unusual reponse in four patients which has not previously been recorded. PMID:656281

  2. Does Training Affect Growth? Answers to Common Questions.

    ERIC Educational Resources Information Center

    Daly, Robin M.; Bass, Shona; Caine, Dennis; Howe, Warren

    2002-01-01

    Adolescent athletes may be at risk of restricted growth and delayed maturation when combining intense training with insufficient energy intake. Because catch-up growth commonly occurs with reduced training, final adult stature is generally not compromised. However, in athletes with long-term, clinically delayed maturation, catch-up growth may be…

  3. Tumours of the thymus

    PubMed Central

    Sellors, T. Holmes; Thackray, A. C.; Thomson, A. D.

    1967-01-01

    Eighty-eight cases of thymoma are discussed with the object of trying to co-ordinate the histological and clinical features. The pathological specimens were in all cases obtained at operation. The pathology classification introduced by Thomson and Thackray in 1957 has been found to correspond adequately with the clinical pattern. The most common groups of tumours are basically epithelial and can be separated into five or six subdivisions, each of which has a separate pattern of behaviour. Lymphoid and teratomatous tumours also occur, but there were only two examples in this series. Clinically, separation of patients who suffered from myasthenia (38) and those who did not (50) affords the first main grouping. The majority of patients who had myasthenia gravis had tumours classified as epidermoid (19) and lymphoepithelial (14), the former with a more malignant appearance and behaviour than the latter. Removal of the tumour with or without radiation gave considerable and sometimes complete relief from myasthenic symptoms. Non-myasthenic thymoma (50) was usually discovered as a result of pressure signs or in the course of routine radiography. Spindle or oval celled tumours followed a benign pattern whereas undifferentiated thymoma was in every sense malignant, as also were teratomatous growths. Granulomatous or Hodgkin-like thymomas were of special interest and had an unpredictable course, some patients surviving many years after what was regarded as inadequate treatment. The place of radiotherapy as a pre- or post-operative agent complementary to surgery is discussed. Images PMID:6033387

  4. Engineered affinity proteins for tumour-targeting applications.

    PubMed

    Friedman, Mikaela; Ståhl, Stefan

    2009-05-01

    Targeting of tumour-associated antigens is an expanding treatment modality in clinical oncology as an alternative to, or in combination with, conventional treatments, such as chemotherapy, external-radiation therapy and surgery. Targeting of antigens that are unique or more highly expressed in tumours than in normal tissues can be used to increase the specificity and reduce the cytotoxic effect on normal tissues. Several targeting agents have been studied for clinical use, where monoclonal antibodies have been the ones most widely used. More than 20 monoclonal antibodies are approved for therapy today and the largest field is oncology. Advances in genetic engineering and in vitro selection technology has enabled the feasible high-throughput generation of monoclonal antibodies, antibody derivatives [e.g. scFvs, Fab molecules, dAbs (single-domain antibodies), diabodies and minibodies] and more recently also non-immunoglobulin scaffold proteins. Several of these affinity proteins have been investigated for both in vivo diagnostics and therapy. Affinity proteins in tumour-targeted therapy can affect tumour progression by altering signal transduction or by delivering a payload of toxin, drug or radionuclide. The ErbB receptor family has been extensively studied as biomarkers in tumour targeting, primarily for therapy using monoclonal antibodies. Two receptors in the ErbB family, EGFR (epidermal growth factor receptor) and HER2 (epidermal growth factor receptor 2), are overexpressed in various malignancies and associated with poor patient prognosis and are therefore interesting targets for solid tumours. In the present review, strategies are described for tumour targeting of solid tumours using affinity proteins to deliver radionuclides, either for molecular imaging or radiotherapy. Antibodies, antibody derivatives and non-immunoglobulin scaffold proteins are discussed with a certain focus on the affibody (Affibody) molecule. PMID:19341363

  5. The novel desmopressin analogue [V4Q5]dDAVP inhibits angiogenesis, tumour growth and metastases in vasopressin type 2 receptor-expressing breast cancer models

    PubMed Central

    GARONA, JUAN; PIFANO, MARINA; ORLANDO, ULISES D.; PASTRIAN, MARIA B.; IANNUCCI, NANCY B.; ORTEGA, HUGO H.; PODESTA, ERNESTO J.; GOMEZ, DANIEL E.; RIPOLL, GISELLE V.; ALONSO, DANIEL F.

    2015-01-01

    Desmopressin (dDAVP) is a safe haemostatic agent with previously reported antitumour activity. It acts as a selective agonist for the V2 vasopressin membrane receptor (V2r) present on tumour cells and microvasculature. The purpose of this study was to evaluate the novel peptide derivative [V4Q5]dDAVP in V2r-expressing preclinical mouse models of breast cancer. We assessed antitumour effects of [V4Q5]dDAVP using human MCF-7 and MDA-MB-231 breast carcinoma cells, as well as the highly metastatic mouse F3II cell line. Effect on in vitro cancer cell growth was evaluated by cell proliferation and clonogenic assays. Cell cycle distribution was analysed by flow cytometry. In order to study the effect of intravenously administered [V4Q5]dDAVP on tumour growth and angiogenesis, breast cancer xenografts were generated in athymic mice. F3II cells were injected into syngeneic mice to evaluate the effect of [V4Q5]dDAVP on spontaneous and experimental metastatic spread. In vitro cytostatic effects of [V4Q5]dDAVP against breast cancer cells were greater than those of dDAVP, and associated with V2r-activated signal transduction and partial cell cycle arrest. In MDA-MB-231 xenografts, [V4Q5]dDAVP (0.3 μg/kg, thrice a week) reduced tumour growth and angiogenesis. Treatment of F3II mammary tumour-bearing immunocompetent mice resulted in complete inhibition of metastatic progression. [V4Q5]dDAVP also displayed greater antimetastatic efficacy than dDAVP on experimental lung colonisation by F3II cells. The novel analogue was well tolerated in preliminary acute toxicology studies, at doses ≥300-fold above that required for anti-angiogenic/antimetastatic effects. Our data establish the preclinical activity of [V4Q5]dDAVP in aggressive breast cancer, providing the rationale for further clinical trials. PMID:25846632

  6. Systemic anti-tumour effects of local thermally sensitive liposome therapy

    PubMed Central

    Viglianti, Benjamin L.; Dewhirst, Mark W.; Boruta, R.J.; Park, Ji-Young; Landon, Chelsea; Fontanella, Andrew N.; Guo, Jing; Manzoor, Ashley; Hofmann, Christina L.; Palmer, Gregory M.

    2015-01-01

    Purpose There were two primary objectives of this study: (1) to determine whether treatment of a tumour site with systemically administered thermally sensitive liposomes and local hyperthermia (HT) for triggered release would have dual anti-tumour effect on the primary heated tumour as well as an unheated secondary tumour in a distant site, and (2) to determine the ability of non-invasive optical spectroscopy to predict treatment outcome. The optical end points studied included drug levels, metabolic markers flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide phosphate (NAD(P)H), and physiological markers (total haemoglobin (Hb) and Hb oxygen saturation) before and after treatment. Materials and methods Mice were inoculated with SKOV3 human ovarian carcinoma in both hind legs. One tumour was selected for local hyperthermia and subsequent systemic treatment. There were four treatment groups: control, DOXIL® (non-thermally sensitive liposomes containing doxorubicin), and two different thermally sensitive liposome formulations containing doxorubicin. Optical spectroscopy was performed prior to therapy, immediately after treatment, and 6, 12, and 24 h post therapy. Results Tumour growth delay was seen with DOXIL and the thermally sensitive liposomes in the tumours that were heated, similar to previous studies. Tumour growth delay was also seen in the opposing tumour in the thermally sensitive liposome-treated groups. Optical spectroscopy demonstrated correlation between growth delay, doxorubicin (DOX) levels, and changes of NAD(P)H from baseline levels. Hb and Hb saturation were not correlated with growth delay. Discussion The study demonstrated that thermally sensitive liposomes affect the primary heated tumour as well as systemic efficacy. Non-invasive optical spectroscopy methods were shown to be useful in predicting efficacy at early time points post-treatment. PMID:25164143

  7. Tumour growth rates in squamous carcinoma of the head and neck measured by in vivo bromodeoxyuridine incorporation and flow cytometry.

    PubMed Central

    Forster, G.; Cooke, T. G.; Cooke, L. D.; Stanton, P. D.; Bowie, G.; Stell, P. M.

    1992-01-01

    The cell kinetics of 82 squamous cell carcinomas of the head and neck were studied by in vivo administration of the thymidine analogue, bromodeoxyuridine (BrdUrd). Ploidy, BrdUrd labelling index (LI), duration of S-phase (Ts), potential doubling time (Tpot) and S-phase fraction (SPF) were measured by flow cytometry on 50 microns paraffin embedded sections. The range of values obtained compared well with other in vivo cell kinetic studies of head and neck cancer. Aneuploid tumours had a significantly higher BrdUrd labelling index and SPF, and a short Tpot than diploid tumours. To validate the use of 50 microns sections for measuring cell kinetic parameters by flow cytometry a comparison of values obtained by 50 microns sections and small blocks of tissue was made. No significant difference was found between the two methods. Reproducibility of values between two consecutive thick sections was also good. We conclude that reproducible cell kinetic measurements can be made in tumour samples using 50 microns sections of BrdUrd labelled tissue. PMID:1586597

  8. Anti-tumour activity of oncolytic Western Reserve vaccinia viruses in canine tumour cell lines, xenografts, and fresh tumour biopsies.

    PubMed

    Autio, K; Knuuttila, A; Kipar, A; Ahonen, M; Parviainen, S; Diaconu, I; Kanerva, A; Hakonen, T; Vähä-Koskela, M; Hemminki, A

    2014-10-10

    Cancer is one of the most common reasons for death in dogs. One promising approach is oncolytic virotherapy. We assessed the oncolytic effect of genetically modified vaccinia viruses in canine cancer cells, in freshly excised tumour biopsies, and in mice harbouring canine tumour xenografts. Tumour transduction efficacy was assessed using virus expressing luciferase or fluorescent marker genes and oncolysis was quantified by a colorimetric cell viability assay. Oncolytic efficacy in vivo was evaluated in a nude mouse xenograft model. Vaccinia virus was shown to infect most tested canine cancer cell lines and primary surgical tumour tissues. Virus infection significantly reduced tumour growth in the xenograft model. Oncolytic vaccinia virus has antitumour effects against canine cancer cells and experimental tumours and is able to replicate in freshly excised patient tumour tissue. Our results suggest that oncolytic vaccinia virus may offer an effective treatment option for otherwise incurable canine tumours. PMID:25302859

  9. Role of tumour angiogenesis in haematological malignancies.

    PubMed

    Medinger, Michael; Passweg, Jakob

    2014-01-01

    Tumour angiogenesis plays a key role in the pathogenesis and progression of haematological malignancies. Thereby, pro- and anti-angiogenic growth factors and cytokines regulate the angiogenic process. The most important growth factor, vascular endothelial growth factor (VEGF) and its signaling through its receptors 1 and 2, is not only involved in solid tumours, but there is also emerging evidence that tumour progression in haematological malignancies also depends on the induction of new blood vessel formation. The evidence supporting this theory includes the finding of increased bone marrow microvessel density and increased levels of plasma pro-angiogenic cytokines. Leukaemia cells interact with surrounding host cells and extracellular matrix, this crosstalk affecting the most important aspects of the malignant phenotype. The pathophysiology of leukaemia induced angiogenesis involves both direct production of angiogenic cytokines by leukaemia cells and their interaction with bone marrow microenvironment. The inhibition of VEGF signalling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully used for the treatment of different cancer entities, and multiple new drugs are being tested. This review summarises recent advances in the basic understanding of the role of angiogenesis in haematological malignancies and the translation of such basic findings into clinical studies. PMID:25375891

  10. Organizational Career Growth, Affective Occupational Commitment and Turnover Intentions

    ERIC Educational Resources Information Center

    Weng, Qingxiong; McElroy, James C.

    2012-01-01

    Survey data, collected from the People's Republic of China, were used to test Weng's (2010) four facet model of career growth and to examine its effect on occupational commitment and turnover intentions. Weng conceptualized career growth as consisting of four factors: career goal progress, professional ability development, promotion speed, and…

  11. Kinetics of tumour necrosis factor and prostaglandin production by murine resident peritoneal macrophages as affected by dietary n-3 polyunsaturated fatty acids.

    PubMed Central

    Hardard'ottir, I; Whelan, J; Kinsella, J E

    1992-01-01

    Cell-associated and secreted tumour necrosis factor (TNF), prostaglandin (PG) E2, and 6-keto PGF1 alpha were monitored at various times following in vitro stimulation of resident peritoneal macrophages with lipopolysaccharide (LPS). Macrophages were obtained from mice maintained on diets containing 1.5 wt% n-3 polyunsaturated fatty acids (PUFA)+ 1.5 wt% n-6 fatty acids; 1.5 wt% n-6 fatty acids; or 3 wt% n-6 fatty acids, for 4 weeks. Cell-associated TNF increased transiently in the resident peritoneal macrophages from mice consuming all diets and decreased after TNF secretion had reached maximum and plateaued. Macrophages from mice consuming the n-3 PUFA contained more cell-associated TNF and secreted more TNF than macrophages from mice consuming diets containing n-6 fatty acids only, at all time-points studied. Macrophages from mice consuming the n-3 PUFA showed an earlier increase in cell-associated and secreted TNF compared with macrophages from mice consuming n-6 fatty acids only. Kinetics of maximum TNF production was not affected by the diets and dietary n-3 PUFA did not cause a prolonged increase in TNF secretion. Macrophages from mice consuming the n-3 PUFA produced less PG than macrophages from mice consuming the n-6 fatty acids only. PG secretion increased following appearance of cell-associated TNF but when PG had accumulated in the medium there was no further increase in TNF production. PMID:1398747

  12. Imatinib Mesylate Exerts Anti-Proliferative Effects on Osteosarcoma Cells and Inhibits the Tumour Growth in Immunocompetent Murine Models

    PubMed Central

    Ory, Benjamin; Charrier, Céline; Brion, Régis; Blanchard, Frederic; Redini, Françoise; Heymann, Dominique

    2014-01-01

    Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma), a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1). Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma) and POS-1 (undifferentiated osteosarcoma). Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R), appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor status of patients

  13. Clofarabine, a novel adenosine analogue, reactivates DNA methylation-silenced tumour suppressor genes and inhibits cell growth in breast cancer cells.

    PubMed

    Lubecka-Pietruszewska, Katarzyna; Kaufman-Szymczyk, Agnieszka; Stefanska, Barbara; Cebula-Obrzut, Barbara; Smolewski, Piotr; Fabianowska-Majewska, Krystyna

    2014-01-15

    Clofarabine (2-chloro-2'-fluoro-2'-deoxyarabinosyladenine, ClF) is a second-generation 2'-deoxyadenosine analogue that is structurally related to cladribine (2-chloro-2'-deoxyadenosine, 2CdA) and fludarabine (9-beta-d-arabinosyl-2-fluoroadenine, F-ara-A). It demonstrates potent antitumour activity at much lower doses than parent compounds with high therapeutic efficacy in paediatric blood cancers. Our previous studies in breast cancer cells indicate that 2CdA and F-ara-A are involved in epigenetic regulation of gene transcription. We therefore investigated whether ClF influences methylation and expression of selected tumour suppressor genes, such as adenomatous polyposis coli (APC), phosphatase and tensin homologue (PTEN), and retinoic acid receptor beta 2 (RARbeta2), as well as expression of p53, p21 and DNA methyltransferase 1 (DNMT1) in MCF-7 and MDA-MB-231 breast cancer cell lines with different invasive potential. Promoter methylation and gene expression were estimated using methylation-sensitive restriction analysis (MSRA) and real-time PCR, respectively. ClF demonstrated potent growth inhibitory activity in MCF-7 and MDA-MB-231 cells after 96h treatment with IC50 determined as equal to 640nM and 50nM, respectively. In both breast cancer cell lines, ClF led to hypomethylation and up-regulation of APC, PTEN and RARbeta2 as well as increase in p21 expression. Only in non-invasive MCF-7 cells, these changes were associated with down-regulation of DNMT1. Our results provide first evidence of ClF implications in epigenetic regulation of transcriptional activity of selected tumour suppressor genes in breast cancer. It seems to be a new important element of ClF anticancer activity and may indicate its potential efficacy in epigenetic therapy of solid tumours, especially at early stages of carcinogenesis. PMID:24296317

  14. M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma

    PubMed Central

    Shen, Long; Li, Honghao; Shi, Yuzhi; Wang, Dekun; Gong, Junbo; Xun, Jing; Zhou, Sifan; Xiang, Rong; Tan, Xiaoyue

    2016-01-01

    Effects of M2 tumour-associated macrophages on the pathogenesis of diffuse large B cell lymphoma (DLBCL) are still controversial. Our data showed that the number of CD163-positive M2 macrophages correlated negatively with DLBCL prognosis. Macrophage depletion by clodronate liposomes significantly suppressed tumour growth in a xenograft mouse model of DLBCL using OCI-Ly3 cells. Moreover, M2 polarization of macrophages induced legumain expression in U937 cells. Exogenous legumain promoted degradation of fibronectin and collagen I, which was abolished by administration of a legumain inhibitor RR-11a. Overexpression of legumain in Raw 264.7 cells also induced tube formation of endothelial cells in matrigel. In the xenograft mouse model of DLBCL, decreased fibronectin and collagen I, as well as increased legumain expression and angiogenesis were found at the late stage tumours compared with early stage tumours. Co-localization of legumain and fibronectin was observed in the extracellular matrix of tumour tissues. Administration of the legumain inhibitor to the xenograft DLBCL model suppressed tumour growth, angiogenesis and collagen deposition compared with the control. Taken together, our results suggest that M2 tumour-associated macrophages affect degradation of the extracellular matrix and angiogenesis via overexpression of legumain, and therefore play an active role in the progression of DLBCL. PMID:27464733

  15. M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma.

    PubMed

    Shen, Long; Li, Honghao; Shi, Yuzhi; Wang, Dekun; Gong, Junbo; Xun, Jing; Zhou, Sifan; Xiang, Rong; Tan, Xiaoyue

    2016-01-01

    Effects of M2 tumour-associated macrophages on the pathogenesis of diffuse large B cell lymphoma (DLBCL) are still controversial. Our data showed that the number of CD163-positive M2 macrophages correlated negatively with DLBCL prognosis. Macrophage depletion by clodronate liposomes significantly suppressed tumour growth in a xenograft mouse model of DLBCL using OCI-Ly3 cells. Moreover, M2 polarization of macrophages induced legumain expression in U937 cells. Exogenous legumain promoted degradation of fibronectin and collagen I, which was abolished by administration of a legumain inhibitor RR-11a. Overexpression of legumain in Raw 264.7 cells also induced tube formation of endothelial cells in matrigel. In the xenograft mouse model of DLBCL, decreased fibronectin and collagen I, as well as increased legumain expression and angiogenesis were found at the late stage tumours compared with early stage tumours. Co-localization of legumain and fibronectin was observed in the extracellular matrix of tumour tissues. Administration of the legumain inhibitor to the xenograft DLBCL model suppressed tumour growth, angiogenesis and collagen deposition compared with the control. Taken together, our results suggest that M2 tumour-associated macrophages affect degradation of the extracellular matrix and angiogenesis via overexpression of legumain, and therefore play an active role in the progression of DLBCL. PMID:27464733

  16. Slower Economic Growth Affects the 1995 Labor Market.

    ERIC Educational Resources Information Center

    Gardner, Jennifer M.; Hayghe, Howard V.

    1996-01-01

    Shows how job growth slowed dramatically in 1995, but the unemployment rate remained little changed. Discusses trends in nonfarm payroll employment by industry and changes in employment status of people in various demographic and occupational groups. (Author)

  17. Soluble tumour necrosis factor alpha receptor 2, a serum marker of resistance to the anabolic actions of growth hormone in subjects with HIV disease.

    PubMed

    Gelato, Marie C; Mynarcik, Dennis; McNurlan, Margaret A

    2002-01-01

    Therapies are still being sought for the prevention of loss of body weight and lean body mass in HIV disease. The purpose of the present study was to identify a serum marker that would help in selecting patients who may be appropriate candidates for the use of anabolic agents, such as growth hormone, to restore lean body mass. This study included 26 HIV-infected patients and nine healthy controls, assessed previously for the effectiveness of 2 weeks of growth hormone administration in the stimulation of protein synthesis in skeletal muscle. Serum levels of interleukins-1beta, -6 and -10 were not useful predictors of the anabolic response to growth hormone. Serum concentrations of tumour necrosis factor alpha (TNFalpha) were significantly elevated (P<0.05) in patients with AIDS and AIDS-related weight loss, and there was a significant correlation between the serum concentration of interleukin-1 receptor antagonist and stage of disease (P=0.03). However, the serum concentration of the soluble TNFalpha receptor type 2 was most predictive of an inability of muscle protein synthesis to respond anabolically to growth hormone (r=-0.42, P=0.01). These data suggest that inflammation impacts on the responsiveness of muscle tissue to an anabolic stimulus, and that the soluble TNFalpha receptor type 2 provides a useful serum marker for metabolic dysfunction in HIV disease, which can be used to identify individuals likely to respond to growth hormone-based anabolic therapy. PMID:11749664

  18. Impact of polyunsaturated fatty acids on hepato-pancreatic prostaglandin and leukotriene concentration in ductal pancreatic cancer -- is there a correlation to tumour growth and liver metastasis?

    PubMed

    Heukamp, I; Kilian, M; Gregor, J I; Kiewert, C; Schimke, I; Kristiansen, G; Walz, M K; Jacobi, C A; Wenger, F A

    2006-04-01

    Type and composition of polyunsaturated fatty acids (PUFAs) are suspected to play an important role in carcinogenesis. Thus we investigated the effects of n-3, n-6 and n-9 PUFAs on tumour growth, liver metastasis and concentration of prostaglandins (PG) and leukotrienes (LT) in experimental ductal pancreatic adenocarcinoma. Ninety male hamsters were randomised into six groups (Gr.) (n=15). While Gr. 1-3 were healthy control groups, Gr. 4-6 weekly received subcutaneous injections of 10mg N-nitrosobis-2-oxypropylamine (BOP)/kg body weight for 12 weeks in order to induce ductal pancreatic adenocarcinoma. Between week 1 and 16 all animals were fed with a standard diet with a raw fat content of 2.9%. In week 17 Gr. 1-6 were allocated to three types of diets: Gr. 1: standard high fat (=SHF diet, rich in n-6 PUFAs)/Gr. 2: FISH-OIL (rich in n-3 PUFAs)/Gr. 3: SMOF (=mixture of n-3, n-6 and n-9 PUFAs)/Gr. 4: BOP+SHF/Gr. 5: BOP+SMOF/Gr. 6: BOP+FISH-OIL. After 32 weeks all animals were sacrificed and pancreas as well as liver were analysed histologically. Furthermore pancreatic and hepatic concentrations of prostaglandins (PGF1alpha, PGE(2)) and LT were measured. FISH-OIL decreased number of macroscopically visible pancreatic tumours (Gr. 4-6: 54.5% vs. 45.5% vs. 9.1%, P<0.05) as well as incidence of liver metastasis (Gr. 4-6: 90.9% vs. 72.7% vs. 36.4%, P<0.05). Furthermore concentration of PGF(1)(alpha), PGE(2) and LT were significantly increased in pancreatic carcinoma compared to tumour-free tissue. Moreover levels of PGF(1)(alpha) and PGE(2) were higher in liver metastasis than in extrametastatic hepatic tissue. However, in Gr. 6 (FISH-OIL) intrametastatic concentration of LT was significantly lower than in non-metastatic hepatic tissue as well as in Gr. 4 and Gr. 5. FISH-OIL decreased number of visible pancreatic tumours and incidence of histological proven liver metastasis. This effect might be caused by a decrease of intrametastatic concentration of LT compared to

  19. Factors affecting plant growth in membrane nutrient delivery

    NASA Technical Reports Server (NTRS)

    Dreschel, T. W.; Wheeler, R. M.; Sager, J. C.; Knott, W. M.

    1990-01-01

    The development of the tubular membrane plant growth unit for the delivery of water and nutrients to roots in microgravity has recently focused on measuring the effects of changes in physical variables controlling solution availability to the plants. Significant effects of membrane pore size and the negative pressure used to contain the solution were demonstrated. Generally, wheat grew better in units with a larger pore size but equal negative pressure and in units with the same pore size but less negative pressure. Lettuce also exhibited better plant growth at less negative pressure.

  20. Monitoring the Growth of an Orthotopic Tumour Xenograft Model: Multi-Modal Imaging Assessment with Benchtop MRI (1T), High-Field MRI (9.4T), Ultrasound and Bioluminescence

    PubMed Central

    Stuckey, Daniel J.; David, Anna L.; Pedley, R. Barbara; Lythgoe, Mark F.; Siow, Bernard; Walker-Samuel, Simon

    2016-01-01

    Background Research using orthotopic and transgenic models of cancer requires imaging methods to non-invasively quantify tumour burden. As the choice of appropriate imaging modality is wide-ranging, this study aimed to compare low-field (1T) magnetic resonance imaging (MRI), a novel and relatively low-cost system, against established preclinical techniques: bioluminescence imaging (BLI), ultrasound imaging (US), and high-field (9.4T) MRI. Methods A model of colorectal metastasis to the liver was established in eight mice, which were imaged with each modality over four weeks post-implantation. Tumour burden was assessed from manually segmented regions. Results All four imaging systems provided sufficient contrast to detect tumours in all of the mice after two weeks. No significant difference was detected between tumour doubling times estimated by low-field MRI, ultrasound imaging or high-field MRI. A strong correlation was measured between high-field MRI estimates of tumour burden and all the other modalities (p < 0.001, Pearson). Conclusion These results suggest that both low-field MRI and ultrasound imaging are accurate modalities for characterising the growth of preclinical tumour models. PMID:27223614

  1. Dissolved oxygen concentration affects hybrid striped bass growth

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Management of dissolved oxygen (DO) concentration in ponds at night during the growing season is important because fish growth and yield are greater in ponds with higher nightly DO concentrations. Three studies were conducted to quantify performance traits and metabolic responses of hybrid striped b...

  2. Seed Production Affects Maternal Growth and Senescence in Arabidopsis.

    PubMed

    Wuest, Samuel Elias; Philipp, Matthias Anton; Guthörl, Daniela; Schmid, Bernhard; Grossniklaus, Ueli

    2016-05-01

    Correlative control (influence of one organ over another organ) of seeds over maternal growth is one of the most obvious phenotypic expressions of the trade-off between growth and reproduction. However, the underlying molecular mechanisms are largely unknown. Here, we characterize the physiological and molecular effects of correlative inhibition by seeds on Arabidopsis (Arabidopsis thaliana) inflorescences, i.e. global proliferative arrest (GPA) during which all maternal growth ceases upon the production of a given number of seeds. We observed transcriptional responses to growth- and branching-inhibitory hormones, and low mitotic activity in meristems upon GPA, but found that meristems retain their identity and proliferative potential. In shoot tissues, we detected the induction of stress- and senescence-related gene expression upon fruit production and GPA, and a drop in chlorophyll levels, suggestive of altered source-sink relationships between vegetative shoot and reproductive tissues. Levels of shoot reactive oxygen species, however, strongly decreased upon GPA, a phenomenon that is associated with bud dormancy in some perennials. Indeed, gene expression changes in arrested apical inflorescences after fruit removal resembled changes observed in axillary buds following release from apical dominance. This suggests that GPA represents a form of bud dormancy, and that dominance is gradually transferred from growing inflorescences to maturing seeds, allowing offspring control over maternal resources, simultaneously restricting offspring number. This would provide a mechanistic explanation for the constraint between offspring quality and quantity. PMID:27009281

  3. Phasic temperature change patterns affect growth and tuberization in potatoes

    SciTech Connect

    Cao, W.; Tibbitts, T.W. . Dept. of Horticulture)

    1994-07-01

    This study determined the response of potato (Solanum tuberosum L., cv. Norland) plants to various patterns of air temperature changes over different growth periods. In each of two experiments under controlled environments, eight treatments of temperature changes were carried out in two growth rooms maintained at 17 and 22 C and a constant vapor pressure deficit of 0.60 kPa and 14-hour photoperiod. Plants were grown for 63 days after transplanting of tissue culture plantlets in 20-liter pots containing peat-vermiculite mix. Temperature changes were imposed on days 21 and 42, which were essentially at the beginning of tuber initiation and tuber enlargement, respectively, for this cultivar. Plants were moved between two temperature rooms to obtain eight temperature change patterns: 17-17-17, 17-17-22, 17-22-17, 22-17-17, 17-22-22, 22-17-22, 22-22-17, and 22-22-22C over three 21-day growth periods. At harvest on day 63, total plant dry weight was higher for the treatments beginning with 22 C than for those beginning with 17C, with highest biomass obtained at 22-22-17 and 22-17-17C. Shoot dry weight increased with temperature increased from 17-17-17 to 22-22-22C during the three growth periods. Tuber dry weight was highest with 22-17-17C, and lowest with 17-17-22 and 17-22-22C. With 22-17-17C, both dry weights of stolons and roots were lowest. Total tuber number and number of small tubers were highest with 17-17-17 and 17-17-22C, and lowest with 17-22-22 and 22-22-22C, whereas number of medium tubers was highest with 22-17-22C, and number of large tubers was highest with 22-17-17C. This study indicates that tuber development of potatoes is optimized with a phasic pattern of high temperature during early growth and low temperature during later growth.

  4. Anti tumour necrosis-α therapy increases the number of FOXP3+ regulatory T cells in children affected by Crohn's disease

    PubMed Central

    Ricciardelli, Ida; Lindley, Keith J; Londei, Marco; Quaratino, Sonia

    2008-01-01

    Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Its pathogenesis is not completely understood, though the prevailing model is that the intestinal flora drives a strong intestinal T helper 1 (Th1)/Th17 type immune response and inflammation in the genetically susceptible host. This leads to overly aggressive T-cell responses to normal bacteria causing tissue damage. Intestinal homeostasis and maintenance of tolerance to harmless antigens in the intestine has been shown to be maintained by CD4+ CD25+ T regulatory cells (Treg) in animal models of inflammatory bowel diseases. Here we investigated whether Infliximab, a chimeric monoclonal antibody directed against tumour necrosis factor (TNF)-α shown to be highly effective in the treatment of CD, has any effect on mucosal CD4+ CD25+ (FOXP3+) Tregs. Colonic mucosal biopsies from children with active Crohn's disease treated in vivo with Infliximab and controls were analysed to determine FOXP3 expression by immunofluorescence and reverse transcription–polymerase chain reaction. We observed that FOXP3+ T cells were significantly reduced in mucosa of CD patients with active disease compared with controls and restored to normal following Infliximab treatment. The frequency of FOXP3+ cells and mRNA expression was significantly increased in CD mucosa from patients treated in vivo with Infliximab compared with CD patients treated with conventional therapies. In conclusion, we show that Infliximab treatment does not solely neutralize soluble TNF-α, but also affects activation and possibly expansion of mucosal regulatory T cells. We suggest that anti TNF-α immunotherapy can also restore mucosal homeostasis in Crohn's disease. PMID:18422560

  5. Giant solitary fibrous tumour of the pleura. Case report and review of the literature

    PubMed Central

    Crnjac, Anton; Veingerl, Bojan; Vidovic, Damjan; Kavalar, Rajko; Hojski, Aljaz

    2015-01-01

    Background Solitary fibrous tumours of the pleura (SFTP) are rare tumours. They are mostly benign. Only around 12% of them are malign ant. In the initial stage they are mostly asymptomatic and by growing they cause chest pain, irritating cough and dyspnoea on account of the pressure created on the surrounding structures. Rare giant tumours have compression symptoms on the mediastinal structures. The condition requires tiered diagnostic radiology. Preoperative biopsy is not successful in most cases. The therapy of choice is radical surgical tumour removal. Malignant or non-radically removed benign solitary fibrous tumours of the pleura additionally require neoadjuvant therapy. Case report A 68-year old patient was hospitalized for giant solitary fibrous tumour of the pleura in the right pleural cavity. With its expansive growth the tumour caused the shift of the mediastinum by compressing the lower vena cava, right cardiac auricle as well as the intermediate and lower lobe bronchus. Due to cardiac inflow obstruction and right lung collapse, the patient’s life was endangered with signs of cardio-respiratory failure. After preoperative diagnostic radiology, the tumour was surgically removed. Postoperatively, the patient’s condition improved. No disease recurrence was diagnosed after a year. Conclusions Giant solitary fibrous tumour of the pleura may cause serious and life-threatening conditions by causing compression of the pleural cavity with its expansive growth. Early diagnosis of the condition enables less aggressive as well as video-assisted thoracic surgery in patients with significantly better state of health. Large tumour surgeries in cardio-respiratory affected patients are highly risk-associated procedures. PMID:26834527

  6. Identification of prognostic factors in canine mammary malignant tumours: a multivariable survival study

    PubMed Central

    2013-01-01

    Background Although several histopathological and clinical features of canine mammary gland tumours have been widely studied from a prognostic standpoint, considerable variations in tumour individual biologic behaviour difficult the definition of accurate prognostic factors. It has been suggested that the malignant behaviour of tumours is the end result of several alterations in cellular physiology that culminate in tumour growth and spread. Accordingly, the aim of this study was to determine, using a multivariable model, the independent prognostic value of several immunohistochemically detected tumour-associated molecules, such as MMP-9 and uPA in stromal cells and Ki-67, TIMP-2 and VEGF in cancer cells. Results Eighty-five female dogs affected by spontaneous malignant mammary neoplasias were followed up for a 2-year post-operative period. In univariate analysis, tumour characteristics such as size, mode of growth, regional lymph node metastases, tumour cell MIB-1 LI and MMP-9 and uPA expressions in tumour-adjacent fibroblasts, were associated with both survival and disease-free intervals. Histological type and grade were related with overall survival while VEGF and TIMP-2 were not significantly associated with none of the outcome parameters. In multivariable analysis, only a MIB-1 labelling index higher than 40% and a stromal expression of MMP-9 higher than 50% retained significant relationships with poor overall and disease-free survival. Conclusions The results of this study indicate that MMP-9 and Ki-67 are independent prognostic markers of canine malignant mammary tumours. Furthermore, the high stromal expressions of uPA and MMP-9 in aggressive tumours suggest that these molecules are potential therapeutic targets in the post-operative treatment of canine mammary cancer. PMID:23289974

  7. Organic Matter Loading Affects Lodgepole Pine Seedling Growth

    NASA Astrophysics Data System (ADS)

    Wei, Xiaohua; Li, Qinglin; Waterhouse, M. J.; Armleder, H. M.

    2012-06-01

    Organic matter plays important roles in returning nutrients to the soil, maintaining forest productivity and creating habitats in forest ecosystems. Forest biomass is in increasing demand for energy production, and organic matter has been considered as a potential supply. Thus, an important management question is how much organic matter should be retained after forest harvesting to maintain forest productivity. To address this question, an experimental trial was established in 1996 to evaluate the responses of lodgepole pine seedling growth to organic matter loading treatments. Four organic matter loading treatments were randomly assigned to each of four homogeneous pine sites: removal of all organic matter on the forest floor, organic matter loading quantity similar to whole-tree-harvesting residuals left on site, organic matter loading quantity similar to stem-only-harvesting residuals, and organic matter loading quantity more similar to what would be found in disease- or insect-killed stands. Our 10-year data showed that height and diameter had 29 and 35 % increase, respectively, comparing the treatment with the most organic matter loading to the treatment with the least organic matter loading. The positive response of seedling growth to organic matter loading may be associated with nutrients and/or microclimate change caused by organic matter, and requires further study. The dynamic response of seedling growth to organic matter loading treatments highlights the importance of long-term studies. Implications of those results on organic matter management are discussed in the context of forest productivity sustainability.

  8. Growth in body size affects rotational performance in women's gymnastics.

    PubMed

    Ackland, Timothy; Elliott, Bruce; Richards, Joanne

    2003-07-01

    National and state representative female gymnasts (n = 37), aged initially between 10 and 12 years, completed a mixed longitudinal study over 3.3 years, to investigate the effect of body size on gymnastic performance. Subjects were tested at four-monthly intervals on a battery of measures including structural growth, strength and gymnastic performance. The group were divided into 'high growers' and 'low growers' based on height (> 18 cm or < 14 cm/37 months, respectively) and body mass (> 15 kg or < 12 kg/37 months, respectively) for comparative purposes. Development of gymnastic performance was assessed through generic skills (front and back rotations, a twisting jump and a V-sit action) and a vertical jump for maximum height. The results show that the smaller gymnast, with a high strength to mass ratio, has greater potential for performing skills involving whole-body rotations. Larger gymnasts, while able to produce more power and greater angular momentum, could not match the performance of the smaller ones. The magnitude of growth experienced by the gymnast over this period has a varying effect on performance. While some activities were greatly influenced by rapid increases in whole-body moment of inertia (e.g. back rotation), performance on others like the front rotation and vertical jump, appeared partly immune to the physical and mechanical changes associated with growth. PMID:14737925

  9. Growth and aggressiveness factors affecting Monilinia spp. survival peaches.

    PubMed

    Villarino, M; Melgarejo, P; De Cal, A

    2016-06-16

    Brown rot of stone fruit is caused by three species of Monilinia, Monilinia laxa, M. fructigena, and M. fructicola. Eleven components of 20 different isolates of each of the three Monilinia species were analyzed to determine distinct aggressiveness and growth characteristics among the three fungi. M. fructicola showed the greatest lesion diameter, and the lowest incubation and latency period on fruit postharvest, however isolates of M. fructigena exhibited less aggressiveness components. Five growth characteristics of M. fructicola could be used to distinguish M. fructicola from the other two species. The dendrogram generated from only the presence of sclerotia and lesion length on infected fruit separated the 60 isolates into two clusters (r=0.93). One cluster was composed of the M. laxa and M. fructigena isolates and the other cluster comprised the M. fructicola isolates. However, the dendrogram generated based on the presence of stromata and sclerotia in the same colony of the three species when they were grown on potato dextrose agar, and the lesion diameter on fruit infected with each species separated the 60 isolates into three clusters (r=0.81). Each cluster comprised the isolates of each of three Monilinia spp. We discussed the effect of M. fructicola growth and aggressiveness differences on the displacement of M. laxa and M. fructigena by M. fructicola recorded in Spanish peach orchards and their effect on brown rot at postharvest. PMID:27043383

  10. Growth and aggressiveness factors affecting Monilinia spp. survival peaches.

    PubMed

    Villarino, M; Melgarejo, P; De Cal, A

    2016-05-01

    Brown rot of stone fruit is caused by three species of Monilinia, Monilinia laxa, M. fructigena, and M. fructicola. Eleven components of 20 different isolates of each of the three Monilinia species were analysed to determine distinct aggressiveness and growth characteristics among the three fungi. M. fructicola showed the greatest lesion diameter, and the lowest incubation and latency period on fruit postharvest, however isolates of M. fructigena exhibited less aggressiveness components. Five growth characteristics of M. fructicola could be used to distinguish M. fructicola from the other two species. The dendrogram generated from only the presence of sclerotia and lesion length on infected fruit separated the 60 isolates into two clusters (r=0.93). One cluster was composed of the M. laxa and M. fructigena isolates and the other cluster comprised the M. fructicola isolates. However, the dendrogram generated based on the presence of stromata and sclerotia in the same colony of the three species when they were grown on potato dextrose agar, and the lesion diameter on fruit infected with each species separated the 60 isolates into three clusters (r=0.81). Each cluster comprised the isolates of each of three Monilinia spp. We discussed the effect of M. fructicola growth and aggressiveness differences on the displacement of M. laxa and M. fructigena by M. fructicola recorded in Spanish peach orchards and their effect on brown rot at postharvest. PMID:26918325

  11. Interferon regulatory factor-8 modulates the development of tumour-induced CD11b+Gr-1+ myeloid cells.

    PubMed

    Stewart, Trina J; Greeneltch, Kristy M; Reid, Julia E; Liewehr, David J; Steinberg, Seth M; Liu, Kebin; Abrams, Scott I

    2009-09-01

    Tumour-induced myeloid-derived suppressor cells (MDSC) promote immune suppression and mediate tumour progression. However, the molecular basis for the generation of MDSC, which in mice co-express the CD11b(+) and Gr-1(+) cell surface markers remains unclear. Because CD11b(+)Gr-1(+) cells expand during progressive tumour growth, this suggests that tumour-induced events alter signalling pathways that affect normal myeloid cell development. Interferon regulatory factor-8 (IRF-8), a member of the IFN-gamma regulatory factor family, is essential for normal myelopoiesis. We therefore examined whether IRF-8 modulated tumour-induced CD11b(+)Gr-1(+) cell development or accumulation using both implantable (4T1) and transgenic (MMTV-PyMT) mouse models of mammary tumour growth. In the 4T1 model, both splenic and bone marrow-derived CD11b(+)Gr-1(+) cells of tumour-bearing mice displayed a marked reduction in IRF-8 expression compared to control populations. A causal link between IRF-8 expression and the emergence of tumour-induced CD11b(+)Gr-1(+) cells was explored in vivo using a double transgenic (dTg) mouse model designed to express transgenes for both IRF-8 and mammary carcinoma development. Despite the fact that tumour growth was unaffected, splenomegaly, as well as the frequencies and absolute numbers of CD11b(+)Gr-1(+) cells were significantly lower in dTg mice when compared with single transgenic tumour-bearing mice. Overall, these data reveal that IRF-8 plays an important role in tumour-induced development and/or accumulation of CD11b(+)Gr-1(+) cells, and establishes a molecular basis for the potential manipulation of these myeloid populations for cancer therapy. PMID:20196788

  12. Mexican propolis flavonoids affect photosynthesis and seedling growth.

    PubMed

    King-Díaz, Beatriz; Granados-Pineda, Jessica; Bah, Mustapha; Rivero-Cruz, J Fausto; Lotina-Hennsen, Blas

    2015-10-01

    As a continuous effort to find new natural products with potential herbicide activity, flavonoids acacetin (1), chrysin (2) and 4',7-dimethylnarangenin (3) were isolated from a propolis sample collected in the rural area of Mexico City and their effects on the photosynthesis light reactions and on the growth of Lolium perenne, Echinochloa crus-galli and Physalis ixocarpa seedlings were investigated. Acacetin (1) acted as an uncoupler by enhancing the electron transport under basal and phosphorylating conditions and the Mg(2+)-ATPase. Chrysin (2) at low concentrations behaved as an uncoupler and at concentrations up to 100 μM its behavior was as a Hill reaction inhibitor. Finally, 4',7-dimethylnarangenin (3) in a concentration-dependent manner behaved as a Hill reaction inhibitor. Flavonoids 2 and 3 inhibited the uncoupled photosystem II reaction measured from water to 2,5-dichloro-1,4-benzoquinone (DCBQ), and they did not inhibit the uncoupled partial reactions measured from water to sodium silicomolybdate (SiMo) and from diphenylcarbazide (DPC) to diclorophenol indophenol (DCPIP). These results indicated that chrysin and 4',7-dimethylnarangenin inhibited the acceptor side of PS II. The results were corroborated with fluorescence of chlorophyll a measurements. Flavonoids also showed activity on the growth of seedlings of Lolium perenne and Echinochloa crus-galli. PMID:26318278

  13. Formaldehyde exposure affects growth and metabolism of common bean

    SciTech Connect

    Mutters, R.G.; Madore, M. ); Bytnerowicz, A. )

    1993-01-01

    Recent state and federal directives have slated a substantial increase in the use of methanol as an alternative to gasoline in both fleet and private vehicles in the coming decade. The incomplete combustion of methanol produces formaldehyde vapor, and catalytic converter technology that completely oxidizes formaldehyde has yet to be developed. The approach of this study was to use a range of methanol concentrations encompassing levels currently found or that may occur in the future in the ambient air of some heavily polluted areas to test the potential phytotoxicity of formaldehyde. The study had the following objectives: (1) design and build a formaldehyde vapor generator with sufficient capacity for long-term plant fumigations; (2) determine growth response of common bean to formaldehyde; (3) evaluate physiological and biochemical changes of bean plants associated with formaldehyde exposures. 20 refs., 2 figs., 2 tabs.

  14. Polyamine aza-cyclic compounds demonstrate anti-proliferative activity in vitro but fail to control tumour growth in vivo.

    PubMed

    Wong, Pui Ee; Tetley, Laurence; Dufès, Christine; Chooi, Kar Wai; Bolton, Katherine; Schätzlein, Andreas G; Uchegbu, Ijeoma F

    2010-11-01

    Cationic polyamines such as the poly(propylenimine) dendrimers (DAB16) are anti-tumour agents (Dufes et al., 2005, Cancer Res 65:8079-8084). Their mechanism of action is poorly understood, but the lack of in vivo toxicity suggests cancer specificity. To explore this polyamine pharmacophore we cross-linked the aza-cyclic compound, hexacyclen, with 1,4-dibromobutane or 1,8-dibromooctane to yield the polyamines [poly(butylhexacyclen)--CL4] or [poly(octylhexacyclen)--CL8] respectively, both free of primary amines. We characterised the compounds and their respective nanoparticles and examined their interaction with the putative targets of the cationic polyamines: the cell membrane and DNA. Like DAB 16, CL4 and CL8 bind plasmid DNA and all three compounds interrupted the cell cycle of A431 epidermoid carcinoma cells in the S-phase. Additionally all three compounds disrupted erythrocyte membranes, with CL8 and DAB 16 being more active, in this respect, than CL4. CL4 (IC(50) =775.1 µg mL(-1)) and CL8 (IC(50) =8.4 µg mL(-1)), in a similar manner to DAB 16, were anti-proliferative against A431 cells; although unlike DAB 16, CL4 and CL8 were not tumouricidal against A431 xenografts in mice, indicating that primary amines may play an important role in the in vivo activity of DAB 16. PMID:20845462

  15. Growth of ponderosa pine seedlings as affected by air pollution

    NASA Astrophysics Data System (ADS)

    Momen, B.; Anderson, P. D.; Houpis, J. L. J.; Helms, J. A.

    The effect of air pollution on seedling survival and competitive ability is important to natural and artificial regeneration of forest trees. Although biochemical and physiological processes are sensitive indicators of pollution stress, the cumulative effects of air pollutants on seedling vigor and competitive ability may be assessed directly from whole-plant growth characteristics such as diameter, height, and photosynthetic area. A few studies that have examined intraspecific variation in seedling response to air pollution indicate that genotypic differences are important in assessing potential effects of air pollution on forest regeneration. Here, we studied the effects of acid rain (no-rain, pH 5.1 rain, pH 3.0 rain) and ozone (filtered, ambient, twice-ambient) in the field on height, diameter, volume, the height:diameter ratio, maximum needle length, and time to reach maximum needle length in seedlings of three families of ponderosa pine ( Pinus ponderosa Dougl. ex Laws). Seedling diameter, height, volume, and height:diameter ratio related significantly to their pre-treatment values. Twice-ambient ozone decreased seedling diameter compared with ozone-filtered air. A significant family-by-ozone interaction was detected for seedling height, as the height of only one of the three families was decreased by twice-ambient ozone compared with the ambient level. Seedling diameter was larger and the height:diameter ratio was smaller under pH 3.0 rain compared to either the no-rain or the pH 5.1-rain treatment. This suggests greater seedling vigor, perhaps due to a foliar fertilization effect of the pH 3.0 rain.

  16. Glucose-induced thermogenesis in patients with small cell lung carcinoma. Before and after inhibition of tumour growth by chemotherapy.

