Sample records for blocks tumour growth

  1. Stochastic Gompertz model of tumour cell growth. (United States)

    Lo, C F


    In this communication, based upon the deterministic Gompertz law of cell growth, a stochastic model in tumour growth is proposed. This model takes account of both cell fission and mortality too. The corresponding density function of the size of the tumour cells obeys a functional Fokker--Planck equation which can be solved analytically. It is found that the density function exhibits an interesting "multi-peak" structure generated by cell fission as time evolves. Within this framework the action of therapy is also examined by simply incorporating a therapy term into the deterministic cell growth term.

  2. Coupled modeling of tumour angiogenesis, tumour growth,and blood perfusion

    Institute of Scientific and Technical Information of China (English)


    This paper proposes a more realistic mathematical simulation method to investigate the dynamic process of tumour angio-genesis by fully coupling the vessel growth,tumour growth and associated blood perfusion.The tumour growth and angiogenesis are coupled by the chemical microenvironment and the cell-matrix interaction.The haemodynamic calculation is carried out on the new vasculature,and an estimation of vessel collapse is made according to the wall shear stress criterion.The results are consistent with phy...

  3. 3D Multiscale Modelling of Angiogenesis and Vascular Tumour Growth

    KAUST Repository

    Perfahl, H.


    We present a three-dimensional, multiscale model of vascular tumour growth, which couples nutrient/growth factor transport, blood flow, angiogenesis, vascular remodelling, movement of and interactions between normal and tumour cells, and nutrient-dependent cell cycle dynamics within each cell. We present computational simulations which show how a vascular network may evolve and interact with tumour and healthy cells. We also demonstrate how our model may be combined with experimental data, to predict the spatio-temporal evolution of a vascular tumour.

  4. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways

    Directory of Open Access Journals (Sweden)

    Ferrari Stefano


    Full Text Available Abstract Background Osteosarcoma (OS is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory. Results We investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006 in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice. Conclusion In conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both in vitro and in vivo, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.

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

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    Hiroaki Haga


    Full Text Available 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.

  6. Plasmid-based Stat3 siRNA delivered by hydroxyapatite nanoparticles suppresses mouse prostate tumour growth in vivo

    Institute of Scientific and Technical Information of China (English)

    Zuo-Wen Liang; Ling Zhang; Bao-Xue Yang; Bao-Feng Guo; Yang Li; Xiao-Jie Li; Xin Li; Li-Ting Zhao; Ii-Fang Gao; Hao Yu; Xue-Jian Zhao


    DNA vector-based Stat3-specific RNA interference (si-Stat3) blocks Stat3 signalling and inhibits prostate tumour growth. However, the antitumour activity depends on the efficient delivery of si-Stat3. The effects on the growth of mouse prostate cancer cells of si-Stat3 delivered by hydroxyapatite were determined in this study. RM-1 tumour blocks were transplanted into C57BL/6 mice. CaCl2-modif ied hydroxyapatite carrying si-Stat3 plasmids were injected into tumours, and tumour growth and histology were determined. The expression levels of Stat3, pTyr-Stat3, Bcl-2, Bax, Caspase3, VEGF and cyclin Dl were measured by western blot analysis. Amounts of apoptosis in cancer cells were analysed with immunohistochemistry and the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) assay. The results showed that hydroxyapatite-delivered si-Stat3 significantly suppressed tumour growth up to 74% (P<0.01). Stat3 expression was dramatically downregulated in the tumours. The immunohistochemistry and TUNEL results showed that si-Stet3-induced apoptosis (up to 42%, P<0.01). The Stat3 downstream genes Bcl-2, VEGFand cyclin Dl were also strongly downregulated in the tumour tissues that also displayed significant increases in Bax expression and Caspase3 activity. These results suggest that hydroxyapatite can be used for the in vivo delivery of plasmid-based siRNAs into tumours.

  7. Multiphase modelling of vascular tumour growth in two spatial dimensions

    KAUST Repository

    Hubbard, M.E.


    In this paper we present a continuum mathematical model of vascular tumour growth which is based on a multiphase framework in which the tissue is decomposed into four distinct phases and the principles of conservation of mass and momentum are applied to the normal/healthy cells, tumour cells, blood vessels and extracellular material. The inclusion of a diffusible nutrient, supplied by the blood vessels, allows the vasculature to have a nonlocal influence on the other phases. Two-dimensional computational simulations are carried out on unstructured, triangular meshes to allow a natural treatment of irregular geometries, and the tumour boundary is captured as a diffuse interface on this mesh, thereby obviating the need to explicitly track the (potentially highly irregular and ill-defined) tumour boundary. A hybrid finite volume/finite element algorithm is used to discretise the continuum model: the application of a conservative, upwind, finite volume scheme to the hyperbolic mass balance equations and a finite element scheme with a stable element pair to the generalised Stokes equations derived from momentum balance, leads to a robust algorithm which does not use any form of artificial stabilisation. The use of a matrix-free Newton iteration with a finite element scheme for the nutrient reaction-diffusion equations allows full nonlinearity in the source terms of the mathematical model.Numerical simulations reveal that this four-phase model reproduces the characteristic pattern of tumour growth in which a necrotic core forms behind an expanding rim of well-vascularised proliferating tumour cells. The simulations consistently predict linear tumour growth rates. The dependence of both the speed with which the tumour grows and the irregularity of the invading tumour front on the model parameters is investigated. © 2012 Elsevier Ltd.

  8. Giant growth-hormone secreting pituitary tumour with etracranial extension

    Energy Technology Data Exchange (ETDEWEB)

    Ip Taipang; Chan Fuluk; Kung Annie Waichee; Lam Karen Siuling [Univ. of Hong Kong, Queen Mary Hospital (Hong Kong). Depts. of Medicine and Diagnostic Radiology


    A 19 year old female patient with typical features of acromegaly was found to have an extensive pituitary tumour with suprasellar, lateral and inferior extensions. Magnetic resonance imaging (MRI) also showed a portion of the tumour extending from the right cavernous sinus through the foramen ovale to become extracranial. Serum growth hormone (GH) was 52.6 mU/L basally and remained elevated after oral glucose, confirming the diagnosis of acromegaly. Treatment with the long-acting somatostatin analogue, octreotide, for 6 months led to a 30% reduction in tumour volume of the intracranial portion but no effect on the extracranial and sphenoidal extensions. She was subsequently treated with trans-sphenoidal surgery followed by external irradiation. The possibility of perineural spread of the tumour was considered. 9 refs., 1 tab., 1 fig.

  9. Platelet-activating factor receptor (PAF-R-dependent pathways control tumour growth and tumour response to chemotherapy

    Directory of Open Access Journals (Sweden)

    Rohde Ciro BS


    Full Text Available Abstract Background Phagocytosis of apoptotic cells by macrophages induces a suppressor phenotype. Previous data from our group suggested that this occurs via Platelet-activating factor receptor (PAF-R-mediated pathways. In the present study, we investigated the impact of apoptotic cell inoculation or induction by a chemotherapeutic agent (dacarbazine, DTIC on tumour growth, microenvironmental parameters and survival, and the effect of treatment with a PAF-R antagonist (WEB2170. These studies were performed in murine tumours: Ehrlich Ascitis Tumour (EAT and B16F10 melanoma. Methods Tumour growth was assessed by direct counting of EAT cells in the ascitis or by measuring the volume of the solid tumour. Parameters of the tumour microenvironment, such as the frequency of cells expressing cyclo-oxygenase-2 (COX-2, caspase-3 and galectin-3, and microvascular density, were determined by immunohistochemistry. Levels of vascular endothelium growth factor (VEGF and prostaglandin E2 (PGE2 were determined by ELISA, and levels of nitric oxide (NO by Griess reaction. PAF-R expression was analysed by immunohistochemistry and flow cytometry. Results Inoculation of apoptotic cells before EAT implantation stimulated tumour growth. This effect was reversed by in vivo pre-treatment with WEB2170. This treatment also reduced tumour growth and modified the microenvironment by reducing PGE2, VEGF and NO production. In B16F10 melanoma, WEB2170 alone or in association with DTIC significantly reduced tumour volume. Survival of the tumour-bearing mice was not affected by WEB2170 treatment but was significantly improved by the combination of DTIC with WEB2170. Tumour microenvironment elements were among the targets of the combination therapy since the relative frequency of COX-2 and galectin-3 positive cells and the microvascular density within the tumour mass were significantly reduced by treatment with WEB2170 or DTIC alone or in combination. Antibodies to PAF-R stained

  10. A dynamic model for tumour growth and metastasis formation. (United States)

    Haustein, Volker; Schumacher, Udo


    A simple and fast computational model to describe the dynamics of tumour growth and metastasis formation is presented. The model is based on the calculation of successive generations of tumour cells and enables one to describe biologically important entities like tumour volume, time point of 1st metastatic growth or number of metastatic colonies at a given time. The model entirely relies on the chronology of these successive events of the metastatic cascade. The simulation calculations were performed for two embedded growth models to describe the Gompertzian like growth behaviour of tumours. The initial training of the models was carried out using an analytical solution for the size distribution of metastases of a hepatocellular carcinoma. We then show the applicability of our models to clinical data from the Munich Cancer Registry. Growth and dissemination characteristics of metastatic cells originating from cells in the primary breast cancer can be modelled thus showing its ability to perform systematic analyses relevant for clinical breast cancer research and treatment. In particular, our calculations show that generally metastases formation has already been initiated before the primary can be detected clinically.

  11. Ambit processes; with applications to turbulence and tumour growth

    DEFF Research Database (Denmark)

    Barndorff-Nielsen, Ole Eiler; Schmiegel, Jürgen

    The concept of ambit processes is outlined. Such stochastic processes are of interest in spatio-temporal modelling, and they play a central role in recent studies of velocity fields in turbulence and of the growth of cancer tumours. These studies are reviewed, and some open problems are outlined....

  12. 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).


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


    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 t...