    PubMed

    Simonsen, L; Bülow, J; Sengeløv, H; Madsen, J; Ovesen, L

    1993-07-01

    Seven weight-losing patients with histologically verified small cell lung carcinoma were given an oral glucose load of 75 g before and at least 3 weeks after the end of chemotherapy to examine the effect of glucose on whole body and skeletal muscle thermogenesis before and after reduction of tumour. Whole body energy expenditure was measured by the open circuit ventilated hood system. Forearm blood flow was measured by venous-occlusion strain-gauge plethysmography. The uptake of oxygen in skeletal muscle was calculated as the product of the forearm blood flow and the difference in a-v oxygen concentration. Whole body resting energy expenditure (REE) did not increase, it was 4.4 +/- 0.3 kJ min-1 (mean +/- SE) before chemotherapy and 4.4 +/- 0.2 kJ min-1 after chemotherapy. The glucose-induced thermogenesis in the 180 min following the glucose load was 93.6 +/- 9.9 kJ 180 min-1 before chemotherapy. This is significantly increased compared to that found in a healthy control group (74.7 +/- 4.8 kJ 180 min-1, P < 0.02). The glucose-induced thermogenesis was significantly reduced to 47.7 +/- 10.2 kJ 180 min-1 (P < 0.05) after chemotherapy. The oxygen uptake in resting skeletal muscles was 6.9 +/- 0.3 mumol 100 g-1 min-1 before chemotherapy and 7.0 +/- 0.7 mumol 100 g-1 min-1 after chemotherapy. This did not increase during the first 90 min following the glucose load in either investigations. In the period 90-180 min following the glucose load, the oxygen uptake was significantly increased before chemotherapy as compared to after chemotherapy, which suggests that the reduced whole body thermogenesis after chemotherapy in part was due to reduced skeletal muscle thermogenesis. PMID:8396523

  17. A selective inhibitor of the immunoproteasome subunit LMP2 induces apoptosis in PC-3 cells and suppresses tumour growth in nude mice

    PubMed Central

    Wehenkel, M; Ban, J-O; Ho, Y-K; Carmony, K C; Hong, J T; Kim, K B

    2012-01-01

    Background: Although the proteasome is a validated anticancer target, the clinical application of its inhibitors has been limited because of inherent systemic toxicity. To broaden clinical utility of proteasome inhibitors as anticancer agents, it is critical to develop strategies to selectively target proteasomes in cancer cells. The immunoproteasome is an alternative form of the constitutive proteasome that is expressed at high levels in cancer tissues, but not in most normal cells in the body. Methods: To validate the immunoproteasome as a chemotherapeutic target, an immunoproteasome catalytic subunit LMP2-targeting inhibitor and siRNA were used. The sensitivity of PC-3 prostate cancer cells to these reagents was investigated using viability assays. Further, a xenograft model of prostate cancer was studied to test the in vivo effects of LMP2 inhibition. Results: A small molecule inhibitor of the immunoproteasome subunit LMP2, UK-101, induced apoptosis of PC-3 cells and resulted in significant inhibition (∼50–60%) of tumour growth in vivo. Interestingly, UK-101 did not block degradation of IκBα in PC-3 cells treated with TNF-α, suggesting that its mode of action may be different from that of general proteasome inhibitors, such as bortezomib, which block IκBα degradation. Conclusion: These results strongly suggest that the immunoproteasome has important roles in cancer cell growth and thus provide a rationale for targeting the immunoproteasome in the treatment of prostate cancer. PMID:22677907

  18. Alteration of proteoglycan sulfation affects bone growth and remodeling

    PubMed Central

    Gualeni, Benedetta; de Vernejoul, Marie-Christine; Marty-Morieux, Caroline; De Leonardis, Fabio; Franchi, Marco; Monti, Luca; Forlino, Antonella; Houillier, Pascal; Rossi, Antonio; Geoffroy, Valerie

    2013-01-01

    Diastrophic dysplasia (DTD) is a chondrodysplasia caused by mutations in the SLC26A2 gene, leading to reduced intracellular sulfate pool in chondrocytes, osteoblasts and fibroblasts. Hence, proteoglycans are undersulfated in the cartilage and bone of DTD patients. To characterize the bone phenotype of this skeletal dysplasia we used the Slc26a2 knock-in mouse (dtd mouse), that was previously validated as an animal model of DTD in humans. X-rays, bone densitometry, static and dynamic histomorphometry, and in vitro studies revealed a primary bone defect in the dtd mouse model. We showed in vivo that this primary bone defect in dtd mice is due to decreased bone accrual associated with a decreased trabecular and periosteal appositional rate at the cell level in one month-old mice. Although the osteoclast number evaluated by histomorphometry was not different in dtd compared to wild-type mice, urine analysis of deoxypyridinoline cross-links and serum levels of type I collagen C-terminal telopeptides showed a higher resorption rate in dtd mice compared to wild-type littermates. Electron microscopy studies showed that collagen fibrils in bone were thinner and less organized in dtd compared to wild-type mice. These data suggest that the low bone mass observed in mutant mice could possibly be linked to the different bone matrix compositions/organizations in dtd mice triggering changes in osteoblast and osteoclast activities. Overall, these results suggest that proteoglycan undersulfation not only affects the properties of hyaline cartilage, but can also lead to unbalanced bone modeling and remodeling activities, demonstrating the importance of proteoglycan sulfation in bone homeostasis. PMID:23369989

  19. Contribution of host-derived growth factors to in vivo growth of a transplantable murine mammary carcinoma.

    PubMed Central

    Davies, D. E.; Farmer, S.; White, J.; Senior, P. V.; Warnes, S. L.; Alexander, P.

    1994-01-01

    The contribution of host-derived growth factors to tumour growth in vivo was studied using the transplantable murine mammary carcinoma, MT1, grown in syngeneic mice. Promotion of growth of the mammary carcinoma by a factor(s) from the host was evident in experiments in which the carcinoma cells were inoculated intraperitoneally. In this environment, tumours develop as multiple solid nodules, each probably arising from an individual cell or a small cluster of cells. Tumour growth was found to occur in the peritoneal cavity following inoculation of 10(3) cells, but an inoculum of as few as ten cells grew if a leucocyte-rich exudate had first been induced. To determine which host-derived growth factors might contribute to growth of MT1, extracts of the tumour were first examined for growth factor activity. Fractionation of tumour extracts by either ion-exchange chromatography or gel filtration revealed several peaks of mitogenic activity, but none of this could be attributed to epidermal growth factor (EGF). Accordingly, an anti-EGF antibody was tested as a putative inhibitor of tumour growth as any effect of this antibody could be ascribed to removal of EGF derived from the host. The antibody was found to have potent anti-tumour activity when tested against MT1 tumours that had been inoculated into the peritoneal cavity. In contrast, the antibody had little effect on growth of the discrete tumour mass which formed when MT1 was transplanted subcutaneously. The results suggest that host-derived EGF contributes to establishment of microcolonies of MT1 carcinoma within the peritoneal cavity. This may be directly, by providing growth factors to supplement those produced by the tumour until it reaches a certain critical mass to sustain autocrine growth, or indirectly, by affecting the production of other growth-stimulatory factors or cytokines. PMID:8054274

  20. Differential Expression of Prognostic Proteomic Markers in Primary Tumour, Venous Tumour Thrombus and Metastatic Renal Cell Cancer Tissue and Correlation with Patient Outcome

    PubMed Central

    Laird, Alexander; O’Mahony, Fiach C.; Nanda, Jyoti; Riddick, Antony C. P.; O’Donnell, Marie; Harrison, David J.; Stewart, Grant D.

    2013-01-01

    Renal cell carcinoma (RCC) is the most deadly of urological malignancies. Metastatic disease affects one third of patients at diagnosis with a further third developing metastatic disease after extirpative surgery. Heterogeneity in the clinical course ensures predicting metastasis is notoriously difficult, despite the routine use of prognostic clinico-pathological parameters in risk stratification. With greater understanding of pathways involved in disease pathogenesis, a number of biomarkers have been shown to have prognostic significance, including Ki67, p53, vascular endothelial growth factor receptor 1 (VEGFR1) and ligand D (VEGFD), SNAIL and SLUG. Previous pathway analysis has been from study of the primary tumour, with little attention to the metastatic tumours which are the focus of targeted molecular therapies. As such, in this study a tissue microarray from 177 patients with primary renal tumour, renal vein tumour thrombus and/or RCC metastasis has been created and used with Automated Quantitative Analysis (AQUA) of immunofluorescence to study the prognostic significance of these markers in locally advanced and metastatic disease. Furthermore, this has allowed assessment of differential protein expression between the primary tumours, renal vein tumour thrombi and metastases. The results demonstrate that clinico-pathological parameters remain the most significant predictors of cancer specific survival; however, high VEGFR1 or VEGFD can predict poor cancer specific survival on univariate analysis for locally advanced and metastatic disease. There was significantly greater expression of Ki67, p53, VEGFR1, SLUG and SNAIL in the metastases compared with the primary tumours and renal vein tumour thrombi. With the exception of p53, these differences in protein expression have not been shown previously in RCC. This confirms the importance of proliferation, angiogenesis and epithelial to mesenchymal transition in the pathogenesis and metastasis of RCC. Importantly

  1. A Natural Small Molecule Harmine Inhibits Angiogenesis and Suppresses Tumour Growth through Activation of p53 in Endothelial Cells

    PubMed Central

    Dai, Fujun; Chen, Yihua; Song, Yajuan; Huang, Li; Zhai, Dong; Dong, Yanmin; Lai, Li; Zhang, Tao; Li, Dali; Pang, Xiufeng; Liu, Mingyao; Yi, Zhengfang

    2012-01-01

    Activation of p53 effectively inhibits tumor angiogenesis that is necessary for tumor growth and metastasis. Reactivation of the p53 by small molecules has emerged as a promising new strategy for cancer therapy. Several classes of small-molecules that activate the p53 pathway have been discovered using various approaches. Here, we identified harmine (β-carboline alkaloid) as a novel activator of p53 signaling involved in inhibition of angiogenesis and tumor growth. Harmine induced p53 phosphorylation and disrupted the p53-MDM2 interaction. Harmine also prevented p53 degradation in the presence of cycloheximide and activated nuclear accumulation of p53 followed by increasing its transcriptional activity in endothelial cells. Moreover, harmine not only induced endothelial cell cycle arrest and apoptosis, but also suppressed endothelial cell migration and tube formation as well as induction of neovascularity in a mouse corneal micropocket assay. Finally, harmine inhibited tumor growth by reducing tumor angiogenesis, as demonstrated by a xenograft tumor model. Our results suggested a novel mechanism and bioactivity of harmine, which inhibited tumor growth by activating the p53 signaling pathway and blocking angiogenesis in endothelial cells. PMID:23300602

  2. The ATPase hCINAP regulates 18S rRNA processing and is essential for embryogenesis and tumour growth

    PubMed Central

    Bai, Dongmei; Zhang, Jinfang; Li, Tingting; Hang, Runlai; Liu, Yong; Tian, Yonglu; Huang, Dadu; Qu, Linglong; Cao, Xiaofeng; Ji, Jiafu; Zheng, Xiaofeng

    2016-01-01

    Dysfunctions in ribosome biogenesis cause developmental defects and increased cancer susceptibility; however, the connection between ribosome assembly and tumorigenesis remains unestablished. Here we show that hCINAP (also named AK6) is required for human 18S rRNA processing and 40S subunit assembly. Homozygous CINAP−/− mice show embryonic lethality. The heterozygotes are viable and show defects in 18S rRNA processing, whereas no delayed cell growth is observed. However, during rapid growth, CINAP haploinsufficiency impairs protein synthesis. Consistently, hCINAP depletion in fast-growing cancer cells inhibits ribosome assembly and abolishes tumorigenesis. These data demonstrate that hCINAP reduction is a specific rate-limiting controller during rapid growth. Notably, hCINAP is highly expressed in cancers and correlated with a worse prognosis. Genome-wide polysome profiling shows that hCINAP selectively modulates cancer-associated translatome to promote malignancy. Our results connect the role of hCINAP in ribosome assembly with tumorigenesis. Modulation of hCINAP expression may be a promising target for cancer therapy. PMID:27477389

  3. Naturally occurring tumours in the basal metazoan Hydra.

    PubMed

    Domazet-Lošo, Tomislav; Klimovich, Alexander; Anokhin, Boris; Anton-Erxleben, Friederike; Hamm, Mailin J; Lange, Christina; Bosch, Thomas C G

    2014-01-01

    The molecular nature of tumours is well studied in vertebrates, although their evolutionary origin remains unknown. In particular, there is no evidence for naturally occurring tumours in pre-bilaterian animals, such as sponges and cnidarians. This is somewhat surprising given that recent computational studies have predicted that most metazoans might be prone to develop tumours. Here we provide first evidence for naturally occurring tumours in two species of Hydra. Histological, cellular and molecular data reveal that these tumours are transplantable and might originate by differentiation arrest of female gametes. Growth of tumour cells is independent from the cellular environment. Tumour-bearing polyps have significantly reduced fitness. In addition, Hydra tumours show a greatly altered transcriptome that mimics expression shifts in vertebrate cancers. Therefore, this study shows that spontaneous tumours have deep evolutionary roots and that early branching animals may be informative in revealing the fundamental mechanisms of tumorigenesis. PMID:24957317

  4. Acceleration of onset of collagen-induced arthritis by intra-articular injection of tumour necrosis factor or transforming growth factor-beta.

    PubMed Central

    Cooper, W O; Fava, R A; Gates, C A; Cremer, M A; Townes, A S

    1992-01-01

    We examined whether tumour necrosis factor (TNF) or transforming growth factor-beta 1 (TGF-beta 1) could alter the course of collagen-induced arthritis (CIA). Injection of 100 ng TNF or 500 ng TGF-beta 1 into ankle joints of normal rats induced a very limited inflammatory response, observable only upon histological analysis. However, when injected into ankle joints of rats 9 days after immunization with bovine type II collagen (CII), identical doses of TNF or TGF-beta 1 induced a sustained, clinically obvious inflammation and oedema that began within 8 h on average, as compared to 90 h in CII-immunized control rats given no injections or intra-articular injections of buffer. The incidence of arthritis at 2 weeks post-immunization was 100% for TNF-injected hindpaws, compared with 55% for the control groups, a statistically significant difference. In rats passively immunized with a subarthritic dose of affinity purified antibody to rat-CII, intra-articular injection of 100 ng TNF or 500 ng of TGF-beta 1 also induced intense, though transient arthritis. The rapid proinflammatory effects in CIA described in this study and the synergy demonstrated between anti-CII IgG and either cytokine, suggest that these cytokines can participate locally in the pathogenesis of arthritis. PMID:1638767

  5. Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis

    PubMed Central

    2011-01-01

    Somatic gene mutations constitute key events in the malignant transformation of human cells. Somatic mutation can either actively speed up the growth of tumour cells or relax the growth constraints normally imposed upon them, thereby conferring a selective (proliferative) advantage at the cellular level. Neurofibromatosis type-1 (NF1) affects 1/3,000-4,000 individuals worldwide and is caused by the inactivation of the NF1 tumour suppressor gene, which encodes the protein neurofibromin. Consistent with Knudson's two-hit hypothesis, NF1 patients harbouring a heterozygous germline NF1 mutation develop neurofibromas upon somatic mutation of the second, wild-type, NF1 allele. While the identification of somatic mutations in NF1 patients has always been problematic on account of the extensive cellular heterogeneity manifested by neurofibromas, the classification of NF1 somatic mutations is a prerequisite for understanding the complex molecular mechanisms underlying NF1 tumorigenesis. Here, the known somatic mutational spectrum for the NF1 gene in a range of NF1-associated neoplasms --including peripheral nerve sheath tumours (neurofibromas), malignant peripheral nerve sheath tumours, gastrointestinal stromal tumours, gastric carcinoid, juvenile myelomonocytic leukaemia, glomus tumours, astrocytomas and phaeochromocytomas -- have been collated and analysed. PMID:22155606

  6. Brain tumour cells interconnect to a functional and resistant network.

    PubMed

    Osswald, Matthias; Jung, Erik; Sahm, Felix; Solecki, Gergely; Venkataramani, Varun; Blaes, Jonas; Weil, Sophie; Horstmann, Heinz; Wiestler, Benedikt; Syed, Mustafa; Huang, Lulu; Ratliff, Miriam; Karimian Jazi, Kianush; Kurz, Felix T; Schmenger, Torsten; Lemke, Dieter; Gömmel, Miriam; Pauli, Martin; Liao, Yunxiang; Häring, Peter; Pusch, Stefan; Herl, Verena; Steinhäuser, Christian; Krunic, Damir; Jarahian, Mostafa; Miletic, Hrvoje; Berghoff, Anna S; Griesbeck, Oliver; Kalamakis, Georgios; Garaschuk, Olga; Preusser, Matthias; Weiss, Samuel; Liu, Haikun; Heiland, Sabine; Platten, Michael; Huber, Peter E; Kuner, Thomas; von Deimling, Andreas; Wick, Wolfgang; Winkler, Frank

    2015-12-01

    Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease. PMID:26536111

  7. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis

    PubMed Central

    Iozzo, Renato V; Sanderson, Ralph D

    2011-01-01

    Proteoglycans, key molecular effectors of cell surface and pericellular microenvironments, perform multiple functions in cancer and angiogenesis by virtue of their polyhedric nature and their ability to interact with both ligands and receptors that regulate neoplastic growth and neovascularization. Some proteoglycans such as perlecan, have pro- and anti-angiogenic activities, whereas other proteoglycans, such as syndecans and glypicans, can also directly affect cancer growth by modulating key signalling pathways. The bioactivity of these proteoglycans is further modulated by several classes of enzymes within the tumour microenvironment: (i) sheddases that cleave transmembrane or cell-associated syndecans and glypicans, (ii) various proteinases that cleave the protein core of pericellular proteoglycans and (iii) heparanases and endosulfatases which modify the structure and bioactivity of various heparan sulphate proteoglycans and their bound growth factors. In contrast, some of the small leucine-rich proteoglycans, such as decorin and lumican, act as tumour repressors by physically antagonizing receptor tyrosine kinases including the epidermal growth factor and the Met receptors or integrin receptors thereby evoking anti-survival and pro-apoptotic pathways. In this review we will critically assess the expanding repertoire of molecular interactions attributed to various proteoglycans and will discuss novel proteoglycan functions modulating cancer progression, invasion and metastasis and how these factors regulate the tumour microenvironment. PMID:21155971

  8. Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids.

    PubMed Central

    Lohmeyer, M.; Workman, P.

    1995-01-01

    A panel of 25 different lipid agents was evaluated for in vitro activity against HT29 human colon carcinoma and HL60 promyelocytic leukaemia cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The structure-activity relationships seen with this series, including those for four sets of positional or stereoisomers, indicate that specific receptor proteins are unlikely as targets for anti-tumour lipid (ATL) action. Additional data confirm the lack of involvement of the platelet-activating factor receptor in particular and suggest that metabolic stability is a most important determinant of ATL activity. More detailed studies, with 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET18-OCH3) and (+/-)-2-(Hydroxy[tetrahydro-2-(octadecyloxy)methylfuran-2- yl]methoxyphosphinyloxy)-N,N,N,-trimethylethaniminium hydroxide (SRI 62-834), suggest three different modes of activity, depending on drug concentration and exposure time. Low doses of up to 5 microM in standard serum-containing medium cause population growth arrest after prolonged exposure. Growth arrest was associated with a leaky G2/M block as determined by flow cytometry. These effects are reversible. Intermediate concentrations (5-40 microM) were cytotoxic, causing a net reduction in cell numbers after 2-3 days. At even higher concentrations, all lipids caused rapid, direct membrane lysis. When the clonogenic assay was used to assess the effects of ATLs, most agents reduced colony formation at concentrations above 5 microM. However, some compounds proved stimulatory at nanomolar concentrations, suggesting that they might possess mitogenic properties. These results, particularly those concerning the concentration and time dependence, may be relevant to current clinical trials with ether lipids. PMID:7640206

  9. Calf and disease factors affecting growth in female Holstein calves in Florida, USA.

    PubMed

    Donovan, G A; Dohoo, I R; Montgomery, D M; Bennett, F L

    1998-01-01

    A prospective cohort study was undertaken to determine calf-level factors that affect performance (growth) between birth and 14 months of age in a convenience sample of approximately 3300 female Holstein calves born in 1991 on two large Florida dairy farms. Data collected on each calf at birth included farm of origin, birth date, weight, height at the pelvis, and serum total protein (a measure of colostral immunoglobulin absorption). Birth season was dichotomized into summer and winter using meteorological data collected by University of Florida Agricultural Research Stations. Data collected at approximately 6 and 14 months of age included age, weight, height at the pelvis, and height at the withers. Growth in weight and stature (height) was calculated for each growth period; growth period 1 (GP1) = birth to 6 months, and growth period 2 (GP2) = 6 to 14 months. Health data collected included data of initial treatment and number of treatments for the diseases diarrhea, omphalitis, septicemia, pneumonia and keratoconjunctivitis. After adjusting for disease occurrence, passive transfer of colostral immunoglobulins had no significant effect on body weight gain or pelvic height growth. Season of birth and occurrence of diarrhea, septicemia and respiratory disease were significant variables decreasing heifer growth (height and weight) in GP1. These variables plus farm, birth weight and exact age when '6 month' data were collected explained 20% and 31% of the variation in body weight gain and pelvic height growth, respectively, in GP1. The number of days treated for pneumonia before 6 months of age significantly decreased average daily weight gain in GP2 (P < 0.025), but did not affect stature growth. Treatment for pneumonia after 6 months of age did not significantly affect weight or height gain after age 6 months. Neither omphalitis nor keratoconjunctivitis explained variability in growth in either of the growth periods. PMID:9500160

  10. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer

    PubMed Central

    van Geldermalsen, M; Wang, Q; Nagarajah, R; Marshall, A D; Thoeng, A; Gao, D; Ritchie, W; Feng, Y; Bailey, C G; Deng, N; Harvey, K; Beith, J M; Selinger, C I; O'Toole, S A; Rasko, J E J; Holst, J

    2016-01-01

    Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo. Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS, in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4. This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but

  11. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer.

    PubMed

    van Geldermalsen, M; Wang, Q; Nagarajah, R; Marshall, A D; Thoeng, A; Gao, D; Ritchie, W; Feng, Y; Bailey, C G; Deng, N; Harvey, K; Beith, J M; Selinger, C I; O'Toole, S A; Rasko, J E J; Holst, J

    2016-06-16

    Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo. Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS, in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4. This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but

  12. Tumour-specific CD4 T cells eradicate melanoma via indirect recognition of tumour-derived antigen.

    PubMed

    Shklovskaya, Elena; Terry, Alexandra M; Guy, Thomas V; Buckley, Adrian; Bolton, Holly A; Zhu, Erhua; Holst, Jeff; Fazekas de St. Groth, Barbara

    2016-07-01

    The importance of CD4 T cells in tumour immunity has been increasingly recognised, with recent reports describing robust CD4 T cell-dependent tumour control in mice whose immune-regulatory mechanisms have been disturbed by irradiation, chemotherapy, immunomodulatory therapy and/or constitutive immunodeficiency. Tumour control in such models has been attributed in large part to direct Major Histocompatibility Complex (MHC) class II-dependent CD4 T cell killing of tumour cells. To test whether CD4 T cells can eradicate tumours without directly killing tumour cells, we developed an animal model in which tumour-derived antigen could be presented to T-cell receptor (TCR)-transgenic CD4 T cells by host but not tumour MHC class II molecules. In I-E(+) mice bearing I-E(null) tumours, naive I-E-restricted CD4 T cells proliferated locally in tumour-draining lymph nodes after recognising tumour-derived antigen on migratory dendritic cells. In lymphopaenic but not immunosufficient hosts, CD4 T cells differentiated into polarised T helper type 1 (Th1) cells expressing interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα) and interleukin (IL)-2 but little IL-17, and cleared established tumours. Tumour clearance was enhanced by higher TCR affinity for tumour antigen-MHC class II and was critically dependent on IFNγ, as demonstrated by early tumour escape in animals treated with an IFNγ blocking antibody. Thus, CD4 T cells and IFNγ can control tumour growth without direct T-cell killing of tumour cells, and without requiring additional adaptive immune cells such as CD8 T cells and B cells. Our results support a role for effective CD4 T cell-dependent tumour immunity against MHC class II-negative tumours. PMID:26837456

  13. Dissecting the Role of Curcumin in Tumour Growth and Angiogenesis in Mouse Model of Human Breast Cancer

    PubMed Central

    Bimonte, Sabrina; Barbieri, Antonio; Palma, Giuseppe; Luciano, Antonio; D'Aiuto, Massimiliano; Arra, Claudio; Izzo, Francesco

    2015-01-01

    Breast cancer is considered the most common cancer for women worldwide and it is now the second leading cause of cancer-related deaths among females in the world. Since breast cancer is highly resistant to chemotherapy, alternative anticancer strategies have been developed. In particular, many studies have demonstrated that curcumin, a derivative of turmeric, can be used as natural agent in treatment of some types of cancer by playing antiproliferative and antioxidant effects. In our study, we assessed the antitumor activities of curcumin in ER-negative human breast cancer cell line resistant to chemotherapy, MDA.MB231 by in vitro and in vivo experiments. In vitro data allowed us to demonstrate that curcumin played a role in regulation of proliferation and apoptosis in MDA.MB231 cells. In vivo, by generation of mouse model of breast cancer, we showed that treatment of curcumin inhibited tumor growth and angiogenesis. Specifically, we showed that curcumin is able to deregulate the expression of cyclin D1, PECAM-1, and p65, which are regulated by NF-κB. Our data demonstrated that curcumin could be used as an adjuvant agent to chemotherapy in treatment of triple negative breast cancer. PMID:25879038

  14. Electrochemotherapy on liver tumours in rabbits.

    PubMed Central

    Ramirez, L. H.; Orlowski, S.; An, D.; Bindoula, G.; Dzodic, R.; Ardouin, P.; Bognel, C.; Belehradek, J.; Munck, J. N.; Mir, L. M.

    1998-01-01

    Electrochemotherapy (ECT) is a new therapeutic approach combining the effects of a low-permeant cytotoxic drug, bleomycin (BLM), administered i.v. and cell-permeabilizing electric pulses (EPs) locally delivered to tumours. The transient permeabilization of the cell membrane by the EPs allows free access of BLM to its intracellular targets, largely enhancing BLM's cytotoxic effects. ECT efficacy has been proved so far on transplanted subcutaneous murine tumours and on subcutaneous metastases in humans. Here, we present the first study of the effects of ECT on tumours transplanted to livers in rabbits. We used a recently developed EP applicator consisting of an array of parallel and equidistant needles to be inserted in tissues. Effects of EPs alone or of ECT were assessed by histological analysis, tumour growth rates and survival of the treated animals. A transient blood hypoperfusion was seen in the electropulsed areas, with or without BLM, related to EP-dependent vasoconstriction but this had no major effects on cell survival. Long-term effects depended on the presence of BLM at the time of EP delivery. Almost complete tumour necrosis was observed after ECT, resulting from both BLM direct cytotoxic effects on electropermeabilized tumour cells and indirect effects on the tumour vessels. A large reduction in tumour growth rate and significantly longer survival times were scored in comparison with control rabbits. Moreover, ECT of liver tumours was well tolerated and devoid of systemic side-effects. When ECT was associated with a local interleukin 2-based immunotherapy, increased local anti-tumour effectiveness as well as a large decrease in the number of metastases were observed. Thus, ECT could become a novel treatment modality for liver tumours and other solid internal malignancies. Images Figure 1 Figure 2 PMID:9649121

  15. Postnatal nutritional restriction affects growth and immune function of piglets with intra-uterine growth restriction.

    PubMed

    Hu, Liang; Liu, Yan; Yan, Chuan; Peng, Xie; Xu, Qin; Xuan, Yue; Han, Fei; Tian, Gang; Fang, Zhengfeng; Lin, Yan; Xu, Shengyu; Zhang, Keying; Chen, Daiwen; Wu, De; Che, Lianqiang

    2015-07-14

    Postnatal rapid growth by excess intake of nutrients has been associated with an increased susceptibility to diseases in neonates with intra-uterine growth restricted (IUGR). The aim of the present study was to determine whether postnatal nutritional restriction could improve intestinal development and immune function of neonates with IUGR using piglets as model. A total of twelve pairs of normal-birth weight (NBW) and IUGR piglets (7 d old) were randomly assigned to receive adequate nutrient intake or restricted nutrient intake (RNI) by artificially liquid feeding for a period of 21 d. Blood samples and intestinal tissues were collected at necropsy and were analysed for morphology, digestive enzyme activities, immune cells and expression of innate immunity-related genes. The results indicated that both IUGR and postnatal nutritional restriction delayed the growth rate during the sucking period. Irrespective of nutrient intake, piglets with IUGR had a significantly lower villous height and crypt depth in the ileum than the NBW piglets. Moreover, IUGR decreased alkaline phosphatase activity while enhanced lactase activity in the jejunum and mRNA expressions of Toll-like receptor 9 (TLR-9) and DNA methyltransferase 1 (DNMT1) in the ileum of piglets. Irrespective of body weight, RNI significantly decreased the number and/or percentage of peripheral leucocytes, lymphocytes and monocytes of piglets, whereas the percentage of neutrophils and the ratio of CD4+ to CD8+ were increased. Furthermore, RNI markedly enhanced the mRNA expression of TLR-9 and DNMT1, but decreased the expression of NOD2 and TRAF-6 in the ileum of piglets. In summary, postnatal nutritional restriction led to abnormal cellular and innate immune response, as well as delayed the growth and intestinal development of IUGR piglets. PMID:26059215

  16. Brown tumour of the jaw

    PubMed Central

    Nair, Preeti P; Gharote, Harshkant P; Thomas, Shaji; R, Guruprasad; Singh, Neha

    2011-01-01

    Brown tumours are classic bony lesions that arise as a result of the effect of parathyroid hormone on bone tissue in some patients with hyperparathyroidism. They are erosive bony lesions caused by rapid osteolysis and peritrabecular fibrosis, resulting in a local destructive phenomenon. Facial skeleton is involved in about 2% of all cases of which the mandible is frequently affected. A 35-year-old female who was diagnosed with osteomalacia and brown tumour in posterior mandible as the sign of secondary hyperparathyroidism secondary to vitamin D deficiency is presented. PMID:22669885

  17. Soil type affects Pinus ponderosa var. scopulorum (Pinaceae) seedling growth in simulated drought experiments1

    PubMed Central

    Lindsey, Alexander J.; Kilgore, Jason S.

    2013-01-01

    • Premise of the study: Effects of drought stress and media type interactions on growth of Pinus ponderosa var. scopulorum germinants were investigated. • Methods and Results: Soil properties and growth responses under drought were compared across four growth media types: two native soils (dolomitic limestone and granite), a soil-less industry standard conifer medium, and a custom-mixed conifer medium. After 35 d of growth, the seedlings under drought stress (reduced watering) produced less shoot and root biomass than watered control seedlings. Organic media led to decreased root biomass, but increased root length and shoot biomass relative to the mineral soils. • Conclusions: Media type affected root-to-shoot biomass partitioning of P. ponderosa var. scopulorum, which may influence net photosynthetic rates, growth, and long-term seedling survival. Further work should examine how specific soil properties like bulk density and organic matter influence biomass allocation in greenhouse studies. PMID:25202578

  18. An affective-cognitive processing model of post-traumatic growth.

    PubMed

    Joseph, Stephen; Murphy, David; Regel, Stephen

    2012-01-01

    A topic that has begun to attract interest from clinical psychologists and psychotherapists is post-traumatic growth. First, we provide a general overview of the field, setting out the historical development, main concepts, measurement issues and research findings. Second, we review evidence showing that the relationship between post-traumatic stress and post-traumatic growth is likely curvilinear. Third, a new affective-cognitive processing model of post-traumatic growth will be introduced in which post-traumatic stress is understood to be the engine of post-traumatic growth. Fourth, points of clinical intervention are described showing the ways in which therapists can facilitate post-traumatic growth. PMID:22610981

  19. Chemotherapy sensitivity testing in human tumours.

    PubMed Central

    Richmond, H G; Billington, R W

    1981-01-01

    We have attempted to establish in vitro growth in a consecutive series of 245 malignant tumours submitted for routine histopathology. Initially, three disaggregation procedures were used: mechanical separation, digestion by trypsin, and digestion by collagenase. The resulting cell fractions had varying success rates in establishing growth. Abundant epithelial cell growth was achieved in monolayer culture in 63 tumours, and the sensitivity of the cells to cytotoxic agents was tested. There was no indiscriminate cytotoxic effect, and each tumour type varied in its sensitivity from one patient's lesion to another. While testing of all solid tumours is not possible with present-day techniques, we believe that the employment of in vitro sensitivity testing as a routine procedure may be possible in the future if a suitable system giving correlation between in vitro and in vivo sensitivity can be developed. Images PMID:7240421

  20. TLR3 engagement induces IRF-3-dependent apoptosis in androgen-sensitive prostate cancer cells and inhibits tumour growth in vivo.

    PubMed

    Gambara, Guido; Desideri, Marianna; Stoppacciaro, Antonella; Padula, Fabrizio; De Cesaris, Paola; Starace, Donatella; Tubaro, Andrea; Del Bufalo, Donatella; Filippini, Antonio; Ziparo, Elio; Riccioli, Anna

    2015-02-01

    Toll-like receptors (TLRs) are a family of highly conserved transmembrane proteins expressed in epithelial and immune cells that recognize pathogen associated molecular patterns. Besides their role in immune response against infections, numerous studies have shown an important role of different TLRs in cancer, indicating these receptors as potential targets for cancer therapy. We previously demonstrated that the activation of TLR3 by the synthetic double-stranded RNA analogue poly I:C induces apoptosis of androgen-sensitive prostate cancer (PCa) LNCaP cells and, much less efficiently, of the more aggressive PC3 cell line. Therefore, in this study we selected LNCaP cells to investigate the mechanism of TLR3-mediated apoptosis and the in vivo efficacy of poly I:C-based therapy. We show that interferon regulatory factor-3 (IRF-3) signalling plays an essential role in TLR3-mediated apoptosis in LNCaP cells through the activation of the intrinsic and extrinsic apoptotic pathways. Interestingly, hardly any apoptosis was induced by poly I:C in normal prostate epithelial cells RWPE-1. We also demonstrate for the first time the direct anticancer effect of poly I:C as a single therapeutic agent in a well-established human androgen-sensitive PCa xenograft model, by showing that tumour growth is highly impaired in poly I:C-treated immunodeficient mice. Immunohistochemical analysis of PCa xenografts highlights the antitumour role of poly I:C in vivo both on cancer cells and, indirectly, on endothelial cells. Notably, we show the presence of TLR3 and IRF-3 in both human normal and PCa clinical samples, potentially envisaging poly I:C-based therapy for PCa. PMID:25444175

  1. TLR3 engagement induces IRF-3-dependent apoptosis in androgen-sensitive prostate cancer cells and inhibits tumour growth in vivo

    PubMed Central

    Gambara, Guido; Desideri, Marianna; Stoppacciaro, Antonella; Padula, Fabrizio; De Cesaris, Paola; Starace, Donatella; Tubaro, Andrea; del Bufalo, Donatella; Filippini, Antonio; Ziparo, Elio; Riccioli, Anna

    2015-01-01

    Toll-like receptors (TLRs) are a family of highly conserved transmembrane proteins expressed in epithelial and immune cells that recognize pathogen associated molecular patterns. Besides their role in immune response against infections, numerous studies have shown an important role of different TLRs in cancer, indicating these receptors as potential targets for cancer therapy. We previously demonstrated that the activation of TLR3 by the synthetic double-stranded RNA analogue poly I:C induces apoptosis of androgen-sensitive prostate cancer (PCa) LNCaP cells and, much less efficiently, of the more aggressive PC3 cell line. Therefore, in this study we selected LNCaP cells to investigate the mechanism of TLR3-mediated apoptosis and the in vivo efficacy of poly I:C-based therapy. We show that interferon regulatory factor-3 (IRF-3) signalling plays an essential role in TLR3-mediated apoptosis in LNCaP cells through the activation of the intrinsic and extrinsic apoptotic pathways. Interestingly, hardly any apoptosis was induced by poly I:C in normal prostate epithelial cells RWPE-1. We also demonstrate for the first time the direct anticancer effect of poly I:C as a single therapeutic agent in a well-established human androgen-sensitive PCa xenograft model, by showing that tumour growth is highly impaired in poly I:C-treated immunodeficient mice. Immunohistochemical analysis of PCa xenografts highlights the antitumour role of poly I:C in vivo both on cancer cells and, indirectly, on endothelial cells. Notably, we show the presence of TLR3 and IRF-3 in both human normal and PCa clinical samples, potentially envisaging poly I:C-based therapy for PCa. PMID:25444175

  2. Long non-coding RNA MALAT1 promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2 complex

    PubMed Central

    Ji, Q; Zhang, L; Liu, X; Zhou, L; Wang, W; Han, Z; Sui, H; Tang, Y; Wang, Y; Liu, N; Ren, J; Hou, F; Li, Q

    2014-01-01

    Background: Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) is a functional long non-coding RNA (lncRNA), which is highly expressed in several tumours, including colorectal cancer (CRC). Its biological function and mechanism in the prognosis of human CRC is still largely under investigation. Methods: This study aimed to investigate the new effect mechanism of MALAT1 on the proliferation and migration of CRC cells in vitro and in vivo, and detect the expression of MALAT1, SFPQ (also known as PSF (PTB-associated splicing factor)), and PTBP2 (also known as PTB (polypyrimidine-tract-binding protein)) in CRC tumour tissues, followed by correlated analysis with clinicopathological parameters. Results: We found that overexpression of MALAT1 could promote cell proliferation and migration in vitro, and promote tumour growth and metastasis in nude mice. The underlying mechanism was associated with tumour suppressor gene SFPQ and proto-oncogene PTBP2. In CRC, MALAT1 could bind to SFPQ, thus releasing PTBP2 from the SFPQ/PTBP2 complex. In turn, the increased SFPQ-detached PTBP2 promoted cell proliferation and migration. SFPQ critically mediated the regulatory effects of MALAT1. Moreover, in CRC tissues, MALAT1 and PTBP2 were overexpressed, both of which were associated closely with the invasion and metastasis of CRC. However, the SFPQ showed unchanged expression either in CRC tissues or adjacent normal tissues. Conclusions: Our findings implied that MALAT1 might be a potential predictor for tumour metastasis and prognosis. Furthermore, the interaction between MALAT1 and SFPQ could be a novel therapeutic target for CRC. PMID:25025966

  3. Disruption of the lower food web in Lake Ontario: Did it affect alewife growth or condition?

    USGS Publications Warehouse

    O'Gorman, R.; Prindle, S.E.; Lantry, J.R.; Lantry, B.F.

    2008-01-01

    From the early 1980s to the late 1990s, a succession of non-native invertebrates colonized Lake Ontario and the suite of consequences caused by their colonization became known as "food web disruption". For example, the native burrowing amphipod Diporeia spp., a key link in the profundal food web, declined to near absence, exotic predaceous cladocerans with long spines proliferated, altering the zooplankton community, and depth distributions of fishes shifted. These changes had the potential to affect growth and condition of planktivorous alewife Alosa pseudoharengus, the most abundant fish in the lake. To determine if food web disruption affected alewife, we used change-point analysis to examine alewife growth and adult alewife condition during 1976-2006 and analysis-of-variance to determine if values between change points differed significantly. There were no change points in growth during the first year of life. Of three change points in growth during the second year of life, one coincided with the shift in springtime distribution of alewife to deeper water but it was not associated with a significant change in growth. After the second year of life, no change points in growth were evident, although growth in the third year of life spiked in those years when Bythotrephes, the largest of the exotic cladocerans, was abundant suggesting that it was a profitable prey item for age-2 fish. We detected two change points in condition of adult alewife in fall, but the first occurred in 1981, well before disruption began. A second change point occurred in 2003, well after disruption began. After the springtime distribution of alewife shifted deeper during 1992-1994, growth in the first two years of life became more variable, and growth in years of life two and older became correlated (P < 0.05). In conclusion, food web disruption had no negative affect on growth and condition of alewife in Lake Ontario although it appears to have resulted in growth in the first two years of

  4. Anti-vascular endothelial growth factor antibody and nimustine as combined therapy: effects on tumour growth and angiogenesis in human glioblastoma xenografts.

    PubMed Central

    Takano, Shingo; Tsuboi, Koji; Matsumura, Akira; Nose, Tadao

    2003-01-01

    We evaluated the effectiveness of vascular endothelial growth factor (VEGF) blockade alone and in combination with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU, nimustine), a cytotoxic agent commonly used in the treatment of malignant gliomas, to eradicate tumors of human glioblastoma cell lines implanted in SCID (severe combined immunodeficiency) mice. ACNU, but not cisplatin and etoposide, elevated VEGF expression in a glioma cell line in vitro. VEGF antibody alone inhibited glioma growth in vivo as a result of angiogenesis inhibition. The combination with ACNU resulted in an additive effect for inhibition of glioma growth. ACNU also induced VEGF up-regulation in glioma tissues, which was decreased with VEGF antibody treatment. One of the mechanisms of the additive effect of the VEGF antibody and ACNU combination is the blockade of VEGF up-regulation induced by ACNU. As such, the combination of antiangiogenic therapy with conventional therapy is promising for glioma treatment in the future. PMID:12626127

  5. Potential role of TRIM3 as a novel tumour suppressor in colorectal cancer (CRC) development.

    PubMed

    Piao, Mei-Yu; Cao, Hai-Long; He, Na-Na; Xu, Meng-Que; Dong, Wen-Xiao; Wang, Wei-Qiang; Wang, Bang-Mao; Zhou, Bing

    2016-05-01

    Objective Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in the United States. Recent cancer genome-sequencing efforts and complementary functional studies have led to the identification of a collection of candidate 'driver' genes involved in CRC tumorigenesis. Tripartite motif (TRIM3) is recently identified as a tumour suppressor in glioblastoma but this tumour-suppressive function has not been investigated in CRC. Material and methods In this study, we investigated the potential role of TRIM3 as a tumour suppressor in CRC development by manipulating the expression of TRIM3 in two authentic CRC cell lines, HCT116 and DLD1, followed by various functional assays, including cell proliferation, colony formation, scratch wound healing, soft agar, and invasion assays. Xenograft experiment was performed to examine in vivo tumour-suppressive properties of TRIM3. Results Small-interfering RNA (siRNA) mediated knockdown of TRIM3 conferred growth advantage in CRC cells. In contrast, overexpression of TRIM3 affected cell survival, cell migration, anchorage independent growth and invasive potential in CRC cells. In addition, TRIM3 was found to be down-regulated in human colon cancer tissues compared with matched normal colon tissues. Overexpression of TRIM3 significantly inhibited tumour growth in vivo using xenograft mouse models. Mechanistic investigation revealed that TRIM3 can regulate p53 protein level through its stabilisation. Conclusions TRIM3 functions as a tumour suppressor in CRC progression. This tumour-suppressive function is exerted partially through regulation of p53 protein. Therefore, this protein may represent a novel therapeutic target for prevention or intervention of CRC. PMID:26691157

  6. CO2 enrichment at night affects the growth and yield of common beans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Some experiments to determine the crop yield increase expected with rising atmospheric carbon dioxide concentration added carbon dioxide only during the daytime, without tests of whether elevation of carbon dioxide at night affected plant growth. In this experiment, two cultivars of common bean wer...

  7. Sertoliform cystadenoma: a rare benign tumour of the rete testis

    PubMed Central

    2013-01-01

    Abstract Sertoliform cystadenoma of the rete testis represents an uncommon benign tumour. They appear in patients from 26 to 62 years of age. We describe a case of a 66-year-old man with a tumour in the area of the epididymal head. The tumour markers were not increased. Under the assumption of a malignant testicular tumour an inguinal orchiectomy was performed. The cut surface of this tumour was of grey/white color and showed small cysts. The tumour consisted of two compartments. The epithelial like tumour cells showed a sertoliform growth pattern and cystic dilatations. In between the tumour cells repeatedly actin expressing sclerotic areas could be recognized as the second tumour component. Proliferative activity was not increased. Immunohistochemically the tumour cells were positiv for inhibin, S-100, and CD 99. Alpha feto protein (AFP), human chorionic gonadotropin (ß-HCG) and placental alkaline phosphatase (PLAP) as well as synaptophysin, epithelial membrane antigene (EMA), and BCL-2 were not expressed. As far as we know this is the sixth reported case of this tumour. Because of the benign nature of this tumour the correct diagnosis is important for the intra- and postoperative management. Here we present a case of this rare tumour and discuss potential differential diagnosis. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1956026143857335 PMID:23406299

  8. Dental caries affects body weight, growth and quality of life in pre-school children.

    PubMed

    Sheiham, A

    2006-11-25

    The effect of a relatively common chronic disease, severe dental caries, affects young childrens' growth and well-being. Treating dental caries in pre-school children would increase growth rates and the quality of life of millions of children. Severe untreated dental caries is common in pre-school children in many countries. Children with severe caries weighed less than controls, and after treatment of decayed teeth there was more rapid weight gain and improvements in their quality of life. This may be due to dietary intake improving because pain affected the quantity and variety of food eaten, and second, chronic inflammation from caries related pulpitis and abscesses is known to suppress growth through a metabolic pathway and to reduce haemoglobin as a result of depressed erythrocyte production. PMID:17128231

  9. Quercetin mediated reduction of angiogenic markers and chaperones in DLA-induced solid tumours.

    PubMed

    Anand, Kushi; Asthana, Pallavi; Kumar, Anup; Ambasta, Rashmi K; Kumar, Pravir

    2011-01-01

    Diet-derived flavonoids, in particular quercetin, may play advantageous roles by preventing or/and inhibiting oncogenesis. Evidence suggests that quercetin can elicit various properties depending on the cell type. The aim of this study was to evaluate its effects on Dalton's lymphoma ascites (DLA) induced solid tumours and to identify the target(s) of action. We addressed this question by inducing subcutaneous solid tumours in Swiss albino mice and investigated whether the quercetin affects essential biological processes that are responsible for tumour growth, morphology, angiogenesis and apoptosis. We also studied influence on several heat shock proteins (HSPs). Our findings demonstrate that intra-tumour administration of quercetin results in decreased volume/weight. Furthermore, we demonstrate that quercetin promotes apoptosis of cancer cells by down-regulating the levels of Hsp90 and Hsp70. Depletion of these two chaperones by quercetin might result in triggering of caspase-3 in treated tumours. Moreover, it also down-regulated the expression of major key angiogenic or pro-angiogenic factors, like HIF-1α and VEGF In addition, H and E staining together with immunofluorescence of fixed tumour tissue provided evidence in support of increased cell death in quercetin-treated mice. PMID:22393949

  10. Tailored nanoparticles for tumour therapy.

    PubMed

    Jiang, Pei-Shin; Drake, Philip; Cho, Hui-Ju; Kao, Chao-Hung; Lee, Kun-Feng; Kuo, Chien-Hung; Lin, Xi-Zhang; Lin, Yuh-Jiuan

    2012-06-01

    Gd doped iron-oxide nanoparticles were developed for use in tumour therapy via magnetic fluid hyperthermia (MFH). The effect of the Gd3+ dopant on the particle size and magnetic properties was investigated. The final particle composition varied from Gd0.01Fe2.99O4 to Gd0.04Fe2.96O4 as determined by Inductively coupled plasma atomic emission spectroscopy (ICP-AES). TEM image analysis showed the average magnetic core diameters to be 12 nm and 33 nm for the lowest and highest Gd levels respectively. The specific power adsorption rate (SAR) determined with a field strength of 246 Oe and 52 kHz had a maximum of 38Wg(-1) [Fe] for the Gd0.03Fe2.97O4 sample. This value is about 4 times higher than the reported SAR values for Fe3O4. The potential for in vivo tumour therapy was investigated using a mouse model. The mouse models treated with Gd0.02Fe2.98O4 displayed much slower tumour growth after the first treatment cycle, the tumour had increased its mass by 25% after 7 days post treatment compared to a 79% mass increase over the same period for those models treated with standard iron-oxide or saline solution. After a second treatment cycle the mouse treated with Gd0.02Fe2.98O4 showed complete tumour regression with no tumour found for at least 5 days post treatment. PMID:22905580

  11. In vivo photoacoustic imaging of tyrosinase expressing tumours in mice

    NASA Astrophysics Data System (ADS)

    Laufer, Jan; Jathoul, Amit; Johnson, Peter; Zhang, Edward; Lythgoe, Mark; Pedley, R. Barbara; Pule, Martin; Beard, Paul

    2012-02-01

    Two human tumour cell lines (K562, 293T) were stably transfected to achieve the genetic expression of tyrosinase, which is involved in the production of the pigment eumelanin. The cells were injected subcutaneously into nude mice to form tumour xenografts, which were imaged over a period of up to 26 days using an all-optical photoacoustic imaging system. 3D photoacoustic images of the tumours and the surrounding vasculature were acquired at excitation wavelengths ranging from 600nm to 770nm. The images showed tumour growth and continued tyrosinase expression over the full 26 day duration of the study. These findings were confirmed by histological analysis of excised tumour samples.

  12. Fusarium Oxysporum Volatiles Enhance Plant Growth Via Affecting Auxin Transport and Signaling

    PubMed Central

    Bitas, Vasileios; McCartney, Nathaniel; Li, Ningxiao; Demers, Jill; Kim, Jung-Eun; Kim, Hye-Seon; Brown, Kathleen M.; Kang, Seogchan

    2015-01-01

    Volatile organic compounds (VOCs) have well-documented roles in plant-plant communication and directing animal behavior. In this study, we examine the less understood roles of VOCs in plant-fungal relationships. Phylogenetically and ecologically diverse strains of Fusarium oxysporum, a fungal species complex that often resides in the rhizosphere of assorted plants, produce volatile compounds that augment shoot and root growth of Arabidopsis thaliana and tobacco. Growth responses of A. thaliana hormone signaling mutants and expression patterns of a GUS reporter gene under the auxin-responsive DR5 promoter supported the involvement of auxin signaling in F. oxysporum volatile-mediated growth enhancement. In addition, 1-naphthylthalamic acid, an inhibitor of auxin efflux, negated F. oxysporum volatile-mediated growth enhancement in both plants. Comparison of the profiles of volatile compounds produced by F. oxysporum strains that differentially affected plant growth suggests that the relative compositions of both growth inhibitory and stimulatory compounds may determine the degree of plant growth enhancement. Volatile-mediated signaling between fungi and plants may represent a potentially conserved, yet mostly overlooked, mechanism underpinning plant-fungus interactions and fungal niche adaption. PMID:26617587

  13. Controlled Cu nanoparticle growth on wrinkle affecting deposition of large scale graphene

    NASA Astrophysics Data System (ADS)

    Ahmed, Mohsin; Uddin, Md Jasim; Rahman, Muhammad Anisur; Kishi, Naoki; Soga, Tetsuo

    2016-09-01

    For Chemical Vapor Deposition (CVD) grown graphene on Cu substrate, deviation from atomic orientation in crystals may be resulted from diffusion of abnormalities in the form of Cu nanoparticle (NP) formation or defects and affects graphene quality and properties drastically. However, for the uniform graphene deposition, mechanism of nanoparticle formation and its suppression procedure need to be better understood. We report growth of graphene, affected by Cu nanoparticles (NPs) emergence on Cu substrates. In the current study, growth of these nanoparticles has been suppressed by fine tuning of carrier gas by two-fold gas insertion mechanism and hence, quality and uniformity of graphene is significantly improved. It has been also observed that during the deposition by CVD, Cu nanoparticles cluster preferentially on wrinkles or terrace of the Cu surface. Composition of NP is extensively studied and found to be the oxide nanoparticle of Cu. Our result, controlled NP growth affecting deposition of graphene layer would provide useful insight on the growth of uniform and high quality Single layer or bilayer graphene for numerous electronics applications.