  13. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues (United States)

    Zanganeh, Saeid; Hutter, Gregor; Spitler, Ryan; Lenkov, Olga; Mahmoudi, Morteza; Shaw, Aubie; Pajarinen, Jukka Sakari; Nejadnik, Hossein; Goodman, Stuart; Moseley, Michael; Coussens, Lisa Marie; Daldrup-Link, Heike Elisabeth


    Until now, the Food and Drug Administration (FDA)-approved iron supplement ferumoxytol and other iron oxide nanoparticles have been used for treating iron deficiency, as contrast agents for magnetic resonance imaging and as drug carriers. Here, we show an intrinsic therapeutic effect of ferumoxytol on the growth of early mammary cancers, and lung cancer metastases in liver and lungs. In vitro, adenocarcinoma cells co-incubated with ferumoxytol and macrophages showed increased caspase-3 activity. Macrophages exposed to ferumoxytol displayed increased mRNA associated with pro-inflammatory Th1-type responses. In vivo, ferumoxytol significantly inhibited growth of subcutaneous adenocarcinomas in mice. In addition, intravenous ferumoxytol treatment before intravenous tumour cell challenge prevented development of liver metastasis. Fluorescence-activated cell sorting (FACS) and histopathology studies showed that the observed tumour growth inhibition was accompanied by increased presence of pro-inflammatory M1 macrophages in the tumour tissues. Our results suggest that ferumoxytol could be applied 'off label' to protect the liver from metastatic seeds and potentiate macrophage-modulating cancer immunotherapies.

  14. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. (United States)

    Marusyk, Andriy; Tabassum, Doris P; Altrock, Philipp M; Almendro, Vanessa; Michor, Franziska; Polyak, Kornelia


    Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumours. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumour phenotypes and the competitive expansion of individual clones. We found that tumour growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumour by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumour collapse. We developed a mathematical modelling framework to identify the rules underlying the generation of intra-tumour clonal heterogeneity. We found that non-cell-autonomous driving of tumour growth, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits.

  15. Renal space-occupying solid growth of uncertain tumour status in metastasising tumour of the testicles

    Energy Technology Data Exchange (ETDEWEB)

    Engelhard, K.; Sarmiento-Garcia, G.; Worlicek, H.


    On the basis of a particular case of 'atypical' hypernephroma the main differential diagnosis of solid renal masses are described with reference to the basis disease: testicle tumour causing metastasis. The problems of determining the dignity of the disease by methods of sonography, pyelogram and CT are pointed out as well as the differences between those characteristics of the said tumour revealed by X-ray diagnosis and the known characteristics of substantial kidney deformations as described in medical literature.

  16. Human recombinant erythropoietin (rEpo) has no effect on tumour growth or angiogenesis. (United States)

    Hardee, M E; Kirkpatrick, J P; Shan, S; Snyder, S A; Vujaskovic, Z; Rabbani, Z N; Dewhirst, M W; Blackwell, K L


    Tumour hypoxia has been shown to increase mutation rate, angiogenesis, and metastatic potential, and decrease response to conventional therapeutics. Improved tumour oxygenation should translate into increased treatment response. Exogenous recombinant erythropoietin (rEpo) has been recently shown to increase tumour oxygenation in a mammary carcinoma model. The mechanism of this action is not yet understood completely. The presence of Epo and its receptor (EpoR) have been demonstrated on several normal and neoplastic tissues, including blood vessels and various solid tumours. In addition, rEpo has been shown in two recent prospective, randomized clinical trials to negatively impact treatment outcome. In this study, we attempt to characterize the direct effects of rEpo on tumour growth and angiogenesis in two separate rodent carcinomas. The effect of rEpo on R3230 rat mammary adenocarcinomas, CT-26 mouse colon carcinomas, HCT-116 human colon carcinomas, and FaDu human head and neck tumours, all of which express EpoR, was examined. There were no differences in tumour growth or proliferation (measured by Ki-67) between placebo-treated and rEpo-treated tumours. In the mammary window chamber, vascular length density (VLD) measurements in serial images of both placebo-treated and Epo-treated rats revealed no difference in angiogenesis between the Epo-treated tumours and placebo-treated tumours at any time point. These experiments are important because they suggest that the recent clinical detriment seen with the use of Epo is not due to its tumour growth effects or angiogenesis. These studies also suggest that further preclinical studies need to examine rEpo's direct tumour effects in efforts to improve the therapeutic benefits of Epo in solid tumour patients.

  17. Effects of Cross-Correlation Colour Noises on Tumour Growth Process

    Institute of Scientific and Technical Information of China (English)

    WANG Xian-Ju; ZENG Chang-Chun; DENG Xiao-Yuan; LIU Song-Hao; LIU Liang-Gang


    @@ We present a tumour cell growth process model including a multiplicative coloured noise and an additive coloured noise correlated. How the noise cross-correlation intensity λ and correlation time - can affect the steady state properties of tumour cell growth model are discussed by solving an approximative Fokker-Planck equation. It is found that the increase of noise correlation time т- can cause the tumour cell number increasing, but the increase of multiplicative noise intensity can cause the tumour cell number extinction. We also find that the increase of cross-correlation intensity λ in the case of 0 <λ< 1 can cause the tumour cell number extinction, whereas increase of cross-correlation intensity λ in the case of λ< 0 can cause the tumour cell number increasing.

  18. Tuberous sclerosis--A model for tumour growth. (United States)

    Dodd, Kayleigh M; Dunlop, Elaine A


    Tuberous sclerosis complex (TSC) is a rare genetic disorder where patients develop benign tumours in several organ systems. Central to TSC pathology is hyper-activation of the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, which is a key controller of cell growth. As a result, TSC model systems are a valuable tool for examining mTORC1-driven cellular processes. The immunosuppressant, rapamycin, is a specific inhibitor of mTORC1 and has shown promise as a therapeutic agent in TSC as well as in malignancy. This review will focus on the cellular processes controlled by mTORC1 and how TSC-deficient cell lines and mouse models have broadened our understanding of the mTORC1 signalling network. It will also discuss how our knowledge of TSC signalling can help us understand sporadic conditions where mTORC1 activity is implicated in disease onset or progression, and the possibility of using rapamycin to treat sporadic disease.

  19. Oscillatory dynamics in a model of vascular tumour growth - implications for chemotherapy

    Directory of Open Access Journals (Sweden)

    Maini PK


    Full Text Available Abstract Background Investigations of solid tumours suggest that vessel occlusion may occur when increased pressure from the tumour mass is exerted on the vessel walls. Since immature vessels are frequently found in tumours and may be particularly sensitive, such occlusion may impair tumour blood flow and have a negative impact on therapeutic outcome. In order to study the effects that occlusion may have on tumour growth patterns and therapeutic response, in this paper we develop and investigate a continuum model of vascular tumour growth. Results By analysing a spatially uniform submodel, we identify regions of parameter space in which the combination of tumour cell proliferation and vessel occlusion give rise to sustained temporal oscillations in the tumour cell population and in the vessel density. Alternatively, if the vessels are assumed to be less prone to collapse, stable steady state solutions are observed. When spatial effects are considered, the pattern of tumour invasion depends on the dynamics of the spatially uniform submodel. If the submodel predicts a stable steady state, then steady travelling waves are observed in the full model, and the system evolves to the same stable steady state behind the invading front. When the submodel yields oscillatory behaviour, the full model produces periodic travelling waves. The stability of the waves (which can be predicted by approximating the system as one of λ-ω type dictates whether the waves develop into regular or irregular spatio-temporal oscillations. Simulations of chemotherapy reveal that treatment outcome depends crucially on the underlying tumour growth dynamics. In particular, if the dynamics are oscillatory, then therapeutic efficacy is difficult to assess since the fluctuations in the size of the tumour cell population are enhanced, compared to untreated controls. Conclusions We have developed a mathematical model of vascular tumour growth formulated as a system of partial

  20. Targeting of Interferon Gamma to Stromal Fibroblasts Using a PDGF Receptor Recognizing Carrier Reduces Tumour Growth in Vivo

    NARCIS (Netherlands)

    Prakash, J.; Bansal, R.; Tomar, T.; Ostman, A.; Poelstra, K.


    Background: Stromal fibroblasts are the key cell types in tumour stroma, that support angiogenesis, tumour cell proliferation and metastasis. Therefore, inhibition of stromal fibroblasts activity might inhibit tumour growth. Interferon gamma (IFNγ) is a potent cytokine and has been used for the trea

  1. The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice.

    NARCIS (Netherlands)

    Rennel, E.; Waine, E.; Guan, H.; Schuler, Y.; Leenders, W.P.J.; Woolard, J.; Sugiono, M.; Gillatt, D.; Kleinerman, E.; Bates, D.; Harper, S.


    Vascular endothelial growth factor-A is widely regarded as the principal stimulator of angiogenesis required for tumour growth. VEGF is generated as multiple isoforms of two families, the pro-angiogenic family generated by proximal splice site selection in the terminal exon, termed VEGFxxx, and the

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

    Energy Technology Data Exchange (ETDEWEB)

    McAneney, H [School of Mathematics and Physics, Queen' s University Belfast, Belfast (United Kingdom); O' Rourke, S F C [School of Mathematics and Physics, Queen' s University Belfast, Belfast (United Kingdom)


    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 {alpha}/{beta} ratio, where {alpha} and {beta} 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

  3. Investigation of various growth mechanisms of solid tumour growth within the linear-quadratic model for radiotherapy (United States)

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


    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

  4. Perfluorocarbon nanoparticles enhance reactive oxygen levels and tumour growth inhibition in photodynamic therapy. (United States)

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


    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.

  5. A Stochastic and State Space Model for Tumour Growth and Applications

    Directory of Open Access Journals (Sweden)

    Wai-Yuan Tan


    Full Text Available We develop a state space model documenting Gompertz behaviour of tumour growth. The state space model consists of two sub-models: a stochastic system model that is an extension of the deterministic model proposed by Gyllenberg and Webb (1991, and an observation model that is a statistical model based on data for the total number of tumour cells over time. In the stochastic system model we derive through stochastic equations the probability distributions of the numbers of different types of tumour cells. Combining with the statistic model, we use these distribution results to develop a generalized Bayesian method and a Gibbs sampling procedure to estimate the unknown parameters and to predict the state variables (number of tumour cells. We apply these models and methods to real data and to computer simulated data to illustrate the usefulness of the models, the methods, and the procedures.

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

    Directory of Open Access Journals (Sweden)

    Antje M. Richter


    Full Text Available 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

  7. Tumour necrosis factor (TNF)-blocking agents in juvenile psoriatic arthritis: are they effective?

    NARCIS (Netherlands)

    Otten, M.H.; Prince, F.H.; Cate, R. ten; Rossum, M.A. van; Twilt, M.; Hoppenreijs, E.P.A.H.; Koopman-Keemink, Y.; Oranje, A.P.; Waard-van der Spek, F.B. de; Gorter, S.L.; Armbrust, W.; Dolman, K.M.; Wulffraat, N.M.; Suijlekom-Smit, L.W. van


    OBJECTIVES: To evaluate the effectiveness of tumour necrosis factor (TNF) blockers in juvenile psoriatic arthritis (JPsA). METHODS: The study was a prospective ongoing multicentre, observational study of all Dutch juvenile idiopathic arthritis (JIA) patients using biologicals. The response of arthri

  8. Tumour necrosis factor (TNF)-blocking agents in juvenile psoriatic arthritis: are they effective?

    NARCIS (Netherlands)

    M.H. Otten; F.H.M. Prince; R. ten Cate; M.A.J. van Rossum; M. Twilt; E.P.A.H. Hoppenreijs; Y. Koopman-Keemink; A.P. Oranje; F.B. de Waard-van de Spek; S.L. Gorter; W. Armbrust; K.M. Dolman; N.M. Wulffraat; L.W.A. van Suijlekom-Smit


    Objectives To evaluate the effectiveness of tumour necrosis factor (TNF) blockers in juvenile psoriatic arthritis (JPsA). Methods The study was a prospective ongoing multicentre, observational study of all Dutch juvenile idiopathic arthritis (JIA) patients using biologicals. The response of arthriti

  9. Tumour necrosis factor (TNF)-blocking agents in juvenile psoriatic arthritis : are they effective?

    NARCIS (Netherlands)

    Otten, Marieke H; Prince, Femke H M; Ten Cate, Rebecca; van Rossum, Marion A J; Twilt, Marinka; Hoppenreijs, Esther P A H; Koopman-Keemink, Yvonne; Oranje, Arnold P; de Waard-van der Spek, Flora B; Gorter, Simone L; Armbrust, Wineke; Dolman, Koert M; Wulffraat, Nico M; van Suijlekom-Smit, Lisette W A


    OBJECTIVES: To evaluate the effectiveness of tumour necrosis factor (TNF) blockers in juvenile psoriatic arthritis (JPsA). METHODS: The study was a prospective ongoing multicentre, observational study of all Dutch juvenile idiopathic arthritis (JIA) patients using biologicals. The response of arthri

  10. A cellular automaton model examining the effects of oxygen, hydrogen ions and lactate on early tumour growth. (United States)

    Al-Husari, Maymona; Murdoch, Craig; Webb, Steven D


    Some tumours are known to exhibit an extracellular pH that is more acidic than the intracellular, creating a 'reversed pH gradient' across the cell membrane and this has been shown to affect their invasive and metastatic potential. Tumour hypoxia also plays an important role in tumour development and has been directly linked to both tumour morphology and aggressiveness. In this paper, we present a hybrid mathematical model of intracellular pH regulation that examines the effect of oxygen and pH on tumour growth and morphology. In particular, we investigate the impact of pH regulatory mechanisms on the cellular pH gradient and tumour morphology. Analysis of the model shows that: low activity of the Na+/H+ exchanger or a high rate of anaerobic glycolysis can give rise to a "fingering" tumour morphology; and a high activity of the lactate/H+ symporter can result in a reversed transmembrane pH gradient across a large portion of the tumour mass. Also, the reversed pH gradient is spatially heterogeneous within the tumour, with a normal pH gradient observed within an intermediate growth layer within the spheroid. We also include a fractal dimension analysis of the simulated tumour contours, in which we compare the fractal dimensions of the simulated tumour surfaces with those found experimentally via photomicrographs.

  11. Interleukin-10 promotes B16-melanoma growth by inhibition of macrophage functions and induction of tumour and vascular cell proliferation (United States)

    García-Hernández, M L; Hernández-Pando, R; Gariglio, P; Berumen, J


    The aim of this study was to investigate the mechanisms by which interleukin-10 (IL-10) induces tumour growth in a mouse-melanoma model. A B16-melanoma cell line (B16-0) was transfected with IL-10 cDNA and three clones that secreted high (B16-10), medium and low amounts of IL-10 were selected. Cell proliferation and IL-10 production were compared in vitro, and tumour growth, percentages of necrotic areas, tumour cells positive for proliferating cell nuclear antigen (PCNA), IL-10 receptor (IL-10R) and major histocompatibility complex type I (MHC-I) and II (MHC-II), as well as infiltration of macrophages, CD4+ and CD8+ lymphocytes and blood vessels were compared in vivo among IL-10-transfected and non-transfected tumours. Proliferation and tumour growth were greater for IL-10-transfected than for non-transfected cells (P < 0·001), and correlated with IL-10 concentration (r ≥ 0·79, P < 0·006). Percentages of tumour cells positive for PCNA and IL-10R were 4·4- and 16·7-fold higher, respectively, in B16-10 than in B16-0 tumours (P < 0·001). Macrophage distribution changed from a diffuse pattern in non-transfected (6·4 ± 1·7%) to a peripheral pattern in IL-10-transfected (3·8 ± 1·7%) tumours. The percentage of CD4+ lymphocytes was 7·6 times higher in B16-10 than in B16-0 tumours (P = 0·002). The expression of MHC-I molecules was present in all B16-0 tumour cells and completely negative in B16–10 tumour cells. In B16-0 tumours, 89 ± 4% of the whole tumour area was necrotic, whereas tumours produced by B16-10 cells showed only 4·3 ± 6% of necrotic areas. IL-10-transfected tumours had 17-fold more blood vessels than non-transfected tumours (61·8 ± 8% versus 3·5 ± 1·7% blood vessels/tumour; P < 0·001). All the effects induced by IL-10 were prevented in mice treated with a neutralizing anti-IL-10 monoclonal antibody. These data indicate that IL-10 could induce tumour growth in this B16-melanoma model by stimulation of tumour-cell proliferation

  12. Complement-mediated tumour growth: implications for cancer nanotechnology and nanomedicines

    DEFF Research Database (Denmark)

    Moghimi, S. M.; Andresen, Thomas Lars


    The recent unexpected observation that complement activation helps turnout growth and progression has an important bearing on the future development of cancer nanomedicines for site-specific tumour targeting as these entities are capable of triggering complement. These issues are discussed...... and suggestions are provided for future design and development of safer and effective cancer nanomedicines....

  13. Three Dimensional Simulation Method in Early Process of Division and Growth for Tumour Cells

    Institute of Scientific and Technical Information of China (English)

    XIA Zhi-qiu; ZHAO Ting-ting


    The process of division, growth and death for tumour cell mass in the early is simulated. An integrated GUI is provided for users to set the value of each parameters, which are cell growth rates, cell mass division rates, cell mass death rates, simulate type, maximum running time, polarity and cell colour. It can display the growth process of each cell on result GUI. Also, it can display the values of each parameters for observing and analysing in current life cycle on result GUI, which are cell mass division times, cell mass death rate, cell mass division rate and cell mass growth rate. In the process of simulation, The cell growth rate is described by the approach to combine the exponential model with the linear model. In addition, a linked list data structure to store the tumour cells is used by the cellular automata for a reference to determine the position of each cell. It sets up two linked list to store the cells, one of them save the new small division cells and the other one save the big cell. That can make the painting process of cells on result GUI clearer and more organized. At last, the polarity of tumour growth is described for determining the growth direction of cells.

  14. A generalization of Gompertz law compatible with the Gyllenberg-Webb theory for tumour growth. (United States)

    d'Onofrio, Alberto; Fasano, Antonio; Monechi, Bernardo


    We present a new extension of Gompertz law for tumour growth and anti-tumour therapy. After discussing its qualitative and analytical properties, we show, in the spirit of [16], that, like the standard Gompertz model, it is fully compatible with the two-population model of Gyllenberg and Webb, formulated in [14] in order to provide a theoretical basis to Gompertz law. Compatibility with the model proposed in [17] is also investigated. Comparisons with some experimental data confirm the practical applicability of the model. Numerical simulations about the method performance are presented.

  15. Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced mitochondrial mutagenesis in inflammatory arthritis

    LENUS (Irish Health Repository)

    Biniecka, Monika


    Abstract Introduction To examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress. Methods Eighteen inflammatory arthritis patients underwent synovial tissue oxygen (tpO2) measurements and clinical assessment of disease activity (DAS28-CRP) at baseline (T0) and three months (T3) after starting biologic therapy. Synovial tissue lipid peroxidation (4-HNE), T and B cell specific markers and synovial vascular endothelial growth factor (VEGF) were quantified by immunohistochemistry. Synovial levels of random mitochondrial DNA (mtDNA) mutations were assessed using Random Mutation Capture (RMC) assay. Results 4-HNE levels pre\\/post anti TNF-α therapy were inversely correlated with in vivo tpO2 (P < 0.008; r = -0.60). Biologic therapy responders showed a significantly reduced 4-HNE expression (P < 0.05). High 4-HNE expression correlated with high DAS28-CRP (P = 0.02; r = 0.53), tender joint count for 28 joints (TJC-28) (P = 0.03; r = 0.49), swollen joint count for 28 joints (SJC-28) (P = 0.03; r = 0.50) and visual analogue scale (VAS) (P = 0.04; r = 0.48). Strong positive association was found between the number of 4-HNE positive cells and CD4+ cells (P = 0.04; r = 0.60), CD8+ cells (P = 0.001; r = 0.70), CD20+ cells (P = 0.04; r = 0.68), CD68+ cells (P = 0.04; r = 0.47) and synovial VEGF expression (P = 0.01; r = 063). In patients whose in vivo tpO2 levels improved post treatment, significant reduction in mtDNA mutations and DAS28-CRP was observed (P < 0.05). In contrast in those patients whose tpO2 levels remained the same or reduced at T3, no significant changes for mtDNA mutations and DAS28-CRP were found. Conclusions High levels of synovial oxidative stress and mitochondrial mutation burden are strongly associated with low in vivo oxygen tension and synovial inflammation. Furthermore these significant mitochondrial genome alterations are rescued following successful anti TNF

  16. Tumour growth environment modulates Chk1 signalling pathways and Chk1 inhibitor sensitivity (United States)

    Massey, Andrew J.