  14. Tumour-associated tenascin-C isoforms promote breast cancer cell invasion and growth by matrix metalloproteinase-dependent and independent mechanisms

    PubMed Central

    Hancox, Rachael A; Allen, Michael D; Holliday, Deborah L; Edwards, Dylan R; Pennington, Caroline J; Guttery, David S; Shaw, Jacqueline A; Walker, Rosemary A; Pringle, J Howard; Jones, J Louise

    2009-01-01

    Introduction The stromal microenvironment has a profound influence on tumour cell behaviour. In tumours, the extracellular matrix (ECM) composition differs from normal tissue and allows novel interactions to influence tumour cell function. The ECM protein tenascin-C (TNC) is frequently up-regulated in breast cancer and we have previously identified two novel isoforms – one containing exon 16 (TNC-16) and one containing exons 14 plus 16 (TNC-14/16). Methods The present study has analysed the functional significance of this altered TNC isoform profile in breast cancer. TNC-16 and TNC-14/16 splice variants were generated using PCR-ligation and over-expressed in breast cancer cells (MCF-7, T47D, MDA-MD-231, MDA-MB-468, GI101) and human fibroblasts. The effects of these variants on tumour cell invasion and proliferation were measured and compared with the effects of the large (TNC-L) and fully spliced small (TNC-S) isoforms. Results TNC-16 and TNC-14/16 significantly enhanced tumour cell proliferation (P < 0.05) and invasion, both directly (P < 0.01) and as a response to transfected fibroblast expression (P < 0.05) with this effect being dependent on tumour cell interaction with TNC, because TNC-blocking antibodies abrogated these responses. An analysis of 19 matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinases 1 to 4 (TIMP 1 to 4) revealed that TNC up-regulated expression of MMP-13 and TIMP-3 two to four fold relative to vector, and invasion was reduced in the presence of MMP inhibitor GM6001. However, this effect was not isoform-specific but was elicited equally by all TNC isoforms. Conclusions These results demonstrate a dual requirement for TNC and MMP in enhancing breast cancer cell invasion, and identify a significant role for the tumour-associated TNC-16 and TNC-14/16 in promoting tumour invasion, although these isoform-specific effects appear to be mediated through MMP-independent mechanisms. PMID:19405959

  15. Primary malignant tumours of the duodenum.

    PubMed

    Nix, G A; Wilson, J H; Dees, J

    1985-04-01

    The clinical and radiological findings in 19 patients with primary duodenal malignancy are described. Weight loss, abdominal pain, nausea and vomiting were the main symptoms. Diagnosis was made by endoscopy or ERCP (71%) or by barium studies (68%). In retrospect the tumour was visible in 97% of the studies. Tumour growth was longitudinal, circular or spiral, the inner curvature being involved over a greater length than the outer curvature. Exophytic tumour growth, involvement of the papilla of Vater, malignant spikes, transient, non-constant tumour image, skip lesions and ulceration were often seen. Mean survival time was 18 months from start of symptoms in 10 inoperable patients, and 24 months in 9 patients undergoing resection. PMID:2986213

  16. Brain and spinal tumour.

    PubMed

    Goh, C H; Lu, Y Y; Lau, B L; Oy, J; Lee, H K; Liew, D; Wong, A

    2014-12-01

    This study reviewed the epidemiology of brain and spinal tumours in Sarawak from January 2009 till December 2012. The crude incidence of brain tumour in Sarawak was 4.6 per 100,000 population/year with cumulative rate 0.5%. Meningioma was the most common brain tumour (32.3%) and followed by astrocytoma (19.4%). Only brain metastases showed a rising trend and cases were doubled in 4 years. This accounted for 15.4% and lung carcinoma was the commonest primary. Others tumour load were consistent. Primitive neuroectodermal tumour (PNET) and astrocytoma were common in paediatrics (60%). We encountered more primary spinal tumour rather than spinal metastases. Intradural schwannoma was the commonest and frequently located at thoracic level. The current healthcare system in Sarawak enables a more consolidate data collection to reflect accurate brain tumours incidence. This advantage allows subsequent future survival outcome research and benchmarking for healthcare resource planning. PMID:25934956

  17. MicroRNA-497 targets insulin-like growth factor 1 receptor and has a tumour suppressive role in human colorectal cancer

    PubMed Central

    Guo, S T; Jiang, C C; Wang, G P; Li, Y P; Wang, C Y; Guo, X Y; Yang, R H; Feng, Y; Wang, F H; Tseng, H-Y; Thorne, R F; Jin, L; Zhang, X D

    2013-01-01

    Past studies have shown that amplified insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1-R) signalling has an important role in colorectal cancer (CRC) development, progression and resistance to treatment. In this report, we demonstrate that downregulation of microRNA-497 (miR-497) as a result of DNA copy number reduction is involved in upregulation of IGF1-R in CRC cells. MiR-497 and miR-195 of the miR-15/16/195/424/497 family that share the same 3′ untranslated region (3′UTR) binding seed sequence and are predicted to target IGF1-R were concurrently downregulated in the majority of CRC tissues relative to paired adjacent normal mucosa. However, only overexpression of miR-497 led to suppression of the IGF1-R 3′UTR activity and downregulation of the endogenous IGF1-R protein in CRC cells. This was associated with inhibition of cell survival, proliferation and invasion, and increased sensitivity to apoptosis induced by various stimuli including the chemotherapeutic drugs cisplatin and 5-fluorouracil, and the death ligand tumour necrosis factor-related apoptosis-inducing ligand. The biological effect of miR-497 on CRC cells was largely mediated by inhibition of phosphatidylinositol 3-kinase/Akt signalling, as overexpression of an active form of Akt reversed its impact on cell survival and proliferation, recapitulating the effect of overexpression of IGF1-R. Downregulation of miR-497 and miR-195 appeared to associate with copy number loss of a segment of chromosome 17p13.1, where these miRs are located at proximity. Similarly to miR-195, the members of the same miR family, miR-424 that was upregulated, and miR-15a, miR-15b and miR-16 that were unaltered in expression in CRC tissues compared with paired adjacent normal mucosa, did not appear to have a role in regulating the expression of IGF1-R. Taken together, these results identify downregulation of miR-497 as an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of

  18. Experimental icing affects growth, mortality, and flowering in a high Arctic dwarf shrub.

    PubMed

    Milner, Jos M; Varpe, Øystein; van der Wal, René; Hansen, Brage Bremset

    2016-04-01

    Effects of climate change are predicted to be greatest at high latitudes, with more pronounced warming in winter than summer. Extreme mid-winter warm spells and heavy rain-on-snow events are already increasing in frequency in the Arctic, with implications for snow-pack and ground-ice formation. These may in turn affect key components of Arctic ecosystems. However, the fitness consequences of extreme winter weather events for tundra plants are not well understood, especially in the high Arctic. We simulated an extreme mid-winter rain-on-snow event at a field site in high Arctic Svalbard (78°N) by experimentally encasing tundra vegetation in ice. After the subsequent growing season, we measured the effects of icing on growth and fitness indices in the common tundra plant, Arctic bell-heather (Cassiope tetragona). The suitability of this species for retrospective growth analysis enabled us to compare shoot growth in pre and postmanipulation years in icing treatment and control plants, as well as shoot survival and flowering. Plants from icing treatment plots had higher shoot mortality and lower flowering success than controls. At the individual sample level, heavily flowering plants invested less in shoot growth than nonflowering plants, while shoot growth was positively related to the degree of shoot mortality. Therefore, contrary to expectation, undamaged shoots showed enhanced growth in ice treatment plants. This suggests that following damage, aboveground resources were allocated to the few remaining undamaged meristems. The enhanced shoot growth measured in our icing treatment plants has implications for climate studies based on retrospective analyses of Cassiope. As shoot growth in this species responds positively to summer warming, it also highlights a potentially complex interaction between summer and winter conditions. By documenting strong effects of icing on growth and reproduction of a widespread tundra plant, our study contributes to an understanding of

  19. Insulin-like growth factor- I and factors affecting it in thalassemia major

    PubMed Central

    Soliman, Ashraf T.; Sanctis, Vincenzo De; Elalaily, Rania; Yassin, Mohamed

    2015-01-01

    Despite improvement of blood transfusion regimens and iron chelation therapy growth and maturational delay, cardiomyopathy, endocrinopathies and osteoporosis still occur in good number of thalassemic patients. Decreased IGF-1 secretion occurs in the majority of the thalassemic patients particularly those with growth and pubertal delay. Many factors contribute to this decreased synthesis of IGF-I including disturbed growth hormone (GH) - insulin-like growth factor - I (IGF-I) axis. The possible factors contributing to low IGF-I synthesis in thalassemia and the possible interaction between low IGF-I secretion and the occurrence of these complications is discussed in this mini-review. Improvement of IGF-I secretion in thalassemic patients should be intended to improve linear growth and bone mineral accretion in thalassemic patients. This can be attained through adequate correction of anemia and proper chelation, nutritional supplementation (increasing caloric intake), correction of vitamin D and zinc deficiencies, induction of puberty and correction of hypogonadism at the proper time and treating GH deficiency. This review paper provides a summary of the current state of knowledge regarding IGF-I and factors affecting it in patients with thalassaemia major (TM). Search on PubMed and reference lists of articles with the term ‘IGF-I, GH, growth, thalassemia, thyroxine, anemia, vitamin D, and zinc’ was carried out. A hundred and forty-eight articles were found and used in the write up and the data analyzed was included in this report. PMID:25729686

  20. Pleiotropic Genes Affecting Carcass Traits in Bos indicus (Nellore) Cattle Are Modulators of Growth.

    PubMed

    G T Pereira, Anirene; Utsunomiya, Yuri T; Milanesi, Marco; Torrecilha, Rafaela B P; Carmo, Adriana S; Neves, Haroldo H R; Carvalheiro, Roberto; Ajmone-Marsan, Paolo; Sonstegard, Tad S; Sölkner, Johann; Contreras-Castillo, Carmen J; Garcia, José F

    2016-01-01

    Two complementary methods, namely Multi-Trait Meta-Analysis and Versatile Gene-Based Test for Genome-wide Association Studies (VEGAS), were used to identify putative pleiotropic genes affecting carcass traits in Bos indicus (Nellore) cattle. The genotypic data comprised over 777,000 single-nucleotide polymorphism markers scored in 995 bulls, and the phenotypic data included deregressed breeding values (dEBV) for weight measurements at birth, weaning and yearling, as well visual scores taken at weaning and yearling for carcass finishing precocity, conformation and muscling. Both analyses pointed to the pleomorphic adenoma gene 1 (PLAG1) as a major pleiotropic gene. VEGAS analysis revealed 224 additional candidates. From these, 57 participated, together with PLAG1, in a network involved in the modulation of the function and expression of IGF1 (insulin like growth factor 1), IGF2 (insulin like growth factor 2), GH1 (growth hormone 1), IGF1R (insulin like growth factor 1 receptor) and GHR (growth hormone receptor), suggesting that those pleiotropic genes operate as satellite regulators of the growth pathway. PMID:27410030

  1. Pleiotropic Genes Affecting Carcass Traits in Bos indicus (Nellore) Cattle Are Modulators of Growth

    PubMed Central

    Milanesi, Marco; Torrecilha, Rafaela B. P.; Carmo, Adriana S.; Neves, Haroldo H. R.; Carvalheiro, Roberto; Ajmone-Marsan, Paolo; Sonstegard, Tad S.; Sölkner, Johann; Contreras-Castillo, Carmen J.; Garcia, José F.

    2016-01-01

    Two complementary methods, namely Multi-Trait Meta-Analysis and Versatile Gene-Based Test for Genome-wide Association Studies (VEGAS), were used to identify putative pleiotropic genes affecting carcass traits in Bos indicus (Nellore) cattle. The genotypic data comprised over 777,000 single-nucleotide polymorphism markers scored in 995 bulls, and the phenotypic data included deregressed breeding values (dEBV) for weight measurements at birth, weaning and yearling, as well visual scores taken at weaning and yearling for carcass finishing precocity, conformation and muscling. Both analyses pointed to the pleomorphic adenoma gene 1 (PLAG1) as a major pleiotropic gene. VEGAS analysis revealed 224 additional candidates. From these, 57 participated, together with PLAG1, in a network involved in the modulation of the function and expression of IGF1 (insulin like growth factor 1), IGF2 (insulin like growth factor 2), GH1 (growth hormone 1), IGF1R (insulin like growth factor 1 receptor) and GHR (growth hormone receptor), suggesting that those pleiotropic genes operate as satellite regulators of the growth pathway. PMID:27410030

  2. Inhibition of Lysyl Oxidase and Lysyl Oxidase-Like Enzymes Has Tumour-Promoting and Tumour-Suppressing Roles in Experimental Prostate Cancer

    PubMed Central

    Nilsson, Maria; Adamo, Hanibal; Bergh, Anders; Halin Bergström, Sofia

    2016-01-01

    Lysyl oxidase (LOX) and LOX-like (LOXL) enzymes are key players in extracellular matrix deposition and maturation. LOX promote tumour progression and metastasis, but it may also have tumour-inhibitory effects. Here we show that orthotopic implantation of rat prostate AT-1 tumour cells increased LOX and LOXLs mRNA expressions in the tumour and in the surrounding non-malignant prostate tissue. Inhibition of LOX enzymes, using Beta-aminopropionitrile (BAPN), initiated before implantation of AT-1 cells, reduced tumour growth. Conversely, treatment that was started after the tumours were established resulted in unaffected or increased tumour growth. Moreover, treatment with BAPN did not suppress the formation of spontaneous lymph node metastases, or lung tumour burden, when tumour cells were injected intravenously. A temporal decrease in collagen fibre content, which is a target for LOX, was observed in tumours and in the tumour-adjacent prostate tissue. This may explain why early BAPN treatment is more effective in inhibiting tumour growth compared to treatment initiated later. Our data suggest that the enzymatic function of the LOX family is context-dependent, with both tumour-suppressing and tumour-promoting properties in prostate cancer. Further investigations are needed to understand the circumstances under which LOX inhibition may be used as a therapeutic target for cancer patients. PMID:26804196

  3. SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours

    PubMed Central

    Khatri, A; Williams, B W; Fisher, J; Brundage, R C; Gurvich, V J; Lis, L G; Skubitz, K M; Dudek, A Z; Greeno, E W; Kratzke, R A; Lamba, J K; Kirstein, M N

    2014-01-01

    Background: Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition. Methods: Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development. Results: The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m−2 min−1 and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP. Conclusion: Prolonged dFdCTP systemic exposures (⩾72 h) were commonly observed. Infusion rate <25 mg m−2 min−1 and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear. PMID:24300978

  4. Growth of Bacillus cereus on solid media as affected by agar, sodium chloride, and potassium sorbate.

    PubMed

    Stecchini, M L; Del Torre, M; Donda, S; Maltini, E

    2000-07-01

    The effect of two independent variables: microstructure, as modified by the agar content (1.0, 4.0, 7.0%), and water activity (a(w)), as modified by the NaCl content (0.5, 2.5, 4.5%), in the absence or in the presence of potassium sorbate (0.0; 2,000 ppm) on Bacillus cereus growth on solid media was studied. The time to visible growth (TVG) and the radial growth rate (RGR) of colonies were evaluated. TVG was not affected by microstructure and K-sorbate, although when a(w) was reduced, TVG tended to increase. RGR depended on linear effects of microstructure and a(w) variables and their interaction. When K-sorbate was added to cultural media, RGR was reduced significantly. However, in the presence of K-sorbate, RGR was found to change only when a(w) vas varied. PMID:10914662

  5. Gonadotropin ratio affects the in vitro growth of rhesus ovarian preantral follicles.

    PubMed

    Kim, Yoon Young; Yun, Jun-Won; Kim, Jong Min; Park, Chung Gyu; Rosenwaks, Zev; Liu, Hung Ching; Kang, Byeong-Cheol; Ku, Seung-Yup

    2016-04-01

    In vitro follicle growth (IVFG) strategy is critical in the fertility preservation of cancer survivors; however, its optimal protocol needs to be developed using primate models since the availability of human samples is limited. Only a few previous studies have reported the successful IVFG of rhesus monkey ovaries using low-dose follicle-stimulating hormone (FSH) (0.3 or 3 ng/mL) and long-term culture (up to 5 weeks) and it is still uncertain in regard to the optimal culture duration and effective dose of treated gonadotropins applicable to the IVFG of rhesus preantral follicles. Recently, we have reported that the FSH to luteinizing hormone (LH) ratio affects the in vitro growth of murine ovarian follicles. We aimed to investigate whether gonadotropin ratios affect the efficiency of rhesus follicular growth in vitro Ovaries were collected from six necropsied rhesus macaques (4-9 years) and preantral follicles were retrieved and cultured for 14 days using 200 mIU/mL FSH. The characteristics of follicular growth were compared between the FSH:LH=1:1 (n=24) and FSH:LH=2:1 (n=24) groups. High concentration gonadotropin treatment shortened the duration required for in vitro maturation of rhesus preantral follicles. The FSH:LH=2:1 group showed a faster follicular growth and enabled the acquisition of mature oocytes, although the expression of growth differentiation factor (GDF)-9 and anti-Müllerian hormone (AMH) did not differ significantly between the two groups. Taken together, high dose gonadotropin treatment can shorten the duration of IVFG and the gonadotropin ratio is important in the IVFG of rhesus monkey ovaries. PMID:26980777

  6. Gonadotropin ratio affects the in vitro growth of rhesus ovarian preantral follicles

    PubMed Central

    Kim, Yoon Young; Yun, Jun-Won; Kim, Jong Min; Park, Chung Gyu; Rosenwaks, Zev; Liu, Hung Ching; Kang, Byeong-Cheol; Ku, Seung-Yup

    2016-01-01

    In vitro follicle growth (IVFG) strategy is critical in the fertility preservation of cancer survivors; however, its optimal protocol needs to be developed using primate models since the availability of human samples is limited. Only a few previous studies have reported the successful IVFG of rhesus monkey ovaries using low-dose follicle-stimulating hormone (FSH) (0.3 or 3 ng/mL) and long-term culture (up to 5 weeks) and it is still uncertain in regard to the optimal culture duration and effective dose of treated gonadotropins applicable to the IVFG of rhesus preantral follicles. Recently, we have reported that the FSH to luteinizing hormone (LH) ratio affects the in vitro growth of murine ovarian follicles. We aimed to investigate whether gonadotropin ratios affect the efficiency of rhesus follicular growth in vitro. Ovaries were collected from six necropsied rhesus macaques (4–9 years) and preantral follicles were retrieved and cultured for 14 days using 200 mIU/mL FSH. The characteristics of follicular growth were compared between the FSH:LH=1:1 (n=24) and FSH:LH=2:1 (n=24) groups. High concentration gonadotropin treatment shortened the duration required for in vitro maturation of rhesus preantral follicles. The FSH:LH=2:1 group showed a faster follicular growth and enabled the acquisition of mature oocytes, although the expression of growth differentiation factor (GDF)-9 and anti-Müllerian hormone (AMH) did not differ significantly between the two groups. Taken together, high dose gonadotropin treatment can shorten the duration of IVFG and the gonadotropin ratio is important in the IVFG of rhesus monkey ovaries. PMID:26980777

  7. Genes related to growth regulation, DNA repair and apoptosis in an oestrogen receptor-negative (MDA-231) versus an oestrogen receptor-positive (MCF-7) breast tumour cell line.

    PubMed

    Skog, Sven; He, Qimin; Khoshnoud, Reza; Fornander, Tommy; Rutqvist, Lars-Erik

    2004-01-01

    The molecular mechanism(s) behind the development of endocrine resistance in breast cancer remains controversial. Here, we compare the capability of oestrogen receptor (ER)-negative cells (MDA-231) versus ER-positive tamoxifen-sensitive cells (MCF-7) to handle DNA repair, transmit signals from damaged DNA, initiate cell death via apoptosis, and then to control transmitted signals from the cell cycle and to synthesize growth factors and receptors. Genes related to these events were studied by cDNA micro-array. Normal human breast cells (H2F) and human lymphoblastoid tumour cells (CEM) were used as controls. Of the 18 genes investigated, 10 genes showed differences in their expression between the cell types. The ER-negative cells showed higher expressions of BRCA1, BRCA2, cdc2, cyclin B1, cyclin D1, cyclin E, IGFBP-3, TGF-alpha, TGF beta 2 and a lower expression of TGF beta R1. No differences in the expressions of bax, bcl-2, p53, p21 and GADD45 were found between the two cell lines. We found that the ER-negative cells were characterized by: (1) a stimulated expression of growth factors and cell cycle regulation compounds, (2) improved DNA repair capacity, but (3) no change in DNA damage signals and apoptotic pathways. Improved DNA repair capacity of ER-negative cells would have a growth advantage over ER-positive tumours when receiving antitumour therapy. PMID:15192311

  8. Rearing Tenebrio molitor in BLSS: Dietary fiber affects larval growth, development, and respiration characteristics

    NASA Astrophysics Data System (ADS)

    Li, Leyuan; Stasiak, Michael; Li, Liang; Xie, Beizhen; Fu, Yuming; Gidzinski, Danuta; Dixon, Mike; Liu, Hong

    2016-01-01

    Rearing of yellow mealworm (Tenebrio molitor L.) will provide good animal nutrition for astronauts in a bioregenerative life support system. In this study, growth and biomass conversion data of T. molitor larvae were tested for calculating the stoichiometric equation of its growth. Result of a respiratory quotient test proved the validity of the equation. Fiber had the most reduction in mass during T. molitor‧s consumption, and thus it is speculated that fiber is an important factor affecting larval growth of T. molitor. In order to further confirm this hypothesis and find out a proper feed fiber content, T. molitor larvae were fed on diets with 4 levels of fiber. Larval growth, development and respiration in each group were compared and analyzed. Results showed that crude-fiber content of 5% had a significant promoting effect on larvae in early instars, and is beneficial for pupa eclosion. When fed on feed of 5-10% crude-fiber, larvae in later instars reached optimal levels in growth, development and respiration. Therefore, we suggest that crude fiber content in feed can be controlled within 5-10%, and with the consideration of food palatability, a crude fiber of 5% is advisable.

  9. Root cooling strongly affects diel leaf growth dynamics, water and carbohydrate relations in Ricinus communis.

    PubMed

    Poiré, Richard; Schneider, Heike; Thorpe, Michael R; Kuhn, Arnd J; Schurr, Ulrich; Walter, Achim

    2010-03-01

    In laboratory and greenhouse experiments with potted plants, shoots and roots are exposed to temperature regimes throughout a 24 h (diel) cycle that can differ strongly from the regime under which these plants have evolved. In the field, roots are often exposed to lower temperatures than shoots. When the root-zone temperature in Ricinus communis was decreased below a threshold value, leaf growth occurred preferentially at night and was strongly inhibited during the day. Overall, leaf expansion, shoot biomass growth, root elongation and ramification decreased rapidly, carbon fluxes from shoot to root were diminished and carbohydrate contents of both root and shoot increased. Further, transpiration rate was not affected, yet hydrostatic tensions in shoot xylem increased. When root temperature was increased again, xylem tension reduced, leaf growth recovered rapidly, carbon fluxes from shoot to root increased, and carbohydrate pools were depleted. We hypothesize that the decreased uptake of water in cool roots diminishes the growth potential of the entire plant - especially diurnally, when the growing leaf loses water via transpiration. As a consequence, leaf growth and metabolite concentrations can vary enormously, depending on root-zone temperature and its heterogeneity inside pots. PMID:19968824

  10. Shoot Turgor Does Not Limit Shoot Growth of NaCl-Affected Wheat and Barley 1

    PubMed Central

    Termaat, Annie; Passioura, John B.; Munns, Rana

    1985-01-01

    The aim of this work was to test the hypothesis that the reduced growth rate of wheat and barley that results when the roots are exposed to NaCl is due to inadequate turgor in the expanding cells of the leaves. The hypothesis was tested by exposing plants to 100 millimolar NaCl (which reduced their growth rates by about 20%), growing them for 7 to 10 days with their roots in pressure chambers, and applying sufficient pneumatic pressure in the chambers to offset the osmotic pressure of the NaCl, namely, 0.48 megapascals. The results showed that applying the pressure had no sustained effect (relative to unpressurized controls) on growth rates, transpiration rates, or osmotic pressures of the cell sap, in either the fully expanded or currently expanding leaf tissue, of both wheat and barley. The results indicate that the applied pressure correspondingly increased turgor in the shoot although this was not directly measured. We conclude that shoot turgor alone was not regulating the growth of these NaCl-affected plants, and, after discussing other possible influences, argue that a message arising in the roots may be regulating the growth of the shoot. PMID:16664152

  11. Ozone affects gas exchange, growth and reproductive development in Brassica campestris (Wisconsin fast plants).

    PubMed

    Black, V J; Stewart, C A; Roberts, J A; Black, C R

    2007-01-01

    Exposure to ozone (O(3)) may affect vegetative and reproductive development, although the consequences for yield depend on the effectiveness of the compensatory processes induced. This study examined the impact on reproductive development of exposing Brassica campestris (Wisconsin Fast Plants) to ozone during vegetative growth. Plants were exposed to 70 ppb ozone for 2 d during late vegetative growth or 10 d spanning most of the vegetative phase. Effects on gas exchange, vegetative growth, reproductive development and seed yield were determined. Impacts on gas exchange and foliar injury were related to pre-exposure stomatal conductance. Exposure for 2 d had no effect on growth or reproductive characteristics, whereas 10-d exposure reduced vegetative growth and reproductive site number on the terminal raceme. Mature seed number and weight per pod and per plant were unaffected because seed abortion was reduced. The observation that mature seed yield per plant was unaffected by exposure during the vegetative phase, despite adverse effects on physiological, vegetative and reproductive processes, shows that indeterminate species such as B. campestris possess sufficient compensatory flexibility to avoid reductions in seed production. PMID:17803646

  12. Tumours of the lung

    PubMed Central

    Stünzi, H.; Head, K. W.; Nielsen, S. W.

    1974-01-01

    Lung tumours are not common in domestic animals; there has not been the increase in epidermoid carcinomas and anaplastic small-cell carcinomas that has occurred in man this century. Adenocarcinoma is the most common type in animals. The biological behaviour of each type of tumour in animals seems to be much the same as in man. The tumours are described histologically, the main categories being: epidermoid carcinoma, anaplastic carcinoma, adenocarcinoma, combined epidermoid and adenocarcinoma, carcinoid tumours, bronchial gland tumours, benign tumours, and sarcomas. ImagesFig. 13Fig. 14Fig. 15Fig. 16Fig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11Fig. 12 PMID:4371738

  13. Spatial heterogeneity of soil biochar content affects soil quality and wheat growth and yield.

    PubMed

    Olmo, Manuel; Lozano, Ana María; Barrón, Vidal; Villar, Rafael

    2016-08-15

    Biochar (BC) is a carbonaceous material obtained by pyrolysis of organic waste materials and has been proposed as a soil management strategy to mitigate global warming and to improve crop productivity. Once BC has been applied to the soil, its imperfect and incomplete mixing with soil during the first few years and the standard agronomic practices (i.e. tillage, sowing) may generate spatial heterogeneity of the BC content in the soil, which may have implications for soil properties and their effects on plant growth. We investigated how, after two agronomic seasons, the spatial heterogeneity of olive-tree prunings BC applied to a vertisol affected soil characteristics and wheat growth and yield. During the second agronomic season and just before wheat germination, we determined the BC content in the soil by an in-situ visual categorization based on the soil darkening, which was strongly correlated to the BC content of the soil and the soil brightness. We found a high spatial heterogeneity in the BC plots, which affected soil characteristics and wheat growth and yield. Patches with high BC content showed reduced soil compaction and increased soil moisture, pH, electrical conductivity, and nutrient availability (P, Ca, K, Mn, Fe, and Zn); consequently, wheat had greater tillering and higher relative growth rate and grain yield. However, if the spatial heterogeneity of the soil BC content had not been taken into account in the data analysis, most of the effects of BC on wheat growth would not have been detected. Our study reveals the importance of taking into account the spatial heterogeneity of the BC content. PMID:27110980

  14. Crack growth rates of irradiated austenitic stainless steel weld heat affected zone in BWR environments.

    SciTech Connect

    Chopra, O. K.; Alexandreanu, B.; Gruber, E. E.; Daum, R. S.; Shack, W. J.; Energy Technology

    2006-01-31

    Austenitic stainless steels (SSs) are used extensively as structural alloys in the internal components of reactor pressure vessels because of their superior fracture toughness. However, exposure to high levels of neutron irradiation for extended periods can exacerbate the corrosion fatigue and stress corrosion cracking (SCC) behavior of these steels by affecting the material microchemistry, material microstructure, and water chemistry. Experimental data are presented on crack growth rates of the heat affected zone (HAZ) in Types 304L and 304 SS weld specimens before and after they were irradiated to a fluence of 5.0 x 10{sup 20} n/cm{sup 2} (E > 1 MeV) ({approx} 0.75 dpa) at {approx}288 C. Crack growth tests were conducted under cycling loading and long hold time trapezoidal loading in simulated boiling water reactor environments on Type 304L SS HAZ of the H5 weld from the Grand Gulf reactor core shroud and on Type 304 SS HAZ of a laboratory-prepared weld. The effects of material composition, irradiation, and water chemistry on growth rates are discussed.

  15. TRIM13 (RFP2) downregulation decreases tumour cell growth in multiple myeloma through inhibition of NF Kappa B pathway and proteasome activity

    PubMed Central

    Gatt, Moshe E; Takada, Kohichi; Mani, Mala; Lerner, Mikael; Pick, Marjorie; Hideshima, Teru; Carrasco, Daniel E.; Protopopov, Alexei; Ivanova, Elena; Sangfelt, Olle; Grandér, Dan; Barlogie, Bart; Shaughnessy, John D.; Anderson, Kenneth C.; Carrasco, Daniel R.

    2013-01-01

    Multiple myeloma (MM) is an incurable neoplasm caused by proliferation of malignant plasma cells in the bone marrow (BM). MM is characterized frequently by a complete or partial deletion of chromosome 13q14, seen in more than 50% of patients at diagnosis. Within this deleted region the tripartite motif containing 13 (TRIM13, also termed RFP2) gene product has been proposed to be a tumour suppressor gene (TSG). Here, we show that low expression levels of TRIM13 in MM are associated with chromosome 13q deletion and poor clinical outcome. We present a functional analysis of TRIM13 using a loss-of-function approach, and demonstrate that TRIM13 downregulation decreases tumour cell survival as well as cell cycle progression and proliferation of MM cells. In addition, we provide evidence for the involvement of TRIM13 downregulation in inhibiting the NF kappa B pathway and the activity of the 20S proteasome. Although this data does not support a role of TRIM13 as a TSG, it substantiates important roles of TRIM13 in MM tumour survival and proliferation, underscoring its potential role as a novel target for therapeutic intervention. PMID:23647456

  16. Sesquiterpene lactones isolated from Elephantopus scaber L. inhibits human lymphocyte proliferation and the growth of tumour cell lines and induces apoptosis in vitro.

    PubMed

    Geetha, B S; Nair, Mangalam S; Latha, P G; Remani, P

    2012-01-01

    This study was designed to isolate the compounds responsible for the cytotoxic properties of South Indian Elephantopus scaber L. and further investigate their effects on quiescent and proliferating cells. Bioassay-guided isolation of the whole plant of chloroform extract of South Indian Elephantopus scaber afforded the known sesquiterpene lactone, deoxyelephantopin, and isodeoxyelephantopin whose structures were determined by spectroscopic methods. These compounds caused a dose dependent reduction in the viability of L-929 tumour cells in 72 h culture (IC(50) value of 2.7 μg/mL and 3.3 μg/mL) by the cell viability assay. Both the compounds act selectively on quiescent and PHA-stimulated proliferating human lymphocytes and inhibited tritiated thymidine incorporation into cellular DNA of DLA tumour cells. The compound deoxyelephantopin at a concentration of 3 μg/mL caused maximum apoptotic cells. It also exhibited significant in vivo antitumour efficacy against DLA tumour cells. The results, therefore, indicate that the antiproliferative property of deoxyelephantopin and isodeoxyelephantopin could be used in regimens for treating tumors with extensive proliferative potencies. PMID:22500104

  17. The siRNA cocktail targeting interleukin 10 receptor and transforming growth factor-β receptor on dendritic cells potentiates tumour antigen-specific CD8(+) T cell immunity.

    PubMed

    Ahn, Y-H; Hong, S-O; Kim, J H; Noh, K H; Song, K-H; Lee, Y-H; Jeon, J-H; Kim, D-W; Seo, J H; Kim, T W

    2015-07-01

    Dendritic cells (DCs) are promising therapeutic agents in the field of cancer immunotherapy due to their intrinsic immune-priming capacity. The potency of DCs, however, is readily attenuated immediately after their administration in patients as tumours and various immune cells, including DCs, produce various immunosuppressive factors such as interleukin (IL)-10 and transforming growth factor (TGF)-β that hamper the function of DCs. In this study, we used small interfering RNA (siRNA) to silence the expression of endogenous molecules in DCs, which can sense immunosuppressive factors. Among the siRNAs targeting various immunosuppressive molecules, we observed that DCs transfected with siRNA targeting IL-10 receptor alpha (siIL-10RA) initiated the strongest antigen-specific CD8(+) T cell immune responses. The potency of siIL-10RA was enhanced further by combining it with siRNA targeting TGF-β receptor (siTGF-βR), which was the next best option during the screening of this study, or the previously selected immunoadjuvant siRNA targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN) or Bcl-2-like protein 11 (BIM). In the midst of sorting out the siRNA cocktails, the cocktail of siIL-10RA and siTGF-βR generated the strongest antigen-specific CD8(+) T cell immunity. Concordantly, the knock-down of both IL-10RA and TGF-βR in DCs induced the strongest anti-tumour effects in the TC-1 P0 tumour model, a cervical cancer model expressing the human papillomavirus (HPV)-16 E7 antigen, and even in the immune-resistant TC-1 (P3) tumour model that secretes more IL-10 and TGF-β than the parental tumour cells (TC-1 P0). These results provide the groundwork for future clinical development of the siRNA cocktail-mediated strategy by co-targeting immunosuppressive molecules to enhance the potency of DC-based vaccines. PMID:25753156

  18. A rare solitary fibrous tumour of kidney.

    PubMed

    Pathak, Tilak Bahadur; Nepal, Umesh

    2013-01-01

    A solitary fibrous tumour is an unusual spindle cell neoplasm. It frequently arises from the serosal surface of pleural cavity but has recently been described in diverse extrapleural sites. Urogenital localization is rare and only 36 cases of solitary fibrous tumours of the kidney have been described on published report. We report a case of a large solitary fibrous tumour clinically and radiologically thought to be renal cell carcinoma arising in the kidney of a 30 year old female. The radical nephrectomy was performed. The tumour was a well- circumscribed, solid mass attached to the renal pelvis without necrosis and haemorrhage. Histopathologically, a spindle cell neoplasia with alternating hypo and hypercellular areas, storiform, fascicular and hemangipericytoma like growth pattern and less cellular dense collagen deposits were observed. Immunohistochemical studies revealed reactivity for CD34, CD99 and Bcl-2 protein. PMID:24362666

  19. Factors that affect the quality of life of patients with oral cancer who have had their defects reconstructed immediately after excision of the tumour.

    PubMed

    Yang, Yanjie; Li, Feng; Li, Wenlu

    2016-05-01

    Physical, social, and psychological factors profoundly affect the quality of life (QoL) of patients with oral cancer. Here we have investigated these factors in patients who have had resection and reconstruction of their oral cancer. We have assessed patients who had reconstructions with a pectoralis major myocutaneous (PMM) flap or a free anterolateral thigh (ALT) perforator flap using the University of Washington Quality of Life version 4 questionnaires (Chinese version). Data were analysed to investigate how age, sex, type of neck dissection, size of resection, dental condition, use of radiotherapy and need for mandibulotomy affected their QoL. Of the 72 patients who were sent a questionnaire, 61 (85%) returned them completed. Twenty-eight patients(46%) had had ALT perforator flaps and 33 patients (54%) PMM flaps. In the group who had ALT perforator flaps, age, sex, type of neck dissection, mandibulotomy, and the use of radiotherapy affected QoL. Among those who the PMM flaps, age, neck dissection, mandibulotomy, and use of radiotherapy affected QoL. The only factors that the two flaps had in common were age, neck dissection, use of radiotherapy, and mandibulotomy. PMID:26774899

  20. A primary screen of the bovine genome for quantitative trait loci affecting carcass and growth traits.

    PubMed

    Stone, R T; Keele, J W; Shackelford, S D; Kappes, S M; Koohmaraie, M

    1999-06-01

    A primary genomic screen for quantitative trait loci (QTL) affecting carcass and growth traits was performed by genotyping 238 microsatellite markers on 185 out of 300 total progeny from a Bos indicus x Bos taurus sire mated to Bos taurus cows. The following traits were analyzed for QTL effects: birth weight (BWT), weaning weight (WW), yearling weight (YW), hot carcass weight (HCW), dressing percentage (DP), fat thickness (FT), marbling score (MAR), longissimus muscle area (LMA), rib bone (RibB), rib fat (RibF), and rib muscle (RibM), and the predicted whole carcass traits, retail product yield (RPYD), fat trim yield (FATYD), bone yield (BOYD), retail product weight (RPWT), fat weight (FATWT), and bone weight (BOWT). Data were analyzed by generating an F-statistic profile computed at 1-cM intervals for each chromosome by the regression of phenotype on the conditional probability of receiving the Brahman allele from the sire. There was compelling evidence for a QTL allele of Brahman origin affecting an increase in RibB and a decrease in DP on chromosome 5 (BTA5). Putative QTL at or just below the threshold for genome-wide significance were as follows: an increase in RPYD and component traits on BTA2 and BTA13, an increase in LMA on BTA14, and an increase in BWT on BTA1. Results provided represent a portion of our efforts to identify and characterize QTL affecting carcass and growth traits. PMID:10375215

  1. Dietary blueberry supplementation affects growth but not vascularization of neural transplants

    PubMed Central

    Willis, Lauren M; Small, Brent J; Bickford, Paula C; Umphlet, Claudia D; Moore, Alfred B; Granholm, Ann-Charlotte E

    2009-01-01

    Transplantation of neural tissue has been attempted as a treatment method for neurodegenerative disorders. Grafted neurons survive to a lesser extent into middle-aged or aged hosts, and survival rates of < 10% of grafted neurons is common. Antioxidant diets, such as blueberry, can exert powerful effects on developing neurons and blood vessels in vitro, but studies are lacking that examine the effects of these diets on transplanted tissues. In this study, we examined the effects of a blueberry diet on survival, growth, and vascularization of fetal hippocampal tissue to the anterior chamber of the eye of young or middle-aged female rats. Previous work from our group showed significant increase in neuronal survival and development with blueberry diet in grafts. However, the effects of antioxidant diet on vascular development in grafts have not been explored previously. The age of the host affected individual vessel morphology in that aged hosts contained grafts with thick, undeveloped walls, and wider lumen. The blood–brain barrier also appeared to be affected by the age of the host. The blueberry diet did not affect vessel morphology or density of vessel-associated protein markers but gave rise to significantly increased growth capacity, cytoarchitecture, and the final size of hippocampal grafts. PMID:18285804

  2. Response to long-term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: Patterns of growth, puberty and final height data.

    PubMed

    Tamburrino, Federica; Gibertoni, Dino; Rossi, Cesare; Scarano, Emanuela; Perri, Annamaria; Montanari, Francesca; Fantini, Maria Pia; Pession, Andrea; Tartaglia, Marco; Mazzanti, Laura

    2015-11-01

    RASopathies are developmental disorders caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Reduced growth is a common feature. Several studies generated data on growth, final height (FH), and height velocity (HV) after growth hormone (GH) treatment in patients with these disorders, particularly in Noonan syndrome, the most common RASopathy. These studies, however, refer to heterogeneous cohorts in terms of molecular information, GH status, age at start and length of therapy, and GH dosage. This work reports growth data in 88 patients affected by RASopathies with molecularly confirmed diagnosis, together with statistics on body proportions, pubertal pattern, and FH in 33, including 16 treated with GH therapy for proven GH deficiency. Thirty-three patients showed GH deficiency after pharmacological tests, and were GH-treated for an average period of 6.8 ± 4.8 years. Before starting therapy, HV was -2.6 ± 1.3 SDS, and mean basal IGF1 levels were -2.0 ± 1.1 SDS. Long-term GH therapy, starting early during childhood, resulted in a positive height response compared with untreated patients (1.3 SDS in terms of height-gain), normalizing FH for Ranke standards but not for general population and Target Height. Pubertal timing negatively affected pubertal growth spurt and FH, with IGF1 standardized score increased from -2.43 to -0.27 SDS. During GH treatment, no significant change in bone age velocity, body proportions, or cardiovascular function was observed. PMID:26227443

  3. Kinetics of grain growth in the weld heat-affected zone of Alloy 718

    SciTech Connect

    Radhakrishnan, B.; Thompson, R.G.

    1993-12-01

    Grain-boundary liquation occurs in the weld heat-affected zone (HAZ) of the Ni-base superalloy 718 at locations where the peak temperatures are greater than about 1,200 C. The evolution of the grain structure at the HAZ locations depends upon the interaction between the grains and the grain-boundary liquid. The evolution of grain structure in the presence of grain-boundary liquid was simulated by subjecting samples to controlled thermal cycles using resistance heating. A measurement of grain size as a function of isothermal hold at two peak temperatures of 1,200 C and 1,227 C indicated that in alloy 718, the kinetics of grain growth depended upon the prior thermal history of the alloy. In the solution-treated alloy, the presence of grain-boundary liquid did not arrest grain growth at either peak temperature. In the homogenized and aged alloy, a grain refinement was observed at the peak temperature of 1,227 C, while an arrest of grain growth was observed at a peak temperature of 1,200 C. Liquid film migration (LFM) and subgrain coalescence, either acting alone or simultaneously, are shown to explain most of the observed microstructural phenomena and the kinetics of grain growth in the alloy.

  4. Kinetics of grain growth in the weld heat-affected zone of alloy 718

    NASA Astrophysics Data System (ADS)

    Radhakrishnan, B.; Thompson, R. G.

    1993-12-01

    Grain-boundary liquation occurs in the weld heat-affected zone (HAZ) of the Ni-base superalloy 718 at locations where the peak temperatures are greater than about 1200 ‡C. The evolution of the grain structure at these HAZ locations depends upon the interaction between the grains and the grain-boundary liquid. The evolution of grain structure in the presence of grain-boundary liquid was simulated by subjecting samples to controlled thermal cycles using resistance heating. A measurement of grain size as a function of isothermal hold at two peak temperatures of 1200 ‡C and 1227 ‡C indicated that in alloy 718, the kinetics of grain growth depended upon the prior thermal history of the alloy. In the solution-treated alloy, the presence of grain-boundary liquid did not arrest grain growth at either peak temperature. In the homogenized and aged alloy, a grain refinement was observed at the peak temperature of 1227 ‡C, while an arrest of grain growth was observed at a peak temperature of 1200‡C. Liquid film migration (LFM) and subgrain coalescence, either acting alone or simultaneously, are shown to explain most of the observed microstructural phenomena and the kinetics of grain growth in the alloy.

  5. Alkyl-methylimidazolium ionic liquids affect the growth and fermentative metabolism of Clostridium sp

    SciTech Connect

    Nancharaiah, Y.V.; Francis, A.

    2011-06-01

    In this study, the effect of ionic liquids, 1-ethyl-3-methylimidazolium acetate [EMIM][Ac], 1-ethyl-3-methylimidazolium diethylphosphate [EMIM][DEP], and 1-methyl-3-methylimidazolium dimethylphosphate [MMIM][DMP] on the growth and glucose fermentation of Clostridium sp. was investigated. Among the three ionic liquids tested, [MMIM][DMP] was found to be least toxic. Growth of Clostridium sp. was not inhibited up to 2.5, 4 and 4 g L{sup -1} of [EMIM][Ac], [EMIM][DEP] and [MMIM][DMP], respectively. [EMIM][Ac] at <2.5 g L{sup -1}, showed hormetic effect and stimulated the growth and fermentation by modulating medium pH. Total organic acid production increased in the presence of 2.5 and 2 g L{sup -1} of [EMIM][Ac] and [MMIM][DMP]. Ionic liquids had no significant influence on alcohol production at <2.5 g L{sup -1}. Total gas production was affected by ILs at {ge}2.5 g L{sup -1} and varied with type of methylimidazolium IL. Overall, the results show that the growth and fermentative metabolism of Clostridium sp. is not impacted by ILs at concentrations below 2.5 g L{sup -1}.

  6. Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines

    SciTech Connect

    Maneckjee, R.; Minna, J.D. Uniformed Services Univ. of the Health Sciences, Bethesda, MD )

    1990-05-01

    Using specific radioactively-labeled ligands, the authors find that lung cancer cell lines of diverse histologic types express multiple, high-affinity membrane receptors for {mu}, {delta}, and {kappa} opioid agonists and for nicotine and {alpha}-bungarotoxin. These receptors are biologically active because cAMP levels decreased in lung cancer cells after opioid and nicotine application. Nicotine at concentrations found in the blood of smokers had no effect on in vitro lung cancer cell growth, whereas {mu}, {delta}, and {kappa} opioid agonists at low concentrations inhibited lung cancer growth in vitro. They also found that lung cancer cells expressed various combinations of immunoreactive opioid peptides ({beta}-endorphin, enkephalin, or dynorphin), suggesting the participation of opioids in a negative autocrine loop or tumor-suppressing system. Due to the almost universal exposure of patients with lung cancer to nicotine, they tested whether nicotine affected the response of lung cancer cell growth to opioids and found that nicotine at concentrations of 100-200 nM partially or totally reversed opioid-induced growth inhibition in 9/14 lung cancer cell lines. These in vitro results for lung cancer cells suggest that opioids could function as part of a tumor suppressor system and that nicotine can function to circumvent this system in the pathogenesis of lung cancer.