    Clinical development of Chk1 inhibitors is currently focussed on evaluating activity as monotherapy and as potentiators of chemotherapy. To aid translation of pre-clinical studies, we sought to understand the effects of the tumour growth environment on Chk1 signalling and sensitivity to small molecule Chk1 inhibition. Spheroid culture altered Chk1 signalling to a more xenograft like state but decreased sensitivity to Chk1 inhibition. Growth in low serum did not alter DDR signalling but increased the sensitivity of A2058 and U2OS tumour cells to Chk1 inhibition. An analysis of the expression levels of replication associated proteins identified a correlation between Cdc6 and pChk1 (S296) as well as total Chk1 in xenograft derived samples and between Cdc6 and total Chk1 in anchorage-dependent growth derived protein samples. No apparent correlation between Chk1 or Cdc6 expression and sensitivity to Chk1 inhibition in vitro was observed. A database analysis revealed upregulation of CDC6 mRNA expression in tumour compared to normal tissue and a correlation between CDC6 and CHEK1 mRNA expression in human cancers. We suggest that Cdc6 overexpression in human tumours requires a concomitant increase in Chk1 to counterbalance the deleterious effects of origin hyperactivation-induced DNA damage. PMID:27775084

  17. A study of tumour growth based on stoichiometric principles: a continuous model and its discrete analogue. (United States)

    Saleem, M; Agrawal, Tanuja; Anees, Afzal


    In this paper, we consider a continuous mathematically tractable model and its discrete analogue for the tumour growth. The model formulation is based on stoichiometric principles considering tumour-immune cell interactions in potassium (K (+))-limited environment. Our both continuous and discrete models illustrate 'cancer immunoediting' as a dynamic process having all three phases namely elimination, equilibrium and escape. The stoichiometric principles introduced into the model allow us to study its dynamics with the variation in the total potassium in the surrounding of the tumour region. It is found that an increase in the total potassium may help the patient fight the disease for a longer period of time. This result seems to be in line with the protective role of the potassium against the risk of pancreatic cancer as has been reported by Bravi et al. [Dietary intake of selected micronutrients and risk of pancreatic cancer: An Italian case-control study, Ann. Oncol. 22 (2011), pp. 202-206].

  18. All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice. (United States)

    Tabata, C; Tabata, R; Hirayama, N; Yasumitsu, A; Yamada, S; Murakami, A; Iida, S; Tamura, K; Terada, T; Kuribayashi, K; Fukuoka, K; Nakano, T


    Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour of mesothelial origin associated with asbestos exposure. Because MPM has limited response to conventional chemotherapy and radiotherapy, the prognosis is very poor. Several researchers have reported that cytokines such as interleukin (IL)-6 play an important role in the growth of MPM. Previously, it was reported that all-trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-beta1 in experiments using lung fibroblasts. We investigated whether ATRA had an inhibitory effect on the cell growth of MPM, the origin of which was mesenchymal cells similar to lung fibroblasts, using a subcutaneous xenograft mouse model. We estimated the tumour growth and performed quantitative measurements of IL-6, TGF-beta1 and platelet-derived growth factor (PDGF) receptor (PDGFR)-beta mRNA levels both of cultured MPM cells and cells grown in mice with or without the administration of ATRA. ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-beta1, TGF-beta1 receptors and PDGFR-beta, and 2) TGF-beta1-dependent proliferation and PDGF-BB-dependent migration of MPM cells. These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM.

  19. Immunity against the mouse mammary tumour virus : immunologic events during tumour growth and studies on vaccination in mice

    NARCIS (Netherlands)

    P.C. Creemers (Paula)


    textabstractDevelopment of mouse mammary tumours is a complex phenomenon, to which environmental factors, genetic background and the presence of an oncovirus contribute. The mammary tumour virus (MTV) of the mouse, first discovered by Bittner (1936), is a so-called B-type particle (Bernhard, 1958) a

  20. Bayesian Calibration, Validation and Uncertainty Quantification for Predictive Modelling of Tumour Growth: A Tutorial. (United States)

    Collis, Joe; Connor, Anthony J; Paczkowski, Marcin; Kannan, Pavitra; Pitt-Francis, Joe; Byrne, Helen M; Hubbard, Matthew E


    In this work, we present a pedagogical tumour growth example, in which we apply calibration and validation techniques to an uncertain, Gompertzian model of tumour spheroid growth. The key contribution of this article is the discussion and application of these methods (that are not commonly employed in the field of cancer modelling) in the context of a simple model, whose deterministic analogue is widely known within the community. In the course of the example, we calibrate the model against experimental data that are subject to measurement errors, and then validate the resulting uncertain model predictions. We then analyse the sensitivity of the model predictions to the underlying measurement model. Finally, we propose an elementary learning approach for tuning a threshold parameter in the validation procedure in order to maximize predictive accuracy of our validated model.

  1. Hypoxia optimises tumour growth by controlling nutrient import and acidic metabolite export. (United States)

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


    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.

  2. The effect of PLC-γ2 inhibitors on the growth of human tumour cells. (United States)

    Feng, Linda; Reynisdóttir, Inga; Reynisson, Jóhannes


    The phosphoinositide specific-phospholipase C-γ (PLC-γ1 and 2) enzymes are plausible anticancer targets implicated in cell motility important to invasion and dissemination of tumour cells. A host of known PLC-γ2 inhibitors were tested against the NCI60 panel of human tumour cell lines as well as their commercially available structural derivatives. A class of thieno[2,3-b]pyridines showed excellent growth arrest with derivative 3 giving GI(50) = 58 nM for the melanoma MDA-MB-435 cell line. The PLC-γ2 is uniquely expressed in haematopoietic cells and the leukaemia tumour cell lines were growth restricted on average GI(50) = 275 nM by derivative 3 indicating a specific interaction with this isoform. Furthermore, a moderate growth inhibition was found for compound classes of indoles and 1H-pyrazoles. It is likely that the active compounds do not only inhibit the PLC-γ2 isoform but other PLCs as well due to their conserved binding site. The compounds tested were identified by applying the tools of chemoinformatics, which supports the use of in silico methods in drug design.

  3. Isthmin is a novel secreted angiogenesis inhibitor that inhibits tumour growth in mice. (United States)

    Xiang, Wei; Ke, Zhiyuan; Zhang, Yong; Cheng, Grace Ho-Yuet; Irwan, Ishak Darryl; Sulochana, K N; Potturi, Padma; Wang, Zhengyuan; Yang, He; Wang, Jingyu; Zhuo, Lang; Kini, R Manjunatha; Ge, Ruowen


    Anti-angiogenesis represents a promising therapeutic strategy for the treatment of various malignancies. Isthmin (ISM) is a gene highly expressed in the isthmus of the midbrain-hindbrain organizer in Xenopus with no known functions. It encodes a secreted 60 kD protein containing a thrombospondin type 1 repeat domain in the central region and an adhesion-associated domain in MUC4 and other proteins (AMOP) domain at the C-terminal. In this work, we demonstrate that ISM is a novel angiogenesis inhibitor. Recombinant mouse ISM inhibited endothelial cell (EC) capillary network formation on Matrigel through its C-terminal AMOP domain. It also suppressed vascular endothelial growth factor (VEGF)-basic fibroblast growth factor (bFGF) induced in vivo angiogenesis in mouse. It mitigated VEGF-stimulated EC proliferation without affecting EC migration. Furthermore, ISM induced EC apoptosis in the presence of VEGF through a caspase-dependent pathway. ISM binds to αvβ(5) integrin on EC surface and supports EC adhesion. Overexpression of ISM significantly suppressed mouse B16 melanoma tumour growth through inhibition of tumour angiogenesis without affecting tumour cell proliferation. Knockdown of isthmin in zebrafish embryos using morpholino antisense oligonucleotides led to disorganized intersegmental vessels in the trunk. Our results demonstrate that ISM is a novel endogenous angiogenesis inhibitor with functions likely in physiological as well as pathological angiogenesis.

  4. A proposed fractional-order Gompertz model and its application to tumour growth data. (United States)

    Bolton, Larisse; Cloot, Alain H J J; Schoombie, Schalk W; Slabbert, Jacobus P


    A fractional-order Gompertz model of orders between 0 and 2 is proposed. The main purpose of this investigation is to determine whether the ordinary or proposed fractional Gompertz model would best fit our experimental dataset. The solutions for the proposed model are obtained using fundamental concepts from fractional calculus. The closed-form equations of both the proposed model and the ordinary Gompertz model are calibrated using an experimental dataset containing tumour growth volumes of a Rhabdomyosarcoma tumour in a mouse. With regard to the proposed model, the order, within the interval mentioned, that resulted in the best fit to the data was used in a further investigation into the prediction capability of the model. This was compared to the prediction capability of the ordinary Gompertz model. The result of the investigation was that a fractional-order Gompertz model of order 0.68 produced a better fit to our experimental dataset than the well-known ordinary Gompertz model.

  5. Seminal plasma enhances cervical adenocarcinoma cell proliferation and tumour growth in vivo.

    Directory of Open Access Journals (Sweden)

    Jason R Sutherland

    Full Text Available Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2, cytokines interleukin (IL -6, and -11 and vascular endothelial growth factor-A (VEGF-A. To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway.

  6. Increased tumour extracellular pH induced by Bafilomycin A1 inhibits tumour growth and mitosis in vivo and alters 5-fluorouracil pharmacokinetics. (United States)

    McSheehy, P M J; Troy, H; Kelland, L R; Judson, I R; Leach, M O; Griffiths, J R


    The aim was to determine if a specific inhibitor of vacuolar H(+)-ATPases (V-ATPases), Bafilomycin A1 (BFM), could increase the low extracellular pH (pHe) typical of solid tumours and thus inhibit their growth in vivo. BFM inhibited the proliferation of various human cells and rat pituitary GH3 tumour cells in vitro (IC50: 2.5-19.2 nM), and flow cytometry on GH3 cells showed a marked increase in S and G2M phases after 16-48 h, but no evidence of increased apoptosis. BFM caused significant inhibition of GH3 xenograft growth, and histomorphometry showed a 30% decrease in mitosis but no change in apoptosis. 31P-magnetic resonance spectroscopy (MRS) in vivo of GH3 xenografts showed that BFM increased pHe, but did not affect pHi, resulting in a decrease in the negative pH gradient (-delta pH). BFM decreased lactate formation suggesting a reduction in glycolysis. We suggest that BFM reduces extracellular H(+)-transport by inhibition of V-ATPases leading to an increase in pHe and decreased glycolysis, and thus reduced tumour cell proliferation. 19F-MRS in vivo showed that a smaller -delta pH was associated with decreased retention of 5-fluorouracil (5FU) which was consistent with our previous data in vivo implying the -delta pH controls tumour retention of 5 FU.

  7. A Validated Multiscale In-Silico Model for Mechano-sensitive Tumour Angiogenesis and Growth (United States)

    Loizidou, Marilena; Stylianopoulos, Triantafyllos; Hawkes, David J.


    Vascularisation is a key feature of cancer growth, invasion and metastasis. To better understand the governing biophysical processes and their relative importance, it is instructive to develop physiologically representative mathematical models with which to compare to experimental data. Previous studies have successfully applied this approach to test the effect of various biochemical factors on tumour growth and angiogenesis. However, these models do not account for the experimentally observed dependency of angiogenic network evolution on growth-induced solid stresses. This work introduces two novel features: the effects of hapto- and mechanotaxis on vessel sprouting, and mechano-sensitive dynamic vascular remodelling. The proposed three-dimensional, multiscale, in-silico model of dynamically coupled angiogenic tumour growth is specified to in-vivo and in-vitro data, chosen, where possible, to provide a physiologically consistent description. The model is then validated against in-vivo data from murine mammary carcinomas, with particular focus placed on identifying the influence of mechanical factors. Crucially, we find that it is necessary to include hapto- and mechanotaxis to recapitulate observed time-varying spatial distributions of angiogenic vasculature. PMID:28125582

  8. Acromegaly caused by a growth hormonereleasing hormone secreting carcinoid tumour of the lung : the effect of octreotide treatment

    NARCIS (Netherlands)

    De Heide, L. J. M.; Van den Berg, G.; Wolthuis, A.; Van Schelven, W. D.


    in acromegaly, the overproduction of growth hormone is usually caused by a pituitary adenoma. We report a 74-year-old woman with acromegaly caused by ectopic overproduction of growth hormone-releasing hormone (GHRH), a rare diagnosis. The GHRH appeared to be produced by a carcinoid tumour of the lun

  9. Insulin-like Growth Factor (IGF) system and gastrointestinal stromal tumours (GIST): present and future. (United States)

    Nannini, Margherita; Biasco, Guido; Astolfi, Annalisa; Urbini, Milena; Pantaleo, Maria A


    In the last decades, the concept that Insulin-like Growth Factor (IGF) axis plays a key role in several steps of tumorigenesis, cancer growth and metastasis has been widely documented. The aberration of the IGF system has been described in many kinds of tumours, providing several lines of evidence in support of IGF receptor type 1 (IGF1R) as molecular target in cancer treatment. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract, commonly characterized in most cases by KIT and PDGFRA gain mutations. Beyond to the well recognized KIT and PDGFRA gain mutations, in the last years other molecular aberrations have been investigated. Recently, several lines of evidence about the involvement of the IGF system in GIST have been accumulated. The aim of this review is to report all current data about the IGF system involvement in GIST, focusing on the current clinical implication and future perspectives.

  10. Quantitative evaluation of the combination between cytotoxic drug and efflux transporter inhibitors based on a tumour growth inhibition model. (United States)

    Sostelly, Alexandre; Payen, Léa; Guitton, Jérôme; Di Pietro, Attilio; Falson, Pierre; Honorat, Mylène; Boumendjel, Ahcène; Gèze, Annabelle; Freyer, Gilles; Tod, Michel


    ATP-Binding Cassette transporters such as ABCG2 confer resistance to various anticancer drugs including irinotecan and its active metabolite, SN38. Early quantitative evaluation of efflux transporter inhibitors-cytotoxic combination requires quantitative drug-disease models. A proof-of-concept study has been carried out for studying the effect of a new ABCG2 transporter inhibitor, MBLI87 combined to irinotecan in mice xenografted with cells overexpressing ABCG2. Mice were treated with irinotecan alone or combined to MBLI87, and tumour size was periodically measured. To model those data, a tumour growth inhibition model was developed. Unperturbed tumour growth was modelled using Simeoni's model. Drug effect kinetics was accounted for by a Kinetic-Pharmacodynamic approach. Effect of inhibitor was described with a pharmacodynamic interaction model where inhibitor enhances activity of cytotoxic. This model correctly predicted tumour growth dynamics from our study. MBLI87 increased irinotecan potency by 20% per μmol of MBLI87. This model retains enough complexity to simultaneously describe tumour growth and effect of this type of drug combination. It can thus be used as a template to early evaluate efflux transporter inhibitors in-vivo.

  11. 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. (United States)

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


    [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

  12. Model for tumour growth with treatment by continuous and pulsed chemotherapy. (United States)

    Borges, F S; Iarosz, K C; Ren, H P; Batista, A M; Baptista, M S; Viana, R L; Lopes, S R; Grebogi, C


    In this work we investigate a mathematical model describing tumour growth under a treatment by chemotherapy that incorporates time-delay related to the conversion from resting to hunting cells. We study the model using values for the parameters according to experimental results and vary some parameters relevant to the treatment of cancer. We find that our model exhibits a dynamical behaviour associated with the suppression of cancer cells, when either continuous or pulsed chemotherapy is applied according to clinical protocols, for a large range of relevant parameters. When the chemotherapy is successful, the predation coefficient of the chemotherapic agent acting on cancer cells varies with the infusion rate of chemotherapy according to an inverse relation. Finally, our model was able to reproduce the experimental results obtained by Michor and collaborators [Nature 435 (2005) 1267] about the exponential decline of cancer cells when patients are treated with the drug glivec.

  13. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth (United States)

    Kim, Sung Eun; Zhang, Li; Ma, Kai; Riegman, Michelle; Chen, Feng; Ingold, Irina; Conrad, Marcus; Turker, Melik Ziya; Gao, Minghui; Jiang, Xuejun; Monette, Sebastien; Pauliah, Mohan; Gonen, Mithat; Zanzonico, Pat; Quinn, Thomas; Wiesner, Ulrich; Bradbury, Michelle S.; Overholtzer, Michael


    The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (<10 nm in diameter) poly(ethylene glycol)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumour xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential.

  14. Evolution of growth hormone neurosecretory disturbance after cranial irradiation for childhood brain tumours: a prospective study

    Energy Technology Data Exchange (ETDEWEB)

    Spoudeas, H.A.; Hindmarsh, P.C.; Brook, C.G.D. [Middlesex Hospital, London (United Kingdom); Matthews, D.R. [Radcliffe Infirmary, Oxford (United Kingdom)


    To determine the aetiopathology of post-irradiation growth hormone (GH) deficiency, we performed a mixed longitudinal analysis of 56 24 h serum GH concentration profiles and 45 paired insulin-induced hypoglycaemia tests (ITT) in 35 prepubertal children, aged 1.5-11.8 years, with brain tumours in the posterior foss (n = 25) or cerebral hemispheres (n 10). Assessments were made before (n = 16), 1 year (n = 25) and 2 to 5 years (n = 15) after a cranial irradiation (DXR) dose of at least 30 Gy. Fourier transforms, occupancy percentage, first-order derivatives (FOD) and mean concentrations were determined from the GH profiles taken after neurosurgery but before radiotherapy (n = 16) and in three treatment groups: Group 1: neurosurgery only without DXR (9n 9); Group 2: {>=} 30 Gy DXR only (n = 22); Group 3: {>=} 30 Gy DXR with additional chemotherapy (n = 9). Results were compared with those from 26 short normally growing (SN) children. (author).

  15. Vascular endothelial growth factor blocking agents in retinal vein occlusion

    Directory of Open Access Journals (Sweden)

    Chris Canning


    Full Text Available This paper summarises the current status of the use of vascular endothelial growth factor (VEGF blocking agents in retinal vein occlusion. There have been no randomised controlled trials comparing this treatment with the current standard treatment (largely laser so the lower grade evidence of single treatment case series and anecdotal reports are discussed. VEGF blockers are good at reducing macular oedema in the short term, do improve visual acuity in many cases, and do not seem to adversely affect the long term revascularisation that is necessary to overcome the vein occlusion. VEGF blocking agents are not used in isolation in this condition - they will remain an adjunct to systemic and other local treatments. The literature was reviewed in online searches of Embase and Ovid and the papers quoted are a representative sample of a larger body of publications.

  16. Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma. (United States)

    Wang, Jian; Svendsen, Agnete; Kmiecik, Justyna; Immervoll, Heike; Skaftnesmo, Kai Ove; Planagumà, Jesús; Reed, Rolf Kåre; Bjerkvig, Rolf; Miletic, Hrvoje; Enger, Per Øyvind; Rygh, Cecilie Brekke; Chekenya, Martha


    Aberrant expression of the progenitor marker Neuron-glia 2 (NG2/CSPG4) or melanoma proteoglycan on cancer cells and angiogenic vasculature is associated with an aggressive disease course in several malignancies including glioblastoma multiforme (GBM) and melanoma. Thus, we investigated the mechanism of NG2 mediated malignant progression and its potential as a therapeutic target in clinically relevant GBM and melanoma animal models. Xenografting NG2 overexpressing GBM cell lines resulted in increased growth rate, angiogenesis and vascular permeability compared to control, NG2 negative tumours. The effect of abrogating NG2 function was investigated after intracerebral delivery of lentivirally encoded shRNAs targeting NG2 in patient GBM xenografts as well as in established subcutaneous A375 melanoma tumours. NG2 knockdown reduced melanoma proliferation and increased apoptosis and necrosis. Targeting NG2 in two heterogeneous GBM xenografts significantly reduced tumour growth and oedema levels, angiogenesis and normalised vascular function. Vascular normalisation resulted in increased tumour invasion and decreased apoptosis and necrosis. We conclude that NG2 promotes tumour progression by multiple mechanisms and represents an amenable target for cancer molecular therapy.

  17. Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma.

    Directory of Open Access Journals (Sweden)

    Jian Wang

    Full Text Available Aberrant expression of the progenitor marker Neuron-glia 2 (NG2/CSPG4 or melanoma proteoglycan on cancer cells and angiogenic vasculature is associated with an aggressive disease course in several malignancies including glioblastoma multiforme (GBM and melanoma. Thus, we investigated the mechanism of NG2 mediated malignant progression and its potential as a therapeutic target in clinically relevant GBM and melanoma animal models. Xenografting NG2 overexpressing GBM cell lines resulted in increased growth rate, angiogenesis and vascular permeability compared to control, NG2 negative tumours. The effect of abrogating NG2 function was investigated after intracerebral delivery of lentivirally encoded shRNAs targeting NG2 in patient GBM xenografts as well as in established subcutaneous A375 melanoma tumours. NG2 knockdown reduced melanoma proliferation and increased apoptosis and necrosis. Targeting NG2 in two heterogeneous GBM xenografts significantly reduced tumour growth and oedema levels, angiogenesis and normalised vascular function. Vascular normalisation resulted in increased tumour invasion and decreased apoptosis and necrosis. We conclude that NG2 promotes tumour progression by multiple mechanisms and represents an amenable target for cancer molecular therapy.