  7. Flavonoid accumulation in Arabidopsis repressed in lignin synthesis affects auxin transport and plant growth.

    PubMed

    Besseau, Sébastien; Hoffmann, Laurent; Geoffroy, Pierrette; Lapierre, Catherine; Pollet, Brigitte; Legrand, Michel

    2007-01-01

    In Arabidopsis thaliana, silencing of hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyl transferase (HCT), a lignin biosynthetic gene, results in a strong reduction of plant growth. We show that, in HCT-silenced plants, lignin synthesis repression leads to the redirection of the metabolic flux into flavonoids through chalcone synthase activity. Several flavonol glycosides and acylated anthocyanin were shown to accumulate in higher amounts in silenced plants. By contrast, sinapoylmalate levels were barely affected, suggesting that the synthesis of that phenylpropanoid compound might be HCT-independent. The growth phenotype of HCT-silenced plants was shown to be controlled by light and to depend on chalcone synthase expression. Histochemical analysis of silenced stem tissues demonstrated altered tracheary elements. The level of plant growth reduction of HCT-deficient plants was correlated with the inhibition of auxin transport. Suppression of flavonoid accumulation by chalcone synthase repression in HCT-deficient plants restored normal auxin transport and wild-type plant growth. By contrast, the lignin structure of the plants simultaneously repressed for HCT and chalcone synthase remained as severely altered as in HCT-silenced plants, with a large predominance of nonmethoxylated H units. These data demonstrate that the reduced size phenotype of HCT-silenced plants is not due to the alteration of lignin synthesis but to flavonoid accumulation. PMID:17237352

  8. ZnO Nanoparticles Affect Bacillus subtilis Cell Growth and Biofilm Formation

    PubMed Central

    Hsueh, Yi-Huang; Ke, Wan-Ju; Hsieh, Chien-Te; Lin, Kuen-Song; Tzou, Dong-Ying; Chiang, Chao-Lung

    2015-01-01

    Zinc oxide nanoparticles (ZnO NPs) are an important antimicrobial additive in many industrial applications. However, mass-produced ZnO NPs are ultimately disposed of in the environment, which can threaten soil-dwelling microorganisms that play important roles in biodegradation, nutrient recycling, plant protection, and ecological balance. This study sought to understand how ZnO NPs affect Bacillus subtilis, a plant-beneficial bacterium ubiquitously found in soil. The impact of ZnO NPs on B. subtilis growth, FtsZ ring formation, cytosolic protein activity, and biofilm formation were assessed, and our results show that B. subtilis growth is inhibited by high concentrations of ZnO NPs (≥ 50 ppm), with cells exhibiting a prolonged lag phase and delayed medial FtsZ ring formation. RedoxSensor and Phag-GFP fluorescence data further show that at ZnO-NP concentrations above 50 ppm, B. subtilis reductase activity, membrane stability, and protein expression all decrease. SDS-PAGE Stains-All staining results and FT-IR data further demonstrate that ZnO NPs negatively affect exopolysaccharide production. Moreover, it was found that B. subtilis biofilm surface structures became smooth under ZnO-NP concentrations of only 5–10 ppm, with concentrations ≤ 25 ppm significantly reducing biofilm formation activity. XANES and EXAFS spectra analysis further confirmed the presence of ZnO in co-cultured B. subtilis cells, which suggests penetration of cell membranes by either ZnO NPs or toxic Zn+ ions from ionized ZnO NPs, the latter of which may be deionized to ZnO within bacterial cells. Together, these results demonstrate that ZnO NPs can affect B. subtilis viability through the inhibition of cell growth, cytosolic protein expression, and biofilm formation, and suggest that future ZnO-NP waste management strategies would do well to mitigate the potential environmental impact engendered by the disposal of these nanoparticles. PMID:26039692

  9. Incidence and prevalence of salivary gland tumours in Valparaiso, Chile

    PubMed Central

    Araya, Juan; Martinez, René; Niklander, Sven; Marshall, Maureen

    2015-01-01

    Background To determine the incidence and prevalence of salivary gland tumours in the province of Valparaíso, Chile. Material and Methods Retrospective review of salivary gland tumours diagnosed between the years 2000 and 2011 from four local pathology services. Information on demographics and histopathology were retrieved from the medical records. Results The study sample consisted of 279 salivary gland tumours. Prevalence and incidence rates per 100.000 persons were 15.4 and 2.51, respectively. Most of the neoplasms corresponded to benign tumours (70.3%). The most affected gland was the parotid gland. Pleomorphic adenoma was the most common benign tumour (53.8%) and mucoepidermoid carcinoma was the most common malignant tumour (7.2%). Conclusions Salivary gland tumours are uncommon neoplasms that usually arise in the parotid gland. Pleomorphic adenoma and mucoepidermoid carcinoma were the most common benign and malignant tumours reported in this series. Key words:Salivary gland tumours, benign tumours, malignant tumours, salivary glands neoplasms, cancer, neoplasia. PMID:26034925

  10. Ameloblastin, an Extracellular Matrix Protein, Affects Long Bone Growth and Mineralization.

    PubMed

    Lu, Xuanyu; Fukumoto, Satoshi; Yamada, Yoshihiko; Evans, Carla A; Diekwisch, Thomas Gh; Luan, Xianghong

    2016-06-01

    Matrix molecules such as the enamel-related calcium-binding phosphoprotein ameloblastin (AMBN) are expressed in multiple tissues, including teeth, bones, and cartilage. Here we have asked whether AMBN is of functional importance for timely long bone development and, if so, how it exerts its function related to osteogenesis. Adolescent AMBN-deficient mice (AMBN(Δ5-6) ) suffered from a 33% to 38% reduction in femur length and an 8.4% shorter trunk spinal column when compared with WT controls, whereas there was no difference between adult animals. On a cellular level, AMBN truncation resulted in a shortened growth plate and a 41% to 49% reduction in the number of proliferating tibia chondrocytes and osteoblasts. Bone marrow stromal cells (BMSCs) isolated from AMBN mutant mice displayed defects in proliferation and differentiation potential as well as cytoskeleton organization. Osteogenesis-related growth factors, such as insulin-like growth factor 1 (IGF1) and BMP7, were also significantly (46% to 73%) reduced in AMBN-deficient BMSCs. Addition of exogenous AMBN restored cytoskeleton structures in AMBN mutant BMSCs and resulted in a dramatic 400% to 600% increase in BMP2, BMP7, and Col1A expression. Block of RhoA diminished the effect of AMBN on osteogenic growth factor and matrix protein gene expression. Addition of exogenous BMP7 and IGF1 rescued the proliferation and differentiation potential of AMBN-deficient BMSCs. Confirming the effects of AMBN on long bone growth, back-crossing of mutant mice with full-length AMBN overexpressors resulted in a complete rescue of AMBN(Δ5-6) bone defects. Together, these data indicate that AMBN affects extracellular matrix production and cell adhesion properties in the long bone growth plate, resulting in altered cytoskeletal dynamics, increased osteogenesis-related gene expression, as well as osteoblast and chondrocyte proliferation. We propose that AMBN facilitates rapid long bone growth and an important growth spurt during the

  11. Tumour ablation: technical aspects

    PubMed Central

    Bodner, Gerd; Bale, Reto

    2009-01-01

    Abstract Image-guided percutaneous radiofrequency ablation (RFA) is a minimally invasive, relatively low-risk procedure for tumour treatment. Local recurrence and survival rates depend on the rate of complete ablation of the entire tumour including a sufficient margin of surrounding healthy tissue. Currently a variety of different RFA devices are available. The interventionalist must be able to predict the configuration and extent of the resulting ablation necrosis. Accurate planning and execution of RFA according to the size and geometry of the tumour is essential. In order to minimize complications, individualized treatment strategies may be necessary for tumours close to vital structures. This review examines the state-of-the art of different device technologies, approaches, and treatment strategies for percutaneous RFA of liver tumours. PMID:19965296

  12. Remnant Trees Affect Species Composition but Not Structure of Tropical Second-Growth Forest

    PubMed Central

    Sandor, Manette E.; Chazdon, Robin L.

    2014-01-01

    Remnant trees, spared from cutting when tropical forests are cleared for agriculture or grazing, act as nuclei of forest regeneration following field abandonment. Previous studies on remnant trees were primarily conducted in active pasture or old fields abandoned in the previous 2–3 years, and focused on structure and species richness of regenerating forest, but not species composition. Our study is among the first to investigate the effects of remnant trees on neighborhood forest structure, biodiversity, and species composition 20 years post-abandonment. We compared the woody vegetation around individual remnant trees to nearby plots without remnant trees in the same second-growth forests (“control plots”). Forest structure beneath remnant trees did not differ significantly from control plots. Species richness and species diversity were significantly higher around remnant trees. The species composition around remnant trees differed significantly from control plots and more closely resembled the species composition of nearby old-growth forest. The proportion of old-growth specialists and generalists around remnant trees was significantly greater than in control plots. Although previous studies show that remnant trees may initially accelerate secondary forest growth, we found no evidence that they locally affect stem density, basal area, and seedling density at later stages of regrowth. Remnant trees do, however, have a clear effect on the species diversity, composition, and ecological groups of the surrounding woody vegetation, even after 20 years of forest regeneration. To accelerate the return of diversity and old-growth forest species into regrowing forest on abandoned land, landowners should be encouraged to retain remnant trees in agricultural or pastoral fields. PMID:24454700

  13. Targeting the tumour microenvironment in ovarian cancer.

    PubMed

    Hansen, Jean M; Coleman, Robert L; Sood, Anil K

    2016-03-01

    The study of cancer initiation, growth, and metastasis has traditionally been focused on cancer cells, and the view that they proliferate due to uncontrolled growth signalling owing to genetic derangements. However, uncontrolled growth in tumours cannot be explained solely by aberrations in cancer cells themselves. To fully understand the biological behaviour of tumours, it is essential to understand the microenvironment in which cancer cells exist, and how they manipulate the surrounding stroma to promote the malignant phenotype. Ovarian cancer is the leading cause of death from gynaecologic cancer worldwide. The majority of patients will have objective responses to standard tumour debulking surgery and platinum-taxane doublet chemotherapy, but most will experience disease recurrence and chemotherapy resistance. As such, a great deal of effort has been put forth to develop therapies that target the tumour microenvironment in ovarian cancer. Herein, we review the key components of the tumour microenvironment as they pertain to this disease, outline targeting opportunities and supporting evidence thus far, and discuss resistance to therapy. PMID:26849037

  14. Effects of drought-affected corn and nonstarch polysaccharide enzyme inclusion on nursery pig growth performance.

    PubMed

    Jones, C K; Frantz, E L; Bingham, A C; Bergstrom, J R; DeRouchey, J M; Patience, J F

    2015-04-01

    The effectiveness of carbohydrase enzymes has been inconsistent in corn-based swine diets; however, the increased substrate of nonstarch polysaccharides in drought-affected corn may provide an economic model for enzyme inclusion, but this has not been evaluated. A total of 360 barrows (PIC 1050 × 337, initially 5.85 kg BW) were used to determine the effects of drought-affected corn inclusion with or without supplementation of commercial carbohydrases on growth performance and nutrient digestibility of nursery pigs. Initially, 34 corn samples were collected to find representatives of normal and drought-affected corn. The lot selected to represent the normal corn had a test weight of 719.4 kg/m3, 15.0% moisture, and 4.2% xylan. The lot selected to represent drought-affected corn had a test weight of 698.8 kg/m3, 14.3% moisture, and 4.7% xylan. After a 10-d acclimation period postweaning, nursery pigs were randomly allotted to 1 of 8 dietary treatments in a completely randomized design. Treatments were arranged in a 2 × 4 factorial with main effects of corn (normal vs. drought affected) and enzyme inclusion (none vs. 100 mg/kg Enzyme A vs. 250 mg/kg Enzyme B vs. 100 mg/kg Enzyme A + 250 mg/kg Enzyme B). Both enzymes were included blends of β-glucanase, cellulose, and xylanase (Enzyme A) or hemicellulase and pectinases (Enzyme B). Pigs were fed treatment diets from d 10 to 35 postweaning in 2 phases. Feed and fecal samples were collected on d 30 postweaning to determine apparent total tract digestibility of nutrients. The nutrient concentrations of normal and drought-affected corn were similar, which resulted in few treatment or main effects differences of corn type or enzyme inclusion. No interactions were observed (P > 0.10) between corn source and enzyme inclusion. Overall (d 10 to 35), treatments had no effect on ADG or ADFI, but enzyme A inclusion tended to improve (P < 0.10; 0.74 vs. 0.69) G:F, which was primarily driven by the improved feed efficiency (0

  15. Water potential affects Coniothyrium minitans growth, germination and parasitism of Sclerotinia sclerotiorum sclerotia.

    PubMed

    Jones, E Eirian; Stewart, Alison; Whipps, John M

    2011-09-01

    Water availability is an important environmental factor which has major effects on fungal activity. The effects of osmotic (KCl amended agar) and matric Polyethylene glycol ((PEG) 8000 amended agar) potentials over the range -0.1 to -5.0MPa on mycelial growth and conidial germination of eight isolates of the sclerotial parasite Coniothyrium minitans was assessed. The influence of soil water potential on the ability of three selected isolates (LU112, LU545, and T5R42i) to parasitise sclerotia of the plant pathogen Sclerotinia sclerotiorum was determined. For all eight C. minitans isolates, decreasing osmotic and matric potentials caused a reduction in mycelial growth and conidial germination. Isolates were more sensitive to decreasing matric potential than osmotic potential. Across the isolates, growth at an osmotic potential of -5.0MPa was 30-70% of the growth seen in the control, whereas less than 20% of the control growth was seen at the corresponding matric potential. Across all isolates no conidial germination was seen at matric potential of -5.0MPa. The C. minitans isolates varied in their sensitivity to decreasing water potentials. Mycelial growth and conidial germination of three isolates (LU112, Conio, and CH1) were more tolerant of low osmotic potential and matric potential with respect to mycelial growth. Isolates T5R42i and LU430 were least tolerant. In contrast, conidial germination of isolates Conio, LU545, and T5R42i were less sensitive to decreasing matric potential. Soil water potential was seen to affect infection and viability of sclerotia by the three C. minitans isolates. Isolate LU545 reduced sclerotial viability over a wider water potential range (-0.01 to -1.5MPa) compared with LU112 (-0.01 to -1.0MPa), with isolate T5R42i being intermediate. Indigenous soil fungi (Trichoderma spp. and Clonostachys rosea) were recovered from sclerotia but did not result in reduction in sclerotial viability. The relevance of these results in relation to

  16. Targeting ALCAM in the cryo-treated tumour microenvironment successfully induces systemic anti-tumour immunity.

    PubMed

    Kudo-Saito, Chie; Fuwa, Takafumi; Kawakami, Yutaka

    2016-07-01

    Cryoablative treatment has been widely used for treating cancer. However, the therapeutic efficacies are still controversial. The molecular mechanisms of the cryo-induced immune responses, particularly underlying the ineffectiveness, remain to be fully elucidated. In this study, we identified a new molecular mechanism involved in the cryo failure. We used cryo-ineffective metastatic tumour models that murine melanoma B16-F10 cells were subcutaneously and intravenously implanted into C57BL/6 mice. When the subcutaneous tumours were treated cryoablation on day 7 after tumour implantation, cells expressing activated leucocyte cell adhesion molecule (ALCAM/CD166) were significantly expanded not only locally in the treated tumours but also systemically in spleen and bone marrow of the mice. The cryo-induced ALCAM(+) cells including CD45(-) mesenchymal stem/stromal cells, CD11b(+)Gr1(+) myeloid-derived suppressor cells, and CD4(+)Foxp3(+) regulatory T cells significantly suppressed interferon γ production and cytotoxicity of tumour-specific CD8(+) T cells via ALCAM expressed in these cells. This suggests that systemic expansion of the ALCAM(+) cells negatively switches host-immune directivity to the tumour-supportive mode. Intratumoural injection with anti-ALCAM blocking monoclonal antibody (mAb) following the cryo treatment systemically induced tumour-specific CD8(+) T cells with higher cytotoxic activities, resulting in suppression of tumour growth and metastasis in the cryo-resistant tumour models. These suggest that expansion of ALCAM(+) cells is a determinant of limiting the cryo efficacy. Further combination with an immune checkpoint inhibitor anti-CTLA4 mAb optimized the anti-tumour efficacy of the dual-combination therapy. Targeting ALCAM may be a promising strategy for overcoming the cryo ineffectiveness leading to the better practical use of cryoablation in clinical treatment of cancer. PMID:27208904

  17. Hypoxia-mediated tumour targeting.

    PubMed

    Binley, K; Askham, Z; Martin, L; Spearman, H; Day, D; Kingsman, S; Naylor, S

    2003-04-01

    Hypoxia is a common physiological feature of tumours. It activates a signalling cascade that culminates in the stabilization of the HIF-1 transcription factor and activation of genes that possess a hypoxia response element (HRE). We have used an optimized hypoxia responsive promoter (OBHRE) to investigate hypoxia-targeted gene expression in vivo in the context of an adenovirus vector. The OBHRE promoter showed limited activity in the liver or spleen such that expression was 1000-fold lower than that driven by the strong CMV/IE promoter. However, in the context of the tumour microenvironment, the OBHRE promoter achieved expression levels comparable to that of the CMV/IE promoter. Next, we showed that an adenovirus expressing the human cytochrome P450 (CYP2B6) regulated by the OBHRE promoter delays tumour growth in response to the prodrug cyclophosphamide (CPA). Finally, we exploited the hepatotropism of adenovirus to investigate whether the OBHRE promoter could mitigate the hepatotoxicity of a recombinant adenovirus expressing thymidine kinase (TK) in the context of the prodrug ganciclovir (GCV). High-dose Ad.CMVTK/GCV treatment caused significant liver necrosis whereas the same dose of Ad.HRETK was well tolerated. These in vivo data demonstrate that hypoxia-targeted gene expression via the OBHRE promoter can be used to increase the therapeutic window of cytotoxic cancer gene therapy. PMID:12646859

  18. The chronic syndromes after previous treatment of pituitary tumours.

    PubMed

    Romijn, Johannes A

    2016-09-01

    Ultimately, almost all patients who are appropriately treated for pituitary tumours enter a chronic phase with control or cure of hormonal excess, adequate treatment of pituitary insufficiency and relief of mass effects. This phase is associated with improvement of initial signs and symptoms, but also with the persistent consequences of the initial disease and associated treatments. Pituitary insufficiency is a common denominator in many of these patients, and is associated with a reduction in quality of life, despite adequate endocrine substitution. Hypothalamic dysfunction can be present in patients previously treated for visual impairments caused by large suprasellar adenomas, or craniopharyngiomas. In addition to hypopituitarism, these patients can have multisystem morbidities caused by altered hypothalamic function, including weight gain and disturbed regulation of sleep-wake cycles. Mortality can also be affected. Patients cured of Cushing disease or acromegaly have chronic multisystem morbidities (in the case of Cushing disease, also affecting mortality) caused by irreversible effects of the previous excesses of cortisol in Cushing disease and growth hormone and insulin-like growth factor 1 in acromegaly. In addition to early diagnosis and treatment of pituitary tumours, research should focus on the amenability of these chronic post-treatment syndromes to therapeutic intervention, to improve quality of life and clinical outcomes. PMID:27259177

  19. A growth QTL on chicken chromosome 1 affects emotionality and sociality.

    PubMed

    Wirén, Anna; Jensen, Per

    2011-03-01

    Domestication of animals, regardless of species, is often accompanied by simultaneous changes in several physiological and behavioral traits (e.g. growth rate and fearfulness). In this study we compared the social behavior and emotional reactivity, as measured in a battery of behavioral tests, of two groups of chickens selected from a common genetic background, an advanced intercross line between the ancestral red junglefowl ("RJF") and the domesticated White Leghorn layer ("WL"). The birds were selected for homozygosity for alternative alleles at one locus (a microsatellite marker), centrally positioned in a previously identified pleiotropic growth QTL on chromosome 1, closely linked to one major candidate gene (AVPR1a) for certain aspects of social behavior. Birds homozygous for the WL allele ("WL genotype") had a modified pattern of social and emotional reactions than birds homozygous for the RJF allele ("RJF genotype"), shown by different scores in a principal components analysis. These results suggest that the growth QTL affects a number of domestication related behavioral traits, and may have been a primary target of selection during domestication. The QTL contains a multitude of genes, several of which have been linked to social behavior (for example the vasotocin receptor AVPR1a targeted in this experiment). Future studies aimed at making a higher resolution genotypic characterization of the QTL should give more information about which of these genes may be considered the strongest candidates for bringing about the behavioral changes associated with animal domestication. PMID:20596888

  20. Sodic Soil Properties and Sunflower Growth as Affected by Byproducts of Flue Gas Desulfurization

    PubMed Central

    Wang, Jinman; Bai, Zhongke; Yang, Peiling

    2012-01-01

    The main component of the byproducts of flue gas desulfurization (BFGD) is CaSO4, which can be used to improve sodic soils. The effects of BFGD on sodic soil properties and sunflower growth were studied in a pot experiment. The experiment consisted of eight treatments, at four BFGD rates (0, 7.5, 15 and 22.5 t ha−1) and two leaching levels (750 and 1200 m3 ha−1). The germination rate and yield of the sunflower increased, and the exchangeable sodium percentage (ESP), pH and total dissolved salts (TDS) in the soils decreased after the byproducts were applied. Excessive BFGD also affected sunflower germination and growth, and leaching improved reclamation efficiency. The physical and chemical properties of the reclaimed soils were best when the byproducts were applied at 7.5 t ha−1 and water was supplied at 1200 m3·ha−1. Under these conditions, the soil pH, ESP, and TDS decreased from 9.2, 63.5 and 0.65% to 7.8, 2.8 and 0.06%, and the germination rate and yield per sunflower reached 90% and 36.4 g, respectively. Salinity should be controlled by leaching when sodic soils are reclaimed with BFGD as sunflower growth is very sensitive to salinity during its seedling stage. PMID:23285042

  1. Review of Factors Affecting the Growth and Survival of Follicular Grafts

    PubMed Central

    Parsley, William M; Perez-Meza, David

    2010-01-01

    Great strides have been made in hair restoration over the past 20 years. A better understanding of natural balding and non-balding patterns along with more respect for ageing has helped guide proper hairline design. Additionally, the use of smaller grafts has created a significantly improved natural appearance to the transplanted grafts. Inconsistent growth and survival of follicular grafts, however, has continued to be a problem that has perplexed hair restoration surgeons. This review attempts to explore the stresses affecting grafts during transplantation and some of the complexities involved in graft growth and survival. These authors reviewed the literature to determine the primary scope of aspects influencing growth and survival of follicular grafts. This scope includes patient selection, operating techniques, graft care, storage solutions and additives. The primary focus of the hair restoration surgeons should first be attention to the fundamentals of hair care, hydration, temperature, time out of body and gentle handling. Factors such as advanced storage solutions and additives can be helpful once the fundamentals have been addressed. PMID:21031063

  2. Streptomycin affects the growth and photochemical activity of the alga Chlorella vulgaris.

    PubMed

    Perales-Vela, Hugo Virgilio; García, Roberto Velasco; Gómez-Juárez, Evelyn Alicia; Salcedo-Álvarez, Martha Ofelia; Cañizares-Villanueva, Rosa Olivia

    2016-10-01

    Antibiotics are increasingly being used in human and veterinary medicine, as well as pest control in agriculture. Recently, their emergence in the aquatic environment has become a global concern. The aim of this study was to evaluate the effect of streptomycin on growth and photosynthetic activity of Chlorella vulgaris after 72h exposure. We found that growth, photosynthetic activity and the content of the D1 protein of photosystem II decreased. Analysis of chlorophyll a fluorescence emission shows a reduction in the energy transfer between the antenna complex and reaction center. Also the activity of the oxygen evolution complex and electron flow between QA and QB were significantly reduced; in contrast, we found an increase in the reduction rate of the acceptor side of photosystem I. The foregoing can be attributed to the inhibition of the synthesis of the D1 protein and perhaps other coded chloroplast proteins that are part of the electron transport chain which are essential for the transformation of solar energy in the photosystems. We conclude that micromolar concentrations of streptomycin can affect growth and photosynthetic activity of Chlorella vulgaris. The accumulation of antibiotics in the environment can become an ecological problem for primary producers in the aquatic environment. PMID:27344399

  3. Loss of stromal JUNB does not affect tumor growth and angiogenesis.

    PubMed

    Braun, Jennifer; Strittmatter, Karin; Nübel, Tobias; Komljenovic, Dorde; Sator-Schmitt, Melanie; Bäuerle, Tobias; Angel, Peter; Schorpp-Kistner, Marina

    2014-03-15

    The transcription factor AP-1 subunit JUNB has been shown to play a pivotal role in angiogenesis. It positively controls angiogenesis by regulating Vegfa as well as the transcriptional regulator Cbfb and its target Mmp13. In line with these findings, it has been demonstrated that tumor cell-derived JUNB promotes tumor growth and angiogenesis. In contrast to JUNB's function in tumor cells, the role of host-derived stromal JUNB has not been elucidated so far. Here, we show that ablation of Junb in stromal cells including endothelial cells (ECs), vascular smooth muscle cells (SMCs) and fibroblasts does not affect tumor growth in two different syngeneic mouse models, the B16-F1 melanoma and the Lewis lung carcinoma model. In-depth analyses of the tumors revealed that tumor angiogenesis remains unaffected as assessed by measurements of the microvascular density and relative blood volume in the tumor. Furthermore, we could show that the maturation status of the tumor vasculature, analyzed by the SMC marker expression, α-smooth muscle actin and Desmin, as well as the attachment of pericytes to the endothelium, is not changed upon ablation of Junb. Taken together, these results indicate that the pro-angiogenic functions of stromal JUNB are well compensated with regard to tumor angiogenesis and tumor growth. PMID:24027048

  4. Sodic soil properties and sunflower growth as affected by byproducts of flue gas desulfurization.

    PubMed

    Wang, Jinman; Bai, Zhongke; Yang, Peiling

    2012-01-01

    The main component of the byproducts of flue gas desulfurization (BFGD) is CaSO(4), which can be used to improve sodic soils. The effects of BFGD on sodic soil properties and sunflower growth were studied in a pot experiment. The experiment consisted of eight treatments, at four BFGD rates (0, 7.5, 15 and 22.5 t ha(-1)) and two leaching levels (750 and 1200 m(3) ha(-1)). The germination rate and yield of the sunflower increased, and the exchangeable sodium percentage (ESP), pH and total dissolved salts (TDS) in the soils decreased after the byproducts were applied. Excessive BFGD also affected sunflower germination and growth, and leaching improved reclamation efficiency. The physical and chemical properties of the reclaimed soils were best when the byproducts were applied at 7.5 t ha(-1) and water was supplied at 1200 m(3)·ha(-1). Under these conditions, the soil pH, ESP, and TDS decreased from 9.2, 63.5 and 0.65% to 7.8, 2.8 and 0.06%, and the germination rate and yield per sunflower reached 90% and 36.4 g, respectively. Salinity should be controlled by leaching when sodic soils are reclaimed with BFGD as sunflower growth is very sensitive to salinity during its seedling stage. PMID:23285042

  5. Does forest fragmentation affect the same way all growth-forms?

    PubMed

    Rodríguez-Loinaz, Gloria; Amezaga, Ibone; Onaindia, Miren

    2012-02-01

    Fragmentation of natural habitats is one of the main causes of the loss of biodiversity. However, all plants do not respond to habitat fragmentation in the same way due to differences in species traits. We studied the effect of patch size and isolation on the biodiversity of vegetation in the mixed-oak forests in the north of the Iberian Peninsula. The aim was to evaluate whether all the growth-forms of vegetation are equally affected by forest fragmentation in order to improve the management strategies to restore this type of vegetation. This study has shown that the effect of the area and spatial isolation of the patches was not the same for the different growth-forms. Fragmentation had a mainly negative effect on the richness and diversity of forest specialist species, especially ferns and herbaceous growth-forms. Moreover, the presence and/or cover of woodland herbaceous species (such as Lamiastrum galeobdolon and Helleborus viridis) and of woodland ferns (namely Asplenium adiantum-nigrum, Asplenium trichomanes, Polystichum setiferum, Dryopteris affinis) were negatively affected by patch size, possibly due to the reduction of habitat quality. These species have been replaced by more generalist species (such as Cardamine pratensis, Cirsium sp., Pulmonaria longifolia or Rumex acetosella) in small patches. Patch isolation had a negative effect on the presence of forest specialist species (namely, L. galeobdolon, Frangula alnus, Hypericum androsaemum, A. adiantum-nigrum and Athyrium filix-femina) and favored colonization by more generalist species such as Cirsium sp., Calluna vulgaris, Erica arborea or Ulex sp. Thus, in this region special attention should be paid to the conservation of forest specialist species, especially ferns and herbs. In conservation policy focused on forest specialist species, the most valuable species in forest ecosystems, conservation of large forest areas should be promoted. PMID:21924813

  6. Solitary fibrous tumour of the chest wall.

    PubMed

    Mohtarrudin, N; Nor Hanipah, Z; Mohd Dusa, N

    2016-04-01

    Extrapleural solitary fibrous tumours (SFTs) are rare tumours characterized by patternless spindle cells with haemangiopericytoma-like vascular spaces. Previously the tumours have been classified as haemangiopericytoma, an entity that is now considered obsolete. We report a case of extrapleural SFT arising in the soft tissue of the chest wall. The patient was a 31-year-old Malay lady presenting with a mobile swelling of the right chest wall for more than five years. During excision the tumour was noted to be well-circumscribed and yellowish in colour, giving an impression of lipoma. Microscopically, the tumour had patternless architecture, characterized by hypocellular and hypercellular areas. It was composed of uniform, spindle-shaped cells displaying oval nuclei, inconspicuous nucleoli, pale cytoplasm and indistinct cell borders. The mitotic count was 2 per 10 HPF. Branching, medium-sized thin-walled blood vessels in a haemangiopericytomatous growth pattern, some with hyalinised wall were identified. The neoplastic cells were immunoreactive to CD99 and CD34 and were non-immunoreactive to Desmin, Smooth Muscle Actin, S100 protein and EMA. We elucidate the challenges in diagnosing this tumour in this unusual location. PMID:27126667

  7. Hypoxia signalling in cancer and approaches to enforce tumour regression

    NASA Astrophysics Data System (ADS)

    Pouysségur, Jacques; Dayan, Frédéric; Mazure, Nathalie M.

    2006-05-01

    Tumour cells emerge as a result of genetic alteration of signal circuitries promoting cell growth and survival, whereas their expansion relies on nutrient supply. Oxygen limitation is central in controlling neovascularization, glucose metabolism, survival and tumour spread. This pleiotropic action is orchestrated by hypoxia-inducible factor (HIF), which is a master transcriptional factor in nutrient stress signalling. Understanding the role of HIF in intracellular pH (pHi) regulation, metabolism, cell invasion, autophagy and cell death is crucial for developing novel anticancer therapies. There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pHi-control systems.

  8. Reduction in DNA topoisomerase I level affects growth, phenotype and nucleoid architecture of Mycobacterium smegmatis.

    PubMed

    Ahmed, Wareed; Menon, Shruti; Karthik, Pullela V; Nagaraja, Valakunja

    2015-02-01

    The steady-state negative supercoiling of eubacterial genomes is maintained by the action of DNA topoisomerases. Topoisomerase distribution varies in different species of mycobacteria. While Mycobacterium tuberculosis (Mtb) contains a single type I (TopoI) and a single type II (Gyrase) enzyme, Mycobacterium smegmatis (Msm) and other members harbour additional relaxases. TopoI is essential for Mtb survival. However, the necessity of TopoI or other relaxases in Msm has not been investigated. To recognize the importance of TopoI for growth, physiology and gene expression of Msm, we have developed a conditional knock-down strain of TopoI in Msm. The TopoI-depleted strain exhibited extremely slow growth and drastic changes in phenotypic characteristics. The cessation of growth indicates the essential requirement of the enzyme for the organism in spite of having additional DNA relaxation enzymes in the cell. Notably, the imbalance in TopoI level led to the altered expression of topology modulatory proteins, resulting in a diffused nucleoid architecture. Proteomic and transcript analysis of the mutant indicated reduced expression of the genes involved in central metabolic pathways and core DNA transaction processes. RNA polymerase (RNAP) distribution on the transcription units was affected in the TopoI-depleted cells, suggesting global alteration in transcription. The study thus highlights the essential requirement of TopoI in the maintenance of cellular phenotype, growth characteristics and gene expression in mycobacteria. A decrease in TopoI level led to altered RNAP occupancy and impaired transcription elongation, causing severe downstream effects. PMID:25516959

  9. Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues

    PubMed Central

    Cheng, Xiao Jiao; Lin, Jia Cheng; Ding, Yan Fei; Zhu, Liming; Ye, Jing; Tu, Shui Ping

    2016-01-01

    Survivin overexpression is associated with poor prognosis of human gastric cancer, and is a target for gastric cancer therapy. YM155 is originally identified as a specific inhibitor of survivin. In this study, we investigated the antitumor effect of YM155 on human gastric cancer. Our results showed that YM155 treatment significantly inhibited cell proliferation, reduced colony formation and induced apoptosis of gastric cancer cells in a dose-dependent manner. Accordingly, YM155 treatment significantly decreased survivin expression without affecting XIAP expression and increased the cleavage of apoptosis-associated proteins caspase 3, 7, 8, 9. YM155 significantly inhibited sphere formation of gastric cancer cells, suppressed expansion and growth of the formed spheres (cancer stem cell-like cells, CSCs) and downregulated the protein levels of β-catenin, c-Myc, Cyclin D1 and CD44 in gastric cancer cells. YM155 infusion at 5 mg/kg/day for 7 days markedly inhibited growth of gastric cancer xenograft in a nude mouse model. Immunohistochemistry staining and Western Blot showed that YM155 treatment inhibited expression of survivin and CD44, induced apoptosis and reduced CD44+ CSCs in xenograft tumor tissues in vivo. No obvious pathological changes were observed in organs (e.g. heart, liver, lung and kidney) in YM155-treated mice. Our results demonstrated that YM155 inhibits cell proliferation, induces cell apoptosis, reduces cancer stem cell expansion, and inhibits xenograft tumor growth in gastric cancer cells. Our results elucidate a new mechanism by which YM155 inhibits gastric cancer growth by inhibition of CSCs. YM155 may be a promising agent for gastric cancer treatment. PMID:26771139

  10. Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues.

    PubMed

    Cheng, Xiao Jiao; Lin, Jia Cheng; Ding, Yan Fei; Zhu, Liming; Ye, Jing; Tu, Shui Ping

    2016-02-01

    Survivin overexpression is associated with poor prognosis of human gastric cancer, and is a target for gastric cancer therapy. YM155 is originally identified as a specific inhibitor of survivin. In this study, we investigated the antitumor effect of YM155 on human gastric cancer. Our results showed that YM155 treatment significantly inhibited cell proliferation, reduced colony formation and induced apoptosis of gastric cancer cells in a dose-dependent manner. Accordingly, YM155 treatment significantly decreased survivin expression without affecting XIAP expression and increased the cleavage of apoptosis-associated proteins caspase 3, 7, 8, 9. YM155 significantly inhibited sphere formation of gastric cancer cells, suppressed expansion and growth of the formed spheres (cancer stem cell-like cells, CSCs) and downregulated the protein levels of β-catenin, c-Myc, Cyclin D1 and CD44 in gastric cancer cells. YM155 infusion at 5 mg/kg/day for 7 days markedly inhibited growth of gastric cancer xenograft in a nude mouse model. Immunohistochemistry staining and Western Blot showed that YM155 treatment inhibited expression of survivin and CD44, induced apoptosis and reduced CD44+ CSCs in xenograft tumor tissues in vivo. No obvious pathological changes were observed in organs (e.g. heart, liver, lung and kidney) in YM155-treated mice. Our results demonstrated that YM155 inhibits cell proliferation, induces cell apoptosis, reduces cancer stem cell expansion, and inhibits xenograft tumor growth in gastric cancer cells. Our results elucidate a new mechanism by which YM155 inhibits gastric cancer growth by inhibition of CSCs. YM155 may be a promising agent for gastric cancer treatment. PMID:26771139

  11. Do Amplitudes of Water Level Fluctuations Affect the Growth and Community Structure of Submerged Macrophytes?

    PubMed Central

    Wang, Mo-Zhu; Liu, Zheng-Yuan; Luo, Fang-Li; Lei, Guang-Chun; Li, Hong-Li

    2016-01-01

    Submerged macrophytes are subjected to potential mechanical stresses associated with fluctuating water levels in natural conditions. However, few experimental studies have been conducted to further understand the effects of water level fluctuating amplitude on submerged macrophyte species and their assemblages or communities. We designed a controlled experiment to investigate the responses of three submerged macrophyte species (Hydrilla verticillata, Ceratophyllum demersum and Elodea nuttallii) and their combinations in communities to three amplitudes (static, ± 30 cm, ± 60 cm) of water level fluctuations. Results showed that water level fluctuating amplitude had little effects on the community performance and the three tested species responded differently. H. verticillata exhibited more growth in static water and it was negatively affected by either of the water level fluctuations amplitude, however, growth parameters of H. verticillata in two fluctuating water level treatments (i.e., ± 30 cm, ± 60 cm) were not significantly different. On the other hand, the growth of C. demersum was not significantly correlated with different amplitude treatments. However, it became more abundant when water levels fluctuated. E. nuttallii was inhibited by the two fluctuating water level treatments, and was less in growth parameters compared to the other species especially in water level fluctuating conditions. The inherent differences in the adaptive capabilities of the tested species indicate that C. demersum or other species with similar responses may be dominant species to restore submerged macrophyte communities with great fluctuating water levels. Otherwise, H. verticillata, E. nuttallii or other species with similar responses could be considered for constructing the community in static water conditions. PMID:26735689

  12. Local tumour hyperthermia as immunotherapy for metastatic cancer

    PubMed Central

    Toraya-Brown, Seiko; Fiering, Steven

    2014-01-01

    Abstract Local tumour hyperthermia for cancer treatment is currently used either for ablation purposes as an alternative to surgery or less frequently, in combination with chemotherapy and/or radiation therapy to enhance the effects of those traditional therapies. As it has become apparent that activating the immune system is crucial to successfully treat metastatic cancer, the potential of boosting anti-tumour immunity by heating tumours has become a growing area of cancer research. After reviewing the history of hyperthermia therapy for cancer and introducing methods for inducing local hyperthermia, this review describes different mechanisms by which heating tumours can elicit anti-tumour immune responses, including tumour cell damage, tumour surface molecule changes, heat shock proteins, exosomes, direct effects on immune cells, and changes in the tumour vasculature. We then go over in vivo studies that provide promising results showing that local hyperthermia therapy indeed activates various systemic anti-tumour immune responses that slow growth of untreated tumours. Finally, future research questions that will help bring the use of local hyperthermia as systemic immunotherapy closer to clinical application are discussed. PMID:25430985

  13. Tumour-induced osteomalacia: An emergent paraneoplastic syndrome.

    PubMed

    Alonso, Guillermo; Varsavsky, Mariela

    2016-04-01

    Endocrine paraneoplastic syndromes are distant manifestations of some tumours. An uncommon but increasingly reported form is tumour-induced osteomalacia, a hypophosphatemic disorder associated to fibroblast growth factor 23 (FGF-23) secretion by tumours. The main biochemical manifestations of this disorder include hypophosphatemia, inappropriately low or normal tubular reabsorption of phosphate, low serum calcitriol levels, increased serum alkaline phosphatase levels, and elevated or normal serum FGF-23 levels. These tumours, usually small, benign, slow growing and difficult to discover, are mainly localized in soft tissues of the limbs. Histologically, phosphaturic mesenchymal tumours of the mixed connective tissue type are most common. Various imaging techniques have been suggested with variable results. Treatment of choice is total surgical resection of the tumour. Medical treatment includes oral phosphorus and calcitriol supplements, octreotide, cinacalcet, and monoclonal antibodies. PMID:26718193

  14. Tumour-associated hypoglycaemia in a murine cachexia model.

    PubMed Central

    McDevitt, T. M.; Tisdale, M. J.

    1992-01-01

    Animals bearing a cachexia-inducing tumour, the MAC16 adenocarcinoma, showed a progressive decrease in blood glucose levels with increasing weight loss, while animals bearing a histologically similar tumour, the MAC13 adenocarcinoma, showed no change in either body weight or blood glucose levels with growth of the tumour. The effect of the MAC16 tumour on blood glucose levels appeared to be unrelated to food intake, glucose consumption by the tumour, or to the production of increased levels of IGF-I and IGF-II mRNA by the tumour cells. The relationship between the induction of cachexia and alteration in blood glucose levels remains unknown. Images Figure 4 Figure 5 PMID:1358167

  15. Fibroblast growth factor 9 is a novel modulator of negative affect

    PubMed Central

    Aurbach, Elyse L.; Inui, Edny Gula; Turner, Cortney A.; Hagenauer, Megan H.; Prater, Katherine E.; Li, Jun Z.; Absher, Devin; Shah, Najmul; Blandino, Peter; Bunney, William E.; Myers, Richard M.; Barchas, Jack D.; Schatzberg, Alan F.; Watson, Stanley J.; Akil, Huda

    2015-01-01

    Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9’s function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders. PMID:26351673

  16. The protective function of personal growth initiative among a genocide-affected population in Rwanda.

    PubMed

    Blackie, Laura E R; Jayawickreme, Eranda; Forgeard, Marie J C; Jayawickreme, Nuwan

    2015-07-01

    The aim of the current study was to investigate the extent to which individual differences in personal growth initiative (PGI) were associated with lower reports of functional impairment of daily activities among a genocide-affected population in Rwanda. PGI measures an individual's motivation to develop as a person and the extent to which he or she is active in setting goals that work toward achieving self-improvement. We found that PGI was negatively associated with functional impairment when controlling for depression, posttraumatic stress disorder, and other demographic factors. Our results suggest that PGI may constitute an important mindset for facilitating adaptive functioning in the aftermath of adversity and in the midst of psychological distress, and as such they might have practical applications for the development of intervention programs. PMID:26147518

  17. Transport processes in tumours.

    PubMed

    Quastel, J H

    1965-12-01

    The characteristic features of transport systems controlling influx into tumour cells of nutrients and other chemicals are briefly described. Two notable features of transport of amino acids into tumour cells have been observed: extensive accumulation against a concentration gradient and equal accumulations, whether conditions are aerobic or anaerobic, provided glucose is present. This combination of features has not been observed in the majority of normal mammalian tissues so far examined. Important for considerations of chemotherapy is the ability of tumour transport carriers to transfer substances related in structure to amino acids and other nutrients. Amino acid analogues, for example, can either block transport of natural amino acids or can be transported into the cell where they may interfere with various aspects of amino acid metabolism. The study of transport carriers is essential for an understanding of tumour-host relationships and for considerations of chemotherapy. PMID:5842595

  18. Spatial environmental heterogeneity affects plant growth and thermal performance on a green roof.

    PubMed

    Buckland-Nicks, Michael; Heim, Amy; Lundholm, Jeremy

    2016-05-15

    Green roofs provide ecosystem services, including stormwater retention and reductions in heat transfer through the roof. Microclimates, as well as designed features of green roofs, such as substrate and vegetation, affect the magnitude of these services. Many green roofs are partially shaded by surrounding buildings, but the effects of this within-roof spatial environmental heterogeneity on thermal performance and other ecosystem services have not been examined. We quantified the effects of spatial heterogeneity in solar radiation, substrate depth and other variables affected by these drivers on vegetation and ecosystem services in an extensive green roof. Spatial heterogeneity in substrate depth and insolation were correlated with differential growth, survival and flowering in two focal plant species. These effects were likely driven by the resulting spatial heterogeneity in substrate temperature and moisture content. Thermal performance (indicated by heat flux and substrate temperature) was influenced by spatial heterogeneity in vegetation cover and substrate depth. Areas with less insolation were cooler in summer and had greater substrate moisture, leading to more favorable conditions for plant growth and survival. Spatial variation in substrate moisture (7%-26% volumetric moisture content) and temperature (21°C-36°C) during hot sunny conditions in summer could cause large differences in stormwater retention and heat flux within a single green roof. Shaded areas promote smaller heat fluxes through the roof, leading to energy savings, but lower evapotranspiration in these areas should reduce stormwater retention capacity. Spatial heterogeneity can thus result in trade-offs between different ecosystem services. The effects of these spatial heterogeneities are likely widespread in green roofs. Structures that provide shelter from sun and wind may be productively utilized to design higher functioning green roofs and increase biodiversity by providing habitat

  19. Cronobacter sakazakii in foods and factors affecting its survival, growth, and inactivation.

    PubMed

    Beuchat, Larry R; Kim, Hoikyung; Gurtler, Joshua B; Lin, Li-Chun; Ryu, Jee-Hoon; Richards, Glenner M

    2009-12-31

    Cronobacter sakazakii has been isolated from a wide range of environmental sources and from several foods of animal and plant origin. While infections caused by C. sakazakii have predominantly involved neonates and infants, its presence on or in foods other than powdered infant formula raises concern about the safety risks these foods pose to immunocompromised consumers. We have done a series of studies to better understand the survival and growth characteristics of C. sakazakii in infant formula, infant cereal, fresh-cut produce, and juices made from fresh produce. Over a 12-month storage period, the pathogen survived better in dried formula and cereal at low a(w) (0.25-0.30) than at high a(w) (0.69-0.82) and at 4 degrees C compared to 30 degrees C. C. sakazakii grows in formulas and cereals reconstituted with water or milk and held at 12-30 degrees C. The composition of formulas or cereals does not markedly affect the rate of growth. C. sakazakii grows well on fresh-cut apple, cantaloupe, watermelon, cabbage, carrot, cucumber, lettuce, and tomato at 25 degrees C and in some types of produce at 12 degrees C. Treatment of fresh fruits and vegetables with sanitizers such as chlorine, chlorine dioxide, and a peroxyacetic acid-based solution causes reductions of 1.6-5.4 log CFU/apple, tomato, and lettuce. Cells of C. sakazakii in biofilms formed on stainless steel and enteral feeding tubes or dried on the surface of stainless steel have increased resistance to disinfectants. Death of cells in biofilms is affected by atmospheric relative humidity. These studies have contributed to a better understanding of the behavior of C. sakazakii in and on foods and on food-contact surfaces, thereby enabling the development of more effective strategies and interventions for its control. PMID:19346021

  20. Kinetics of Growth Retardant and Hormone Interactions in Affecting Cucumber Hypocotyl Elongation 1

    PubMed Central

    Moore, Thomas C.

    1967-01-01

    The capacities of indole-3-acetic acid (IAA) and gibberellin A3 (GA3) to counteract the inhibitory effects of (2-chloroethyl) trimethylammonium chloride (CCC), 2-isopropyl-4-dimethylamino-5-methylphenyl-1-piperidinecarboxylate methyl chloride (Amo-1618), and N,N-dimethylaminosuccinamic acid (B-995) on hypocotyl elongation in light-grown cucumber (Cucumis sativus L.) seedlings were investigated. One μg of GA3 applied to the shoot tip was sufficient to completely nullify the effect of 10 μg of Amo-1618 or 25 μg of B-995 applied simultaneously to the shoot tip, and 10 μg of GA3 completely counteracted the effect of 10−3 m CCC added to the root medium. One μg of IAA counteracted the effect of 10−3 m CCC in the root medium, but IAA did not nullify the action of either Amo-1618 or B-995. Experiments were conducted using 2 growth retardants simultaneously, which indicated that Amo-1618 and CCC inhibit a common process, namely GA biosynthesis, essential to hypocotyl elongation. However, since the effect of CCC was overcome by applications of both GA and IAA, growth retardation resulting from treatment with CCC apparently is not due solely to inhibition of GA biosynthesis. B-995 did not interact additively with either Amo-1618 or CCC, which suggests that B-995 affects a process different from those affected by the other 2 retardants. Thus, while inhibition evoked by B-995 is reversible by applied GA, the action of B-995 does not appear to be inhibition of GA biosynthesis. PMID:16656555

  1. Ecosystem regime shifts have not affected growth and survivorship of eastern Beaufort Sea belugas.

    PubMed

    Luque, Sebastián P; Ferguson, Steven H

    2009-05-01

    Large-scale ocean-atmosphere physical dynamics can have profound impacts on the structure and organization of marine ecosystems. These changes have been termed "regime shifts", and five different episodes have been detected in the North Pacific Ocean, with concurrent changes also occurring in the Bering and Beaufort Seas. Belugas from the Eastern Beaufort Sea (EBS) use the Bering Sea during winter and the Beaufort Sea during summer, yet the potential effects of regime shifts on belugas have not been assessed. We investigated whether body size and survivorship of EBS belugas harvested in the Mackenzie River delta region between 1993 and 2003 have been affected by previous purported regime shifts in the North Pacific. Residuals from the relationship between body length and age were calculated and compared among belugas born between 1932 and 1989. Residual body size was not significantly related to birth year for any regime, nor to the age group individuals belonged to during any regime. The percentage deviation in number of belugas born in any given year that survived to be included in the hunt (survivorship) did not show any significant trend within or between regimes. Accounting for lags of 1-5 years did not reveal any evidence of delayed effects. Furthermore, neither population index was significantly related to changes in major climatic variables that precede regime shifts. Our results suggest that EBS beluga body size and survivorship have not been affected by the major regime shifts of the North Pacific and the adjacent Bering and Beaufort Seas. EBS belugas may have been able to modify their diet without compromising their growth and survivorship. Diet and reproductive analyses over large and small time scales can help understand the mechanisms enabling belugas to avoid significant growth and reproductive effects of past regime shifts. PMID:19229560

  2. Breast tumour angiogenesis

    PubMed Central

    Fox, Stephen B; Generali, Daniele G; Harris, Adrian L

    2007-01-01

    The central importance of tumour neovascularization has been emphasized by clinical trials using antiangiogenic therapy in breast cancer. This review gives a background to breast tumour neovascularization in in situ and invasive breast cancer, outlines the mechanisms by which this is achieved and discusses the influence of the microenvironment, focusing on hypoxia. The regulation of angiogenesis and the antivascular agents that are used in an antiangiogenic dosing schedule, both novel and conventional, are also summarized. PMID:18190723

  3. [Tumours and liver transplants].

    PubMed

    Mejzlík, Vladimír; Husová, Libuše; Kuman, Milan; Štěpánková, Soňa; Ondrášek, Jiří; Němec, Petr

    2015-01-01

    Liver transplantation as a curative treatment method can be used for selected primary liver tumours, in particular for hepatocellular carcinoma and rather rare semi-malignant tumours such as epithelioid hemangioendothelioma, further for infiltration of liver by metastatic neuroendocrine tumours (provided that metastases are only located in the liver and the primary tumour was removed) and for benign tumours (hemangiomas and adenomas) with oppression symptoms and size progression. Cholangiocarcinoma is not indicated for liver transplantation at the CKTCH Brno. In recent years liver transplants for hepatocellular carcinoma have increased and hepatocellular carcinoma has also been more frequently found ex post, in the explanted livers. Liver transplantation is indicated in selected patients with a good chance of long-term survival after liver transplantation (a generally accepted limit is 5 year survival of 50 % after transplantation). By 20 March 2015 there were liver transplants carried out on 38 patients - in 25 of them was hepatocellular carcinoma diagnosed before transplantation and in 13 it was found in the liver explants. 5 year survival following transplantation is reached by 53 % of this cohort. 32 % patients suffered from chronic hepatitis C. The longest surviving (32 years) patient at CKTCH Brno had liver transplanted for a big fibrolamellar hepatocellular carcinoma, which points to the prognostic significance of tumour histology: the criterion only considered in some indication schemes for practical reasons. Benign liver tumours (adenomatosis, cystadenoma, hemangioma with oppression symptoms) are rather rare indications and the transplantation results are favourable. 4 patients underwent transplantation for infiltration of liver by carcinoid, tumour recurrence occurred in one. PMID:26375706

  4. Physicochemical Factors Affecting the Growth of Burkholderia pseudomallei in Soil Microcosm

    PubMed Central

    Wang-ngarm, Supunnipa; Chareonsudjai, Sorujsiri; Chareonsudjai, Pisit

    2014-01-01

    Burkholderia pseudomallei causes melioidosis, the third most common cause of death from infectious diseases in northeast Thailand. Four physicochemical factors were set so that their values covered the range of the northeast, which is an endemic area. The soil pH was set at pH 4–10, soil salinity was 0.0–5.0% NaCl, total iron was 50–150 mg/kg soil, and carbon to nitrogen ratio (C/N) was 10:1 to 40:1. The experiments were carried out at 37°C, and soil moisture was maintained for 7 days. The number of viable bacterial cells was counted daily. Soil pH, salinity, Fe, and C/N ratio affected the bacterial growth. The bacterial colony was significantly (P < 0.05) reduced at soil pH > 8, soil salinity > 1% NaCl, and C/N ratio > 40:1. However, the growth of B. pseudomallei was enhanced by increasing the concentrations of iron significantly (P < 0.05). We propose using these findings to control B. pseudomallei in situ. PMID:24445210

  5. Zebra pattern in rocks as a function of grain growth affected by second-phase particles

    NASA Astrophysics Data System (ADS)

    Kelka, Ulrich; Koehn, Daniel; Beaudoin, Nicolas

    2015-09-01

    In this communication we present a simple microdynamic model which can explain the beginning of the zebra pattern formation in rocks. The two dimensional model consists of two main processes, mineral replacement along a reaction front, and grain boundary migration affected by impurities. In the numerical model we assume that an initial distribution of second-phase particles is present due to sedimentary layering. The reaction front percolates the model and redistributes second-phase particles by shifting them until the front is saturated and drops the particles again. This produces and enhances initial layering. Grain growth is hindered in layers with high second-phase particle concentrations whereas layers with low concentrations coarsen. Due to the grain growth activity in layers with low second-phase particle concentrations these impurities are collected at grain boundaries and the crystals become very clean. Therefore the white layers in the pattern contain large grains with low concentration of second-phase particles, whereas the dark layers contain small grains with a large second-phase particle concentration.