  18. A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α (United States)

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


    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

  19. Primary tumour growth in an orthotopic osteosarcoma mouse model is not influenced by analgesic treatment with buprenorphine and meloxicam. (United States)

    Husmann, K; Arlt, M J E; Jirkof, P; Arras, M; Born, W; Fuchs, B


    Little is known about the treatment of bone pain in animal models of bone cancer. In the present study, the orthotopic 143-B human osteosarcoma xenotransplantation model was used to address the following questions: (1) Can repetitive analgesic treatment extend the experimental period by prolonging the time to reach humane endpoints and (2) Does repetitive analgesic treatment affect bone tumour development and metastasis? The analgesics, buprenorphine and meloxicam, were either applied individually or in combination at 12 h intervals as soon as the animals began to avoid using the tumour cell injected leg. While control mice treated with NaCl showed continuous body weight loss, the major criterion previously for terminating the experiments, animals treated with analgesic substances did not. The control mice had to be sacrificed 26 days after tumour cell injection, whereas the groups of animals with the different pain treatments were euthanized after an additional eight days. Importantly, primary intratibial tumour growth was not affected in any of the experimental groups by any of the pain treatment procedures. Between days 26 and 34 after tumour cell injection an increase of about 100% of the number of lung metastases was found for the groups treated with buprenorphine alone or together with meloxicam, but not for the group treated with meloxicam alone. In summary, the results indicated that both buprenorphine and meloxicam are suitable analgesics for prolonging the experimental periods in an experimental intratibial osteosarcoma mouse model.

  20. Growth characteristics and Ha-ras mutations of cell cultures isolated from chemically induced mouse liver tumours. (United States)

    Pedrick, M S; Rumsby, P C; Wright, V; Phillimore, H E; Butler, W H; Evans, J G


    Cells have been isolated from liver tumours that have arisen in control C3H/He mice, in mice given 10 micrograms diethylnitrosamine (DEN) during the neonatal period or in mice given a diet containing phenobarbitone (PB) to allow a daily intake of 85 mg/kg/day. The cells were grown to the 8 degrees subculture when their growth characteristics were investigated in monolayer culture and following suspension in soft agar and on transplantation into nude mice. In addition, DNA was isolated from the cultures and from tumours that grew in nude mice and analysed for mutations at codon 61 of the Ha-ras oncogene. All cells derived from DEN-induced hepatocellular carcinomas (HCC) demonstrated a lack of density inhibition of growth in monolayer culture, grew in soft agar and formed tumours in nude mice with an average mean latency of 29 days. Three of the seven lines showed mutations in Ha-ras: two were CAA-->AAA transversions and one showed a CAA-->CTA transversion. In contrast, cells isolated from eosinophilic nodules in mice given PB showed inhibition of growth at confluence, did not grow in soft agar and only four of eight formed tumours in nude mice with a mean average latent period of 181 days. Cells grown from HCC in mice given PB showed a lack of density inhibition of growth, however, they did not grow in soft agar nor did they form tumours in nude mice. A single spontaneous HCC from a control mouse showed a similar growth pattern to HCC cells isolated from mice given PB. Cells from a basophilic nodule, taken from a control untreated mouse grew vigorously in culture and in soft agar and formed tumours in nude mice with a latency of 6 days. None of the cells isolated from control mice or from mice given PB showed evidence of mutations at codon 61 of Ha-ras. These data confirm that there are fundamental differences in the biology of cells grown from tumours that develop in mice under different treatment regimes. These studies also demonstrate the utility of cell culture

  1. Yessotoxin, a Marine Toxin, Exhibits Anti-Allergic and Anti-Tumoural Activities Inhibiting Melanoma Tumour Growth in a Preclinical Model (United States)

    Tobío, Araceli; Alfonso, Amparo; Madera-Salcedo, Iris; Botana, Luis M.


    Yessotoxins (YTXs) are a group of marine toxins produced by the dinoflagellates Protoceratium reticulatum, Lingulodinium polyedrum and Gonyaulax spinifera. They may have medical interest due to their potential role as anti-allergic but also anti-cancer compounds. However, their biological activities remain poorly characterized. Here, we show that the small molecular compound YTX causes a slight but significant reduction of the ability of mast cells to degranulate. Strikingly, further examination revealed that YTX had a marked and selective cytotoxicity for the RBL-2H3 mast cell line inducing apoptosis, while primary bone marrow derived mast cells were highly resistant. In addition, YTX exhibited strong cytotoxicity against the human B-chronic lymphocytic leukaemia cell line MEC1 and the murine melanoma cell line B16F10. To analyse the potential role of YTX as an anti-cancer drug in vivo we used the well-established B16F10 melanoma preclinical mouse model. Our results demonstrate that a few local application of YTX around established tumours dramatically diminished tumour growth in the absence of any significant toxicity as determined by the absence of weight loss and haematological alterations. Our data support that YTX may have a minor role as an anti-allergic drug, but reveals an important potential for its use as an anti-cancer drug. PMID:27973568

  2. Treatment of transplanted CT26 tumour with dendritic cell vaccine in combination with blockade of vascular endothelial growth factor receptor 2 and CTLA-4

    DEFF Research Database (Denmark)

    Pedersen, Anders Elm; Buus, S; Claesson, M H


    We investigated the anti CT26 tumour effect of dendritic cell based vaccination with the MuLV gp70 envelope protein-derived peptides AH1 and p320-333. Vaccination lead to generation of AH1 specific cytotoxic lymphocytes (CTL) and some decrease in tumour growth of simultaneously inoculated CT26...

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

    Directory of Open Access Journals (Sweden)

    Debajit Bhowmick


    Full Text Available 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.

  4. Tumour Angiogenesis: A Growth Area—From John Hunter to Judah Folkman and Beyond

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    J. A. Stephenson


    Full Text Available Angiogenesis is the growth of new blood vessels in the body. Abnormal angiogenesis is recognised as a “common denominator” in many disease processes, and the development of angiogenesis inhibitors holds great hope in the ongoing battle against cancer. The field of angiogenesis has roots in the Hunterian era of the late eighteenth century but did not begin to blossom until the early 1970s when the then controversial findings and conclusions of Judah Folkman, the “father of angiogenesis,” were first published. There were only 65 publications with angiogenesis in the title in the 10 years after Folkman first proposed the idea of tumour angiogenesis, compared to over 9,000 publications from the year 2000 to 2010. In this review we will explore the voyage of discovery from the first observations of John Hunter in the eighteenth century, via the struggle faced by Folkman to prove the importance of angiogenesis, and finally how his determination has led to modern angiogenesis inhibitors being used in everyday clinical practice.

  5. Hypoxia and prostaglandin E receptor 4 signalling pathways synergise to promote endometrial adenocarcinoma cell proliferation and tumour growth.

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    Rob D Catalano

    Full Text Available The prostaglandin endoperoxide synthase (PTGS pathway is a potent driver of tumour development in humans by enhancing the biosynthesis and signalling of prostaglandin (PG E(2. PTGS2 expression and PGE(2 biosynthesis is elevated in endometrial adenocarcinoma, however the mechanism whereby PTGS and PGE(2 regulate endometrial tumour growth is unknown. Here we investigated (a the expression profile of the PGE synthase enzymes (PTGES, PTGES-2, PTGES-3 and PGE receptors (PTGER1-4 in endometrial adenocarcinomas compared with normal endometrium and (b the role of PTGER4 in endometrial tumorigenesis in vivo. We found elevated expression of PTGES2 and PTGER4 and suppression of PTGER1 and PTGER3 in endometrial adenocarcinomas compared with normal endometrium. Using WT Ishikawa endometrial adenocarcinoma cells and Ishikawa cells stably transfected with the full length PTGER4 cDNA (PTGER4 cells xenografted in the dorsal flanks of nude mice, we show that PTGER4 rapidly and significantly enhances tumour growth rate. Coincident with enhanced PTGER4-mediated tumour growth we found elevated expression of PTGS2 in PTGER4 xenografts compared with WT xenografts. Furthermore we found that the augmented growth rate of the PTGER4 xenografts was not due to enhanced angiogenesis, but regulated by an increased proliferation index and hypoxia. In vitro, we found that PGE(2 and hypoxia independently induce expression of PTGER4 indicating two independent pathways regulating prostanoid receptor expression. Finally we have shown that PGE(2 and hypoxia synergise to promote cellular proliferation of endometrial adenocarcinoma cells.

  6. In vitro growth environment produces lipidomic and electron transport chain abnormalities in mitochondria from non-tumorigenic astrocytes and brain tumours

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    Thomas N Seyfried


    Full Text Available The mitochondrial lipidome influences ETC (electron transport chain and cellular bioenergetic efficiency. Brain tumours are largely dependent on glycolysis for energy due to defects in mitochondria and oxidative phosphorylation. In the present study, we used shotgun lipidomics to compare the lipidome in highly purified mitochondria isolated from normal brain, from brain tumour tissue, from cultured tumour cells and from non-tumorigenic astrocytes. The tumours included the CT-2A astrocytoma and an EPEN (ependymoblastoma, both syngeneic with the C57BL/6J (B6 mouse strain. The mitochondrial lipidome in cultured CT-2A and EPEN tumour cells were compared with those in cultured astrocytes and in solid tumours grown in vivo. Major differences were found between normal tissue and tumour tissue and between in vivo and in vitro growth environments for the content or composition of ethanolamine glycerophospholipids, phosphatidylglycerol and cardiolipin. The mitochondrial lipid abnormalities in solid tumours and in cultured cells were associated with reductions in multiple ETC activities, especially Complex I. The in vitro growth environment produced lipid and ETC abnormalities in cultured non-tumorigenic astrocytes that were similar to those associated with tumorigenicity. It appears that the culture environment obscures the boundaries of the Crabtree and the Warburg effects. These results indicate that in vitro growth environments can produce abnormalities in mitochondrial lipids and ETC activities, thus contributing to a dependency on glycolysis for ATP production.

  7. Influence of Coloured Correlated Noises on Probability Distribution and Mean of Tumour Cell Number in the Logistic Growth Model

    Institute of Scientific and Technical Information of China (English)

    HAN Li-Bo; GONG Xiao-Long; CAO Li; WU Da-Jin


    An approximate Fokker-P1anck equation for the logistic growth model which is driven by coloured correlated noises is derived by applying the Novikov theorem and the Fox approximation. The steady-state probability distribution (SPD) and the mean of the tumour cell number are analysed. It is found that the SPD is the single extremum configuration when the degree of correlation between the multiplicative and additive noises, λ, is in -1<λ ≤ 0 and can be the double extrema in 0<λ<1. A configuration transition occurs because of the variation of noise parameters. A minimum appears in the curve of the mean of the steady-state tumour cell number, 〈x〉, versus λ. The position and the value of the minimum are controlled by the noise-correlated times.