  6. Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells

    PubMed Central

    Akhtar Ali, Muhammad; Younis, Shady; Wallerman, Ola; Gupta, Rajesh; Andersson, Leif; Sjöblom, Tobias

    2015-01-01

    The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle–related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-β, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes. PMID:26056301

  7. Lysyl oxidase-like-2 promotes tumour angiogenesis and is a potential therapeutic target in angiogenic tumours.

    PubMed

    Zaffryar-Eilot, Shelly; Marshall, Derek; Voloshin, Tali; Bar-Zion, Avinoam; Spangler, Rhyannon; Kessler, Ofra; Ghermazien, Haben; Brekhman, Vera; Suss-Toby, Edith; Adam, Dan; Shaked, Yuval; Smith, Victoria; Neufeld, Gera

    2013-10-01

    Lysyl oxidase-like 2 (LOXL2), a secreted enzyme that catalyzes the cross-linking of collagen, plays an essential role in developmental angiogenesis. We found that administration of the LOXL2-neutralizing antibody AB0023 inhibited bFGF-induced angiogenesis in Matrigel plug assays and suppressed recruitment of angiogenesis promoting bone marrow cells. Small hairpin RNA-mediated inhibition of LOXL2 expression or inhibition of LOXL2 using AB0023 reduced the migration and network-forming ability of endothelial cells, suggesting that the inhibition of angiogenesis results from a direct effect on endothelial cells. To examine the effects of AB0023 on tumour angiogenesis, AB0023 was administered to mice bearing tumours derived from SKOV-3 ovarian carcinoma or Lewis lung carcinoma (LLC) cells. AB0023 treatment significantly reduced the microvascular density in these tumours but did not inhibit tumour growth. However, treatment of mice bearing SKOV-3-derived tumours with AB0023 also promoted increased coverage of tumour vessels with pericytes and reduced tumour hypoxia, providing evidence that anti-LOXL2 therapy results in the normalization of tumour blood vessels. In agreement with these data, treatment of mice bearing LLC-derived tumours with AB0023 improved the perfusion of the tumour-associated vessels as determined by ultrasonography. Improved perfusion and normalization of tumour vessels after treatment with anti-angiogenic agents were previously found to improve the delivery of chemotherapeutic agents into tumours and to result in an enhancement of chemotherapeutic efficiency. Indeed, treatment with AB0023 significantly enhanced the anti-tumourigenic effects of taxol. Our results suggest that inhibition of LOXL2 may prove beneficial for the treatment of angiogenic tumours. PMID:23828904

  8. Testicular germ cell tumours.

    PubMed

    Rajpert-De Meyts, Ewa; McGlynn, Katherine A; Okamoto, Keisei; Jewett, Michael A S; Bokemeyer, Carsten

    2016-04-23

    Testicular germ cell tumours are at the crossroads of developmental and neoplastic processes. Their cause has not been fully elucidated but differences in incidences suggest that a combination of genetic and environment factors are involved, with environmental factors predominating early in life. Substantial progress has been made in understanding genetic susceptibility in the past 5 years on the basis of the results of large genome-wide association studies. Testicular germ cell tumours are highly sensitive to radiotherapy and chemotherapy and hence have among the best outcomes of all tumours. Because the tumours occur mainly in young men, preservation of reproductive function, quality of life after treatment, and late effects are crucial concerns. In this Seminar, we provide an overview of advances in the understanding of the epidemiology, genetics, and biology of testicular germ cell tumours. We also summarise the consensus on how to treat testicular germ cell tumours and focus on a few controversies and improvements in the understanding of late effects of treatment and quality of life for survivors. PMID:26651223

  9. Salivary enzymes and exhaled air affect Streptococcus salivarius growth and physiological state in complemented artificial saliva.

    PubMed

    Roger, P; Harn-Arsa, S; Delettre, J; Béal, C

    2011-12-01

    To better understand the phenomena governing the establishment of the oral bacterium Streptococcus salivarius in the mouth, the effect of some environmental factors has been studied in complemented artificial saliva, under oral pH and temperature conditions. Three salivary enzymes at physiological concentrations were tested: peroxidase, lysozyme and amylase, as well as injection of exhaled air. Injection of air containing 5% CO2 and 16% O2 induced a deleterious effect on S. salivarius K12, mainly by increasing redox potential. Addition of lysozyme slightly affected the physiological state of S. salivarius by altering membrane integrity. In contrast, peroxidase was not detrimental as it made it possible to decrease the redox potential. The addition of amylase reduced the specific growth rate of S. salivarius by formation of a complex with amylase and mucins, but led to high final biomass, as a result of enzymatic degradation of some nutrients. Finally, this work demonstrated that salivary enzymes had a slight impact on S. salivarius behaviour. It can thus be concluded that this bacterium was well adapted to in-mouth conditions, as it was able to resist certain salivary enzymes, even if tolerance to expired air was affected, as a result of an increased redox potential. PMID:21892611

  10. Anaesthetic management for caesarean section in a case of previously operated with residual pituitary tumour

    PubMed Central

    Shah, Prerana N; Sonawane, Darshana; Appukutty, Jithesh

    2011-01-01

    Successful anaesthetic management for caesarean section in a case with previous pituitary tumour resection, with residual tumour, is reported. The pituitary gland undergoes global hyperplasia during pregnancy. Functional pituitary tumours may exhibit symptomatic enlargement during pregnancy. Growth hormone secreting tumour is associated with acromegaly which has associated anaesthetic implications of difficult airway, systemic hypertension, and diabetes and electrolyte imbalance. Intracranial space occupying lesions can increase intra cranial pressure and compromise cerebral perfusion or cause herniation. We report management of this case. PMID:22223910

  11. FGFs: crucial factors that regulate tumour initiation and progression.

    PubMed

    Jing, Qian; Wang, Yuanyuan; Liu, Hao; Deng, Xiaowei; Jiang, Lin; Liu, Rui; Song, Haixing; Li, Jingyi

    2016-08-01

    Fibroblast growth factors (FGFs) are crucial signalling molecules involved in normal cell growth, differentiation and proliferation. Over the past few decades, a large body of research has illustrated effects of individual FGFs on tumour initiation and progression. Tumour development is commonly accompanied with generation of new blood and lymph vessels, which support enhanced cell proliferation. Moreover, acquisition of tumour cells of the epithelial-mesenchymal transition (EMT) phenotype, enhances tumour cell migration and invasion potentials, crucial steps in tumour metastasis. This review summarizes recent findings concerning roles of FGFs in angiogenesis, lymphangiogenesis and EMT. PMID:27383016

  12. The perivascular niche regulates breast tumour dormancy.

    PubMed

    Ghajar, Cyrus M; Peinado, Héctor; Mori, Hidetoshi; Matei, Irina R; Evason, Kimberley J; Brazier, Hélène; Almeida, Dena; Koller, Antonius; Hajjar, Katherine A; Stainier, Didier Y R; Chen, Emily I; Lyden, David; Bissell, Mina J

    2013-07-01

    In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth. PMID:23728425

  13. Tumour Angiogenesis and Angiogenic Inhibitors: A Review

    PubMed Central

    Yadav, Lalita; Puri, Naveen; Satpute, Pranali; Sharma, Vandana

    2015-01-01

    Angiogenesis is a complex process depending on the coordination of many regulators and there by activating angiogenic switch. Recent advances in understanding of angiogenic mechanism have lead to the development of several anti-angiogenic and anti-metastatic agents that use the strategy of regulation of angiogenic switch. Antiangiogenic therapy is a form of treatment not cure for cancer and represents a highly effective strategy for destroying tumour because vascular supply is the fundamental requirement for growth of tumour. Because of the quiescent nature of normal adult vasculature, angiogenic inhibitors are expected to confer a degree of specificity when compared to nonspecific modalities of chemo and radiotherapy, so it has the advantage of less toxicities, does not induce drug resistance and deliver a relatively non toxic, long term treatment of tumour. PMID:26266204

  14. Aluminum affects heterogeneous Fe(III) (Hydr)oxide nucleation, growth, and ostwald ripening.

    PubMed

    Hu, Yandi; Li, Qingyun; Lee, Byeongdu; Jun, Young-Shin

    2014-01-01

    Heterogeneous coprecipitation of iron and aluminum oxides is an important process for pollutant immobilization and removal in natural and engineered aqueous environments. Here, using a synchrotron-based small-angle X-ray scattering technique, we studied heterogeneous nucleation and growth of Fe(III) (hydr)oxide on quartz under conditions found in acid mine drainage (at pH = 3.7 ± 0.2, [Fe(3+)] = 10(-4) M) with different initial aqueous Al/Fe ratios (0:1, 1:1, and 5:1). Interestingly, although the atomic ratios of Al/Fe in the newly formed Fe(III) (hydr)oxide precipitates were less than 1%, the in situ particle size and volume evolutions of the precipitates on quartz were significantly influenced by aqueous Al/Fe ratios. At the end of the 3 h experiments, with aqueous Al/Fe ratios of 0:1, 1:1, and 5:1, the average radii of gyration of particles on quartz were 5.7 ± 0.3, 4.6 ± 0.1, and 3.7 ± 0.3 nm, respectively, and the ratio of total particle volumes on quartz was 1.7:3.4:1.0. The Fe(III) (hydr)oxide precipitates were poorly crystallized, and were positively charged in all solutions. In the presence of Al(3+), Al(3+) adsorption onto quartz changed the surface charge of quartz from negative to positive, which caused the slower heterogeneous growth of Fe(III) (hydr)oxide on quartz. Furthermore, Al affected the amount of water included in the Fe(III) (hydr)oxides, which can influence their adsorption capacity. This study yielded important information usable for pollutant removal not only in natural environments, but also in engineered water treatment processes. PMID:24289329

  15. Tumours of the ovary

    PubMed Central

    Nielsen, Svend W.; Misdorp, W.; McEntee, Kenneth

    1976-01-01

    Ovarian tumours are common in animals, the majority occurring in bitches and cows. The two most important germ cell tumours were dysgerminoma and teratoma; these morphologically resemble their counterparts in women, with the exception that teratomas in animals tend less to malignancy. The granulosa cell tumour is the most frequent sex cord-stromal tumour in all six species and it may contain luteinized areas or show differentiation towards a Sertoli cell pattern. The canine papillary adenoma and papillary adenocarcinoma, which are as common as granulosa tumours, have several features in common with their counterparts in women: they are of similar histological appearance, are frequently bilateral, and the adenocarcinomas have a great propensity for peritoneal implantation metastasis. Ovarian cysts are frequent in the bitch, sow, and cow and may originate from five different anatomical structures in the ovary. ImagesFig. 1Fig. 2 and 3Fig. 20-22Fig. 8-10Fig. 15 and 16Fig. 23Fig. 24Fig. 25Fig. 26Fig. 17-19Fig. 4 and 5Fig. 6 and 7Fig. 11Fig. 12Fig. 13 and 14 PMID:1086151

  16. Telomere uncapping by the G-quadruplex ligand RHPS4 inhibits clonogenic tumour cell growth in vitro and in vivo consistent with a cancer stem cell targeting mechanism.

    PubMed

    Phatak, P; Cookson, J C; Dai, F; Smith, V; Gartenhaus, R B; Stevens, M F G; Burger, A M

    2007-04-23

    The pentacyclic acridinium methosulfate salt RHPS4 induces the 3'single-stranded guanine-rich telomeric overhang to fold into a G-quadruplex structure. Stabilisation of the latter is incompatible with an attachment of telomerase to the telomere and thus G-quadruplex ligands can effectively inhibit both the catalytic and capping functions of telomerase. In this study, we examined mechanisms underlying telomere uncapping by RHPS4 in uterus carcinoma cells (UXF1138L) with short telomeres and compared the susceptibility of bulk and clonogenic cancer cells to the G-quadruplex ligand. We show that treatment of UXF1138L cells with RHPS4 leads to the displacement of the telomerase catalytic subunit (hTERT) from the nucleus, induction of telomere-initiated DNA-damage signalling and chromosome fusions. We further report that RHPS4 is more potent against cancer cells that grow as colonies in soft agar than cells growing as monolayers. Human cord blood and HEK293T embryonic kidney cell colony forming units, however, were more resistant to RHPS4. RHPS4-treated UXF1138L xenografts had a decreased clonogenicity, showed loss of nuclear hTERT expression and an induction of mitotic abnormalities compared with controls. Although single-agent RHPS4 had limited in vivo efficacy, a combination of RHPS4 with the mitotic spindle poison Taxol caused tumour remissions and further enhancement of telomere dysfunction. PMID:17406367

  17. A review of current murine models of multiple myeloma used to assess the efficacy of therapeutic agents on tumour growth and bone disease.

    PubMed

    Paton-Hough, J; Chantry, A D; Lawson, M A

    2015-08-01

    Pre-clinical in vivo models of multiple myeloma are essential tools for investigating the pathophysiology of multiple myeloma and for testing new therapeutic agents and strategies prior to their potential use in clinical trials. Over the last five decades, several different types of murine models of multiple myeloma have been developed ranging from immunocompetent syngeneic models, e.g. the 5 T series of myeloma cells, to immunocompromised models including the SCID xenograft models, which use human myeloma cell lines or patient-derived cells. Other models include hybrid models featuring the implantation of SCID mice with bone chips (SCID-hu or SCID-rab) or 3-D bone scaffolds (SCID-synth-hu), and mice that have been genetically engineered to develop myeloma. Bearing in mind the differences in these models, it is not surprising that they reflect to varying degrees different aspects of myeloma. Here we review the past and present murine models of myeloma, with particular emphasis on their advantages and limitations, characteristics, and their use in testing therapeutic agents to treat myeloma tumour burden and bone disease. PMID:25868800

  18. Telomere uncapping by the G-quadruplex ligand RHPS4 inhibits clonogenic tumour cell growth in vitro and in vivo consistent with a cancer stem cell targeting mechanism

    PubMed Central

    Phatak, P; Cookson, J C; Dai, F; Smith, V; Gartenhaus, R B; Stevens, M F G; Burger, A M

    2007-01-01

    The pentacyclic acridinium methosulfate salt RHPS4 induces the 3′single-stranded guanine-rich telomeric overhang to fold into a G-quadruplex structure. Stabilisation of the latter is incompatible with an attachment of telomerase to the telomere and thus G-quadruplex ligands can effectively inhibit both the catalytic and capping functions of telomerase. In this study, we examined mechanisms underlying telomere uncapping by RHPS4 in uterus carcinoma cells (UXF1138L) with short telomeres and compared the susceptibility of bulk and clonogenic cancer cells to the G-quadruplex ligand. We show that treatment of UXF1138L cells with RHPS4 leads to the displacement of the telomerase catalytic subunit (hTERT) from the nucleus, induction of telomere-initiated DNA-damage signalling and chromosome fusions. We further report that RHPS4 is more potent against cancer cells that grow as colonies in soft agar than cells growing as monolayers. Human cord blood and HEK293T embryonic kidney cell colony forming units, however, were more resistant to RHPS4. RHPS4-treated UXF1138L xenografts had a decreased clonogenicity, showed loss of nuclear hTERT expression and an induction of mitotic abnormalities compared with controls. Although single-agent RHPS4 had limited in vivo efficacy, a combination of RHPS4 with the mitotic spindle poison Taxol caused tumour remissions and further enhancement of telomere dysfunction. PMID:17406367

  19. Inhibition of Wnt signalling and breast tumour growth by the multi-purpose drug suramin through suppression of heterotrimeric G proteins and Wnt endocytosis.

    PubMed

    Koval, Alexey; Ahmed, Kamal; Katanaev, Vladimir L

    2016-02-15

    Overactivation of the Wnt signalling pathway underlies oncogenic transformation and proliferation in many cancers, including the triple-negative breast cancer (TNBC), the deadliest form of tumour in the breast, taking about a quarter of a million lives annually worldwide. No clinically approved targeted therapies attacking Wnt signalling currently exist. Repositioning of approved drugs is a promising approach in drug discovery. In the present study we show that a multi-purpose drug suramin inhibits Wnt signalling and proliferation of TNBC cells in vitro and in mouse models, inhibiting a component in the upper levels of the pathway. Through a set of investigations we identify heterotrimeric G proteins and regulation of Wnt endocytosis as the likely target of suramin in this pathway. G protein-dependent endocytosis of plasma membrane-located components of the Wnt pathway was previously shown to be important for amplification of the signal in this cascade. Our data identify endocytic regulation within Wnt signalling as a promising target for anti-Wnt and anti-cancer drug discovery. Suramin, as the first example of such drug or its analogues might pave the way for the appearance of first-in-class targeted therapies against TNBC and other Wnt-dependent cancers. PMID:26604320

  20. Chinese herbal medicine for miscarriage affects decidual micro-environment and fetal growth

    PubMed Central

    Piao, L.; Chen, C.-P.; Yeh, C.-C.; Basar, M.; Masch, R.; Cheng, Y.-C.; Lockwood, C. J.; Schatz, F.; Huang, S. J.

    2015-01-01

    Introduction Intrauterine growth restriction complicates 5 - 10% of pregnancies. This study aims to test the hypothesis that Chinese herbal formula, JLFC01, affects pregnancy and fetal development by modulating the pro-inflammatory decidual micro-environment. Methods Human decidua from gestational age-matched elective terminations or incomplete/missed abortion was immunostained using anti-CD68 + anti-CD86 or anti-CD163 antibodies. qRT-PCR and Luminex assay measured the effects of JLFC01 on IL-1β- or TNF-α-induced cytokine expression in first trimester decidual cells and on an established spontaneous abortion/intrauterine growth restriction (SA/IUGR)-prone mouse placentae. The effect of JLFC01 on human endometrial endothelial cell angiogenesis was evaluated by average area, length and numbers of branching points of tube formation. Food intake, litter size, fetal weight, placental weight and resorption rate were recorded in SA/IUGR-prone mouse treated with JLFC01. qRT-PCR, Western blot and immunohistochemistry assessed the expression of mouse placental IGF-I and IGF-IR. Results In spontaneous abortion, numbers of decidual macrophages expressing CD86 and CD163 are increased and decreased, respectively. JLFC01 reduces IL-1β- or TNF-α-induced GM-CSF, M-CSF, C-C motif ligand 2 (CCL2), interferon-γ-inducible protein-10 (IP-10), CCL5 and IL-8 production in first trimester decidual cells. JLFC01 suppresses the activity of IL-1β- or TNF-α-treated first trimester decidual cells in enhancing macrophage-inhibited angiogenesis. In SA/IUGR-prone mice, JLFC01 increases maternal food intake, litter size, fetal and placental weight, and reduces fetal resorption rate. JLFC01 induces IGF-I and IGF-IR expression and inhibits M-CSF, CCL2, CCL5, CCL11, CCL3 and G-CSF expression in the placentae. Discussion JLFC01 improves gestation by inhibiting decidual inflammation, enhancing angiogenesis and promoting fetal growth. PMID:25771406

  1. Anti-tumour immune effect of oral administration of Lactobacillus plantarum to CT26 tumour-bearing mice.

    PubMed

    Hu, Jingtao; Wang, Chunfeng; Ye, Liping; Yang, Wentao; Huang, Haibin; Meng, Fei; Shi, Shaohua; Ding, Zhuang

    2015-06-01

    Colorectal cancer (CRC) is one of the most prevalent forms of cancer that shows a high mortality and increasing incidence. There are numerous successful treatment options for CRC, including surgery, chemotherapy, radiotherapy and immunotherapy; however, their side effects and limitations are considerable. Probiotics may be an effective strategy for preventing and inhibiting tumour growth through stimulation of host innate and adaptive immunity. We investigated and compared potential anti-tumour immune responses induced by two isolated Lactobacillus strains, Lactobacillus plantarum A and Lactobacillus rhamnosus b, by pre-inoculating mice with lactobacilli for 14 days. Subsequently, subcutaneous and orthotopic intestinal tumours were generated in the pre-inoculated mice using CT26 murine adenocarcinoma cells and were assessed for response against the tumour. Our results indicated that oral administration with L. plantarum inhibited CT26 cell growth in BALB/c mice and prolonged the survival time of tumour-bearing mice compared with mice administered L. rhamnosus. L. plantarum produced protective immunity against the challenge with CT26 cells by increasing the effector functions of CD8+ and natural killer (NK) cell infiltration into tumour tissue, up-regulation of IFN-gamma (but not IL-4 or IL-17) production, and promotion of Th1-type CD4+ T differentiation. Consequently, our results suggest that L. plantarum can enhance the anti-tumour immune response and delay tumour formation. PMID:25963256

  2. Lowering of innate resistance of the lungs to the growth of blood-borne cancer cells in states of topical and systemic stress.

    PubMed Central

    Van Den Brenk, H. A.; Stone, M. G.; Kelly, H.; Sharpington, C.

    1976-01-01

    The survival and clonogenic growth (measured in terms of colony forming efficiency (CFE) of intravenously injected (i.v.) Walker (W256) tumour cells in the lungs of rats was greatly enhanced by states of topical and systemic stress induced by the intraperitoneal (i.p.) injection of rats with a single dose of 10(-5)-10(-3) mmol g-1 body weight of adrenaline and other beta-adrenergic agonists, inflammatory agents (including local x-irradiation), convulsive seizures, "tumbling" or physical restraint. Lowering of innate resistance of the host to growth of seeded tumour cells induced by states of topical and systemic stress, and by the addition of an excess of lethally irradiated (LI) tumour cells to i.v. injected intact tumour cells, were all potentiated by treatment of rats with aminophylline, an inhibitor of cyclic AMP phosphodiesterase. Enhancement of tumour growth by systemic stress was inhibited by bilateral total or medullary adrenalectomy and is attributed to the release and actions of endogenous adreno-medullary hormones. Alpha-adrenergic and most non-adrenergic agents administered in maximum tolerated doses did not significantly affect host resistance to tumour growth in the lungs. These findings, correlated with measurements of cyclic AMP in the lungs of normal and stressed rats, suggest that changes in the resistance of the host to tumour growth involve changes in cyclic nucleotide metabolism in the target tissues (tumour bed); possible mechanisms of action of cyclic nucleotides in this respect are discussed. PMID:175820

  3. Histopathology of growth anomaly affecting the coral, Montipora capitata: implications on biological functions and population viability.

    PubMed

    Burns, John H R; Takabayashi, Misaki

    2011-01-01

    Growth anomalies (GAs) affect the coral, Montipora capitata, at Wai'ōpae, southeast Hawai'i Island. Our histopathological analysis of this disease revealed that the GA tissue undergoes changes which compromise anatomical machinery for biological functions such as defense, feeding, digestion, and reproduction. GA tissue exhibited significant reductions in density of ova (66.1-93.7%), symbiotic dinoflagellates (38.8-67.5%), mesenterial filaments (11.2-29.0%), and nematocytes (28.8-46.0%). Hyperplasia of the basal body wall but no abnormal levels of necrosis and algal or fungal invasion was found in GA tissue. Skeletal density along the basal body wall was significantly reduced in GAs compared to healthy or unaffected sections. The reductions in density of the above histological features in GA tissue were collated with disease severity data to quantify the impact of this disease at the colony and population level. Resulting calculations showed this disease reduces the fecundity of M. capitata colonies at Wai'ōpae by 0.7-49.6%, depending on GA severity, and the overall population fecundity by 2.41±0.29%. In sum, GA in this M. capitata population reduces the coral's critical biological functions and increases susceptibility to erosion, clearly defining itself as a disease and an ecological threat. PMID:22205976

  4. The GI-CDF module of Arabidopsis affects freezing tolerance and growth as well as flowering.

    PubMed

    Fornara, Fabio; de Montaigu, Amaury; Sánchez-Villarreal, Alfredo; Takahashi, Yasuyuki; Ver Loren van Themaat, Emiel; Huettel, Bruno; Davis, Seth J; Coupland, George

    2015-03-01

    Plants monitor and integrate temperature, photoperiod and light quality signals to respond to continuous changes in their environment. The GIGANTEA (GI) protein is central in diverse signaling pathways, including photoperiodic, sugar and light signaling pathways, stress responses and circadian clock regulation. Previously, GI was shown to activate expression of the key floral regulators CONSTANS (CO) and FLOWERING LOCUS T (FT) by facilitating degradation of a family of CYCLING DOF FACTOR (CDF) transcriptional repressors. However, whether CDFs are implicated in other processes affected by GI remains unclear. We investigated the contribution of the GI-CDF module to traits that depend on GI. Transcriptome profiling indicated that mutations in GI and the CDF genes have antagonistic effects on expression of a wider set of genes than CO and FT, whilst other genes are regulated by GI independently of the CDFs. Detailed expression studies followed by phenotypic assays showed that the CDFs function downstream of GI, influencing responses to freezing temperatures and growth, but are not necessary for proper clock function. Thus GI-mediated regulation of CDFs contributes to several processes in addition to flowering, but is not implicated in all of the traits influenced by GI. PMID:25600594

  5. Ice cover affects the growth of a stream-dwelling fish.

    PubMed

    Watz, Johan; Bergman, Eva; Piccolo, John J; Greenberg, Larry

    2016-05-01

    Protection provided by shelter is important for survival and affects the time and energy budgets of animals. It has been suggested that in fresh waters at high latitudes and altitudes, surface ice during winter functions as overhead cover for fish, reducing the predation risk from terrestrial piscivores. We simulated ice cover by suspending plastic sheeting over five 30-m-long stream sections in a boreal forest stream and examined its effects on the growth and habitat use of brown trout (Salmo trutta) during winter. Trout that spent the winter under the artificial ice cover grew more than those in the control (uncovered) sections. Moreover, tracking of trout tagged with passive integrated transponders showed that in the absence of the artificial ice cover, habitat use during the day was restricted to the stream edges, often under undercut banks, whereas under the simulated ice cover condition, trout used the entire width of the stream. These results indicate that the presence of surface ice cover may improve the energetic status and broaden habitat use of stream fish during winter. It is therefore likely that reductions in the duration and extent of ice cover due to climate change will alter time and energy budgets, with potentially negative effects on fish production. PMID:26787075

  6. Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness

    PubMed Central

    Avgustinova, Alexandra; Iravani, Marjan; Robertson, David; Fearns, Antony; Gao, Qiong; Klingbeil, Pamela; Hanby, Andrew M.; Speirs, Valerie; Sahai, Erik; Calvo, Fernando; Isacke, Clare M.

    2016-01-01

    Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease. However, the mechanisms underlying the tumour:fibroblast crosstalk that drive the intertumoural stromal heterogeneity remain poorly understood. Using in vivo models we identify Wnt7a as a key factor secreted exclusively by aggressive breast tumour cells, which induces CAF conversion. Functionally, this results in extracellular matrix remodelling to create a permissive environment for tumour cell invasion and promotion of distant metastasis. Mechanistically, Wnt7a-mediated fibroblast activation is not dependent on classical Wnt signalling. Instead, we demonstrate that Wnt7a potentiates TGFβ receptor signalling both in 3D in vitro and in vivo models, thus highlighting the interaction between two of the key signalling pathways in development and disease. Importantly, in clinical breast cancer cohorts, tumour cell Wnt7a expression correlates with a desmoplastic, poor-prognosis stroma and poor patient outcome. PMID:26777421

  7. The epigenetics of tumour initiation: cancer stem cells and their chromatin.

    PubMed

    Avgustinova, Alexandra; Benitah, Salvador Aznar

    2016-02-01

    Cancer stem cells (CSCs) have been identified in various tumours and are defined by their potential to initiate tumours upon transplantation, self-renew and reconstitute tumour heterogeneity. Modifications of the epigenome can favour tumour initiation by affecting genome integrity, DNA repair and tumour cell plasticity. Importantly, an in-depth understanding of the epigenomic alterations underlying neoplastic transformation may open new avenues for chromatin-targeted cancer treatment, as these epigenetic changes could be inherently more amenable to inhibition and reversal than hard-wired genomic alterations. Here we discuss how CSC function is affected by chromatin state and epigenomic instability. PMID:26874045

  8. Radiotherapy for ocular tumours.

    PubMed

    Stannard, C; Sauerwein, W; Maree, G; Lecuona, K

    2013-02-01

    Ocular tumours present a therapeutic challenge because of the sensitive tissues involved and the necessity to destroy the tumour while minimising visual loss. Radiotherapy (RT) is one of several modalites used apart from surgery, laser, cryotherapy, and chemotherapy. Both external beam RT (EBRT) and brachytherapy are used. Tumours of the bulbar conjunctiva, squamous carcinoma and malignant melanoma, can be treated with a radioactive plaque: strontium-90, ruthenium-106 (Ru-106), or iodine-125 (I-125), after excision. If the tumour involves the fornix or tarsal conjunctiva, proton therapy can treat the conjunctiva and spare most of the eye. Alternatively, an I-125 interstitial implant can be used with shielding of the cornea and lens. Conjunctival mucosal-associated lymphoid tissue lymphoma can be treated with an anterior electron field with lens shielding and 25-30 Gray (Gy) in 2 Gy fractions. Discrete retinoblastoma (RB), too large for cryotherapy or thermolaser, or recurrent after these modalities, can be treated with plaque therapy, I-125, or Ru-106. For large RB, multiple tumours, or vitreous seeds the whole eye can be treated with an I-125 applicator, sparing the bony orbit, or with EBRT, under anaesthetic, using X-rays or proton therapy with vacuum contact lenses to fix the eyes in the required position. Post-enucleated orbits at risk for recurrent RB can be treated with an I-125 implant with shielding to reduce the dose to the bony orbit. Uveal malignant melanomas can be treated with plaque or proton therapy with excellent local control. Preservation of vision will depend on the initial size and location of the tumour. PMID:23174750

  9. Radiotherapy for ocular tumours

    PubMed Central

    Stannard, C; Sauerwein, W; Maree, G; Lecuona, K

    2013-01-01

    Ocular tumours present a therapeutic challenge because of the sensitive tissues involved and the necessity to destroy the tumour while minimising visual loss. Radiotherapy (RT) is one of several modalites used apart from surgery, laser, cryotherapy, and chemotherapy. Both external beam RT (EBRT) and brachytherapy are used. Tumours of the bulbar conjunctiva, squamous carcinoma and malignant melanoma, can be treated with a radioactive plaque: strontium-90, ruthenium-106 (Ru-106), or iodine-125 (I-125), after excision. If the tumour involves the fornix or tarsal conjunctiva, proton therapy can treat the conjunctiva and spare most of the eye. Alternatively, an I-125 interstitial implant can be used with shielding of the cornea and lens. Conjunctival mucosal-associated lymphoid tissue lymphoma can be treated with an anterior electron field with lens shielding and 25–30 Gray (Gy) in 2 Gy fractions. Discrete retinoblastoma (RB), too large for cryotherapy or thermolaser, or recurrent after these modalities, can be treated with plaque therapy, I-125, or Ru-106. For large RB, multiple tumours, or vitreous seeds the whole eye can be treated with an I-125 applicator, sparing the bony orbit, or with EBRT, under anaesthetic, using X-rays or proton therapy with vacuum contact lenses to fix the eyes in the required position. Post-enucleated orbits at risk for recurrent RB can be treated with an I-125 implant with shielding to reduce the dose to the bony orbit. Uveal malignant melanomas can be treated with plaque or proton therapy with excellent local control. Preservation of vision will depend on the initial size and location of the tumour. PMID:23174750

  10. Parallel evolution of tumour subclones mimics diversity between tumours.

    PubMed

    Martinez, Pierre; Birkbak, Nicolai Juul; Gerlinger, Marco; McGranahan, Nicholas; Burrell, Rebecca A; Rowan, Andrew J; Joshi, Tejal; Fisher, Rosalie; Larkin, James; Szallasi, Zoltan; Swanton, Charles

    2013-08-01

    Intratumour heterogeneity (ITH) may foster tumour adaptation and compromise the efficacy of personalized medicine approaches. The scale of heterogeneity within a tumour (intratumour heterogeneity) relative to genetic differences between tumours (intertumour heterogeneity) is unknown. To address this, we obtained 48 biopsies from eight stage III and IV clear cell renal cell carcinomas (ccRCCs) and used DNA copy-number analyses to compare biopsies from the same tumour with 440 single tumour biopsies from the Cancer Genome Atlas (TCGA). Unsupervised hierarchical clustering of TCGA and multi-region ccRCC samples revealed segregation of samples from the same tumour into unrelated clusters; 25% of multi-region samples appeared more similar to unrelated samples than to any other sample originating from the same tumour. We found that the majority of recurrent DNA copy number driver aberrations in single biopsies were not present ubiquitously in late-stage ccRCCs and were likely to represent subclonal events acquired during tumour progression. Such heterogeneous subclonal genetic alterations within individual tumours may impair the identification of robust ccRCC molecular subtypes classified by distinct copy number alterations and clinical outcomes. The co-existence of distinct subclonal copy number events in different regions of individual tumours reflects the diversification of individual ccRCCs through multiple evolutionary routes and may contribute to tumour sampling bias and impact upon tumour progression and clinical outcome. PMID:23716380

  11. Defining the clonal dynamics leading to mouse skin tumour initiation.

    PubMed

    Sánchez-Danés, Adriana; Hannezo, Edouard; Larsimont, Jean-Christophe; Liagre, Mélanie; Youssef, Khalil Kass; Simons, Benjamin D; Blanpain, Cédric

    2016-08-18

    The changes in cell dynamics after oncogenic mutation that lead to the development of tumours are currently unknown. Here, using skin epidermis as a model, we assessed the effect of oncogenic hedgehog signalling in distinct cell populations and their capacity to induce basal cell carcinoma, the most frequent cancer in humans. We found that only stem cells, and not progenitors, initiated tumour formation upon oncogenic hedgehog signalling. This difference was due to the hierarchical organization of tumour growth in oncogene-targeted stem cells, characterized by an increase in symmetric self-renewing divisions and a higher p53-dependent resistance to apoptosis, leading to rapid clonal expansion and progression into invasive tumours. Our work reveals that the capacity of oncogene-targeted cells to induce tumour formation is dependent not only on their long-term survival and expansion, but also on the specific clonal dynamics of the cancer cell of origin. PMID:27459053

  12. mTOR inhibition improves fibroblast growth factor receptor targeting in hepatocellular carcinoma

    PubMed Central

    Scheller, T; Hellerbrand, C; Moser, C; Schmidt, K; Kroemer, A; Brunner, S M; Schlitt, H J; Geissler, E K; Lang, S A

    2015-01-01

    Background: Systemic therapy has proven only marginal effects in hepatocellular carcinoma (HCC) so far. The aim of this study was to evaluate the effect of targeting fibroblast growth factor receptor (FGFR) on tumour and stromal cells in HCC models. Methods: Human and murine HCC cells, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), hepatic stellate cells (HSCs), human HCC samples, FGFR inhibitor BGJ398 and mammalian target of rapamycin (mTOR) inhibitor rapamycin were used. Effects on growth, motility, signalling and angiogenic markers were determined. In vivo subcutaneous and syngeneic orthotopic tumour models were used. Results: In tumour cells and ECs, targeting FGFR showed significant inhibitory effects on signalling and motility. Minor effects of FGFR inhibition were observed on VSMCs and HSCs, which were significantly enhanced by combining FGFR and mTOR blockade. In vivo daily (5 mg kg−1) treatment with BGJ398 led to a significant growth inhibition in subcutaneous tumour models, but only a combination of FGFR and mTOR blockade impaired tumour growth in the orthotopic model. This was paralleled by reduced tumour cell proliferation, vascularisation, pericytes and increased apoptosis. Conclusions: Targeting FGFR with BGJ398 affects tumour cells and ECs, whereas only a combination with mTOR inhibition impairs recruitment of VSMCs and HSCs. Therefore, this study provides evidence for combined FGFR/mTOR inhibition in HCC. PMID:25688743

  13. Culture surfaces coated with various implant materials affect chondrocyte growth and metabolism.

    PubMed

    Hambleton, J; Schwartz, Z; Khare, A; Windeler, S W; Luna, M; Brooks, B P; Dean, D D; Boyan, B D

    1994-07-01

    The effect on chondrocyte metabolism of culture surfaces sputter-coated with various materials used for orthopaedic implants was studied and correlated with the stage of cartilage cell maturation. Confluent, fourth-passage chondrocytes from the costochondral resting zone and growth zone of rats were cultured for 6 or 9 days on 24-well plates sputter-coated with ultrathin films of titanium, titanium dioxide, aluminum oxide, zirconium oxide, and calcium phosphate (1.67:1). Corona-discharged tissue culture plastic served as the control. The effect of surface material was examined with regard to cell morphology; cell proliferation (cell number) and DNA synthesis ([3H]thymidine incorporation); RNA synthesis ([3H]uridine incorporation); collagenase-digestible protein, noncollagenase-digestible protein, and percentage of collagen production; and alkaline phosphatase-specific activity, both in the cell layer and in trypsinized chondrocytes. Cell morphology was dependent on surface material; only cells cultured on titanium had an appearance similar to that of cells cultured on plastic. While titanium or titanium dioxide surfaces had no effect on cell number or [3H]thymidine incorporation, aluminum oxide, calcium phosphate, and zirconium oxide surfaces inhibited both parameters. Cells cultured on aluminum oxide, calcium phosphate, zirconium oxide, and titanium dioxide exhibited decreased collagenase-digestible protein, noncollagenase-digestible protein, and percentage of collagen production, but [3H]uridine incorporation was decreased only in those chondrocytes cultured on aluminum oxide, calcium phosphate, or zirconium oxide. Chondrocytes cultured on titanium had greater alkaline phosphatase-specific activity than did cells cultured on plastic, but the incorporation of [3H]uridine and production of collagenase-digestible protein, noncollagenase-digestible protein, and percentage of collagen was comparable. The response of chondrocytes from the growth zone and resting zone

  14. Does seawater acidification affect survival, growth and shell integrity in bivalve juveniles?

    PubMed

    Bressan, M; Chinellato, A; Munari, M; Matozzo, V; Manci, A; Marčeta, T; Finos, L; Moro, I; Pastore, P; Badocco, D; Marin, M G

    2014-08-01

    Anthropogenic emissions of carbon dioxide are leading to decreases in pH and changes in the carbonate chemistry of seawater. Ocean acidification may negatively affect the ability of marine organisms to produce calcareous structures while also influencing their physiological responses and growth. The aim of this study was to evaluate the effects of reduced pH on the survival, growth and shell integrity of juveniles of two marine bivalves from the Northern Adriatic sea: the Mediterranean mussel Mytilus galloprovincialis and the striped venus clam Chamelea gallina. An outdoor flow-through plant was set up and two pH levels (natural seawater pH as a control, pH 7.4 as the treatment) were tested in long-term experiments. Mortality was low throughout the first experiment for both mussels and clams, but a significant increase, which was sensibly higher in clams, was observed at the end of the experiment (6 months). Significant decreases in the live weight (-26%) and, surprisingly, in the shell length (-5%) were observed in treated clams, but not in mussels. In the controls of both species, no shell damage was ever recorded; in the treated mussels and clams, damage proceeded via different modes and to different extents. The severity of shell injuries was maximal in the mussels after just 3 months of exposure to a reduced pH, whereas it progressively increased in clams until the end of the experiment. In shells of both species, the damaged area increased throughout the experiment, peaking at 35% in mussels and 11% in clams. The shell thickness of the treated and control animals significantly decreased after 3 months in clams and after 6 months in mussels. In the second experiment (3 months), only juvenile mussels were exposed to a reduced pH. After 3 months, the mussels at a natural pH level or pH 7.4 did not differ in their survival, shell length or live weight. Conversely, shell damage was clearly visible in the treated mussels from the 1st month onward. Monitoring the

  15. Glutathione and the rate of cellular proliferation determine tumour cell sensitivity to tumour necrosis factor in vivo.

    PubMed Central

    Obrador, E; Navarro, J; Mompo, J; Asensi, M; Pellicer, J A; Estrela, J M

    1997-01-01

    Low rates of cellular proliferation are associated with low GSH content and enhanced sensitivity of Ehrlich ascites-tumour (EAT) cells to the cytotoxic effects of recombinant human tumour necrosis factor (rhTNF-alpha). Buthionine sulphoximine, a selective inhibitor of GSH synthesis, inhibited tumour growth and increased rhTNF-alpha cytoxicity in vitro. Administration of sublethal doses (10(6)units/kg per day) of rhTNF-alpha to EAT-bearing mice promoted oxidative stress (as measured by increases in intracellular peroxide levels, O2(-); generation and mitochondrial GSSG) and resulted in a slight reduction (19%) in tumour cell number when controls showed the highest rate of cellular proliferation. ATP (1mmol/kg per day)-induced selective GSH depletion, when combined with rhTNF-alpha administration, afforded a 61% inhibition of tumour growth and resulted in a significant extension of host survival. Administration of N-acetylcysteine (1mmol/kg per day) or GSH ester (5mmol/kg per day) abolished the rhTNF-alpha- and ATP-induced effects on tumour growth by maintaining high GSH levels in the cancer cells. Our results demonstrate that the sensitivity of tumour cells to rhTNF-alpha in vivo depends on their GSH content and their rate of proliferation. PMID:9224645

  16. Compensatory growth strategies are affected by the strength of environmental time constraints in anuran larvae.

    PubMed

    Orizaola, Germán; Dahl, Emma; Laurila, Anssi

    2014-01-01

    Organisms normally grow at a sub-maximal rate. After experiencing a period of arrested growth, individuals often show compensatory growth responses by modifying their life-history, behaviour and physiology. However, the strength of compensatory responses may vary across broad geographic scales as populations differ in their exposition to varying time constraints. We examined differences in compensatory growth strategies in common frog (Rana temporaria) populations from southern and northern Sweden. Tadpoles from four populations were reared in the laboratory and exposed to low temperature to evaluate the patterns and mechanisms of compensatory growth responses. We determined tadpoles' growth rate, food intake and growth efficiency during the compensation period. In the absence of arrested growth conditions, tadpoles from all the populations showed similar (size-corrected) growth rates, food intake and growth efficiency. After being exposed to low temperature for 1 week, only larvae from the northern populations increased growth rates by increasing both food intake and growth efficiency. These geographic differences in compensatory growth mechanisms suggest that the strategies for recovering after a period of growth deprivation may depend on the strength of time constraints faced by the populations. Due to the costs of fast growth, only populations exposed to the strong time constraints are prone to develop fast recovering strategies in order to metamorphose before conditions deteriorate. Understanding how organisms balance the cost and benefits of growth strategies may help in forecasting the impact of fluctuating environmental conditions on life-history strategies of populations likely to be exposed to increasing environmental variation in the future. PMID:23996230

  17. Pre-Analytical Parameters Affecting Vascular Endothelial Growth Factor Measurement in Plasma: Identifying Confounders

    PubMed Central

    Walz, Johanna M.; Boehringer, Daniel; Deissler, Heidrun L.; Faerber, Lothar; Goepfert, Jens C.; Heiduschka, Peter; Kleeberger, Susannah M.; Klettner, Alexa; Krohne, Tim U.; Schneiderhan-Marra, Nicole; Ziemssen, Focke; Stahl, Andreas

    2016-01-01

    Background Vascular endothelial growth factor-A (VEGF-A) is intensively investigated in various medical fields. However, comparing VEGF-A measurements is difficult because sample acquisition and pre-analytic procedures differ between studies. We therefore investigated which variables act as confounders of VEGF-A measurements. Methods Following a standardized protocol, blood was taken at three clinical sites from six healthy participants (one male and one female participant at each center) twice one week apart. The following pre-analytical parameters were varied in order to analyze their impact on VEGF-A measurements: analyzing center, anticoagulant (EDTA vs. PECT / CTAD), cannula (butterfly vs. neonatal), type of centrifuge (swing-out vs. fixed-angle), time before and after centrifugation, filling level (completely filled vs. half-filled tubes) and analyzing method (ELISA vs. multiplex bead array). Additionally, intrapersonal variations over time and sex differences were explored. Statistical analysis was performed using a linear regression model. Results The following parameters were identified as statistically significant independent confounders of VEGF-A measurements: analyzing center, anticoagulant, centrifuge, analyzing method and sex of the proband. The following parameters were no significant confounders in our data set: intrapersonal variation over one week, cannula, time before and after centrifugation and filling level of collection tubes. Conclusion VEGF-A measurement results can be affected significantly by the identified pre-analytical parameters. We recommend the use of CTAD anticoagulant, a standardized type of centrifuge and one central laboratory using the same analyzing method for all samples. PMID:26730574

  18. Tumour Cell Heterogeneity

    PubMed Central

    Gay, Laura; Baker, Ann-Marie; Graham, Trevor A.

    2016-01-01

    The population of cells that make up a cancer are manifestly heterogeneous at the genetic, epigenetic, and phenotypic levels. In this mini-review, we summarise the extent of intra-tumour heterogeneity (ITH) across human malignancies, review the mechanisms that are responsible for generating and maintaining ITH, and discuss the ramifications and opportunities that ITH presents for cancer prognostication and treatment. PMID:26973786

  19. Evaluation of tumour vascularisation in two rat sarcoma models for studying isolated lung perfusion. Injection route determines the origin of tumour vessels.

    PubMed

    Pan, Youmin; Krueger, T; Tran, Nam; Yan, Hua; Ris, H-B; McKee, T A

    2005-01-01

    Isolated cytostatic lung perfusion (ILP) is an attractive technique allowing delivery of a high-dose of cytostatic agents to the lungs while limiting systemic toxicity. In developing a rat model of ILP, we have analysed the effect of the route of tumour cell injection on the source of tumour vessels. Pulmonary sarcomas were established by injecting a sarcoma cell suspension either by the intravenous (i.v.) route or directly into the lung parenchyma. Ink perfusion through either pulmonary artery (PA) or bronchial arteries (BA) was performed and the characteristics of the tumour deposits defined. i.v. and direct injection methods induced pulmonary sarcoma nodules, with similar histological features. The intraparenchymal injection of tumour cells resulted in more reliable and reproducible tumour growth and was associated with a longer survival of the animals. i.v. injected tumours developed a PA-derived vascular tree whereas directly injected tumours developed a BA-derived vasculature. PMID:15905614

  20. High frequency of tumours in Mulibrey nanism.

    PubMed

    Karlberg, Niklas; Karlberg, Susann; Karikoski, Riitta; Mikkola, Sakari; Lipsanen-Nyman, Marita; Jalanko, Hannu

    2009-06-01

    Mulibrey nanism (MUL) is a monogenic disorder with prenatal-onset growth failure, typical clinical characteristics, cardiopathy and tendency for a metabolic syndrome. It is caused by recessive mutations in the TRIM37 gene encoding for the peroxisomal TRIM37 protein with ubiquitin-ligase activity. In this work, the frequency and pathology of malignant and benign tumours were analysed in a national cohort of 89 Finnish MUL patients aged 0.7-76 years. The subjects had a clinical and radiological evaluation, and histological and immunohistocemical analyses on specimens obtained from biopsy, surgery or autopsy, were performed. The results show that the MUL patients have disturbed architecture with ectopic tissues and a high frequency of both benign and malignant tumours detectable in several internal organs. A total of 210 tumorous lesions were detected in 66/89 patients (74%). Fifteen malignancies occurred in 13 patients (15%), seven of them in the kidney (five Wilms' tumours), three in the thyroid gland, two gynaecological cancers, one gastrointestinal carcinoid tumour, one neuropituitary Langerhans cell histiocytosis and one case of acute lymphoblastic leukaemia (ALL). Tumours detected by radiology in the liver and other organs mainly comprised strongly dilated blood vessels (peliosis), vascularized cysts and nodular lesions. The lesions showed strong expression of the endothelial cell markers CD34 and CD31 as well as the myocyte marker alpha-smooth muscle actin (alpha-SMA). Our findings show that MUL is associated with frequent malignant tumours and benign adenomatous and vascular lesions, as well as disturbed organ development. PMID:19334051

  1. Anthropogenic selection enhances cancer evolution in Tasmanian devil tumours.

    PubMed

    Ujvari, Beata; Pearse, Anne-Maree; Swift, Kate; Hodson, Pamela; Hua, Bobby; Pyecroft, Stephen; Taylor, Robyn; Hamede, Rodrigo; Jones, Menna; Belov, Katherine; Madsen, Thomas

    2014-02-01

    The Tasmanian Devil Facial Tumour Disease (DFTD) provides a unique opportunity to elucidate the long-term effects of natural and anthropogenic selection on cancer evolution. Since first observed in 1996, this transmissible cancer has caused local population declines by >90%. So far, four chromosomal DFTD variants (strains) have been described and karyotypic analyses of 253 tumours showed higher levels of tetraploidy in the oldest strain. We propose that increased ploidy in the oldest strain may have evolved in response to effects of genomic decay observed in asexually reproducing organisms. In this study, we focus on the evolutionary response of DFTD to a disease suppression trial. Tumours collected from devils subjected to the removal programme showed accelerated temporal evolution of tetraploidy compared with tumours from other populations where no increase in tetraploid tumours were observed. As ploidy significantly reduces tumour growth rate, we suggest that the disease suppression trial resulted in selection favouring slower growing tumours mediated by an increased level of tetraploidy. Our study reveals that DFTD has the capacity to rapidly respond to novel selective regimes and that disease eradication may result in novel tumour adaptations, which may further imperil the long-term survival of the world's largest carnivorous marsupial. PMID:24567746

  2. Anthropogenic selection enhances cancer evolution in Tasmanian devil tumours

    PubMed Central

    Ujvari, Beata; Pearse, Anne-Maree; Swift, Kate; Hodson, Pamela; Hua, Bobby; Pyecroft, Stephen; Taylor, Robyn; Hamede, Rodrigo; Jones, Menna; Belov, Katherine; Madsen, Thomas

    2014-01-01

    The Tasmanian Devil Facial Tumour Disease (DFTD) provides a unique opportunity to elucidate the long-term effects of natural and anthropogenic selection on cancer evolution. Since first observed in 1996, this transmissible cancer has caused local population declines by >90%. So far, four chromosomal DFTD variants (strains) have been described and karyotypic analyses of 253 tumours showed higher levels of tetraploidy in the oldest strain. We propose that increased ploidy in the oldest strain may have evolved in response to effects of genomic decay observed in asexually reproducing organisms. In this study, we focus on the evolutionary response of DFTD to a disease suppression trial. Tumours collected from devils subjected to the removal programme showed accelerated temporal evolution of tetraploidy compared with tumours from other populations where no increase in tetraploid tumours were observed. As ploidy significantly reduces tumour growth rate, we suggest that the disease suppression trial resulted in selection favouring slower growing tumours mediated by an increased level of tetraploidy. Our study reveals that DFTD has the capacity to rapidly respond to novel selective regimes and that disease eradication may result in novel tumour adaptations, which may further imperil the long-term survival of the world's largest carnivorous marsupial. PMID:24567746

  3. Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis.

    PubMed

    Batista, Silvia; Maniati, Eleni; Reynolds, Louise E; Tavora, Bernardo; Lees, Delphine M; Fernandez, Isabelle; Elia, George; Casanovas, Oriol; Lo Celso, Cristina; Hagemann, Thorsten; Hodivala-Dilke, Kairbaan

    2014-01-01

    Metastasis is the main cause of cancer-related death and thus understanding the molecular and cellular mechanisms underlying this process is critical. Here, our data demonstrate, contrary to established dogma, that loss of haematopoietic-derived focal adhesion kinase (FAK) is sufficient to enhance tumour metastasis. Using both experimental and spontaneous metastasis models, we show that genetic ablation of haematopoietic FAK does not affect primary tumour growth but enhances the incidence of metastasis significantly. At a molecular level, haematopoietic FAK deletion results in an increase in PU-1 levels and decrease in GATA-1 levels causing a shift of hematopoietic homeostasis towards a myeloid commitment. The subsequent increase in circulating granulocyte number, with an increase in serum CXCL12 and granulocyte CXCR4 levels, was required for augmented metastasis in mice lacking haematopoietic FAK. Overall our findings provide a mechanism by which haematopoietic FAK controls cancer metastasis. PMID:25270220

  4. Growth characteristics of Listeria monocytogenes as affected by a -native microflora in cooked ham under refrigerated and temperature abuse conditions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study examined the growth characteristics of L. monocytogenes as affected by a native microflora in cooked ham at refrigerated and abuse temperatures. A five-strain mixture of L. monocytogenes and a native microflora isolated from cooked meat were inoculated alone (monocultured) or co-inoculate...

  5. Energy composition of diet affects muscle fiber recruitment, body composition, and growth trajectory in rainbow trout (Oncorhnychus mykiss)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Energy composition of diet affects muscle fiber recruitment, body composition, and growth trajectory in rainbow trout (Oncorhnychus mykiss) The cost and scarcity of key ingredients for aquaculture feed formulation call for a wise use of resources, especially dietary proteins and energy. For years t...

  6. Karyotypic abnormalities in tumours of the pancreas.

    PubMed Central

    Bardi, G.; Johansson, B.; Pandis, N.; Mandahl, N.; Bak-Jensen, E.; Andrén-Sandberg, A.; Mitelman, F.; Heim, S.

    1993-01-01

    Short-term cultures from 20 pancreatic tumours, three endocrine and 17 exocrine, were cytogenetically analysed. All three endocrine tumours had a normal chromosome complement. Clonal chromosome aberrations were detected in 13 of the 17 exocrine tumours: simple karyotypic changes were found in five carcinomas and numerous numerical and/or structural changes in eight. When the present findings and those previously reported by our group were viewed in conjunction, the most common numerical imbalances among the 22 karyotypically abnormal pancreatic carcinomas thus available for evaluation turned out to be, in order of falling frequency, -18, -Y, +20, +7, +11 and -12. Imbalances brought about by structural changes most frequently affected chromosomes 1 (losses in 1p but especially gains of 1q), 8 (in particular 8q gains but also 8p losses), and 17 (mostly 17q gain but also loss of 17p). Chromosomal bands 1p32, 1q10, 6q21, 7p22, 8p21, 8q11, 14p11, 15q10-11, and 17q11 were the most common breakpoint sites affected by the structural rearrangements. Abnormal karyotypes were detected more frequently in poorly differentiated and anaplastic carcinomas than in moderately and well differentiated tumours. Images Figure 1 PMID:8494707

  7. Growth factors and hormones which affect survival, growth, and differentiation of the MCF-7 stem cells and their descendants

    SciTech Connect

    Resnicoff, M.; Medrano, E.E. )

    1989-03-01

    The human breast tumor cell line was separated by Percoll density gradient centrifugation into six different subpopulations, A to F, of which (E) appears to contain the stem cells on the basis of several criteria. The authors analyzed the response of the isolated subpopulations to insulin, thrombin, PGF{sub 2{alpha}}, estradiol, and 13-cis-retinal. They demonstrate that the first two growth factors stimulate ({sup 3}H)thymidine incorporation in the more differentiated subpopulations (D and F), while PGF{sub 2{alpha}} has mitogenic activity in subpopulations C and D. In the absence of any added growth factor, estradiol has the extreme and transient capacity of allowing the stem cell to detach from the tissue culture dish and to grow in suspension as multicellular aggregates (MCF-7/SE cells). 13-cis-Retinal acts as a negative modulator of differentiation and protects the cells from the inhibitory and differentiation activity in Na-butyrate.

  8. Fatty tumours of the uterus.

    PubMed Central

    Pounder, D J

    1982-01-01

    Uterine fatty tumours (UFT) are uncommon and have received little attention in the English literature. They have aroused interest as a consequence of occasional diagnostic confusion with sarcomas and the continuing unresolved dispute as to their histogenesis. Three cases of UFT are described and the pathological features of note discussed. The viewpoint that these tumours are hamartomas/choristomas is rejected. UFT most probably represent tumour metaplasia within a leiomyoma. There is no uniform accepted nomenclature for such tumours and it is suggested that they be designated "uterine fatty tumours" and subdivided into "lipoma" and "mixed lipoma/leiomyoma" (synonym lipoleiomyoma). Images PMID:7174848

  9. Phenotypic integration of skeletal traits during growth buffers genetic variants affecting the slenderness of femora in inbred mouse strains

    PubMed Central

    Jepsen, Karl J.; Hu, Bin; Tommasini, Steven M.; Courtland, Hayden-William; Price, Christopher; Cordova, Matthew; Nadeau, Joseph H.

    2009-01-01

    Compensatory interactions among adult skeletal traits are critical for establishing strength but complicate the search for fracture susceptibility genes by allowing many genetic variants to exist in a population without loss of function. A better understanding of how these interactions arise during growth will provide new insight into genotype-phenotype relationships and the biological controls that establish skeletal strength. We tested the hypothesis that genetic variants affecting growth in width relative to growth in length (slenderness) are coordinated with movement of the inner bone surface and matrix mineralization to match stiffness with weight-bearing loads during postnatal growth. Midshaft femoral morphology and tissue-mineral density were quantified at ages of 1 day and at 4, 8, and 16 weeks for a panel of 20 female AXB/BXA recombinant inbred mouse strains. Path Analyses revealed significant compensatory interactions among outer-surface expansion rate, inner-surface expansion rate, and tissue-mineral density during postnatal growth, indicating that genetic variants affecting bone slenderness were buffered mechanically by the precise regulation of bone surface movements and matrix mineralization. Importantly, the covariation between morphology and mineralization resulted from a heritable constraint limiting the amount of tissue that could be used to construct a functional femur. The functional interactions during growth explained 56-99% of the variability in adult traits and mechanical properties. These functional interactions provide quantitative expectations of how genetic or environmental variants affecting one trait should be compensated by changes in other traits. Variants that impair this process or that cannot be fully compensated are expected to alter skeletal growth leading to underdesigned (weak) or overdesigned (bulky) structures. PMID:19082857

  10. Melanoma miRNA trafficking controls tumour primary niche formation.

    PubMed

    Dror, Shani; Sander, Laureen; Schwartz, Hila; Sheinboim, Danna; Barzilai, Aviv; Dishon, Yuval; Apcher, Sebastien; Golan, Tamar; Greenberger, Shoshana; Barshack, Iris; Malcov, Hagar; Zilberberg, Alona; Levin, Lotan; Nessling, Michelle; Friedmann, Yael; Igras, Vivien; Barzilay, Ohad; Vaknine, Hananya; Brenner, Ronen; Zinger, Assaf; Schroeder, Avi; Gonen, Pinchas; Khaled, Mehdi; Erez, Neta; Hoheisel, Jörg D; Levy, Carmit

    2016-09-01

    Melanoma originates in the epidermis and becomes metastatic after invasion into the dermis. Prior interactions between melanoma cells and dermis are poorly studied. Here, we show that melanoma cells directly affect the formation of the dermal tumour niche by microRNA trafficking before invasion. Melanocytes, cells of melanoma origin, are specialized in releasing pigment vesicles, termed melanosomes. In melanoma in situ, we found melanosome markers in distal fibroblasts before melanoma invasion. The melanosomes carry microRNAs into primary fibroblasts triggering changes, including increased proliferation, migration and pro-inflammatory gene expression, all known features of cancer-associated fibroblasts (CAFs). Specifically, melanosomal microRNA-211 directly targets IGF2R and leads to MAPK signalling activation, which reciprocally encourages melanoma growth. Melanosome release inhibitor prevented CAF formation. Since the first interaction of melanoma cells with blood vessels occurs in the dermis, our data suggest an opportunity to block melanoma invasion by preventing the formation of the dermal tumour niche. PMID:27548915

  11. A New Model for Inducing Malignant Ovarian Tumours in Rats*

    PubMed Central

    Hilfrich, J.

    1973-01-01

    After the implantation of ovarian tissue into the spleen of gonadectomized female Sprague-Dawley rats (splenic ovary), luteomata and later benign granulosa or granulosa-theca cell tumours develop. Treatment of these rats with 7,12 dimethylbenz(a)anthracene (DMBA), given intravenously, 2 mg/kg body weight weekly, total dosage 40 mg/kg, immediately and especially 25 weeks after implantation of ovarian tissue into the spleen, led to malignant, partially metastasizing granulosa, and in one case theca cell tumours, 16-46 weeks after beginning the carcinogen treatment. No malignant neoplastic growth was seen when diethylnitrosamine (DEN), 20 mg/kg once weekly for life, was injected subcutaneously immediately or 25 weeks after implanting ovarian tissue. Since the normal, non-implanted rat ovary was not affected by DMBA treatment the malignant transformation of splenic ovaries in the respective experimental groups may be related to the increased stimulation by pituitary gonadotrophins and formation of luteomata or beginning granulosa and theca cell proliferations. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9 PMID:4353388

  12. Tumour biology: Herceptin acts as an anti-angiogenic cocktail

    NASA Astrophysics Data System (ADS)

    Izumi, Yotaro; Xu, Lei; di Tomaso, Emmanuelle; Fukumura, Dai; Jain, Rakesh K.

    2002-03-01

    Malignant tumours secrete factors that enable them to commandeer their own blood supply (angiogenesis), and blocking the action of these factors can inhibit tumour growth. But because tumours may become resistant to treatments that target individual angiogenic factors by switching over to other angiogenic molecules, a cocktail of multiple anti-angiogenic agents should be more effective. Here we show that herceptin, a monoclonal antibody against the cell-surface receptor HER2 (for human epidermal growth factor receptor-2; ref. 4), induces normalization and regression of the vasculature in an experimental human breast tumour that overexpresses HER2 in mice, and that it works by modulating the effects of different pro- and anti-angiogenic factors. As a single agent that acts against multiple targets, herceptin, or drugs like it, may offer a simple alternative to combination anti-angiogenic treatments.

  13. Functional properties of ion channels and transporters in tumour vascularization

    PubMed Central

    Fiorio Pla, Alessandra; Munaron, Luca

    2014-01-01

    Vascularization is crucial for solid tumour growth and invasion, providing metabolic support and sustaining metastatic dissemination. It is now accepted that ion channels and transporters play a significant role in driving the cancer growth at all stages. They may represent novel therapeutic, diagnostic and prognostic targets for anti-cancer therapies. On the other hand, although the expression and role of ion channels and transporters in the vascular endothelium is well recognized and subject of recent reviews, only recently has their involvement in tumour vascularization been recognized. Here, we review the current literature on ion channels and transporters directly involved in the angiogenic process. Particular interest will be focused on tumour angiogenesis in vivo as well as in the different steps that drive this process in vitro, such as endothelial cell proliferation, migration, adhesion and tubulogenesis. Moreover, we compare the ‘transportome’ system of tumour vascular network with the physiological one. PMID:24493751

  14. Tumours with cancer stem cells: A PDE model.

    PubMed

    Fasano, A; Mancini, A; Primicerio, M

    2016-02-01

    The role of cancer stem cells (CSC) in tumour growth has received increasing attention in the recent literature. Here we stem from an integro-differential system describing the evolution of a population of CSC and of ordinary (non-stem) tumour cells formulated and studied in a previous paper, and we investigate an approximation in which the system reduces to a pair of nonlinear coupled parabolic equation. We prove that the new system is well posed and we examine some general properties. Numerical simulations show more on the qualitative behaviour of the solutions, concerning in particular the so-called tumour paradox, according to which an increase of the mortality rate of ordinary (non-stem) tumour cells results asymptotically in a faster growth. PMID:26719124

  15. Survey of naturally and conventionally cured commercial frankfurters, ham, and bacon for physio-chemical characteristics that affect bacterial growth.

    PubMed

    Sullivan, Gary A; Jackson-Davis, Armitra L; Schrader, Kohl D; Xi, Yuan; Kulchaiyawat, Charlwit; Sebranek, Joseph G; Dickson, James S

    2012-12-01

    Natural and organic food regulations preclude the use of sodium nitrite/nitrate and other antimicrobials for processed meat products. Consequently, processors have begun to use natural nitrate/nitrite sources, such as celery juice/powder, sea salt, and turbinado sugar, to manufacture natural and organic products with cured meat characteristics but without sodium nitrite. The objective of this study was to compare physio-chemical characteristics that affect Clostridium perfringens and Listeria monocytogenes growth in naturally cured and traditionally cured commercial frankfurters, hams, and bacon. Correlations of specific product characteristics to pathogen growth varied between products and pathogens, though water activity, salt concentration, and product composition (moisture, protein and fat) were common intrinsic factors correlated to pathogen growth across products. Other frequently correlated traits were related to curing reactions such as % cured pigment. Residual nitrite and nitrate were significantly correlated to C. perfringens growth but only for the ham products. PMID:22857852

  16. Does solar radiation affect the growth of tomato seeds relative to their environment?

    SciTech Connect

    Holzer, K.

    1995-09-01

    The purpose of this experiment is to sequentially study and analyze the data collected from the germination and growth of irradiated Rutgers Supreme tomato seeds to adult producing plants. This experiment will not use irradiated seeds as a control as the authors plans to note growth in artificial verses natural environment as the basic experiment.

  17. Does solar radiation affect the growth of tomato seeds relative to their environment?

    NASA Technical Reports Server (NTRS)

    Holzer, Kristi

    1995-01-01

    The purpose of this experiment is to sequentially study and analyze the data collected from the germination and growth of irradiated Rutgers Supreme tomato seeds to adult producing plants. This experiment will not use irradiated seeds as a control as I plan to note growth in artificial verses natural environment as the basic experiment.

  18. Dissolved oxygen levels affect dimorphic growth by the entomopathogenic fungus Isaria fumosorosea

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The entomopathogenic fungus Isaria fumosorosea is capable of dimorphic growth (hyphal or yeast-like) in submerged culture. In shake flask studies, we evaluated the impact of aeration on the mode of growth of I. fumosorosea. Using 250 mL baffled Erlenmeyer flasks, culture volumes of 50, 100, 150, a...

  19. Glomus tumour of the stomach.

    PubMed

    Troller, Rebekka; Soll, Christopher; Breitenstein, Stefan

    2016-01-01

    Glomus tumours are benign tumours typically arising from the glomus bodies and primarily found under the fingernails or toenails. These rare neoplasms account for <2% of all soft tissue tumours and are generally not found in the gastrointestinal tract. We report a case of a 40-year-old man presenting with recurrent epigastric pain and pyrosis. Endoscopy revealed a solitary tumour in the antrum of the stomach. Fine-needle aspiration biopsy was suspicious for a gastrointestinal stroma tumour. After CT indicated the resectability of the tumour, showing neither lymphatic nor distant metastases, a laparoscopic-assisted gastric wedge resection was performed. Surprisingly, histology revealed a glomus tumour of the stomach. PMID:27343282

  20. Role of the Placental Vitamin D Receptor in Modulating Feto-Placental Growth in Fetal Growth Restriction and Preeclampsia-Affected Pregnancies

    PubMed Central

    Murthi, Padma; Yong, Hannah E. J.; Ngyuen, Thy P. H.; Ellery, Stacey; Singh, Harmeet; Rahman, Rahana; Dickinson, Hayley; Walker, David W.; Davies-Tuck, Miranda; Wallace, Euan M.; Ebeling, Peter R.

    2016-01-01

    Fetal growth restriction (FGR) is a common pregnancy complication that affects up to 5% of pregnancies worldwide. Recent studies demonstrate that Vitamin D deficiency is implicated in reduced fetal growth, which may be rescued by supplementation of Vitamin D. Despite this, the pathway(s) by which Vitamin D modulate fetal growth remains to be investigated. Our own studies demonstrate that the Vitamin D receptor (VDR) is significantly decreased in placentae from human pregnancies complicated by FGR and contributes to abnormal placental trophoblast apoptosis and differentiation and regulation of cell-cycle genes in vitro. Thus, Vitamin D signaling is important for normal placental function and fetal growth. This review discusses the association of Vitamin D with fetal growth, the function of Vitamin D and its receptor in pregnancy, as well as the functional significance of a placental source of Vitamin D in FGR. Additionally, we propose that for Vitamin D to be clinically effective to prevent and manage FGR, the molecular mechanisms of Vitamin D and its receptor in modulating fetal growth requires further investigation. PMID:26924988

  1. Role of the Placental Vitamin D Receptor in Modulating Feto-Placental Growth in Fetal Growth Restriction and Preeclampsia-Affected Pregnancies.

    PubMed

    Murthi, Padma; Yong, Hannah E J; Ngyuen, Thy P H; Ellery, Stacey; Singh, Harmeet; Rahman, Rahana; Dickinson, Hayley; Walker, David W; Davies-Tuck, Miranda; Wallace, Euan M; Ebeling, Peter R

    2016-01-01

    Fetal growth restriction (FGR) is a common pregnancy complication that affects up to 5% of pregnancies worldwide. Recent studies demonstrate that Vitamin D deficiency is implicated in reduced fetal growth, which may be rescued by supplementation of Vitamin D. Despite this, the pathway(s) by which Vitamin D modulate fetal growth remains to be investigated. Our own studies demonstrate that the Vitamin D receptor (VDR) is significantly decreased in placentae from human pregnancies complicated by FGR and contributes to abnormal placental trophoblast apoptosis and differentiation and regulation of cell-cycle genes in vitro. Thus, Vitamin D signaling is important for normal placental function and fetal growth. This review discusses the association of Vitamin D with fetal growth, the function of Vitamin D and its receptor in pregnancy, as well as the functional significance of a placental source of Vitamin D in FGR. Additionally, we propose that for Vitamin D to be clinically effective to prevent and manage FGR, the molecular mechanisms of Vitamin D and its receptor in modulating fetal growth requires further investigation. PMID:26924988

  2. Cyclic Stretch Affects Pulmonary Endothelial Cell Control of Pulmonary Smooth Muscle Cell Growth

    PubMed Central

    Ochoa, Cristhiaan D.; Baker, Haven; Hasak, Stephen; Matyal, Robina; Salam, Aleya; Hales, Charles A.; Hancock, William; Quinn, Deborah A.

    2008-01-01

    Endothelial cells are subjected to mechanical forces in the form of cyclic stretch resulting from blood pulsatility. Pulmonary artery endothelial cells (PAECs) produce factors that stimulate and inhibit pulmonary artery smooth muscle cell (PASMC) growth. We hypothesized that PAECs exposed to cyclic stretch secrete proteins that inhibit PASMC growth. Media from PAECs exposed to cyclic stretch significantly inhibited PASMC growth in a time-dependent manner. Lyophilized material isolated from stretched PAEC-conditioned media significantly inhibited PASMC growth in a dose-dependent manner. This inhibition was reversed by trypsin inactivation, which is consistent with the relevant factor being a protein(s). To identify proteins that inhibited cell growth in conditioned media from stretched PAECs, we used proteomic techniques and found that thrombospondin (TSP)-1, a natural antiangiogenic factor, was up-regulated by stretch. In vitro, exogenous TSP-1 inhibited PASMC growth. TSP-1–blocking antibodies reversed conditioned media–induced inhibition of PASMC growth. Cyclic stretched PAECs secrete protein(s) that inhibit PASMC proliferation. TSP-1 may be, at least in part, responsible for this inhibition. The complete identification and understanding of the secreted proteome of stretched PAECs may lead to new insights into the pathophysiology of pulmonary vascular remodeling. PMID:18314539

  3. Severe dietary lysine restriction affects growth and body composition and hepatic gene expression for nitrogen metabolism in growing rats.

    PubMed

    Kim, J; Lee, K S; Kwon, D-H; Bong, J J; Jeong, J Y; Nam, Y S; Lee, M S; Liu, X; Baik, M

    2014-02-01

    Dietary lysine restriction may differentially affect body growth and lipid and nitrogen metabolism, depending on the degree of lysine restriction. This study was conducted to examine the effect of dietary lysine restriction on growth and lipid and nitrogen metabolism with two different degree of lysine restriction. Isocaloric amino acid-defined diets containing 1.4% lysine (adequate), 0.70% lysine (50% moderate lysine restriction) and 0.35% lysine (75% severe lysine restriction) were fed from the age of 52 to 77 days for 25 days in male Sprague-Dawley rats. The 75% severe lysine restriction increased (p < 0.05) food intake, but retarded (p < 0.05) growth, increased (p < 0.05) liver and muscle lipid contents and abdominal fat accumulation, increased (p < 0.05) blood urea nitrogen levels and mRNA levels of the serine-synthesizing 3-phosphoglycerate dehydrogenase gene, but decreased (p < 0.05) urea cycle arginase gene mRNA levels. In contrast, the 50% lysine restriction did not significantly (p > 0.05) affect body growth and lipid and nitrogen metabolism. Our results demonstrate that severe 75% lysine restriction has detrimental effects on body growth and deregulate lipid and nitrogen metabolism. PMID:23441935

  4. Induction of IL-25 secretion from tumour-associated fibroblasts suppresses mammary tumour metastasis.

    PubMed

    Yin, Shu-Yi; Jian, Feng-Yin; Chen, Yung-Hsiang; Chien, Shih-Chang; Hsieh, Mao-Chih; Hsiao, Pei-Wen; Lee, Wen-Hwa; Kuo, Yueh-Hsiung; Yang, Ning-Sun

    2016-01-01

    Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression. Here we investigate the role of IL-25, an endogenous anticancer factor secreted from TAFs, in suppression of mouse 4T1 mammary tumour metastasis. We show that a synthetic dihydrobenzofuran lignan (Q2-3), the dimerization product of plant caffeic acid methyl ester, suppresses 4T1 metastasis by increasing fibroblastic IL-25 activity. The secretion of IL-25 from treated human or mouse fibroblasts is enhanced in vitro, and this activity confers a strong suppressive effect on growth activity of test carcinoma cells. Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel. Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities. PMID:27089063

  5. Induction of IL-25 secretion from tumour-associated fibroblasts suppresses mammary tumour metastasis

    PubMed Central

    Yin, Shu-Yi; Jian, Feng-Yin; Chen, Yung-Hsiang; Chien, Shih-Chang; Hsieh, Mao-Chih; Hsiao, Pei-Wen; Lee, Wen-Hwa; Yang, Ning-Sun

    2016-01-01

    Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression. Here we investigate the role of IL-25, an endogenous anticancer factor secreted from TAFs, in suppression of mouse 4T1 mammary tumour metastasis. We show that a synthetic dihydrobenzofuran lignan (Q2-3), the dimerization product of plant caffeic acid methyl ester, suppresses 4T1 metastasis by increasing fibroblastic IL-25 activity. The secretion of IL-25 from treated human or mouse fibroblasts is enhanced in vitro, and this activity confers a strong suppressive effect on growth activity of test carcinoma cells. Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel. Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities. PMID:27089063

  6. Borderline ovarian tumours.

    PubMed

    Tropé, Claes Göran; Kaern, Janne; Davidson, Ben

    2012-06-01

    Borderline ovarian tumours account for 10-20% of all epithelial ovarian cancer. Historically, standard primary surgery has included borderline ovarian tumours, omentectomy, peritoneal washing and multiple biopsies. As one-third of borderline ovarian tumours are diagnosed in women under the age of 40 years, fertility-sparing treatment has been more frequently used in the past 10 years. Fertility drugs are well tolerated in women with infertility after fertility-sparing surgery. Careful selection of candidates is necessary. Laparoscopic techniques can be used, but should be reserved for oncologic surgeons. This conservative treatment increases the rate of recurrence, albeit with no effect on survival. The pregnancy rate is nearly 50%, and most are achieved spontaneously. These women should be closely followed up. The question is whether this is acceptable from a gynaecologic oncologic point of view. For this reason, we will discuss recently published studies and gynaecologic oncologic concerns about the mode of fertility-sparing surgery and its consequences. PMID:22321906

  7. Tumours of the kidney

    PubMed Central

    Nielsen, Svend W.; Mackey, L. J.; Misdorp, W.

    1976-01-01

    The most frequent renal tumours of animals are renal cell carcinoma and nephroblastoma. Renal cell carcinomas are seen mainly in dogs and cattle and nephroblastoma is encountered in pigs, puppies, and calves. Renal cell carcinomas are usually papillary in the dog. They show a marked propensity for vascular invasion, penetration of the posterior vena cava, and subsequent pulmonary metastasis. Nephroblastoma, which is morphologically identical to Wilms' tumour of children, is almost always a benign tumour in animals. It is one of the most frequent neoplasms of pigs, possibly owing to the fact that most pigs are slaughtered (and examined) when a few months old. Lymphosarcoma involving the kidney is particularly frequent in the cat, but is also seen in other species as part of a generalized disease. ImagesFig. 5,6Fig. 7Fig. 8Fig. 1,2Fig. 3,4Fig. 16,17,18,19Fig. 9,10Fig. 11Fig. 12Fig. 13Fig. 14,15 PMID:1086154

  8. Anti-tumour effect of metformin in canine mammary gland tumour cells.

    PubMed

    Saeki, K; Watanabe, M; Tsuboi, M; Sugano, S; Yoshitake, R; Tanaka, Y; Ong, S M; Saito, T; Matsumoto, K; Fujita, N; Nishimura, R; Nakagawa, T

    2015-08-01

    Metformin is an oral hypoglycaemic drug used in type 2 diabetes. Its pharmacological activity reportedly involves mitochondrial respiratory complex I, and mitochondrial respiratory complex inhibitors have a strong inhibitory effect on the growth of metastatic canine mammary gland tumour (CMGT) cell lines. It is hypothesised that metformin has selective anti-tumour effects on metastatic CMGT cells. The aim of this study was to investigate the in vitro effect of metformin on cell growth, production of ATP and reactive oxygen species (ROS), and the AMP-activated protein kinase (AMPK) mammalian target of rapamycin (mTOR) pathway in two CMGT clonal cell lines with different metastatic potential. In addition, transcriptome analysis was used to determine cellular processes disrupted by metformin and in vivo anti-tumour effects were examined in a mouse xenograft model. Metformin inhibited CMGT cell growth in vitro, with the metastatic clone (CHMp-5b) displaying greater sensitivity. ATP depletion and ROS elevation were observed to a similar extent in the metastatic and non-metastatic (CHMp-13a) cell lines after metformin exposure. However, subsequent AMPK activation and mTOR pathway inhibition were prominent only in metformin-insensitive non-metastatic cells. Microarray analysis revealed inhibition of cell cycle progression by metformin treatment in CHMp-5b cells, which was further confirmed by Western blotting and cell cycle analysis. Additionally, metformin significantly suppressed tumour growth in xenografted metastatic CMGT cells. In conclusion, metformin exhibited an anti-tumour effect in metastatic CMGT cells through AMPK-independent cell cycle arrest. Its mechanism of action differed in the non-metastatic clone, where AMPK activation and mTOR inhibition were observed. PMID:25981932

  9. Do variations in leaf phenology affect radial growth variations in Fagus sylvatica?

    NASA Astrophysics Data System (ADS)

    Čufar, Katarina; De Luis, Martin; Prislan, Peter; Gričar, Jožica; Črepinšek, Zalika; Merela, Maks; Kajfež-Bogataj, Lučka

    2015-08-01

    We used a dendrochronological and leaf phenology network of European beech ( Fagus sylvatica) in Slovenia, a transitional area between Mediterranean, Alpine and continental climatic regimes, for the period 1955-2007 to test whether year to year variations in leaf unfolding and canopy duration (i.e. time between leaf unfolding and colouring) influence radial growth (annual xylem production and tree ring widths) and if such influences are more pronounced at higher altitudes. We showed that variability in leaf phenology has no significant effect on variations in radial growth. The results are consistent in the entire region, irrespective of the climatic regime or altitude, although previous studies have shown that leaf phenology and tree ring variation depend on altitude. The lack of relationship between year to year variability in leaf phenology and radial growth may suggest that earlier leaf unfolding—as observed in a previous study—probably does not cause increased tree growth rates in beech in Slovenia.

  10. Density but not climate affects the population growth rate of guanacos ( Lama guanicoe) (Artiodactyla, Camelidae).

    PubMed

    Zubillaga, María; Skewes, Oscar; Soto, Nicolás; Rabinovich, Jorge E

    2013-01-01

    We analyzed the effects of population density and climatic variables on the rate of population growth in the guanaco ( Lama guanicoe), a wild camelid species in South America. We used a time series of 36 years (1977-2012) of population sampling in Tierra del Fuego, Chile. Individuals were grouped in three age-classes: newborns, juveniles, and adults; for each year a female population transition matrix was constructed, and the population growth rate (λ) was estimated for each year as the matrix highest positive eigenvalue. We applied a regression analysis with finite population growth rate (λ) as dependent variable, and total guanaco population, sheep population, annual mean precipitation, and winter mean temperature as independent variables, with and without time lags. The effect of guanaco population size was statistically significant, but the effects of the sheep population and the climatic variables on guanaco population growth rate were not statistically significant. PMID:25187878

  11. Density but not climate affects the population growth rate of guanacos ( Lama guanicoe) (Artiodactyla, Camelidae)

    PubMed Central

    Zubillaga, María; Skewes, Oscar; Soto, Nicolás; Rabinovich, Jorge E

    2014-01-01

    We analyzed the effects of population density and climatic variables on the rate of population growth in the guanaco ( Lama guanicoe), a wild camelid species in South America. We used a time series of 36 years (1977-2012) of population sampling in Tierra del Fuego, Chile. Individuals were grouped in three age-classes: newborns, juveniles, and adults; for each year a female population transition matrix was constructed, and the population growth rate (λ) was estimated for each year as the matrix highest positive eigenvalue. We applied a regression analysis with finite population growth rate (λ) as dependent variable, and total guanaco population, sheep population, annual mean precipitation, and winter mean temperature as independent variables, with and without time lags. The effect of guanaco population size was statistically significant, but the effects of the sheep population and the climatic variables on guanaco population growth rate were not statistically significant. PMID:25187878

  12. Affective Determinants of Anxiety and Depression Development in Children and Adolescents: An Individual Growth Curve Analysis

    ERIC Educational Resources Information Center

    De Bolle, Marleen; De Clercq, Barbara; Decuyper, Mieke; De Fruyt, Filip

    2011-01-01

    The tripartite model (in Clark and Watson, "J Abnorm Psychol" 100:316-336, 1991) comprises Negative Affect (NA), Positive Affect (PA), and Physiological Hyperarousal (PH), three temperamental-based dimensions. The current study examined the tripartite model's assumptions that (a) NA interacts with PA to predict subsequent depressive (but not…

  13. Mortality affects adaptive allocation to growth and reproduction: field evidence from a guild of body snatchers

    PubMed Central

    2010-01-01

    Background The probability of being killed by external factors (extrinsic mortality) should influence how individuals allocate limited resources to the competing processes of growth and reproduction. Increased extrinsic mortality should select for decreased allocation to growth and for increased reproductive effort. This study presents perhaps the first clear cross-species test of this hypothesis, capitalizing on the unique properties offered by a diverse guild of parasitic castrators (body snatchers). I quantify growth, reproductive effort, and expected extrinsic mortality for several species that, despite being different species, use the same species' phenotype for growth and survival. These are eight trematode parasitic castrators—the individuals of which infect and take over the bodies of the same host species—and their uninfected host, the California horn snail. Results As predicted, across species, growth decreased with increased extrinsic mortality, while reproductive effort increased with increased extrinsic mortality. The trematode parasitic castrator species (operating stolen host bodies) that were more likely to be killed by dominant species allocated less to growth and relatively more to current reproduction than did species with greater life expectancies. Both genders of uninfected snails fit into the patterns observed for the parasitic castrator species, allocating as much to growth and to current reproduction as expected given their probability of reproductive death (castration by trematode parasites). Additionally, species differences appeared to represent species-specific adaptations, not general plastic responses to local mortality risk. Conclusions Broadly, this research illustrates that parasitic castrator guilds can allow unique comparative tests discerning the forces promoting adaptive evolution. The specific findings of this study support the hypothesis that extrinsic mortality influences species differences in growth and reproduction

  14. Contamination by uranium mine drainages affects fungal growth and interactions between fungal species and strains.

    PubMed

    Ferreira, Verónica; Gonçalves, Ana Lúcia; Pratas, João; Canhoto, Cristina

    2010-01-01

    The presence of aquatic hyphomycetes has been reported for several heavy metal-contaminated waters. Tolerance probably is one adaptation to coping with heavy metals. To help clarify this issue strains of two species of aquatic hyphomycetes (Tricladium splendens Ingold and Varicosporium elodeae Kegel) were isolated from a reference stream and a stream contaminated with heavy metals and grown on malt extract agar prepared with reference and contaminated water to characterize colony morphology, growth rate, growth inhibition and interaction among species and strains. In V. elodeae the morphology of colonies differed between strains. Colony diameter increased linearly over time with growth rates being lower for strains isolated from contaminated than from reference streams (mostly for V. elodeae). Strains from the contaminated stream grew faster in medium prepared with contaminated water than in medium prepared with reference water, while for strains from the reference stream there was no significant difference in growth rates on the two media. In interacting isolates radial growth toward the opposing colony was generally lower than toward the dish edge. Percentage growth inhibition was higher for isolates in intraspecific interactions (13-37%) than in interspecific interactions (3-27%). However differences in growth inhibition experienced by interacting isolates were observed only in three cases out of 16. The difference between the percentage inhibition caused and experienced by a given isolate was highest in interactions involving isolates with distinct growth rates. Our results suggest that strains from the reference stream tolerate heavy metals while strains from the contaminated stream seem to be adapted to contaminated waters. We hypothesize that in natural environments fungal species-specific limits of tolerance to metal contamination might determine an abrupt or gradual response of the original fungal community to mine pollution giving origin to a poorer

  15. Augmenting drug–carrier compatibility improves tumour nanotherapy efficacy

    DOE PAGESBeta

    Zhao, Yiming; Fay, Francois; Hak, Sjoerd; Manuel Perez-Aguilar, Jose; Sanchez-Gaytan, Brenda L.; Goode, Brandon; Duivenvoorden, Raphael; de Lange Davies, Catharina; Bjorkoy, Astrid; Weinstein, Harel; et al

    2016-04-13

    A major goal of cancer nanotherapy is to use nanoparticles as carriers for targeted delivery of anti-tumour agents. The drug–carrier association after intravenous administration is essential for efficient drug delivery to the tumour. However, a large number of currently available nanocarriers are self-assembled nanoparticles whose drug-loading stability is critically affected by the in vivo environment. Here we used in vivo FRET imaging to systematically investigate how drug–carrier compatibility affects drug release in a tumour mouse model. We found the drug’s hydrophobicity and miscibility with the nanoparticles are two independent key parameters that determine its accumulation in the tumour. Next, wemore » applied these findings to improve chemotherapeutic delivery by augmenting the parent drug’s compatibility; as a result, we achieved better antitumour efficacy. Lastly, our results help elucidate nanomedicines’ in vivo fate and provide guidelines for efficient drug delivery.« less

  16. Augmenting drug-carrier compatibility improves tumour nanotherapy efficacy.

    PubMed

    Zhao, Yiming; Fay, François; Hak, Sjoerd; Manuel Perez-Aguilar, Jose; Sanchez-Gaytan, Brenda L; Goode, Brandon; Duivenvoorden, Raphaël; de Lange Davies, Catharina; Bjørkøy, Astrid; Weinstein, Harel; Fayad, Zahi A; Pérez-Medina, Carlos; Mulder, Willem J M

    2016-01-01

    A major goal of cancer nanotherapy is to use nanoparticles as carriers for targeted delivery of anti-tumour agents. The drug-carrier association after intravenous administration is essential for efficient drug delivery to the tumour. However, a large number of currently available nanocarriers are self-assembled nanoparticles whose drug-loading stability is critically affected by the in vivo environment. Here we used in vivo FRET imaging to systematically investigate how drug-carrier compatibility affects drug release in a tumour mouse model. We found the drug's hydrophobicity and miscibility with the nanoparticles are two independent key parameters that determine its accumulation in the tumour. Next, we applied these findings to improve chemotherapeutic delivery by augmenting the parent drug's compatibility; as a result, we achieved better antitumour efficacy. Our results help elucidate nanomedicines' in vivo fate and provide guidelines for efficient drug delivery. PMID:27071376

  17. Augmenting drug–carrier compatibility improves tumour nanotherapy efficacy

    PubMed Central

    Zhao, Yiming; Fay, François; Hak, Sjoerd; Manuel Perez-Aguilar, Jose; Sanchez-Gaytan, Brenda L.; Goode, Brandon; Duivenvoorden, Raphaël; de Lange Davies, Catharina; Bjørkøy, Astrid; Weinstein, Harel; Fayad, Zahi A.; Pérez-Medina, Carlos; Mulder, Willem J. M.

    2016-01-01

    A major goal of cancer nanotherapy is to use nanoparticles as carriers for targeted delivery of anti-tumour agents. The drug–carrier association after intravenous administration is essential for efficient drug delivery to the tumour. However, a large number of currently available nanocarriers are self-assembled nanoparticles whose drug-loading stability is critically affected by the in vivo environment. Here we used in vivo FRET imaging to systematically investigate how drug–carrier compatibility affects drug release in a tumour mouse model. We found the drug's hydrophobicity and miscibility with the nanoparticles are two independent key parameters that determine its accumulation in the tumour. Next, we applied these findings to improve chemotherapeutic delivery by augmenting the parent drug's compatibility; as a result, we achieved better antitumour efficacy. Our results help elucidate nanomedicines' in vivo fate and provide guidelines for efficient drug delivery. PMID:27071376

  18. Augmenting drug-carrier compatibility improves tumour nanotherapy efficacy

    NASA Astrophysics Data System (ADS)

    Zhao, Yiming; Fay, François; Hak, Sjoerd; Manuel Perez-Aguilar, Jose; Sanchez-Gaytan, Brenda L.; Goode, Brandon; Duivenvoorden, Raphaël; de Lange Davies, Catharina; Bjørkøy, Astrid; Weinstein, Harel; Fayad, Zahi A.; Pérez-Medina, Carlos; Mulder, Willem J. M.

    2016-04-01

    A major goal of cancer nanotherapy is to use nanoparticles as carriers for targeted delivery of anti-tumour agents. The drug-carrier association after intravenous administration is essential for efficient drug delivery to the tumour. However, a large number of currently available nanocarriers are self-assembled nanoparticles whose drug-loading stability is critically affected by the in vivo environment. Here we used in vivo FRET imaging to systematically investigate how drug-carrier compatibility affects drug release in a tumour mouse model. We found the drug's hydrophobicity and miscibility with the nanoparticles are two independent key parameters that determine its accumulation in the tumour. Next, we applied these findings to improve chemotherapeutic delivery by augmenting the parent drug's compatibility; as a result, we achieved better antitumour efficacy. Our results help elucidate nanomedicines' in vivo fate and provide guidelines for efficient drug delivery.

  19. Clinical features of gastroenteropancreatic tumours

    PubMed Central

    Czarnywojtek, Agata; Bączyk, Maciej; Ziemnicka, Katarzyna; Fischbach, Jakub; Wrotkowska, Elżbieta; Ruchała, Marek

    2015-01-01

    Gastroenteropancreatic (GEP) endocrine tumours (carcinoids and pancreatic islet cell tumours) are composed of multipotent neuroendocrine cells that exhibit a unique ability to produce, store, and secrete biologically active substances and cause distinct clinical syndromes. The classification of GEP tumours as functioning or non-functioning is based on the presence of symptoms that accompany these syndromes secondary to the secretion of hormones, neuropeptides and/or neurotransmitters (functioning tumours). Non-functioning tumours are considered to be neoplasms of neuroendocrine differentiation that are not associated with obvious symptoms attributed to the hypersecretion of metabolically active substances. However, a number of these tumours are either capable of producing low levels of such substances, which can be detected by immunohistochemistry but are insufficient to cause symptoms related to a clinical syndrome, or alternatively, they may secrete substances that are either metabolically inactive or inappropriately processed. In some cases, GEP tumours are not associated with the production of any hormone or neurotransmitter. Both functioning and non-functioning tumours can also produce symptoms due to mass effects compressing vital surrounding structures. Gastroenteropancreatic tumours are usually classified further according to the anatomic site of origin: foregut (including respiratory tract, thymus, stomach, duodenum, and pancreas), midgut (including small intestine, appendix, and right colon), and hindgut (including transverse colon, sigmoid, and rectum). Within these subgroups the biological and clinical characteristics of the tumours vary considerably, but this classification is still in use because a significant number of previous studies, mainly observational, have used it extensively. PMID:26516377

  20. [Inflammatory myofibroblastic tumours of the bladder].

    PubMed

    Dakir, Mohamed; Taha, Abdellatif; Attar, Hicham; Sarf, Ismail; Aboutaib, Rachid; Moussaoui, Ali; Meziane, Fathi

    2004-12-01

    The inflammatory myofibroblastic tumour of the bladder is a rare benign affection that interests mainly young adults. Its etiopathogeny remains unknown, but its tumoral origin was evocated recently by Griffin (1999), incriminating a chromosomic abnormality involving the ALK gene. We will discuss the etiopathogenic, anatopathological and therapeutical aspects of this lesion for which the diagnosis is histological and the treatment remains conservative with a good prognosis. PMID:15751423

  1. Factors that affect bone mineral accrual in the adolescent growth spurt.

    PubMed

    Whiting, Susan J; Vatanparast, Hassanali; Baxter-Jones, Adam; Faulkner, Robert A; Mirwald, Robert; Bailey, Donald A

    2004-03-01

    The development of bone mass during the growing years is an important determinant for risk of osteoporosis in later life. Adequate dietary intake during the growth period may be critical in reaching bone growth potential. The Saskatchewan Bone Mineral Accrual Study (BMAS) is a longitudinal study of bone growth in Caucasian children. We have calculated the times of maximal peak bone mineral content (BMC) velocity to be 14.0 +/- 1.0 y in boys and 12.5 +/- 0.9 y in girls; bone growth is maximal approximately 6 mo after peak height velocity. In the 2 y of peak skeletal growth, adolescents accumulate over 25% of adult bone. BMAS data may provide biological data on calcium requirements through application of calcium accrual values to factorial calculations of requirement. As well, our data are beginning to reveal how dietary patterns may influence attainment of bone mass during the adolescent growth spurt. Replacing milk intake by soft drinks appears to be detrimental to bone gain by girls, but not boys. Fruit and vegetable intake, providing alkalinity to bones and/or acting as a marker of a healthy diet, appears to influence BMC in adolescent girls, but not boys. The reason why these dietary factors appear to be more influential in girls than in boys may be that BMAS girls are consuming less than their requirement for calcium, while boys are above their threshold. Specific dietary and nutrient recommendations for adolescents are needed in order to ensure optimal bone growth and consolidation during this important life stage. PMID:14988470

  2. Bone quality is affected by food restriction and by nutrition-induced catch-up growth.

    PubMed

    Pando, Rakefet; Masarwi, Majdi; Shtaif, Biana; Idelevich, Anna; Monsonego-Ornan, Efrat; Shahar, Ron; Phillip, Moshe; Gat-Yablonski, Galia

    2014-12-01

    Growth stunting constitutes the most common effect of malnutrition. When the primary cause of malnutrition is resolved, catch-up (CU) growth usually occurs. In this study, we have explored the effect of food restriction (RES) and refeeding on bone structure and mechanical properties. Sprague-Dawley male rats aged 24 days were subjected to 10 days of 40% RES, followed by refeeding for 1 (CU) or 26 days long-term CU (LTCU). The rats fed ad libitum served as controls. The growth plates were measured, osteoclasts were identified using tartrate-resistant acid phosphatase staining, and micro-computed tomography (CT) scanning and mechanical testing were used to study structure and mechanical properties. Micro-CT analysis showed that RES led to a significant reduction in trabecular BV/TV and trabecular number (Tb.N), concomitant with an increase in trabecular separation (Tb.Sp). Trabecular BV/TV and Tb.N were significantly greater in the CU group than in the RES in both short- and long-term experiments. Mechanical testing showed that RES led to weaker and less compliant bones; interestingly, bones of the CU group were also more fragile after 1 day of CU. Longer term of refeeding enabled correction of the bone parameters; however, LTCU did not achieve full recovery. These results suggest that RES in young rats attenuated growth and reduced trabecular bone parameters. While nutrition-induced CU growth led to an immediate increase in epiphyseal growth plate height and active bone modeling, it was also associated with a transient reduction in bone quality. This should be taken into consideration when treating children undergoing CU growth. PMID:25248555

  3. Maspin as a Tumour Suppressor in Salivary Gland Tumour

    PubMed Central

    Ashok, Nipun; Sheirawan, Mohammad Kinan; Altamimi, Mohammed Alsakran; Alenzi, Faris; Azzeghaiby, Saleh Nasser; Baroudi, Kusai; Nassani, Mohammad Zakaria

    2014-01-01

    Maspin is a protein that belongs to serin protease inhibitor (serpin) superfamily. The purpose of this study was to review the literature concerning the expression of maspin in salivary gland tumours. A literature search was done using MEDLINE, accessed via the National Library of Medicine PubMed interface. Statistical analysis was not done because only seven studies were available in literature, the collected data were different and the results could not be compared. Expression of maspin was down regulated in more aggressive salivary gland tumours. Maspin may function as a tumour suppressor in salivary gland tumours. PMID:25654053

  4. Slow growth of the overexploited milk shark Rhizoprionodon acutus affects its sustainability in West Africa.

    PubMed

    Ba, A; Diouf, K; Guilhaumon, F; Panfili, J

    2015-10-01

    Age and growth of Rhizoprionodon acutus were estimated from vertebrae age bands. From December 2009 to November 2010, 423 R. acutus between 37 and 112 cm total length (LT ) were sampled along the Senegalese coast. Marginal increment ratio was used to check annual band deposition. Three growth models were adjusted to the length at age and compared using Akaike's information criterion. The Gompertz growth model with estimated size at birth appeared to be the best and resulted in growth parameters of L∞ = 139.55 (LT ) and K = 0.17 year(-1) for females and L∞ = 126.52 (LT ) and K = 0.18 year(-1) for males. The largest female and male examined were 8 and 9 years old, but the majority was between 1 and 3 years old. Ages at maturity estimated were 5.8 and 4.8 years for females and males, respectively. These results suggest that R. acutus is a slow-growing species, which render the species particularly vulnerable to heavy fishery exploitation. The growth parameters estimated in this study are crucial for stock assessments and for demographic analyses to evaluate the sustainability of commercial harvests. PMID:26436372

  5. Final Report: "Collaborative Project. Understanding the Chemical Processes That Affect Growth Rates of Freshly Nucleated Particles"

    SciTech Connect

    Smith, James N.; McMurry, Peter H.