  8. Myeloid cells in tumour-immune interactions. (United States)

    Kareva, Irina; Berezovskaya, Faina; Castillo-Chavez, Carlos


    Despite highly developed specific immune responses, tumour cells often manage to escape recognition by the immune system, continuing to grow uncontrollably. Experimental work suggests that mature myeloid cells may be central to the activation of the specific immune response. Recognition and subsequent control of tumour growth by the cells of the specific immune response depend on the balance between immature (ImC) and mature (MmC) myeloid cells in the body. However, tumour cells produce cytokines that inhibit ImC maturation, altering the balance between ImC and MmC. Hence, the focus of this manuscript is on the study of the potential role of this inhibiting mechanism on tumour growth dynamics. A conceptual predator-prey type model that incorporates the dynamics and interactions of tumour cells, CD8(+) T cells, ImC and MmC is proposed in order to address the role of this mechanism. The prey (tumour) has a defence mechanism (blocking the maturation of ImC) that prevents the predator (immune system) from recognizing it. The model, a four-dimensional nonlinear system of ordinary differential equations, is reduced to a two-dimensional system using time-scale arguments that are tied to the maturation rate of ImC. Analysis shows that the model is capable of supporting biologically reasonable patterns of behaviour depending on the initial conditions. A range of parameters, where healing without external influences can occur, is identified both qualitatively and quantitatively.

  9. Growth hormone receptor antagonism suppresses tumour regrowth after radiotherapy in an endometrial cancer xenograft model. (United States)

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


    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.

  10. ApoA-I mimetic administration, but not increased apoA-I-containing HDL, inhibits tumour growth in a mouse model of inherited breast cancer (United States)

    Cedó, Lídia; García-León, Annabel; Baila-Rueda, Lucía; Santos, David; Grijalva, Victor; Martínez-Cignoni, Melanie Raquel; Carbó, José M.; Metso, Jari; López-Vilaró, Laura; Zorzano, Antonio; Valledor, Annabel F.; Cenarro, Ana; Jauhiainen, Matti; Lerma, Enrique; Fogelman, Alan M.; Reddy, Srinivasa T.; Escolà-Gil, Joan Carles; Blanco-Vaca, Francisco


    Low levels of high-density lipoprotein cholesterol (HDLc) have been associated with breast cancer risk, but several epidemiologic studies have reported contradictory results with regard to the relationship between apolipoprotein (apo) A-I and breast cancer. We aimed to determine the effects of human apoA-I overexpression and administration of specific apoA-I mimetic peptide (D-4F) on tumour progression by using mammary tumour virus-polyoma middle T-antigen transgenic (PyMT) mice as a model of inherited breast cancer. Expression of human apoA-I in the mice did not affect tumour onset and growth in PyMT transgenic mice, despite an increase in the HDLc level. In contrast, D-4F treatment significantly increased tumour latency and inhibited the development of tumours. The effects of D-4F on tumour development were independent of 27-hydroxycholesterol. However, D-4F treatment reduced the plasma oxidized low-density lipoprotein (oxLDL) levels in mice and prevented oxLDL-mediated proliferative response in human breast adenocarcinoma MCF-7 cells. In conclusion, our study shows that D-4F, but not apoA-I-containing HDL, hinders tumour growth in mice with inherited breast cancer in association with a higher protection against LDL oxidative modification. PMID:27808249

  11. Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.

    Directory of Open Access Journals (Sweden)

    Bérengère Gobin

    Full Text Available 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

  12. Tumour growth inhibition and anti-angiogenic effects using curcumin correspond to combined PDE2 and PDE4 inhibition. (United States)

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


    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.

  13. A human monoclonal antibody 264RAD targeting αvβ6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo. (United States)

    Eberlein, C; Kendrew, J; McDaid, K; Alfred, A; Kang, J S; Jacobs, V N; Ross, S J; Rooney, C; Smith, N R; Rinkenberger, J; Cao, A; Churchman, A; Marshall, J F; Weir, H M; Bedian, V; Blakey, D C; Foltz, I N; Barry, S T


    αvβ6 integrin expression is upregulated on a wide range of epithelial tumours, and is thought to play a role in modulating tumour growth. Here we describe a human therapeutic antibody 264RAD, which binds and inhibits αvβ6 integrin function. 264RAD cross-reacts with human, mouse and cynomolgus monkey αvβ6, and inhibits binding to all ligands including the latency-associated peptide of TGF-β. Screening across a range of integrins revealed that 264RAD also binds and inhibits the related integrin αvβ8, but not the integrins α5β1, αvβ3, αvβ5 and α4β1. In vitro 264RAD inhibited invasion of VB6 and Detroit 562 cells in a Matrigel invasion assay and αvβ6 mediated production of matrix metalloproteinase-9 in Calu-3 cells. It inhibited TGF-β-mediated activation of dermal skin fibroblasts by preventing local activation of TGF-β by NCI-H358 tumour cells in a tumour cell-fibroblast co-culture assay. In vivo 264RAD showed dose-dependent inhibition of Detroit 562 tumour growth, regressing established tumours when dosed at 20 mg/kg once weekly. The reduction in growth associated with 264RAD was related to a dose-dependent inhibition of Ki67 and phospho-ERK and a reduction of αvβ6 expression in the tumour cells, coupled to a reduction in fibronectin and alpha smooth muscle actin expression in stromal fibroblasts. 264RAD also reduced the growth and metastasis of orthotopic 4T1 tumours. At 20 mg/kg growth of both the primary tumour and the number of metastatic deposits in lung were reduced. The data support the conclusion that 264RAD is a potent inhibitor of αvβ6 integrin, with some activity against αvβ8 integrin, that reduces both tumour growth and metastasis.

  14. Tumour biology: Herceptin acts as an anti-angiogenic cocktail (United States)

    Izumi, Yotaro; Xu, Lei; di Tomaso, Emmanuelle; Fukumura, Dai; Jain, Rakesh K.


    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.

  15. How effective is external pituitary irradiation for growth hormone-secreting pituitary tumours

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    Feek, C.M.; McLelland, J.; Seth, J.; Toft, A.D.; Irvine, W.J.; Padfield, P.L.; Edwards, C.R.W. (Western General Hospital, Edinburgh (UK); Royal Infirmary, Edinburgh (UK))


    Forty-six patients with GH-secreting pituitary tumours were treated with external pituitary irradiation through two opposed fields to a total dose of 3750 cGy over 15 fractions. Thirty-patients received external radiotherapy as primary treatment; 16 received radiotherapy combined with pituitary surgery. The mean (+- SD) serum GH in the former group was 74.3 +- 74.8 mU/l before treatment, falling by 28% per year over 0-5 years and by 16% per year over 0-20 years. The mean (+- SD) serum GH in the latter group was 265.4 +- 209.3 mU/l before treatment, falling by 76% in the first year-a direct result of surgery-then by 30% per year over 1-5 years and 16% per year over 1-20 years. Progressive failure of normal anterior pituitary function developed by 10 years, with variable loss of gonadotrophin, corticotrophin and thyrotrophin function. The respective figures for patients treated with radiotherapy alone were 47.4, 29.6 and 16.0% and for the combined group 70.2, 53.9 and 38.1%. Whilst external pituitary irradiation appears to reduce serum GH concentrations in patients with GH-secreting pituitary tumours the major disadvantages are the time taken to achieve a cure and the high incidence of hypopituitarism.

  16. Simulating growth dynamics and radiation response of avascular tumour spheroids-model validation in the case of an EMT6/Ro multicellular spheroid. (United States)

    Zacharaki, Evangelia I; Stamatakos, Georgios S; Nikita, Konstantina S; Uzunoglu, Nikolaos K


    The goal of this paper is to provide both the basic scientist and the clinician with an advanced computational tool for performing in silico experiments aiming at supporting the process of biological optimisation of radiation therapy. Improved understanding and description of malignant tumour dynamics is an additional intermediate objective. To this end an advanced three-dimensional (3D) Monte-Carlo simulation model of both the avascular development of multicellular tumour spheroids and their response to radiation therapy is presented. The model is based upon a number of fundamental biological principles such as the transition between the cell cycle phases, the diffusion of oxygen and nutrients and the cell survival probabilities following irradiation. Efficient algorithms describing tumour expansion and shrinkage are proposed and applied. The output of the biosimulation model is introduced into the (3D) visualisation package AVS-Express, which performs the visualisation of both the external surface and the internal structure of the dynamically evolving tumour based on volume or surface rendering techniques. Both the numerical stability and the statistical behaviour of the simulation model have been studied and evaluated for the case of EMT6/Ro spheroids. Predicted histological structure and tumour growth rates have been shown to be in agreement with published experimental data. Furthermore, the underlying structure of the tumour spheroid as well as its response to irradiation satisfactorily agrees with laboratory experience.

  17. XRP44X, an Inhibitor of Ras/Erk Activation of the Transcription Factor Elk3, Inhibits Tumour Growth and Metastasis in Mice (United States)

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


    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

  18. Fibroblast growth factors, old kids on the new block. (United States)

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


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

  19. The epiphyseal growth plate and peripheral cartilaginous tumours : the neighbours matter

    NARCIS (Netherlands)

    Andrea, Carlos Eduardo de


    Chondrocytes interact with their neighbours through their cartilaginous extracellular matrix (ECM). Chondrocyte–matrix interactions compensate the lack of cell–cell contact and are modulated by proteoglycans and other molecules. The epiphyseal growth plate is a highly organized tissue responsible fo

  20. The sodium channel β1 subunit mediates outgrowth of neurite-like processes on breast cancer cells and promotes tumour growth and metastasis. (United States)

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


    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.

  1. Bladder tumours in children: An interesting case report of TCC with a partial inverted growth pattern. (United States)

    El Rahman, Davide Abed; Salvo, Giuseppe; Palumbo, Carlotta; Rocco, Bernardo; Rocco, Francesco


    Bladder urothelial carcinoma is typically a disease of older individuals and rarely occurs below the age of 40 years. There is debate and uncertainty in the literature regarding the clinicopathologic and prognostic characteristics of bladder urothelial neoplasms in younger patients compared with older patients, although no consistent age criteria have been used to define "younger" age group categories. We report on a 16 years old girl with transitional cell carcinoma of the bladder with a partial inverted growth pattern who presented with gross hematuria. Ultrasonography revealed a papillary lesion in the bladder; cystoscopic evaluation showed a 15 mm papillary lesion with a thick stalk located in the left bladder wall. Pathologic evaluation of the specimen was reported as "low grade transitional cell carcinoma of the bladder with a partial inverted growth pattern".