    2015-11-12

    This final technical report describes our research activities that have, as the ultimate goal, the development of a model that explains growth rates of freshly nucleated particles. The research activities, which combine field observations with laboratory experiments, explore the relationship between concentrations of gas-phase species that contribute to growth and the rates at which those species are taken up. We also describe measurements of the chemical composition of freshly nucleated particles in a variety of locales, as well as properties (especially hygroscopicity) that influence their effects on climate. Our measurements include a self-organized, DOE-ARM funded project at the Southern Great Plains site, the New Particle Formation Study (NPFS), which took place during spring 2013. NPFS data are available to the research community on the ARM data archive, providing a unique suite observations of trace gas and aerosols that are associated with the formation and growth of atmospheric aerosol particles.

  6. Antimicrobial Activity, Growth Inhibition of Human Tumour Cell Lines, and Phytochemical Characterization of the Hydromethanolic Extract Obtained from Sapindus saponaria L. Aerial Parts

    PubMed Central

    Ćirić, Ana; Glamočlija, Jasmina; Calhelha, Ricardo C.; Ferreira, Isabel C. F. R.; Soković, Marina

    2013-01-01

    The hydromethanolic extract of Sapindus saponaria L. aerial parts was investigated for antimicrobial activity (against several Gram-positive and Gram-negative bacteria and fungi) and capacity to inhibit the growth of different human tumor cell lines as also nontumor liver cells. The evaluated extract was further characterized in terms of phytochemicals using UV, 1H-NMR, 13C-NMR, and MS spectroscopic tools. The extract has shown a significant antimicrobial activity on all tested bacterial and fungal species. The best activity was achieved against Bacillus cereus and Staphylococcus aureus among bacteria and against all three Penicillium species tested. It also revealed cytotoxicity against human colon (HCT-15), cervical (HeLa), breast (MCF-7), and lung (NCI-H460) carcinoma cell lines, with HeLa being the most susceptible tumor cell line. The extract was not toxic for nontumor liver cells. Chromatographic separation of the extract resulted in the isolation and identification of stigmasterol, oleanolic acid, luteolin, luteolin 8-C-β-glucoside (orientin), luteolin 6-C-β-glucoside (isoorientin), luteolin 7-O-β-glucuronide, and rutin. The results of the present findings may be useful for the discovery of novel antitumor and antimicrobial agents from plant origin. PMID:24455713

  7. Phenotypic plasticity in growth and fecundity induced by strong population fluctuations affects reproductive traits of female fish.

    PubMed

    Karjalainen, Juha; Urpanen, Olli; Keskinen, Tapio; Huuskonen, Hannu; Sarvala, Jouko; Valkeajärvi, Pentti; Marjomäki, Timo J

    2016-02-01

    Fish are known for their high phenotypic plasticity in life-history traits in relation to environmental variability, and this is particularly pronounced among salmonids in the Northern Hemisphere. Resource limitation leads to trade-offs in phenotypic plasticity between life-history traits related to the reproduction, growth, and survival of individual fish, which have consequences for the age and size distributions of populations, as well as their dynamics and productivity. We studied the effect of plasticity in growth and fecundity of vendace females on their reproductive traits using a series of long-term incubation experiments. The wild parental fish originated from four separate populations with markedly different densities, and hence naturally induced differences in their growth and fecundity. The energy allocation to somatic tissues and eggs prior to spawning served as a proxy for total resource availability to individual females, and its effects on offspring survival and growth were analyzed. Vendace females allocated a rather constant proportion of available energy to eggs (per body mass) despite different growth patterns depending on the total resources in the different lakes; investment into eggs thus dictated the share remaining for growth. The energy allocation to eggs per mass was higher in young than in old spawners and the egg size and the relative fecundity differed between them: Young females produced more and smaller eggs and larvae than old spawners. In contrast to earlier observations of salmonids, a shortage of maternal food resources did not increase offspring size and survival. Vendace females in sparse populations with ample resources and high growth produced larger eggs and larvae. Vendace accommodate strong population fluctuations by their high plasticity in growth and fecundity, which affect their offspring size and consequently their recruitment and productivity, and account for their persistence and resilience in the face of high

  8. Does temperature and oxygen affect duration of intramarsupial development and juvenile growth in the terrestrial isopod Porcellio scaber (Crustacea, Malacostraca)?

    PubMed Central

    Horváthová, Terézia; Antol, Andrzej; Czarnoleski, Marcin; Kramarz, Paulina; Bauchinger, Ulf; Labecka, Anna Maria; Kozłowski, Jan

    2015-01-01

    Abstract According to the temperature-size rule (TSR), ectotherms developing under cold conditions experience slower growth as juveniles but reach a larger size at maturity. Whether temperature alone causes this phenomenon is unknown, but oxygen limitation can play a role in the temperature-size relationship. Oxygen may become limited under warm conditions when the resulting higher metabolism creates a greater demand for oxygen, especially in larger individuals. We examined the independent effects of oxygen concentration (10% and 22% O2) and temperature (15 °C and 22 °C) on duration of ontogenic development, which takes place within the maternal brood pouch (marsupium), and juvenile growth in the terrestrial isopod common rough woodlouse (Porcellio scaber). Individuals inside the marsupium undergo the change from the aqueous to the gaseous environment. Under hypoxia, woodlice hatched from the marsupium sooner, but their subsequent growth was not affected by the level of oxygen. Marsupial development and juvenile growth were almost three times slower at low temperature, and marsupial development was longer in larger females but only in the cold treatment. These results show that temperature and oxygen are important ecological factors affecting developmental time and that the strength of the effect likely depends on the availability of oxygen in the environment. PMID:26261441

  9. Collaborative Project: Understanding the Chemical Processes tat Affect Growth rates of Freshly Nucleated Particles

    SciTech Connect

    McMurry, Peter; Smuth, James

    2015-11-12

    This final technical report describes our research activities that have, as the ultimate goal, the development of a model that explains growth rates of freshly nucleated particles. The research activities, which combine field observations with laboratory experiments, explore the relationship between concentrations of gas-phase species that contribute to growth and the rates at which those species are taken up. We also describe measurements of the chemical composition of freshly nucleated particles in a variety of locales, as well as properties (especially hygroscopicity) that influence their effects on climate.

  10. Propagule size and predispersal damage by insects affect establishment and early growth of mangrove seedlings.

    PubMed

    Sousa, Wayne P; Kennedy, Peter G; Mitchell, Betsy J

    2003-05-01

    Variation in rates of seedling recruitment, growth, and survival can strongly influence the rate and course of forest regeneration following disturbance. Using a combination of field sampling and shadehouse experiments, we investigated the influence of propagule size and predispersal insect damage on the establishment and early growth of the three common mangrove species on the Caribbean coast of Panama: Avicennia germinans, Laguncularia racemosa, and Rhizophora mangle. In our field samples, all three species exhibited considerable intraspecific variation in mature propagule size, and suffered moderate to high levels of predispersal attack by larval insects. Rates of insect attack were largely independent of propagule size both within and among trees. Our experimental studies using undamaged mature propagules showed that, for all three species, seedlings established at high rates regardless of propagule size. However, propagule size did have a marked effect on early seedling growth: seedlings that developed from larger propagules grew more rapidly. Predispersal insect infestations that had destroyed or removed a substantial amount of tissue, particularly if that tissue was meristematic or conductive, reduced the establishment of propagules of all three species. The effect of sublethal tissue damage or loss on the subsequent growth of established seedlings varied among the three mangrove species. For Avicennia, the growth response was graded: for a propagule of a given size, the more tissue lost, the slower the growth of the seedling. For Laguncularia, the response to insect attack appeared to be all-or-none. If the boring insect penetrated the outer spongy seed coat and reached the developing embryo, it usually caused sufficient damage to prevent a seedling from developing. On the other hand, if the insect damaged but did not penetrate the seed coat, a completely healthy seedling developed and its growth rate was indistinguishable from a seedling developing from an

  11. Elevated pressure of carbon dioxide affects growth of thermophilic Petrotoga sp.

    NASA Astrophysics Data System (ADS)

    Rakoczy, Jana; Gniese, Claudia; Schippers, Axel; Schlömann, Michael; Krüger, Martin

    2014-05-01

    Carbon capture and storage (CCS) is considered a promising new technology which reduces carbon dioxide emissions into the atmosphere and thereby decelerates global warming. During CCS, carbon dioxide is captured from emission sources (e.g. fossil fuel power plants or other industries), pressurised, and finally stored in deep geological formations, such as former gas or oil reservoirs as well as saline aquifers. However, with CCS being a very young technology, there are a number of unknown factors that need to be investigated before declaring CCS as being safe. Our research investigates the effect of high carbon dioxide concentrations and pressures on an indigenous microorganism that colonises a potential storage site. Growth experiments were conducted using the thermophilic thiosulphate-reducing bacterium Petrotoga sp., isolated from formation water of the gas reservoir Schneeren (Lower Saxony, Germany), situated in the Northern German Plain. Growth (OD600) was monitored over one growth cycle (10 days) at different carbon dioxide concentrations (50%, 100%, and 150% in the gas phase), and was compared to control cultures grown with 20% carbon dioxide. An additional growth experiment was performed over a period of 145 days with repeated subcultivation steps in order to detect long-term effects of carbon dioxide. Cultivation over 10 days at 50% and 100% carbon dioxide slightly reduced cell growth. In contrast, long-term cultivation at 150% carbon dioxide reduced cell growth and finally led to cell death. This suggested a more pronounced effect of carbon dioxide at prolonged cultivation and stresses the need for a closer consideration of long-term effects. Experiments with supercritical carbon dioxide at 100 bar completely inhibited growth of freshly inoculated cultures and also caused a rapid decrease of growth of a pre-grown culture. This demonstrated that supercritical carbon dioxide had a sterilising effect on cells. This effect was not observed in control cultures

  12. Oxidative stress, polarization of macrophages and tumour angiogenesis: Efficacy of caffeic acid.

    PubMed

    Oršolić, Nada; Kunštić, Martina; Kukolj, Marina; Gračan, Romana; Nemrava, Johann

    2016-08-25

    Macrophage polarization is a process when macrophage expresses different functional programs in response to microenvironmental signals and two extreme forms exist; M1 and M2 macrophages. M1 macrophages are highly microbicidal and anticancer with enhanced ability to kill and phagocytose pathogens, upregulate pro-inflammatory cytokines and reactive molecular species, and present antigens; M2 macrophages and the related tumour associated macrophages (TAMs) regulate tissue remodelling and promote tissue repair and angiogenesis and can amplification of metabolic pathways that can suppress adaptive immune responses. It is demonstrated that ROS production, critical for the activation and functions of M1 macrophages, is necessary for the differentiation of M2 macrophages and TAMs, and that antioxidant therapy blocks TAMs differentiation and tumorigenesis in mouse models of cancer. In order to study how caffeic acid (CA), a natural antioxidant, affects macrophage function, polarization, angiogenesis and tumour growth we injected mice with Ehrlich ascites tumour (EAT) cells and treated them for 10 days with CA in a dose of 40 and/or 80 mg kg(-1.) Macrophage polarization was further characterized by quantifying secreted pro- and anti-inflammatory cytokines, nitric oxide and arginase 1 activity. CA may increase the cytotoxic actions of M1 macrophages and inhibit tumour growth; inhibitory activity on TAMs may be mediated through its antioxidative activity. Taken together, we conclude that the antitumour activity of CA was the result of the synergistic activities of different mechanisms by which CA acts on proliferation, angiogenesis, immunomodulation and survival. The continuous administration of CA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models. Targeting TAMs by antioxidants can be a potentially effective method for cancer treatment. PMID:27378625

  13. Runoff nutrient transport as affected by land application method, swine growth stage, and runoff rate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was conducted to measure the effects of slurry application method, swine growth stage, and flow rate on runoff nutrient transport. Swine slurry was obtained from production units containing grower pigs, finisher pigs, or sows and gilts. The swine slurry was applied using broadcast, disk, ...

  14. Propagation container and timing of propagation affects growth and quality of oak seedlings

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two experiments were conducted to determine the container effect and the timeline of seed propagation on germination and subsequent shoot and root development for container-grown oaks. Quercus nigra and Q. texana had equal or better growth and better root ratings when acorns were sown in Anderson t...

  15. Luciferase expression and bioluminescence does not affect tumor cell growth in vitro or in vivo.

    PubMed

    Tiffen, Jessamy C; Bailey, Charles G; Ng, Cynthia; Rasko, John E J; Holst, Jeff

    2010-01-01

    Live animal imaging is becoming an increasingly common technique for accurate and quantitative assessment of tumor burden over time. Bioluminescence imaging systems rely on a bioluminescent signal from tumor cells, typically generated from expression of the firefly luciferase gene. However, previous reports have suggested that either a high level of luciferase or the resultant light reaction produced upon addition of D-luciferin substrate can have a negative influence on tumor cell growth. To address this issue, we designed an expression vector that allows simultaneous fluorescence and luminescence imaging. Using fluorescence activated cell sorting (FACS), we generated clonal cell populations from a human breast cancer (MCF-7) and a mouse melanoma (B16-F10) cell line that stably expressed different levels of luciferase. We then compared the growth capabilities of these clones in vitro by MTT proliferation assay and in vivo by bioluminescence imaging of tumor growth in live mice. Surprisingly, we found that neither the amount of luciferase nor biophotonic activity was sufficient to inhibit tumor cell growth, in vitro or in vivo. These results suggest that luciferase toxicity is not a necessary consideration when designing bioluminescence experiments, and therefore our approach can be used to rapidly generate high levels of luciferase expression for sensitive imaging experiments. PMID:21092230

  16. Seed Production Affects Maternal Growth and Senescence in Arabidopsis1[OPEN

    PubMed Central

    Philipp, Matthias Anton; Guthörl, Daniela

    2016-01-01

    Correlative control (influence of one organ over another organ) of seeds over maternal growth is one of the most obvious phenotypic expressions of the trade-off between growth and reproduction. However, the underlying molecular mechanisms are largely unknown. Here, we characterize the physiological and molecular effects of correlative inhibition by seeds on Arabidopsis (Arabidopsis thaliana) inflorescences, i.e. global proliferative arrest (GPA) during which all maternal growth ceases upon the production of a given number of seeds. We observed transcriptional responses to growth- and branching-inhibitory hormones, and low mitotic activity in meristems upon GPA, but found that meristems retain their identity and proliferative potential. In shoot tissues, we detected the induction of stress- and senescence-related gene expression upon fruit production and GPA, and a drop in chlorophyll levels, suggestive of altered source-sink relationships between vegetative shoot and reproductive tissues. Levels of shoot reactive oxygen species, however, strongly decreased upon GPA, a phenomenon that is associated with bud dormancy in some perennials. Indeed, gene expression changes in arrested apical inflorescences after fruit removal resembled changes observed in axillary buds following release from apical dominance. This suggests that GPA represents a form of bud dormancy, and that dominance is gradually transferred from growing inflorescences to maturing seeds, allowing offspring control over maternal resources, simultaneously restricting offspring number. This would provide a mechanistic explanation for the constraint between offspring quality and quantity. PMID:27009281

  17. Study of factors affecting growth and cold acclimation of Vitis callus cultures

    SciTech Connect

    Deng, L.

    1987-01-01

    In vitro grape tissue culture initiation, growth, and cold acclimation were studied. Factors involved were genotypes, media, plant growth regulators, age, light, temperature, antioxidant, clearing and adsorbing agents, sucrose level, osmotic potential, ABA, chilling and freezing treatments. Murashige and Skoog (MS) medium containing 1 ..mu..M 2,4-d + 0.1 uM Ba, MS containing 1 uM 2,4-D, and woody plant medium containing 1 uM 2,4-D + 0.1 uM BA produced abundant callus tissue for most grape genotypes; either WPM or MS containing 1 uM BA stimulated shoot growth in all the 12 genotypes tested. Adding 1 uM abscisic acid (ABA) to the B5 medium with 1 uM 2,4-D and 0.5 uM BA enhanced growth and quality of Chancellor callus. /sup 3/H-ABA was taken up actively by callus tissue at 12 days after subculture, but by 20 d this effect disappeared. When /sup 14/C-sucrose was added to the medium. /sup 14/C level of cells reached a plateau after 48 h; this plateau was higher if ABA was also present in the medium. Cells on media containing ABA were larger in size, lighter in color, and more loosely connected.

  18. Intrauterine Cannabis Exposure Affects Fetal Growth Trajectories: The Generation R Study

    ERIC Educational Resources Information Center

    El Marroun, Hanan; Tiemeier, Henning; Steegers, Eric A. P.; Jaddoe, Vincent W. V.; Hofman, Albert; Verhulst, Frank C.; van den Brink, Wim; Huizink, Anja C.

    2009-01-01

    Objective: Cannabis is the most commonly consumed illicit drug among pregnant women. Intrauterine exposure to cannabis may result in risks for the developing fetus. The importance of intrauterine growth on subsequent psychological and behavioral child development has been demonstrated. This study examined the relation between maternal cannabis use…

  19. Does Year Round Schooling Affect the Outcome and Growth of California's API Scores?

    ERIC Educational Resources Information Center

    Wu, Amery D.; Stone, Jake E.

    2010-01-01

    This paper examined whether year round schooling (YRS) in California had an effect upon the outcome and growth of schools' Academic Performance Index (API) scores. While many previous studies had examined the connection between YRS and academic achievement, most had lacked the statistical rigour required to provide reliable interpretations. As a…

  20. Lysine supplementation of commercial fishmeal-free diet in hybrid striped bass affect growth expression genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Substitution of fishmeal with alternate proteins in aquafeeds often results in dietary imbalances of first-limiting essential amino acids (EAA) and poorer fish performance. Previously, we conducted a growth trial to test the hypothesis that ideal protein theory accurately predicts first-limiting ami...

  1. A mutation affecting carbon catabolite repression suppresses growth defects in pyruvate carboxylase mutants from Saccharomyces cerevisiae.

    PubMed

    Blázquez, M A; Gamo, F J; Gancedo, C

    1995-12-18

    Yeasts with disruptions in the genes PYC1 and PYC2 encoding the isoenzymes of pyruvate carboxylase cannot grow in a glucose-ammonium medium (Stucka et al. (1991) Mol. Gen. Genet. 229, 307-315). We have isolated a dominant mutation, BPC1-1, that allows growth in this medium of yeasts with interrupted PYC1 and PYC2 genes. The BPC1-1 mutation abolishes catabolite repression of a series of genes and allows expression of the enzymes of the glyoxylate cycle during growth in glucose. A functional glyoxylate cycle is necessary for suppression as a disruption of gene ICL1 encoding isocitrate lyase abolished the phenotypic effect of BPC1-1 on growth in glucose-ammonium. Concurrent expression from constitutive promoters of genes ICL1 and MLS1 (encoding malate synthase) also suppressed the growth phenotype of pyc1 pyc2 mutants. The mutation BPC1-1 is either allelic or closely linked to the mutation DGT1-1. PMID:8543050

  2. The Ecology of Technological Progress: How Symbiosis and Competition Affect the Growth of Technology Domains

    ERIC Educational Resources Information Center

    Carnabuci, Gianluca

    2010-01-01

    We show that the progress of technological knowledge is an inherently ecological process, wherein the growth rate of each technology domain depends on dynamics occurring in "other" technology domains. We identify two sources of ecological interdependence among technology domains. First, there are symbiotic interdependencies, implying that the rate…

  3. Stocker growth on rye and ryegrass pastures affects subsequent feedlot gains and carcass traits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Stocker calves were stocked on annual rye (Secale cereale L.) and ryegrass (Lolium multiflorum Lam.) pastures using stocking strategies (STK) to create graded levels of gain to assess subsequent growth rates, feedlot performance, and carcass traits. During two consecutive years, yearling Angus, Here...

  4. A chloroplast-localized protein LESION AND LAMINA BENDING affects defence and growth responses in rice.

    PubMed

    Tamiru, Muluneh; Takagi, Hiroki; Abe, Akira; Yokota, Takao; Kanzaki, Hiroyuki; Okamoto, Haruko; Saitoh, Hiromasa; Takahashi, Hideyuki; Fujisaki, Koki; Oikawa, Kaori; Uemura, Aiko; Natsume, Satoshi; Jikumaru, Yusuke; Matsuura, Hideyuki; Umemura, Kenji; Terry, Matthew J; Terauchi, Ryohei

    2016-06-01

    Understanding how plants allocate their resources to growth or defence is of long-term importance to the development of new and improved varieties of different crops. Using molecular genetics, plant physiology, hormone analysis and Next-Generation Sequencing (NGS)-based transcript profiling, we have isolated and characterized the rice (Oryza sativa) LESION AND LAMINA BENDING (LLB) gene that encodes a chloroplast-targeted putative leucine carboxyl methyltransferase. Loss of LLB function results in reduced growth and yield, hypersensitive response (HR)-like lesions, accumulation of the antimicrobial compounds momilactones and phytocassanes, and constitutive expression of pathogenesis-related genes. Consistent with these defence-associated responses, llb shows enhanced resistance to rice blast (Magnaporthe oryzae) and bacterial blight (Xanthomonas oryzae pv. oryzae). The lesion and resistance phenotypes are likely to be caused by the over-accumulation of jasmonates (JAs) in the llb mutant including the JA precursor 12-oxo-phytodienoic acid. Additionally, llb shows an increased lamina inclination and enhanced early seedling growth due to elevated brassinosteroid (BR) synthesis and/or signalling. These findings show that LLB functions in the chloroplast to either directly or indirectly repress both JA- and BR-mediated responses, revealing a possible mechanism for controlling how plants allocate resources for defence and growth. PMID:26864209

  5. Does the introduced brook trout ( Salvelinus fontinalis) affect growth of the native brown trout ( Salmo trutta)?

    NASA Astrophysics Data System (ADS)

    Korsu, Kai; Huusko, Ari; Muotka, Timo

    2009-03-01

    Non-native brook trout have become widely established in North European streams. We combined evidence from an artificial-stream experiment and drainage-scale field surveys to examine whether brook trout suppressed the growth of the native brown trout (age 0 to age 2). Our experimental results demonstrated that brown trout were unaffected by the presence of brook trout but that brook trout showed reduced growth in the presence of brown trout. However, the growth reduction only appeared in the experimental setting, indicating that the reduced spatial constraint of the experimental system may have forced the fish to unnaturally intense interactions. Indeed, in the field, no effect of either species on the growth of the putative competitor was detected. These results caution against uncritical acceptance of findings from small-scale experiments because they rarely scale up to more complex field situations. This and earlier work suggest that the establishment of brook trout in North European streams has taken place mainly because of the availability of unoccupied (or underutilized) niche space, rather than as a result of species trait combinations or interspecific competition per se.

  6. Factors affecting growth and survival of the asiatic clam Corbicula sp. under controlled laboratory conditions

    SciTech Connect

    Double, D.D.; Daly, D.S.; Abernethy, C.S.

    1983-04-01

    Growth of Corbicula sp. was determined in relation to food supply, water temperature, and clam size as an aid to researchers conducting chronic effects toxicity studies. Water temperatures for the two 84-day test series were 10, 20, and 30/sup 0/C. Linear models provided good relationships (r/sup 2/ > 0.90) between clam shell length (SL), total weight (TW), and wet/dry tissue weights. Clam growth was minimal during low phytoplankton densities (approx. 300 cells/ml), and all three size groups lost weight at 20 and 30/sup 0/C. Mortality of small clams at 30/sup 0/C was 100% after 71 days. At phytoplankton densities > 1000 cells/ml, overall differences in growth with respect to clam size and temperature were detectable at p < 0.01; growth of all clam groups was greatest at 30/sup 0/C. Small clams exhibited the greatest absolute increase in mean shell length at all test temperatures, and weight gains were similar to those of medium and large clams.

  7. Rate of Physical Growth and Its Affect on Head Start Children's Motor and Cognitive Development.

    ERIC Educational Resources Information Center

    Marcon, Rebecca A.

    In the United States, growth retardation is higher among low-income children, with adverse cognitive effects of undernutrition more prevalent when combined with poverty. This study examined anthropometric indicators of physical development and their relationship to motor and cognitive development in Head Start children. Motor integration and…

  8. Induction of Salmonella pathogenicity island 1 under different growth conditions can affect Salmonella–host cell interactions in vitro

    PubMed Central

    Ibarra, J. Antonio; Knodler, Leigh A.; Sturdevant, Daniel E.; Virtaneva, Kimmo; Carmody, Aaron B.; Fischer, Elizabeth R.; Porcella, Stephen F.; Steele-Mortimer, Olivia

    2010-01-01

    Salmonella invade non-phagocytic cells by inducing massive actin rearrangements, resulting in membrane ruffle formation and phagocytosis of the bacteria. This process is mediated by a cohort of effector proteins translocated into the host cell by type III secretion system 1, which is encoded by genes in the Salmonella pathogenicity island (SPI) 1 regulon. This network is precisely regulated and must be induced outside of host cells. In vitro invasive Salmonella are prepared by growth in synthetic media although the details vary. Here, we show that culture conditions affect the frequency, and therefore invasion efficiency, of SPI1-induced bacteria and also can affect the ability of Salmonella to adapt to its intracellular niche following invasion. Aerobically grown late-exponential-phase bacteria were more invasive and this was associated with a greater frequency of SPI1-induced, motile bacteria, as revealed by single-cell analysis of gene expression. Culture conditions also affected the ability of Salmonella to adapt to the intracellular environment, since they caused marked differences in intracellular replication. These findings show that induction of SPI1 under different pre-invasion growth conditions can affect the ability of Salmonella to interact with eukaryotic host cells. PMID:20035008

  9. Growth of and fumitremorgin production by Neosartorya fischeri as affected by temperature, light, and water activity.

    PubMed Central

    Nielsen, P V; Beuchat, L R; Frisvad, J C

    1988-01-01

    The effects of temperature, light, and water activity (aw) on the growth and fumitremorgin production of a heat-resistant mold, Neosartorya fischeri, cultured on Czapek Yeast Autolysate agar (CYA) were studied for incubation periods of up to 74 days. Colonies were examined visually, and extracts of mycelia and CYA on which the mold was cultured were analyzed for mycotoxin content by high-performance liquid chromatography. Growth always resulted in the production of the tremorgenic mycotoxins verruculogen and fumitremorgins A and C. The optimum temperatures for the production of verruculogen and fumitremorgins A and C on CYA at pH 7.0 were 25, 30, and 37 degrees C, respectively. The production of fumitremorgin C by N. fischeri has not been previously reported. Fumitremorgin production was retarded at 15 degrees C, but an extension of the incubation period resulted in concentrations approaching those observed at 25 degrees C. Light clearly enhanced fumitremorgin production on CYA (pH 7.0, 25 degrees C), but not as dramatically as did the addition of glucose, fructose, or sucrose to CYA growth medium (pH 3.5, 25 degrees C). Growth and fumitremorgin production was greatest at aw of 0.980 on CYA supplemented with glucose or fructose and at aw of 0.990 on CYA supplemented with sucrose. Growth and fumitremorgin production were observed at aw as low as 0.925 on glucose-supplemented CYA but not at aw lower than 0.970 on CYA supplemented with sucrose. Verruculogen was produced in the highest amount on all test media, followed by fumitremorgin A and fumitremorgin C. PMID:3415223

  10. Growth of and fumitremorgin production by Neosartorya fischeri as affected by temperature, light, and water activity.

    PubMed

    Nielsen, P V; Beuchat, L R; Frisvad, J C

    1988-06-01

    The effects of temperature, light, and water activity (aw) on the growth and fumitremorgin production of a heat-resistant mold, Neosartorya fischeri, cultured on Czapek Yeast Autolysate agar (CYA) were studied for incubation periods of up to 74 days. Colonies were examined visually, and extracts of mycelia and CYA on which the mold was cultured were analyzed for mycotoxin content by high-performance liquid chromatography. Growth always resulted in the production of the tremorgenic mycotoxins verruculogen and fumitremorgins A and C. The optimum temperatures for the production of verruculogen and fumitremorgins A and C on CYA at pH 7.0 were 25, 30, and 37 degrees C, respectively. The production of fumitremorgin C by N. fischeri has not been previously reported. Fumitremorgin production was retarded at 15 degrees C, but an extension of the incubation period resulted in concentrations approaching those observed at 25 degrees C. Light clearly enhanced fumitremorgin production on CYA (pH 7.0, 25 degrees C), but not as dramatically as did the addition of glucose, fructose, or sucrose to CYA growth medium (pH 3.5, 25 degrees C). Growth and fumitremorgin production was greatest at aw of 0.980 on CYA supplemented with glucose or fructose and at aw of 0.990 on CYA supplemented with sucrose. Growth and fumitremorgin production were observed at aw as low as 0.925 on glucose-supplemented CYA but not at aw lower than 0.970 on CYA supplemented with sucrose. Verruculogen was produced in the highest amount on all test media, followed by fumitremorgin A and fumitremorgin C. PMID:3415223

  11. Measuring the Affective and Cognitive Growth of Regularly Admitted and Developmental Studies Students Using the "Learning and Study Strategies Inventory" (LASSI).

    ERIC Educational Resources Information Center

    Nist, Sherrie L.; And Others

    1990-01-01

    Investigates the utility and predictive validity of the Learning and Study Strategies Inventory (LASSI) as a means of measuring college students' cognitive and affective growth following a study strategies course. Finds cognitive and affective growth in both regularly admitted and developmental studies students. Finds that LASSI cannot yet be used…

  12. Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes.

    PubMed Central

    Clifford, S. C.; Czapla, K.; Richards, F. M.; O'Donoghue, D. J.; Maher, E. R.

    1998-01-01

    Hepatocyte growth factor (HGF/SF) is a potent renal proximal tubular cell (PTEC) mitogen involved in renal development. HGF/SF is the functional ligand for the c-met proto-oncogene, and germline c-met mutations are associated with familial papillary renal cell carcinoma. Somatic von Hippel-Lindau disease tumour-suppressor gene (VHL) mutations are frequently detected in sporadic clear cell renal cell carcinomas (RCC), and germline VHL mutations are the commonest cause of familial clear cell RCC. pVHL binds to the positive regulatory components of the trimeric elongin (SIII) complex (elongins B and C) and has been observed to deregulate expression of the vascular endothelial growth factor (VEGF) gene. HGF/SF has similarly been reported to up-regulate expression of the VEGF gene in non-renal experimental systems. To investigate the mechanism of HGF/SF action in PTECs and, specifically, to examine potential interactions between the HGF/c-met and the VHL-mediated pathways for renal tubular growth control, we have isolated untransformed PTECs from normal kidneys, developed conditions for their culture in vitro and used these cells to investigate changes in mRNA levels of the VHL, elongin A, B and C, VEGF, c-myc, c-fos and c-met genes after HGF/SF exposure. Significant elevations in the mRNA levels of VEGF, c-myc, c-fos, c-met and elongins A, B and C, but not VHL, were detected after HGF/SF stimulation of human PTECs (P < 0.02), with a consistent order of peak levels observed over successive replicates (c-fos at 1 h, VEGF at 2-4 h, c-myc, at 4 h, followed by c-met and all three elongin subunits at 8 h). This study highlights the spectrum of changes in gene expression observed in PTECs after HGF/SF stimulation and has identified possible candidate mediators of the HGF/SF-induced mitogenic response. Our evidence would suggest that the changes in PTEC VEGF expression induced by HGF/SF are mediated by a VHL-independent pathway. Images Figure 1 PMID:9652757

  13. Patchy Distributions of Competitors Affect the Growth of a Clonal Plant When the Competitor Density Is High

    PubMed Central

    Xue, Wei; Huang, Lin; Dong, Bi-Cheng; Zhang, Ming-Xiang; Yu, Fei-Hai

    2013-01-01

    Environments are patchy in not only abiotic factors but also biotic ones. Many studies have examined effects of spatial heterogeneity in abiotic factors such as light, water and nutrients on the growth of clonal plants, but few have tested those in biotic factors. We conducted a greenhouse experiment to examine how patchy distributions of competitors affect the growth of a rhizomatous wetland plant Bolboschoenus planiculmis and whether such effects depend on the density of the competitors. We grew one ramet of B. planiculmis in the center of each of the experimental boxes without competitors (Schoenoplectus triqueter), with a homogeneous distribution of the competitors of low or high density, and with a patchy distribution of the competitors of low or high density. The presence of competitors markedly decreased the growth (biomass, number of ramets, number of tubers and rhizome length) of the B. planiculmis clones. When the density of the competitors was low, the growth of B. planiculmis did not differ significantly between the competitor patches and competitor-free patches. However, when the density of the competitors was high, the growth of B. planiculmis was significantly higher in the competitor-free patches than in the competitor patches. Therefore, B. planiculmis can respond to patchy distributions of competitors by placing more ramets in competition-free patches when the density of competitors is high, but cannot do so when the density of competitors is low. PMID:24205165

  14. Mathematical modelling of the Warburg effect in tumour cords.

    PubMed

    Astanin, Sergey; Preziosi, Luigi

    2009-06-21

    The model proposed here links together two approaches to describe tumours: a continuous medium to describe the movement and the mechanical properties of the tissue, and a population dynamics approach to represent internal genetic inhomogeneity and instability of the tumour. In this way one can build models which cover several stages of tumour progression. In this paper we focus on describing transition from aerobic to purely glycolytic metabolism (the Warburg effect) in tumour cords. From the mathematical point of view this model leads to a free boundary problem where domains in contact are characterized by different sets of equations. Accurate stitching of the solution was possible with a modified ghost fluid method. Growth and death of the cells and uptake of the nutrients are related through ATP production and energy costs of the cellular processes. In the framework of the bi-population model this allowed to keep the number of model parameters relatively small. PMID:19232360

  15. Neonatal and fetal exposure to trans-fatty acid retards early growth and adiposity while adversely affecting glucose in mice

    PubMed Central

    Kavanagh, Kylie; Sajadian, Soraya; Jenkins, Kurt A.; Wilson, Martha D.; Carr, J. Jeffery; Wagner, Janice D.; Rudel, Lawrence L.

    2010-01-01

    Industrially produced trans fatty acids (TFAs) consumed in western diets are incorporated into maternal and fetal tissues, and are passed linearly to offspring via breast milk. We hypothesized that TFA exposure in utero and during lactation in infants would promote obesity and poor glycemic control as compared to unmodified fatty acids. We further hypothesized that in utero exposure alone may program for these outcomes in adulthood. To test this hypothesis we fed female C57/BL6 mice identical western diets that differed only in cis- or trans-isomers of C18:1 and then aimed to determine whether maternal transfer of TFAs through pregnancy and lactation alters growth, body composition and glucose metabolism. Mice were unexposed, exposed during pregnancy, during lactation, or throughout pregnancy and lactation to TFA. Body weight and composition (by computed tomography), and glucose metabolism we assessed at weaning and adulthood. TFA exposure through breast milk caused significant early growth retardation (p<0.001) and higher fasting glucose (p=0.01) but insulin sensitivity was not different. Elevated plasma insulin-like growth factor-1 in mice consuming TFA-enriched milk (p=0.02) may contribute to later catch-up growth, leanness and preserved peripheral insulin sensitivity observed in these mice. Mice exposed to TFA in utero underwent rapid early neonatal growth with TFA-free breast milk and had significantly impaired insulin sensitivity (p<0.05) and greater abdominal fat (p=0.01). We conclude that very early catch-up growth resulted in impaired peripheral insulin sensitivity in this model of diet-related fetal and neonatal programming. TFA surprisingly retarded growth and adiposity while still adversely affecting glucose metabolism. PMID:20650350

  16. Submerged Conidiation and Product Formation by Aspergillus niger at Low Specific Growth Rates Are Affected in Aerial Developmental Mutants ▿

    PubMed Central

    Jørgensen, Thomas R.; Nielsen, Kristian F.; Arentshorst, Mark; Park, JooHae; van den Hondel, Cees A.; Frisvad, Jens C.; Ram, Arthur F.

    2011-01-01

    Exposure to an aerial environment or severe nutrient limitation induces asexual differentiation in filamentous fungi. Submerged cultivation of Aspergillus niger in carbon- and energy-limited retentostat cultures both induces and fuels conidiation. Physiological and transcriptomic analyses have revealed that this differentiation strongly affects product formation. Since conidiation is inherent in the aerial environment, we hypothesized that product formation near zero growth can be influenced by affecting differentiation or development of aerial hyphae in general. To investigate this idea, three developmental mutants (ΔfwnA, scl-1, and scl-2 mutants) that have no apparent vegetative growth defects were cultured in maltose-limited retentostat cultures. The secondary-metabolite profile of the wild-type strain defined flavasperone, aurasperone B, tensidol B, and two so far uncharacterized compounds as associated with conidium formation, while fumonisins B2, B4, and B6 were characteristic of early response to nutrient limitation by the vegetative mycelium. The developmental mutants responded differently to the severe substrate limitation, which resulted in distinct profiles of growth and product formation. fwnA encodes the polyketide synthase responsible for melanin biosynthesis during aerial differentiation, and we show that conidial melanin synthesis in submerged retentostat cultures and aurasperone B production are fwnA dependent. The scl-1 and scl-2 strains are two UV mutants generated in the ΔfwnA background that displayed reduced asexual conidiation and formed sclerotium-like structures on agar plates. The reduced conidiation phenotypes of the scl-1 and scl-2 strains are reflected in the retentostat cultivation and are accompanied by elimination or severely reduced accumulation of secondary metabolites and distinctly enhanced accumulation of extracellular protein. This investigation shows that submerged conidiation and product formation of a mitosporic fungus

  17. Attenuating tumour angiogenesis: a preventive role of metformin against breast cancer.

    PubMed

    Gao, Shan; Jiang, Jingcheng; Li, Pan; Song, Huijuan; Wang, Weiwei; Li, Chen; Kong, Deling

    2015-01-01

    Metformin is one of the most widely prescribed antidiabetics for type 2 diabetes. A critical role of metformin against tumorigenesis has recently been implicated, although several studies also reported the lack of anticancer property of the antidiabetics. Given the controversies regarding the potential role of metformin against tumour progression, the effect of metformin against breast, cervical, and ovarian tumour cell lines was examined followed by in vivo assessment of metformin on tumour growth using xenograft breast cancer models. Significant inhibitory impact of metformin was observed in MCF-7, HeLa, and SKOV-3 cells, suggesting an antiproliferative property of metformin against breast, cervical, and ovarian tumour cells, respectively, with the breast tumour cells, MCF-7, being the most responsive. In vivo assessment was subsequently carried out, where mice with breast tumours were treated with metformin (20 mg/kg body weight) or sterile PBS solution for 15 consecutive days. No inhibition of breast tumour progression was detected. However, tumour necrosis was significantly increased in the metformin-treated group, accompanied by decreased capillary formation within the tumours. Thus, despite the lack of short-term benefit of metformin against tumour progression, a preventive role of metformin against breast cancer was implicated, which is at partially attributable to the attenuation of tumour angiogenesis. PMID:25883966

  18. Attenuating Tumour Angiogenesis: A Preventive Role of Metformin against Breast Cancer

    PubMed Central

    Gao, Shan; Jiang, Jingcheng; Li, Pan; Song, Huijuan; Wang, Weiwei; Li, Chen; Kong, Deling

    2015-01-01

    Metformin is one of the most widely prescribed antidiabetics for type 2 diabetes. A critical role of metformin against tumorigenesis has recently been implicated, although several studies also reported the lack of anticancer property of the antidiabetics. Given the controversies regarding the potential role of metformin against tumour progression, the effect of metformin against breast, cervical, and ovarian tumour cell lines was examined followed by in vivo assessment of metformin on tumour growth using xenograft breast cancer models. Significant inhibitory impact of metformin was observed in MCF-7, HeLa, and SKOV-3 cells, suggesting an antiproliferative property of metformin against breast, cervical, and ovarian tumour cells, respectively, with the breast tumour cells, MCF-7, being the most responsive. In vivo assessment was subsequently carried out, where mice with breast tumours were treated with metformin (20 mg/kg body weight) or sterile PBS solution for 15 consecutive days. No inhibition of breast tumour progression was detected. However, tumour necrosis was significantly increased in the metformin-treated group, accompanied by decreased capillary formation within the tumours. Thus, despite the lack of short-term benefit of metformin against tumour progression, a preventive role of metformin against breast cancer was implicated, which is at partially attributable to the attenuation of tumour angiogenesis. PMID:25883966

  19. The epidemiology of neonatal tumours. Report of an international working group.

    PubMed

    Moore, S W; Satgé, D; Sasco, A J; Zimmermann, A; Plaschkes, J

    2003-09-01

    Neonatal tumours occur every 12,500-27,500 live births and comprise 2% of childhood malignancies, but there is little clarity as to their real prevalence, sites of origin and pathological nature as reported series vary. As an entity, neonatal tumours provide a unique window of opportunity to study tumours in which minimal environmental interference has occurred. The majority of tumours present with a mass at birth (e.g., teratomas, neuroblastomas, mesoblastic nephroma, fibromatosis), which are not infrequently identified on antenatal ultrasound. Histologically, teratoma and neuroblastoma remain the two main tumour types encountered with soft tissue sarcoma, renal tumours, CNS tumours and leukaemia being the next most common tumour types identified. Malignant tumours are uncommon in the neonatal period per se and benign tumours may have malignant potential. A particular problem exists in clinical classification, as histological features of malignancy do not always correlate with clinical behaviour. Benign tumours may also be life threatening because of their size and location. Other tumours may demonstrate local invasiveness, but no metastatic potential, and tumours that are clearly malignant may demonstrate unpredictable or uncertain behaviour. Screening programmes have brought more tumours to light, but do not appear to affect the overall prognosis. They may provide clues to the stage at which tumours develop in foetu. The aetiology of cancer in children is multifactorial and includes both genetic and environmental factors. The association between congenital abnormalities and tumours is well established (15% of neonatal tumours). Genetic defects are highly likely in neonatal tumours and include those with a high risk of malignancy (e.g., retinoblastoma), but also genetically determined syndromes with an increased risk of malignancy and complex genetic rearrangements. Tumours are mostly genetically related at a cellular level and factors influencing cellular

  20. Watermelon seedling growth and mortality as affected by Anasa tristis (Heteroptera: Coreidae).

    PubMed

    Edelson, J V; Duthie, J; Roberts, W

    2002-06-01

    Adult squash bugs, Anasa tristis (De Geer), were confined on seedling watermelon plants at densities of zero, one, two, and four per plant. Squash bugs were allowed to feed on the plants until plants died or reached 30 cm in height. Number of leaves and length of plant vine were recorded at 2- or 3-d intervals. Seedling foliage, stems, and roots were harvested and dried after plants reached 30 cm in height. Growth of seedlings was regressed on number of squash bugs and results indicated that an increasing density of squash bugs feeding on seedlings resulted in a significant reduction in plant growth. Additionally, increased density of squash bugs resulted in reduced weight of foliage and root dry biomass. Seedling mortality increased as the density of squash bugs increased. PMID:12076005

  1. Infrared warming affects intrarow soil carbon dioxide efflux during early vegetative growth of spring wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Global warming will likely affect carbon cycles in agricultural soils. Our objective was to deploy infrared (IR) warming to characterize the effect of global warming on soil temperature (Ts), volumetric soil-water content ('s), and intrarow soil CO2 efflux (Fs) of an open-field spring wheat (Triticu...

  2. Nutrient availability affects pigment production but not growth in lichens of biological soil crusts

    USGS Publications Warehouse

    Bowker, M.A.; Koch, G.W.; Belnap, J.; Johnson, N.C.

    2008-01-01

    Recent research suggests that micronutrients such as Mn may limit growth of slow-growing biological soil crusts (BSCs) in some of the drylands of the world. These soil surface communities contribute strongly to arid ecosystem function and are easily degraded, creating a need for new restoration tools. The possibility that Mn fertilization could be used as a restoration tool for BSCs has not been tested previously. We used microcosms in a controlled greenhouse setting to investigate the hypothesis that Mn may limit photosynthesis and consequently growth in Collema tenax, a dominant N-fixing lichen found in BSCs worldwide. We found no evidence to support our hypothesis; furthermore, addition of other nutrients (primarily P, K, and Zn) had a suppressive effect on gross photosynthesis (P = 0.05). We also monitored the growth and physiological status of our microcosms and found that other nutrients increased the production of scytonemin, an important sunscreen pigment, but only when not added with Mn (P = 0.01). A structural equation model indicated that this effect was independent of any photosynthesis-related variable. We propose two alternative hypotheses to account for this pattern: (1) Mn suppresses processes needed to produce scytonemin; and (2) Mn is required to suppress scytonemin production at low light, when it is an unnecessary photosynthate sink. Although Mn fertilization does not appear likely to increase photosynthesis or growth of Collema, it could have a role in survivorship during environmentally stressful periods due to modification of scytonemin production. Thus, Mn enrichment should be studied further for its potential to facilitate BSC rehabilitation. ?? 2008 Elsevier Ltd.

  3. Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease

    PubMed Central

    Contreras, Miguel Agustin; Ries, William Louis; Shanmugarajan, Srinivasan; Arboleda, Gonzalo; Singh, Inderjit; Singh, Avtar Kaur

    2010-01-01

    Krabbe disease is an inherited lysosomal disorder in which galactosylsphingosine (psychosine) accumulates mainly in the central nervous system. To gain insight into the possible mechanism(s) that may be participating in the inhibition of the postnatal somatic growth described in the animal model of this disease (twitcher mouse, twi), we studied their femora. This study reports that twi femora are smaller than of those of wild type (wt), and present with abnormality of marrow cellularity, bone deposition (osteoblastic function), and osteoclastic activity. Furthermore, lipidomic analysis indicates altered sphingolipid homeostasis, but without significant changes in the levels of sphingolipid-derived intermediates of cell death (ceramide) or the levels of the osteoclast-osteoblast coupling factor (sphingosine-1-phosphate). However, there was significant accumulation of psychosine in the femora of adult twi animals as compared to wt, without induction of tumor necrosis factor-alpha or interleukin-6. Analysis of insulin-like growth factor-1 (IGF-1) plasma levels, a liver secreted hormone known to play a role in bone growth, indicated a drastic reduction in twi animals when compared to wt. To identify the cause of the decrease, we examined the IGF-1 mRNA expression and protein levels in the liver. The results indicated a significant reduction of IGF-1 mRNA as well as protein levels in the liver from twi as compared to wt littermates. Our data suggest that a combination of endogenous (psychosine) and endocrine (IGF-1) factors play a role in the inhibition of postnatal bone growth in twi mice; and further suggest that derangements of liver function may be contributing, at least in part, to this alteration. PMID:20441793

  4. Phosphorylation of Measles Virus Nucleoprotein Affects Viral Growth by Changing Gene Expression and Genomic RNA Stability

    PubMed Central

    Sugai, Akihiro; Sato, Hiroki; Yoneda, Misako

    2013-01-01

    The measles virus (MV) nucleoprotein associates with the viral RNA genome to form the N-RNA complex, providing a template for viral RNA synthesis. In our previous study, major phosphorylation sites of the nucleoprotein were identified as S479 and S510. However, the functions of these phosphorylation sites have not been clarified. In this study, we rescued recombinant MVs (rMVs) whose phosphorylation sites in the nucleoprotein were substituted (rMV-S479A, rMV-S510A, and rMV-S479A/S510A) by reverse genetics and used them in subsequent analyses. In a one-step growth experiment, rMVs showed rapid growth kinetics compared with wild-type MV, although the peak titer of the wild-type MV was the same as or slightly higher than those of the rMVs. Time course analysis of nucleoprotein accumulation also revealed that viral gene expression of rMV was enhanced during the early phase of infection. These findings suggest that nucleoprotein phosphorylation has an important role in controlling viral growth rate through the regulation of viral gene expression. Conversely, multistep growth curves revealed that nucleoprotein-phosphorylation intensity inversely correlated with viral titer at the plateau phase. Additionally, the phosphorylation intensity of the wild-type nucleoprotein in infected cells was significantly reduced through nucleoprotein-phosphoprotein binding. Excessive nucleoprotein-phosphorylation resulted in lower stability against RNase and faster turnover of viral genomic RNA. These results suggest that nucleoprotein-phosphorylation is also involved in viral genomic RNA stability. PMID:23966404

  5. Longitudinal measures of circulating leptin and ghrelin concentrations are associated with the growth of young Peruvian children but are not affected by zinc supplementation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Leptin, ghrelin and insulin are hormonal regulators of energy balance and, therefore, may be related to growth during infancy. Zinc is essential for growth and may have an effect on growth through these hormones. Objectives: To determine whether supplemental zinc affects plasma leptin an...

  6. Insights into Embryo Defenses of the Invasive Apple Snail Pomacea canaliculata: Egg Mass Ingestion Affects Rat Intestine Morphology and Growth

    PubMed Central

    Gimeno, Eduardo J.; Heras, Horacio

    2014-01-01

    Background The spread of the invasive snail Pomacea canaliculata is expanding the rat lungworm disease beyond its native range. Their toxic eggs have virtually no predators and unusual defenses including a neurotoxic lectin and a proteinase inhibitor, presumably advertised by a warning coloration. We explored the effect of egg perivitellin fluid (PVF) ingestion on the rat small intestine morphology and physiology. Methodology/Principal Findings Through a combination of biochemical, histochemical, histopathological, scanning electron microscopy, cell culture and feeding experiments, we analyzed intestinal morphology, growth rate, hemaglutinating activity, cytotoxicity and cell proliferation after oral administration of PVF to rats. PVF adversely affects small intestine metabolism and morphology and consequently the standard growth rate, presumably by lectin-like proteins, as suggested by PVF hemaglutinating activity and its cytotoxic effect on Caco-2 cell culture. Short-term effects of ingested PVF were studied in growing rats. PVF-supplemented diet induced the appearance of shorter and wider villi as well as fused villi. This was associated with changes in glycoconjugate expression, increased cell proliferation at crypt base, and hypertrophic mucosal growth. This resulted in a decreased absorptive surface after 3 days of treatment and a diminished rat growth rate that reverted to normal after the fourth day of treatment. Longer exposure to PVF induced a time-dependent lengthening of the small intestine while switching to a control diet restored intestine length and morphology after 4 days. Conclusions/Significance Ingestion of PVF rapidly limits the ability of potential predators to absorb nutrients by inducing large, reversible changes in intestinal morphology and growth rate. The occurrence of toxins that affect intestinal morphology and absorption is a strategy against predation not recognized among animals before. Remarkably, this defense is rather similar to

  7. Carboxyl-modified single-walled carbon nanotubes negatively affect bacterial growth and denitrification activity

    NASA Astrophysics Data System (ADS)

    Zheng, Xiong; Su, Yinglong; Chen, Yinguang; Wan, Rui; Li, Mu; Wei, Yuanyuan; Huang, Haining

    2014-07-01

    Single-walled carbon nanotubes (SWNTs) have been used in a wide range of fields, and the surface modification via carboxyl functionalization can further improve their physicochemical properties. However, whether carboxyl-modified SWNT poses potential risks to microbial denitrification after its release into the environment remains unknown. Here we present the possible effects of carboxyl-modified SWNT on the growth and denitrification activity of Paracoccus denitrificans (a model denitrifying bacterium). It was found that carboxyl-modified SWNT were present both outside and inside the bacteria, and thus induced bacterial growth inhibition at the concentrations of 10 and 50 mg/L. After 24 h of exposure, the final nitrate concentration in the presence of 50 mg/L carboxyl-modified SWNT was 21-fold higher than that in its absence, indicating that nitrate reduction was substantially suppressed by carboxyl-modified SWNT. The transcriptional profiling revealed that carboxyl-modified SWNT led to the transcriptional activation of the genes encoding ribonucleotide reductase in response to DNA damage and also decreased the gene expressions involved in glucose metabolism and energy production, which was an important reason for bacterial growth inhibition. Moreover, carboxyl-modified SWNT caused the significant down-regulation and lower activity of nitrate reductase, which was consistent with the decreased efficiency of nitrate reduction.

  8. Carboxyl-modified single-walled carbon nanotubes negatively affect bacterial growth and denitrification activity

    PubMed Central

    Zheng, Xiong; Su, Yinglong; Chen, Yinguang; Wan, Rui; Li, Mu; Wei, Yuanyuan; Huang, Haining

    2014-01-01

    Single-walled carbon nanotubes (SWNTs) have been used in a wide range of fields, and the surface modification via carboxyl functionalization can further improve their physicochemical properties. However, whether carboxyl-modified SWNT poses potential risks to microbial denitrification after its release into the environment remains unknown. Here we present the possible effects of carboxyl-modified SWNT on the growth and denitrification activity of Paracoccus denitrificans (a model denitrifying bacterium). It was found that carboxyl-modified SWNT were present both outside and inside the bacteria, and thus induced bacterial growth inhibition at the concentrations of 10 and 50 mg/L. After 24 h of exposure, the final nitrate concentration in the presence of 50 mg/L carboxyl-modified SWNT was 21-fold higher than that in its absence, indicating that nitrate reduction was substantially suppressed by carboxyl-modified SWNT. The transcriptional profiling revealed that carboxyl-modified SWNT led to the transcriptional activation of the genes encoding ribonucleotide reductase in response to DNA damage and also decreased the gene expressions involved in glucose metabolism and energy production, which was an important reason for bacterial growth inhibition. Moreover, carboxyl-modified SWNT caused the significant down-regulation and lower activity of nitrate reductase, which was consistent with the decreased efficiency of nitrate reduction. PMID:25008009

  9. How microRNA172 affects fruit growth in different species is dependent on fruit type.

    PubMed

    Yao, Jia-Long; Tomes, Sumathi; Xu, Juan; Gleave, Andrew P

    2016-04-01

    microRNA172 (miR172) expression has been shown to have a positive effect on Arabidopsis fruit (siliques) growth. In contrast, over-expression of miR172 has a negative influence on fruit growth in apple, resulting in a dramatic reduction in fruit size. This negative influence is supported by the results of analyzing a transposable element (TE) insertional allele of a MIR172 gene that has reduced expression of the miRNA and is associated with an increase in fruit size. Arabidopsis siliques are a dry fruit derived from ovary tissues, whereas apple is a fleshy pome fruit derived mostly from hypanthium tissues. A model has been developed to explain the contrasting impact of miR172 expression in these two plant species based on the differences in their fruit structure. Transgenic apple plants with extremely high levels of miR172 overexpression produced flowers consisting of carpel tissues only, which failed to produce fruit. By comparison, in tomato, a fleshy berry fruit derived from the ovary, high level over-expression of the same miR172 resulted in carpel-only flowers which developed into parthenocarpic fruit. These results further indicate that the influence of miR172 on fruit growth in different plant species depends on its fruit type. PMID:26926448

  10. Regulation of Expansin Gene Expression Affects Growth and Development in Transgenic Rice Plants

    PubMed Central

    Choi, Dongsu; Lee, Yi; Cho, Hyung-Taeg; Kende, Hans

    2003-01-01

    To investigate the in vivo functions of expansins, we generated transgenic rice plants that express sense and antisense constructs of the expansin gene OsEXP4. In adult plants with constitutive OsEXP4 expression, 12% of overexpressors were taller and 88% were shorter than the average control plants, and most overexpressors developed at least two additional leaves. Antisense plants were shorter and flowered earlier than the average control plants. In transgenic plants with inducible OsEXP4 expression, we observed a close correlation between OsEXP4 protein levels and seedling growth. Coleoptile and mesocotyl length increased by up to 31 and 97%, respectively, in overexpressors, whereas in antisense seedlings, they decreased by up to 28 and 43%, respectively. The change in seedling growth resulted from corresponding changes in cell size, which in turn appeared to be a function of altered cell wall extensibility. Our results support the hypothesis that expansins are involved in enhancing growth by mediating cell wall loosening. PMID:12782731

  11. Nanoplastic affects growth of S. obliquus and reproduction of D. magna.

    PubMed

    Besseling, Ellen; Wang, Bo; Lürling, Miquel; Koelmans, Albert A

    2014-10-21

    The amount of nano- and microplastic in the aquatic environment rises due to the industrial production of plastic and the degradation of plastic into smaller particles. Concerns have been raised about their incorporation into food webs. Little is known about the fate and effects of nanoplastic, especially for the freshwater environment. In this study, effects of nano-polystyrene (nano-PS) on the growth and photosynthesis of the green alga Scenedesmus obliquus and the growth, mortality, neonate production, and malformations of the zooplankter Daphnia magna were assessed. Nano-PS reduced population growth and reduced chlorophyll concentrations in the algae. Exposed Daphnia showed a reduced body size and severe alterations in reproduction. Numbers and body size of neonates were lower, while the number of neonate malformations among neonates rose to 68% of the individuals. These effects of nano-PS were observed between 0.22 and 103 mg nano-PS/L. Malformations occurred from 30 mg of nano-PS/L onward. Such plastic concentrations are much higher than presently reported for marine waters as well as freshwater, but may eventually occur in sediment pore waters. As far as we know, these results are the first to show that direct life history shifts in algae and Daphnia populations may occur as a result of exposure to nanoplastic. PMID:25268330

  12. The Garlic Allelochemical Diallyl Disulfide Affects Tomato Root Growth by Influencing Cell Division, Phytohormone Balance and Expansin Gene Expression

    PubMed Central

    Cheng, Fang; Cheng, Zhihui; Meng, Huanwen; Tang, Xiangwei

    2016-01-01

    Diallyl disulfide (DADS) is a volatile organosulfur compound derived from garlic (Allium sativum L.), and it is known as an allelochemical responsible for the strong allelopathic potential of garlic. The anticancer properties of DADS have been studied in experimental animals and various types of cancer cells, but to date, little is known about its mode of action as an allelochemical at the cytological level. The current research presents further studies on the effects of DADS on tomato (Solanum lycopersicum L.) seed germination, root growth, mitotic index, and cell size in root meristem, as well as the phytohormone levels and expression profile of auxin biosynthesis genes (FZYs), auxin transport genes (SlPINs), and expansin genes (EXPs) in tomato root. The results showed a biphasic, dose-dependent effect on tomato seed germination and root growth under different DADS concentrations. Lower concentrations (0.01–0.62 mM) of DADS significantly promoted root growth, whereas higher levels (6.20–20.67 mM) showed inhibitory effects. Cytological observations showed that the cell length of root meristem was increased and that the mitotic activity of meristematic cells in seedling root tips was enhanced at lower concentrations of DADS. In contrast, DADS at higher concentrations inhibited root growth by affecting both the length and division activity of meristematic cells. However, the cell width of the root meristem was not affected. Additionally, DADS increased the IAA and ZR contents of seedling roots in a dose-dependent manner. The influence on IAA content may be mediated by the up-regulation of FZYs and PINs. Further investigation into the underlying mechanism revealed that the expression levels of tomato EXPs were significantly affected by DADS. The expression levels of EXPB2 and beta-expansin precursor were increased after 3 d, and those of EXP1, EXPB3 and EXLB1 were increased after 5 d of DADS treatment (0.41 mM). This result suggests that tomato root growth may be

  13. The Garlic Allelochemical Diallyl Disulfide Affects Tomato Root Growth by Influencing Cell Division, Phytohormone Balance and Expansin Gene Expression.

    PubMed

    Cheng, Fang; Cheng, Zhihui; Meng, Huanwen; Tang, Xiangwei

    2016-01-01

    Diallyl disulfide (DADS) is a volatile organosulfur compound derived from garlic (Allium sativum L.), and it is known as an allelochemical responsible for the strong allelopathic potential of garlic. The anticancer properties of DADS have been studied in experimental animals and various types of cancer cells, but to date, little is known about its mode of action as an allelochemical at the cytological level. The current research presents further studies on the effects of DADS on tomato (Solanum lycopersicum L.) seed germination, root growth, mitotic index, and cell size in root meristem, as well as the phytohormone levels and expression profile of auxin biosynthesis genes (FZYs), auxin transport genes (SlPINs), and expansin genes (EXPs) in tomato root. The results showed a biphasic, dose-dependent effect on tomato seed germination and root growth under different DADS concentrations. Lower concentrations (0.01-0.62 mM) of DADS significantly promoted root growth, whereas higher levels (6.20-20.67 mM) showed inhibitory effects. Cytological observations showed that the cell length of root meristem was increased and that the mitotic activity of meristematic cells in seedling root tips was enhanced at lower concentrations of DADS. In contrast, DADS at higher concentrations inhibited root growth by affecting both the length and division activity of meristematic cells. However, the cell width of the root meristem was not affected. Additionally, DADS increased the IAA and ZR contents of seedling roots in a dose-dependent manner. The influence on IAA content may be mediated by the up-regulation of FZYs and PINs. Further investigation into the underlying mechanism revealed that the expression levels of tomato EXPs were significantly affected by DADS. The expression levels of EXPB2 and beta-expansin precursor were increased after 3 d, and those of EXP1, EXPB3 and EXLB1 were increased after 5 d of DADS treatment (0.41 mM). This result suggests that tomato root growth may be

  14. Metabolic consequences of methotrexate therapy in tumour-bearing rats.

    PubMed

    Rofe, A M; Bourgeois, C S; Washington, J M; Philcox, J C; Coyle, P

    1994-02-01

    The metabolic response of the tumour-bearing host to methotrexate (MTX) therapy was investigated with particular attention to effects resulting from MTX-induced anorexia. Biochemical changes in female Dark Agouti rats bearing mammary adenocarcinomas and treated with MTX (0.5 mg/kg, 2 i.m. injections, 24 h apart) were compared with untreated (CON) tumour-bearing rats, and tumour-bearing rats pair-fed (PF) to the MTX group. MTX treatment halted progression of the tumour (tumour 6% of bodyweight) while the tumour burden doubled in the CON and PF groups. A number of biochemical and haematological changes were specific to MTX treatment and did not result from decreased food intake. MTX treatment was associated with significantly decreased plasma calcium, bilirubin, alkaline phosphatase, aspartate aminotransferase and the total white cell count. Decreases in plasma albumin and total protein concentrations were observed in both MTX and PF rats. Other parameters commonly used to assess renal and liver function were not significantly affected by MTX. MTX reversed the hypoglycaemia, hyperketonaemia and hypertriglyceridaemia induced by tumour-bearing. In contrast, PF rats had an even more pronounced hypoglycaemia and hyperketonaemia than the CON rats. Measurement of glucose uptake in vivo with 2-deoxy[U-14C]-glucose showed that MTX treatment halved the glucose requirement of the tumour (8.2% of bodyweight compared to 12.2% in the control). It is concluded that the potentially adverse effects of MTX treatment on host metabolism are outweighed by the beneficial effects of a reduced metabolic demand resulting from inhibition of tumour progression. PMID:8157287

  15. Peptide receptor radionuclide therapy of neuroendocrine tumours.

    PubMed

    Brabander, Tessa; Teunissen, Jaap J M; Van Eijck, Casper H J; Franssen, Gaston J H; Feelders, Richard A; de Herder, Wouter W; Kwekkeboom, Dik J

    2016-01-01

    In the past decades, the number of neuroendocrine tumours that are detected is increasing. A relative new and promising therapy for patients with metastasised or inoperable disease is peptide receptor radionuclide therapy (PRRT). This therapy involves an infusion of somatostatin analogues linked to radionuclides like Yttrium-90 or Lutetium-177. Objective response rates are reported in 15-35%. Response rates may vary between type of tumour and radionuclide. Besides the objective response rate, overall survival and progression free survival increase significantly. Also, the quality of life improves as well. Serious side-affects are rare. PRRT is usually well tolerated, also in patients with extensive metastasised disease. Recent studies combined PRRT with other types of therapies. Unfortunately no randomised trials comparing these strategies are available. In the future, more research is needed to evaluate the best therapy combinations or sequence of therapies. PMID:26971847

  16. Mutational patterns in oncogenes and tumour suppressors.

    PubMed

    Baeissa, Hanadi M; Benstead-Hume, Graeme; Richardson, Christopher J; Pearl, Frances M G

    2016-06-15

    All cancers depend upon mutations in critical genes, which confer a selective advantage to the tumour cell. Knowledge of these mutations is crucial to understanding the biology of cancer initiation and progression, and to the development of targeted therapeutic strategies. The key to understanding the contribution of a disease-associated mutation to the development and progression of cancer, comes from an understanding of the consequences of that mutation on the function of the affected protein, and the impact on the pathways in which that protein is involved. In this paper we examine the mutation patterns observed in oncogenes and tumour suppressors, and discuss different approaches that have been developed to identify driver mutations within cancers that contribute to the disease progress. We also discuss the MOKCa database where we have developed an automatic pipeline that structurally and functionally annotates all proteins from the human proteome that are mutated in cancer. PMID:27284061

  17. Rice LGD1 containing RNA binding activity affects growth and development through alternative promoters.

    PubMed

    Thangasamy, Saminathan; Chen, Pei-Wei; Lai, Ming-Hsing; Chen, Jychian; Jauh, Guang-Yuh

    2012-07-01

    Tiller initiation and panicle development are important agronomical traits for grain production in Oryza sativa L. (rice), but their regulatory mechanisms are not yet fully understood. In this study, T-DNA mutant and RNAi transgenic approaches were used to functionally characterize a unique rice gene, LAGGING GROWTH AND DEVELOPMENT 1 (LGD1). The lgd1 mutant showed slow growth, reduced tiller number and plant height, altered panicle architecture and reduced grain yield. The fewer unelongated internodes and cells in lgd1 led to respective reductions in tiller number and to semi-dwarfism. Several independent LGD1-RNAi lines exhibited defective phenotypes similar to those observed in lgd1. Interestingly, LGD1 encodes multiple transcripts with different transcription start sites (TSSs), which were validated by RNA ligase-mediated rapid amplification of 5' and 3' cDNA ends (RLM-RACE). Additionally, GUS assays and a luciferase promoter assay confirmed the promoter activities of LGD1.1 and LGD1.5. LGD1 encoding a von Willebrand factor type A (vWA) domain containing protein is a single gene in rice that is seemingly specific to grasses. GFP-tagged LGD1 isoforms were predominantly detected in the nucleus, and weakly in the cytoplasm. In vitro northwestern analysis showed the RNA-binding activity of the recombinant C-terminal LGD1 protein. Our results demonstrated that LGD1 pleiotropically regulated rice vegetative growth and development through both the distinct spatiotemporal expression patterns of its multiple transcripts and RNA binding activity. Hence, the study of LGD1 will strengthen our understanding of the molecular basis of the multiple transcripts, and their corresponding polypeptides with RNA binding activity, that regulate pleiotropic effects in rice. PMID:22409537

  18. Honokiol affects melanoma cell growth by targeting the AMPK signaling pathway

    PubMed Central

    Kaushik, Gaurav; Kwatra, Deep; Subramaniam, Dharmalingam; Jensen, Roy A.; Anant, Shrikant; Mammen, Joshua M.V.

    2015-01-01

    Background Malignant melanoma is an aggressive form of skin cancer with limited effective therapeutic options. Melanoma research concentrates on maximizing the effect on cancer cells with minimal toxicity to normal cells. AMP-activated protein kinase (AMPK) is an important regulator of cellular energy homeostasis and has been shown to control tumor progression regulating the cell cycle, protein synthesis and cell growth and/or survival. Honokiol (HNK) is a biphenolic compound derived from Magnolia officianalis, a plant that has been used in traditional Chinese and Japanese medicine for the treatment of various pathological conditions. Recent studies have shown that HNK has antitumor activity with relatively low toxicity. In this study we demonstrated that the growth inhibitory effects of HNK on melanoma and melanoma cancer stem cells (CSCs) was mediated through the activation of AMPK and hence AMPK signaling in melanoma cells. Methods We determined the effects of HNK treatment on various melanoma cell lines. HNK induced cell growth inhibitory effects were determined using hexosaminidase assay. Protein expression studies were done by immunoblotting. Primary spheroid assay was used to assess stemness by growing single suspension cells in ultra-low attachment plates. Results HNK is highly effective in inhibiting melanoma cells by attenuating AKT/mammalian target of rapamycin and AMPK signaling. HNK showed significant inhibition of the spheroid forming capacity of melanoma cells and, hence, stemness. HNK significantly decreased the number and size of melanospheres in a dose dependent manner. Western blot analyses showed enhanced phosphorylation of AMPK in melanoma cells. Furthermore, HNK decreased the cellular ATP pool in a dose-dependent manner with maximum effects observed at 48 h. Conclusion The results suggest that HNK can target melanoma cells and mark them for cell death through AMPK signaling. Further studies are warranted for developing HNK as an effective

  19. Mutations in NADH:ubiquinone oxidoreductase of Escherichia coli affect growth on mixed amino acids.

    PubMed Central

    Prüss, B M; Nelms, J M; Park, C; Wolfe, A J

    1994-01-01

    We isolated and characterized mutants defective in nuo, encoding NADH dehydrogenase I, the multisubunit complex homologous to eucaryotic mitochondrial complex I. By Southern hybridization and/or sequence analysis, we characterized three distinct mutations: a polar insertion designated nuoG::Tn10-1, a nonpolar insertion designated nuoF::Km-1, and a large deletion designated delta(nuoFGHIJKL)-1. Cells carrying any of these three mutations exhibited identical phenotypes. Each mutant exhibited reduced NADH oxidase activity, grew poorly on minimal salts medium containing acetate as the sole carbon source, and failed to produce the inner, L-aspartate chemotactic band on tryptone swarm plates. During exponential growth in tryptone broth, nuo mutants grew as rapidly as wild-type cells and excreted similar amounts of acetate into the medium. As they began the transition to stationary phase, in contrast to wild-type cells, the mutant cells abruptly slowed their growth and continued to excrete acetate. The growth defect was entirely suppressed by L-serine or D-pyruvate, partially suppressed by alpha-ketoglutarate or acetate, and not suppressed by L-aspartate or L-glutamate. We extended these studies, analyzing the sequential consumption of amino acids by both wild-type and nuo mutant cells growing in tryptone broth. During the lag and exponential phases, both wild-type and mutant cells consumed, in order, L-serine and L-aspartate. As they began the transition to stationary phase, both cell types consumed L-tryptophan. Whereas wild-type cells then consumed L-glutamate, glycine, L-threonine, and L-alanine, mutant cells utilized these amino acids poorly. We propose that cells defective for NADH dehydrogenase I exhibit all these phenotypes, because large NADH/NAD+ ratios inhibit certain tricarboxylic acid cycle enzymes, e.g., citrate synthase and malate dehydrogenase. Images PMID:8157582

  20. Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours

    PubMed Central

    Lunt, Sarah Jane; Kalliomaki, Tuula MK; Brown, Allison; Yang, Victor X; Milosevic, Michael; Hill, Richard P

    2008-01-01

    Background High tumour interstitial fluid pressure (IFP) has been adversely linked to poor drug uptake in patients, and to treatment response following radiotherapy in cervix cancer patients. In this study we measured IFP values in a selection of murine and xenograft models, spontaneously arising or transplanted either intramuscularly (i/m) or orthotopically and analysed their relationship to tumour vascularity and metastatic spread. Methods KHT-C murine fibrosarcoma, ME180 and SiHa human cervix carcinoma were grown either intramuscularly (i/m), sub-cutaneously (s/c) or orthotopically. Polyoma middle-T (MMTV-PyMT) transgenic spontaneous mammary tumours were studied either as spontaneous tumours or following orthotopic or i/m transplantation. IFP was measured in all tumours using the wick-in-needle method. Spontaneous metastasis formation in the lungs or lymph nodes was assessed in all models. An immunohistochemical analysis of tumour hypoxia, vascular density, lymphatic vascular density and proliferation was carried out in ME180 tumours grown both i/m and orthotopically. Blood flow was also assessed in the ME180 model using high-frequency micro-ultrasound functional imaging. Results Tumour IFP was heterogeneous in all the models irrespective of growth site: KHT-C i/m: 2–42 mmHg, s/c: 1–14 mmHg, ME180: i/m 5–68 mmHg, cervix 4–21 mmHg, SiHa: i/m 20–56 mmHg, cervix 2–26 mmHg, MMTV-PyMT: i/m: 13–45 mmHg, spontaneous 2–20 mmHg and transplanted 2–22 mmHg. Additionally, there was significant variation between individual tumours growing in the same mouse, and there was no correlation between donor and recipient tumour IFP values. Metastatic dissemination to the lungs or lymph nodes demonstrated no correlation with tumour IFP. Tumour hypoxia, proliferation, and lymphatic or blood vessel density also showed no relationship with tumour IFP. Speckle variance analysis of ultrasound images showed no differences in vascular perfusion between ME180 tumours grown

  1. Deiodinase Knockdown during Early Zebrafish Development Affects Growth, Development, Energy Metabolism, Motility and Phototransduction

    PubMed Central

    Bagci, Enise; Heijlen, Marjolein; Vergauwen, Lucia; Hagenaars, An; Houbrechts, Anne M.; Esguerra, Camila V.; Blust, Ronny; Darras, Veerle M.; Knapen, Dries

    2015-01-01

    Thyroid hormone (TH) balance is essential for vertebrate development. Deiodinase type 1 (D1) and type 2 (D2) increase and deiodinase type 3 (D3) decreases local intracellular levels of T3, the most important active TH. The role of deiodinase-mediated TH effects in early vertebrate development is only partially understood. Therefore, we investigated the role of deiodinases during early development of zebrafish until 96 hours post fertilization at the level of the transcriptome (microarray), biochemistry, morphology and physiology using morpholino (MO) knockdown. Knockdown of D1+D2 (D1D2MO) and knockdown of D3 (D3MO) both resulted in transcriptional regulation of energy metabolism and (muscle) development in abdomen and tail, together with reduced growth, impaired swim bladder inflation, reduced protein content and reduced motility. The reduced growth and impaired swim bladder inflation in D1D2MO could be due to lower levels of T3 which is known to drive growth and development. The pronounced upregulation of a large number of transcripts coding for key proteins in ATP-producing pathways in D1D2MO could reflect a compensatory response to a decreased metabolic rate, also typically linked to hypothyroidism. Compared to D1D2MO, the effects were more pronounced or more frequent in D3MO, in which hyperthyroidism is expected. More specifically, increased heart rate, delayed hatching and increased carbohydrate content were observed only in D3MO. An increase of the metabolic rate, a decrease of the metabolic efficiency and a stimulation of gluconeogenesis using amino acids as substrates may have been involved in the observed reduced protein content, growth and motility in D3MO larvae. Furthermore, expression of transcripts involved in purine metabolism coupled to vision was decreased in both knockdown conditions, suggesting that both may impair vision. This study provides new insights, not only into the role of deiodinases, but also into the importance of a correct TH balance

  2. Lichen physiological traits and growth forms affect communities of associated invertebrates.

    PubMed

    Bokhorst, Stef; Asplund, Johan; Kardol, Paul; Wardle, David A

    2015-09-01

    While there has been much interest in the relationships between traits of primary producers and composition of associated invertebrate consumer communities, our knowledge is largely based on studies from vascular plants, while other types of functionally important producers, such as lichens, have rarely been considered. To address how physiological traits of lichens drive community composition of invertebrates, we collected thalli from 27 lichen species from southern Norway and quantified the communities of associated springtails, mites, and nematodes. For each lichen species, we measured key physiological thallus traits and determined whether invertebrate communities were correlated with these traits. We also explored whether invertebrate communities differed among lichen groups, categorized according to nitrogen-fixing ability, growth form, and substratum. Lichen traits explained up to 39% of the variation in abundances of major invertebrate groups. For many invertebrate groups, abundance was positively correlated with lichen N and P concentrations, N:P ratio, and the percentage of water content on saturation (WC), but had few relationships with concentrations of carbon-based secondary compounds. Diversity and taxonomic richness of invertebrate groups were sometimes also correlated with lichen N and N:P ratios. Nitrogen-fixing lichens showed higher abundance and diversity of some invertebrate groups than did non-N-fixing lichens. However, this emerged in part because most N-fixing lichens have a foliose growth form that benefits invertebrates, through, improving the microclimate, independently of N concentration. Furthermore, invertebrate communities associated with terricolous lichens were determined more by their close proximity to the soil invertebrate pool than by lichen traits. Overall, our results reveal that differences between lichen species have a large impact on the invertebrate communities that live among the thalli. Different invertebrate groups show

  3. Medical treatment for gastro-entero-pancreatic neuroendocrine tumours

    PubMed Central

    Berardi, Rossana; Morgese, Francesca; Torniai, Mariangela; Savini, Agnese; Partelli, Stefano; Rinaldi, Silvia; Caramanti, Miriam; Ferrini, Consuelo; Falconi, Massimo; Cascinu, Stefano

    2016-01-01

    Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) represents a various family of rare tumours. Surgery is the first choice in GEP-NENs patients with localized disease whilst in the metastatic setting many other treatment options are available. Somatostatin analogues are indicated for symptoms control in functioning tumours. Furthermore they may be effective to inhibit tumour progression. GEP-NENs pathogenesis has been extensively studied in the last years therefore several driver mutations pathway genes have been identified as crucial factors in their tumourigenesis. GEP-NENs can over-express vascular endothelial growth factor (VEGF), basic-fibroblastic growth factor, transforming growth factor (TGF-α and -β), platelet derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1) and their receptors PDGF receptor, IGF-1 receptor, epidermal growth factor receptor, VEGF receptor, and c-kit (stem cell factor receptor) that can be considered as potential targets. The availability of new targeted agents, such as everolimus and sunitinib that are effective in advanced and metastatic pancreatic neuroendocrine tumours, has provided new treatment opportunities. Many trials combing new drugs are ongoing. PMID:27096034

  4. Molecular analyses of nuclear-cytoplasmic interactions affecting plant growth and yield. Final technical report

    SciTech Connect

    Newton, K.J.

    1998-11-01

    Mitochondria have a central role in the production of cellular energy. The biogenesis and functioning of mitochondria depends on the expression of both mitochondrial and nuclear genes. One approach to investigating the role of nuclear-mitochondrial cooperation in plant growth and development is to identify combinations of nuclear and mitochondrial genomes that result in altered but sublethal phenotypes. Plants that have certain maize nuclear genotypes in combination with cytoplasmic genomes from more distantly-related teosintes can exhibit incompatible phenotypes, such as reduced plant growth and yield and cytoplasmic male sterility, as well as altered mitochondrial gene expression. The characterization of these nuclear-cytoplasmic interactions was the focus of this grant. The authors were investigating the effects of two maize nuclear genes, RcmI and Mct, on mitochondrial function and gene expression. Plants with the teosinte cytoplasms and homozygous for the recessive rcm allele are small (miniature) and-slow-growing and the kernels are reduced in size. The authors mapped this locus to molecular markers on chromosome 7 and attempted to clone this locus by transposon tagging. The effects of the nuclear-cytoplasmic interaction on mitochondrial function and mitochondrial protein profiles were also studied.

  5. Drosophila Ten-m and Filamin Affect Motor Neuron Growth Cone Guidance

    PubMed Central

    Zheng, Lihua; Michelson, Yehudit; Freger, Vita; Avraham, Ziva; Venken, Koen J. T.; Bellen, Hugo J.; Justice, Monica J.; Wides, Ron

    2011-01-01

    The Drosophila Ten-m (also called Tenascin-major, or odd Oz (odz)) gene has been associated with a pair-rule phenotype. We identified and characterized new alleles of Drosophila Ten-m to establish that this gene is not responsible for segmentation defects but rather causes defects in motor neuron axon routing. In Ten-m mutants the inter-segmental nerve (ISN) often crosses segment boundaries and fasciculates with the ISN in the adjacent segment. Ten-m is expressed in the central nervous system and epidermal stripes during the stages when the growth cones of the neurons that form the ISN navigate to their targets. Over-expression of Ten-m in epidermal cells also leads to ISN misrouting. We also found that Filamin, an actin binding protein, physically interacts with the Ten-m protein. Mutations in cheerio, which encodes Filamin, cause defects in motor neuron axon routing like those of Ten-m. During embryonic development, the expression of Filamin and Ten-m partially overlap in ectodermal cells. These results suggest that Ten-m and Filamin in epidermal cells might together influence growth cone progression. PMID:21857973

  6. Phosphoribosyl pyrophosphate synthetase activity affects growth and riboflavin production in Ashbya gossypii

    PubMed Central

    Jiménez, Alberto; Santos, María A; Revuelta, José L

    2008-01-01

    Background Phosphoribosyl pyrophosphate (PRPP) is a central compound for cellular metabolism and may be considered as a link between carbon and nitrogen metabolism. PRPP is directly involved in the de novo and salvage biosynthesis of GTP, which is the immediate precursor of riboflavin. The industrial production of this vitamin using the fungus Ashbya gossypii is an important biotechnological process that is strongly influenced by substrate availability. Results Here we describe the characterization and manipulation of two genes of A. gossypii encoding PRPP synthetase (AGR371C and AGL080C). We show that the AGR371C and AGL080C gene products participate in PRPP synthesis and exhibit inhibition by ADP. We also observed a major contribution of AGL080C to total PRPP synthetase activity, which was confirmed by an evident growth defect of the Δagl080c strain. Moreover, we report the overexpression of wild-type and mutant deregulated isoforms of Agr371cp and Agl080cp that significantly enhanced the production of riboflavin in the engineered A. gossypii strains. Conclusion It is shown that alterations in PRPP synthetase activity have pleiotropic effects on the fungal growth pattern and that an increase in PRPP synthetase enzymatic activity can be used to enhance riboflavin production in A. gossypii. PMID:18782443

  7. Fertilizer residence time affects nitrogen uptake efficiency and growth of sweet corn.

    PubMed

    Zotarelli, L; Scholberg, J M; Dukes, M D; Muñoz-Carpena, R

    2008-01-01

    Understanding plant N uptake dynamics is critical for increasing fertilizer N uptake efficiency (FUE) and minimize the risk of N leaching. The objective of this research was to determine the effect of residence time of N fertilizer on N uptake and FUE of sweet corn. Plants were grown in 25 L columns during the fall and spring to mimic short-term N uptake dynamics. Nitrogen was applied either 1, 3, or 7 d before a weekly leaching event, using KNO3 solution (total of 393 kg N ha(-1)). Residence times (tR) were tR-1, tR-3, and tR-7 d before weekly removal of residual soil N. Plant N uptake was calculated by comparing weekly N recovery from planted with non-planted columns. During the fall, N uptake values at 70 d after emergence were 59, 73, and 126 kg N ha(-1). During the spring, corresponding values were 54, 108, and 159 kg N ha(-1). A linear response of plant growth and yield to the tR was observed under cooler conditions, whereas a quadratic response occurred under warmer conditions. There was correlation between root length density and yield. It is concluded that increasing N fertilizer residence time, which is indicative of better irrigation practices, enhanced overall sweet corn growth, yield, N uptake, and FUE, consequently reduced the risk of N being leached below the root zone before complete N uptake. PMID:18453447

  8. Feed and Feeding Regime Affect Growth Rate and Gonadosomatic Index of Adult Zebrafish (Danio Rerio)

    PubMed Central

    Law, Sheran Hiu Wan

    2013-01-01

    Abstract A 5-week study was conducted to evaluate commercially available Artemia, Ziegler zebrafish diet, and Calamac diet fed in five different feeding regimes on the growth and reproductive development of 7-month-old zebrafish. Zebrafish were fed to satiation three times daily during the normal work week and twice daily during the weekend and holidays. Zebrafish in dietary groups CCC (Calamac three times daily) and CCA (Calamac twice daily, Artemia once daily) had a significantly (p<0.05) greater weight gain and specific growth rate as compared to all other dietary groups. Male zebrafish in dietary group 5 had significantly larger gonadosomatic index (GSI) values than all other groups, while female zebrafish in dietary group CCC had significantly larger GSI values than all other groups. No differences in the fatty acid content of female gonads were detected. Zebrafish fed solely Artemia had the greatest weight loss and lowest GSI values. Preliminary evidence of protein sparing in zebrafish is reported. Collectively, this study sheds more light into the effects of the use of commercially available feeds and feeding regime on the rearing of zebrafish. PMID:23902461

  9. The Stress Corrosion Crack Growth Rate of Alloy 600 Heat Affected Zones Exposed to High Purity Water

    SciTech Connect

    George A. Young; Nathan Lewis

    2003-04-05

    Grain boundary chromium carbides improve the resistance of nickel based alloys to primary water stress corrosion cracking (PWSCC). However, in weld heat affected zones (HAZ's), thermal cycles from fusion welding can solutionize beneficial grain boundary carbides, produce locally high residual stresses and strains, and promote PWSCC. The present research investigates the crack growth rate of an A600 HAZ as a function of test temperature. The A600 HAZ was fabricated by building up a gas-tungsten-arc-weld deposit of EN82H filler metal onto a mill-annealed A600 plate. Fracture mechanics based, stress corrosion crack growth rate testing was performed in high purity water between 600 F and 680 F at an initial stress intensity factor of 40 ksi {radical}in and at a constant electrochemical potential. The HAZ samples exhibited significant SCC, entirely within the HAZ at all temperatures tested. While the HAZ samples showed the same temperature dependence for SCC as the base material (HAZ: 29.8 {+-} 11.2{sub 95%} kcal/mol vs A600 Base: 35.3 {+-} 2.58{sub 95%} kcal/mol), the crack growth rates were {approx} 30X faster than the A600 base material tested at the same conditions. The increased crack growth rates of the HAZ is attributed to fewer intergranular chromium rich carbides and to increased plastic strain in the HAZ as compared to the unaffected base material.

  10. CO2 and fertility affect growth and reproduction but not susceptibility to aphids in field grown Solanum ptycanthum

    SciTech Connect

    Long, T.M.

    1995-09-01

    In general, C3 annual plants respond positively in terms of growth, reproduction and biomass accrued when grown under elevated levels of atmospheric carbon dioxide. However, most studies documenting this response have been conducted in growth chambers where plants can be reared under conditions free form environmental stressors such as nutrient and water constraints, UV exposure and damage from pests. During the 1993 fieldseason, I grew 200 individuals of Solanum ptycanthum in an array of 10 outdoor, open-topped CO2 enclosures (5 @ 700 ppm CO2) at the University of Michigan Biological Station in Pellston, MI. Half of the plants were grown in a 50;50 mix of native C-horizon soil and topsoil (low fertility); the other half were grown in 100% topsoil (high-fertility). Plants were censused throughout the growing season for flower and fruit production, growth rate and degree of infestation of aphids. Fertility and CO2 both significantly affected production of flowers and fruits, but only fertility was significantly related to vegetative growth. Aphid infestation varied significantly among enclosures, but was not related to CO2 or fertility.

  11. Diagnostic accuracy of MRI to evaluate tumour response and residual tumour size after neoadjuvant chemotherapy in breast cancer patients

    PubMed Central

    Acea, Benigno; Soler, Rafaela; Iglesias, Ángela; Santiago, Paz; Mosquera, Joaquín; Calvo, Lourdes; Seoane-Pillado, Teresa; García, Alejandra

    2016-01-01

    Background The aim, of the study was to estimate the accuracy of magnetic resonance imaging (MRI) in assessing residual disease in breast cancer patients receiving neoadjuvant chemotherapy (NAC) and to identify the clinico-pathological factors that affect the diagnostic accuracy of breast MRI to determine residual tumour size following NAC. Patients and methods 91 breast cancer patients undergoing NAC (92 breast lesions) were included in the study. Breast MRI was performed at baseline and after completion of NAC. Treatment response was evaluated by MRI and histopathological examination to investigate the ability of MRI to predict tumour response. Residual tumour size was measured on post-treatment MRI and compared with pathology in 89 lesions. Clinicopathological factors were analyzed to compare MRI-pathologic size differences. Results The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for diagnosing invasive residual disease by using MRI were 75.00%, 78.57%, 88.89%, 57.89%, and 76.09% respectively. The Pearson’s correlation coefficient (r) between tumour sizes determined by MRI and pathology was r = 0.648 (p < 0.001). The size discrepancy was significantly lower in cancers with initial MRI size ≤ 5 cm (p = 0.050), in cancers with high tumour grade (p < 0.001), and in patients with hormonal receptor-negative cancer (p = 0.033). Conclusions MRI is an accurate tool for evaluating tumour response after NAC. The accuracy of MRI in estimating residual tumour size varies with the baseline MRI tumour size, the tumour grade and the hormonal receptor status. PMID:27069452

  12. Niche appropriation by Drosophila intestinal stem cell tumours.

    PubMed

    Patel, Parthive H; Dutta, Devanjali; Edgar, Bruce A

    2015-09-01

    Mutations that inhibit differentiation in stem cell lineages are a common early step in cancer development, but precisely how a loss of differentiation initiates tumorigenesis is unclear. We investigated Drosophila intestinal stem cell (ISC) tumours generated by suppressing Notch (N) signalling, which blocks differentiation. Notch-defective ISCs require stress-induced divisions for tumour initiation and an autocrine EGFR ligand, Spitz, during early tumour growth. On achieving a critical mass these tumours displace surrounding enterocytes, competing with them for basement membrane space and causing their detachment, extrusion and apoptosis. This loss of epithelial integrity induces JNK and Yki/YAP activity in enterocytes and, consequently, their expression of stress-dependent cytokines (Upd2, Upd3). These paracrine signals, normally used within the stem cell niche to trigger regeneration, propel tumour growth without the need for secondary mutations in growth signalling pathways. The appropriation of niche signalling by differentiation-defective stem cells may be a common mechanism of early tumorigenesis. PMID:26237646

  13. microRNA 21-mediated suppression of Sprouty1 by Pokemon affects liver cancer cell growth and proliferation.

    PubMed

    Jin, Xiu-Li; Sun, Qin-Sheng; Liu, Feng; Yang, Hong-Wei; Liu, Min; Liu, Hong-Xia; Xu, Wei; Jiang, Yu-Yang

    2013-07-01

    Transcriptional repressor Pokemon is a critical factor in embryogenesis, development, cell proliferation, differentiation, and oncogenesis, thus behaving as an oncogene. Oncomine database suggests a potential correlation between the expressions of Pokemon and Sprouty1. This study investigated the regulatory role of Pokemon in Sprouty1 expression and the effect on liver cancer cell growth and proliferation, revealing a novel miR-21-mediated regulatory circuit. In normal (HL-7702) and cancer (QGY-7703) liver cell lines, Sprouty1 expression is inversely correlated with Pokemon levels. Targeted expression or siRNA-mediated silencing showed that Pokemon is a repressor of Sprouty1 expression at both mRNA and protein levels, but Pokemon cannot affect the promoter activity of Sprouty1. Sprouty1 is a target of miR-21 and interestingly, we found that miR-21 is up-regulated by Pokemon in liver cancer cells. Luciferase reporter assays showed that Pokemon up-regulated miR-21 transcription in a dose-dependent manner, and ChIP assay exhibited a direct binding of Pokemon to the miR-21 promoter at -747 to -399 bp. Site-directed mutagenesis of the GC boxes at -684 to -679 bp and -652 to -647 bp of miR-21 promoter abolished the regulatory activity by Pokemon. Furthermore, we found that the modulation of Pokemon and miR-21 expression affected the growth and proliferation of liver cancer cells QGY-7703. In summary, our findings demonstrate that Pokemon suppresses Sprouty1 expression through a miR-21-mediated mechanism, affecting the growth and proliferation of liver cancer cells. This study recognized miR-21 and Sprouty1 as novel targets of the Pokemon regulatory network. PMID:23355454

  14. One very rare and one new tracheal tumour found by electron microscopy: glomus tumour and acinic cell tumour resembling carcinoid tumours by light microscopy.

    PubMed Central

    Heard, B E; Dewar, A; Firmin, R K; Lennox, S C

    1982-01-01

    Tracheal tumours were removed surgically from two patients and diagnosed as carcinoid tumours by routine light microscopy. At a later date, electron microscopy was performed on stored tumour tissue and no neurosecretory granules were found in either case. One showed features of a glomus tumour and the other of an acinic cell tumour. Only two glomus tumours appear to have been reported previously in the trachea, and no acinic cell tumours. Electron microscopy is thus sometimes of great assistance in diagnosing accurately unusual tumours of the lower respiratory tract. Images PMID:6281934

  15. Metabolic reprogramming of the tumour microenvironment.

    PubMed

    Xing, Yazhi; Zhao, Shimin; Zhou, Binhua P; Mi, Jun

    2015-10-01

    Tumour cells, stromal cells and the stroma comprise the tumour microenvironment. The metabolism of both tumour cells and several types of tumour stromal cells, such as cancer-associated fibroblasts and tumour-associated macrophages, is reprogrammed. Current studies have found that stromal cells promote tumour progression and metastasis, through not only the paracrine secretion of cytokines or chemokines, but also intermediate metabolites. Here, we summarize the latest insights into the mechanism of metabolic reprogramming in cancer cells, cancer-associated fibroblasts and tumour-associated macrophages, and their potential roles in tumour progression and metastasis. PMID:26255648

  16. Titanium dioxide nanoparticles affect the growth and microRNA expression of tobacco (Nicotiana tabacum).

    PubMed

    Frazier, Taylor P; Burklew, Caitlin E; Zhang, Baohong

    2014-03-01

    Titanium dioxide (TiO(2)) is one of the most widely used pigments in the world. Due to its heavy use in industry and daily life, such as food additives, cosmetics, pharmaceuticals, and paints, many residues are released into the environment and currently TiO(2) nanoparticles are considered an emerging environmental contaminant. Although several studies have shown the effect of TiO(2) nanoparticles on a wide range of organisms including bacteria, algae, plankton, fish, mice, and rats, little research has been performed on land plants. In this study, we investigated the effect of TiO(2) nanoparticles on the growth, development, and gene expression of tobacco, an important economic and agricultural crop in the southeastern USA as well as around the world. We found that TiO(2) nanoparticles significantly inhibited the germination rates, root lengths, and biomasses of tobacco seedlings after 3 weeks of exposure to 0.1, 1, 2.5, and 5 % TiO(2) nanoparticles and that overall growth and development of the tobacco seedlings significantly decreased as TiO(2) nanoparticle concentrations increased. Overall, tobacco roots were the most sensitive to TiO(2) nanoparticle exposure. Nano-TiO(2) also significantly influenced the expression profiles of microRNAs (miRNAs), a recently discovered class of small endogenous noncoding RNAs (∼20-22 nt) that are considered important gene regulators and have been shown to play an important role in plant development as well as plant tolerance to abiotic stresses such as drought, salinity, cold, and heavy metal. Low concentrations (0.1 and 1 %) of TiO(2) nanoparticles dramatically induced miRNA expression in tobacco seedlings with miR395 and miR399 exhibiting the greatest fold changes of 285-fold and 143-fold, respectively. The results of this study show that TiO(2) nanoparticles have a negative impact on tobacco growth and development and that miRNAs may play an important role in tobacco response to heavy metals/nanoparticles by regulating

  17. Growth Performance of Early Finishing Gilts as Affected by Different Net Energy Concentrations in Diets

    PubMed Central

    Lee, Gang Il; Kim, Kwang-Sik; Kim, Jong Hyuk; Kil, Dong Yong

    2015-01-01

    The objectives of the current experiment were to study the response of the growth performance of early finishing gilts to different net energy (NE) concentrations in diets, and to compare the NE values of diets between calculated NE values and measured NE values using French and Dutch CVB (Centraal Veevoederbureau; Central Bureau for Livestock Feeding) NE systems. In a metabolism trail, the NE concentrations in five diets used for the growth trial were determined based on digestible nutrient concentrations, digestible energy, and metabolizable energy using a replicated 5×5 Latin square design with 10 barrows (initial body weight [BW], 39.2±2.2 kg). In a growth trial, a total of 60 early finishing gilts (Landrace×Yorkshire; initial BW, 47.7±3.5 kg) were allotted to five dietary treatments of 8.0, 9.0, 10.0, 11.0, and 12.0 MJ NE/kg (calculated, as-is basis) with 12 replicate pens and one pig per pen in a 42-d feeding experiment. The NE and amino acid (AA) concentrations in all diets were calculated based on the values from NRC (2012). Ratios between standardized ileal digestible AA and NE concentrations in all diets were closely maintained. Pigs were allowed ad libitum access to feed and water. Results indicated that calculated NE concentrations in diets (i.e., five dietary treatments) were close to measured NE concentrations using French NE system in diets. The final BW was increased (linear and quadratic, p<0.05) with increasing NE concentrations in diets. Furthermore, average daily gain (ADG) was increased (linear and quadratic, p<0.01) with increasing NE concentrations in diets. There was a quadratic relationship (p<0.01) between average daily feed intake and NE concentrations in diets. Feed efficiency (G:F) was also increased (linear, p<0.01) as NE concentrations in diets were increased. The NE intake per BW gain (kcal NE/kg of BWG) was increased (linear, p<0.01) with increasing NE concentrations in diets that were predicted from both French and Dutch CVB NE

  18. Father's death does not affect growth and maturation but hinders reproduction: evidence from adolescent girls in post-war Estonia.

    PubMed

    Hõrak, Peeter; Valge, Markus

    2015-12-01

    The popular concept of predictive-adaptive responses poses that girls growing up without a father present in the family mature and start reproduction earlier because the father's absence is a cue for environmental harshness and uncertainty that favours switching to a precocious life-history strategy. Most studies supporting this concept have been performed in situations where the father's absence is caused by divorce or abandonment. Using a dataset of Estonian adolescent girls who had lost their fathers over the period of World War II, we show that father's death did not affect the rate of pubertal maturation (assessed on the basis of development of breasts and axillary hair) or growth. Father's death did not affect the age of first birth but, contrary to predictions, reduced lifetime reproductive success. Our findings thus do not support the concept of predictive-adaptive responses and suggest that alternative explanations for covariation between fatherlessness and early maturation are required. PMID:26673934

  19. Does chronic nitrogen deposition during biomass growth affect atmospheric emissions from biomass burning?

    NASA Astrophysics Data System (ADS)

    Giordano, Michael R.; Chong, Joey; Weise, David R.; Asa-Awuku, Akua A.

    2016-03-01

    Chronic nitrogen deposition has measureable impacts on soil and plant health. We investigate burning emissions from biomass grown in areas of high and low NO x deposition. Gas and aerosol-phase emissions were measured as a function of photochemical aging in an environmental chamber at UC-Riverside. Though aerosol chemical speciation was not available, results indicate a systemic compositional difference between biomass grown in high and low deposition areas. Aerosol emissions from biomass grown in areas of high NO x deposition exhibit a lower volatility than biomass grown in a low deposition area. Furthermore, fuel elemental analysis, NO x emission rates, and aerosol particle number distributions differed significantly between the two sites. Despite the limited scale of fuels explored, there is strong evidence that the atmospheric emissions community must pay attention to the regional air quality of biomass fuels growth areas.

  20. The asymmetrical growth of otoliths in fish is affected by hypergravity.

    PubMed

    Anken, R H; Kappel, T; Rahmann, H

    1999-08-01

    Size and asymmetry (size difference between the left and the right side) of inner ear otoliths of larval cichlid fish were determined after a long-term stay at moderate hypergravity conditions (3g; centrifuge), in the course of which the animals completed their ontogenetic development from hatch to freely swimming. Both the normal morphogenetic development as well as the timely onset and gain of performance of the swimming behaviour was not impaired by the experimental conditions. However, both utricular and saccular otoliths (lapilli and sagittae, respectively) were significantly smaller after hyper-g exposure as compared to parallely raised 1g control specimens. The asymmetry of sagittae was significantly increased in the experimental animals, whereas the respective asymmetry con-cerning lapil