  2. 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.

    Directory of Open Access Journals (Sweden)

    Yan Cai

    Full Text Available 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.

  3. 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. (United States)

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


    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.

  4. Tumour necrosis factor-alpha (TNFα stimulates the growth of human bone marrow stromal cells

    Directory of Open Access Journals (Sweden)

    F. Rougier


    Full Text Available This study reports that TNF-α is a potent mitogen for human bone marrow sternal cells in vitro (assessed by [3H]-thymidine incorporation into DNA and cell counts. In contrast, cytokines such as IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, LIF, SCF, M-CSF, G-CSF and GM-CSF had no effect. The effect of TNF-α on the growth of human bone marrow stromal cells could be of importance during inflammatory processes which take place in the marrow, for example marrow fibrosis.

  5. Follicular infundibulum tumour presenting as cutaneous horn

    Directory of Open Access Journals (Sweden)

    Jayaraman M


    Full Text Available Tumour of follicular infundibulum is an organoid tumour with a plate like growth attached to the epidermis with connection from the follicular epithelium. We are reporting such a case unusually presenting as cutaneous horn.

  6. Absence of transforming growth factor-beta type II receptor is associated with poorer prognosis in HER2-negative breast tumours

    DEFF Research Database (Denmark)

    Paiva, C E; Drigo, S A; Rosa, F E;


    BACKGROUND: The clinical relevance of transforming growth factor-beta (TGF-beta)-signalling pathway in breast carcinomas (BCs) remained elusive. This study aimed to evaluate the prognostic value of TGF-beta1 and transforming growth factor-beta type II receptor (TGF-betaRII) expression levels...... in tumour cells and their association with the established biomarkers in BC. PATIENTS AND METHODS: In 324 BC from patients with long-term follow-up, the TGF-beta1 and TGF-betaRII transcript and protein expression levels were assessed. RESULTS: TGF-beta1 and TGF-betaRII down-expression was significantly...... associated with BC. Negative TGF-beta1 and TGF-betaRII protein status was associated with the development of distant metastasis (P = 0.003 and P = 0.029, respectively). In multivariate analysis, TGF-beta1-positive tumours were associated with increased disease-free survival (DFS) [hazard ratio (HR) = 0...

  7. Local administration of cells containing an inserted IL-2 gene and producing IL-2 inhibits growth of human tumours in nu/nu mice. (United States)

    Bubenik, J; Voitenok, N N; Kieler, J; Prassolov, V S; Chumakov, P M; Bubenikova, D; Simova, J; Jandlova, T


    We have prepared a retroviral expression construct, pPS-IL-2, in which human IL-2 cDNA has been inserted into the polylinker region, and have used the retroviral vector to introduce the functional IL-2 gene into a fibroblast cell line, RAT-1. Peritumoral administration of IL-2-producing RAT-1 cells into congenitally athymic (nu/nu) mice carrying subcutaneous transplants of human carcinoma cells inhibited the growth of the human tumour xenografts.

  8. Override of the radiation-induced mitotic block in human tumour cells by methylxanthines and its relationship to the potentiation of cytotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Musk, S.R.R.; Steel, G.G. (Institute of Cancer Research, Sutton (UK). Surrey Branch)


    Caffeine, theophylline, theobromine and paraxanthine, were tested for ability to override mitotic block induced by ionizing radiation in the human bladder carcinoma cell line RT112. All were found to partially override the block, at a concentration of 1mM in the order caffeine > theophylline > theobromine = paraxanthine. At a concentration of 1 mM only caffeine was found to potentiate cell killing as well as causing block override; at higher concentrations all had a significant effect on survival but little or no further influence on the degree of block override. It is concluded that override of a mitotic block is not in itself sufficient to cause increased killing when irradiated cells are incubated in the presence of caffeine, and that caffeine exerts its potentiating effect by directly inhibiting repair of damage in DNA or by causing override of radiation-induced inhibition of DNA synthesis. (author).

  9. A novel chaotic block image encryption algorithm based on dynamic random growth technique (United States)

    Wang, Xingyuan; Liu, Lintao; Zhang, Yingqian


    This paper proposes a new block image encryption scheme based on hybrid chaotic maps and dynamic random growth technique. Since cat map is periodic and can be easily cracked by chosen plaintext attack, we use cat map in another securer way, which can completely eliminate the cyclical phenomenon and resist chosen plaintext attack. In the diffusion process, an intermediate parameter is calculated according to the image block. The intermediate parameter is used as the initial parameter of chaotic map to generate random data stream. In this way, the generated key streams are dependent on the plaintext image, which can resist the chosen plaintext attack. The experiment results prove that the proposed encryption algorithm is secure enough to be used in image transmission systems.

  10. Morphology-controlled growth of perylene derivative induced by double-hydrophilic block copolymers

    Directory of Open Access Journals (Sweden)

    Minghua Huang


    Full Text Available Controlled growth of technically relevant perylene derivative 3, 4, 9, 10-perylenetetracarboxylic acid potassium salt (PTCAPS, with tuneable morpologies, has been successfully realized by a recrystallization method using a double-hydrophilic block copolymer poly (ethylene glycol-block poly (ethyleneimine (PEG-b-PEI as the structure directing agent. The {001} faces of PTCAPS are most polar and adsorb the oppositively charged polymer additive PEG-b-PEI well by electrostatic attraction. By simply adjusting the PEG-b-PEI concentration, systematic morphogenesis of PTCAPS from plates to microparticles composed of various plates splaying outwards could be realized. Furthermore, the variation of pH value of the recrystallization solution could induce the change of the interaction strength between PEG-b-PEI additive and PTCAPS and thus modify the morphology of PTCAPS from microparticles composed of various plates to ultralong microbelts.

  11. Amygdalin blocks bladder cancer cell growth in vitro by diminishing cyclin A and cdk2. (United States)

    Makarević, Jasmina; Rutz, Jochen; Juengel, Eva; Kaulfuss, Silke; Reiter, Michael; Tsaur, Igor; Bartsch, Georg; Haferkamp, Axel; Blaheta, Roman A


    Amygdalin, a natural compound, has been used by many cancer patients as an alternative approach to treat their illness. However, whether or not this substance truly exerts an anti-tumor effect has never been settled. An in vitro study was initiated to investigate the influence of amygdalin (1.25-10 mg/ml) on the growth of a panel of bladder cancer cell lines (UMUC-3, RT112 and TCCSUP). Tumor growth, proliferation, clonal growth and cell cycle progression were investigated. The cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1, p19, p27 as well as the mammalian target of rapamycin (mTOR) related signals phosphoAkt, phosphoRaptor and phosphoRictor were examined. Amygdalin dose-dependently reduced growth and proliferation in all three bladder cancer cell lines, reflected in a significant delay in cell cycle progression and G0/G1 arrest. Molecular evaluation revealed diminished phosphoAkt, phosphoRictor and loss of Cdk and cyclin components. Since the most outstanding effects of amygdalin were observed on the cdk2-cyclin A axis, siRNA knock down studies were carried out, revealing a positive correlation between cdk2/cyclin A expression level and tumor growth. Amygdalin, therefore, may block tumor growth by down-modulating cdk2 and cyclin A. In vivo investigation must follow to assess amygdalin's practical value as an anti-tumor drug.

  12. Amygdalin blocks bladder cancer cell growth in vitro by diminishing cyclin A and cdk2.

    Directory of Open Access Journals (Sweden)

    Jasmina Makarević

    Full Text Available Amygdalin, a natural compound, has been used by many cancer patients as an alternative approach to treat their illness. However, whether or not this substance truly exerts an anti-tumor effect has never been settled. An in vitro study was initiated to investigate the influence of amygdalin (1.25-10 mg/ml on the growth of a panel of bladder cancer cell lines (UMUC-3, RT112 and TCCSUP. Tumor growth, proliferation, clonal growth and cell cycle progression were investigated. The cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1, p19, p27 as well as the mammalian target of rapamycin (mTOR related signals phosphoAkt, phosphoRaptor and phosphoRictor were examined. Amygdalin dose-dependently reduced growth and proliferation in all three bladder cancer cell lines, reflected in a significant delay in cell cycle progression and G0/G1 arrest. Molecular evaluation revealed diminished phosphoAkt, phosphoRictor and loss of Cdk and cyclin components. Since the most outstanding effects of amygdalin were observed on the cdk2-cyclin A axis, siRNA knock down studies were carried out, revealing a positive correlation between cdk2/cyclin A expression level and tumor growth. Amygdalin, therefore, may block tumor growth by down-modulating cdk2 and cyclin A. In vivo investigation must follow to assess amygdalin's practical value as an anti-tumor drug.

  13. Growth hormone improves growth retardation induced by rapamycin without blocking its antiproliferative and antiangiogenic effects on rat growth plate.

    Directory of Open Access Journals (Sweden)

    Óscar Álvarez-García

    Full Text Available Rapamycin, an immunosuppressant agent used in renal transplantation with antitumoral properties, has been reported to impair longitudinal growth in young individuals. As growth hormone (GH can be used to treat growth retardation in transplanted children, we aimed this study to find out the effect of GH therapy in a model of young rat with growth retardation induced by rapamycin administration. Three groups of 4-week-old rats treated with vehicle (C, daily injections of rapamycin alone (RAPA or in combination with GH (RGH at pharmacological doses for 1 week were compared. GH treatment caused a 20% increase in both growth velocity and body length in RGH animals when compared with RAPA group. GH treatment did not increase circulating levels of insulin-like growth factor I, a systemic mediator of GH actions. Instead, GH promoted the maturation and hypertrophy of growth plate chondrocytes, an effect likely related to AKT and ERK1/2 mediated inactivation of GSK3β, increase of glycogen deposits and stabilization of β-catenin. Interestingly, GH did not interfere with the antiproliferative and antiangiogenic activities of rapamycin in the growth plate and did not cause changes in chondrocyte autophagy markers. In summary, these findings indicate that GH administration improves longitudinal growth in rapamycin-treated rats by specifically acting on the process of growth plate chondrocyte hypertrophy but not by counteracting the effects of rapamycin on proliferation and angiogenesis.

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



    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

  15. Change of the growth hormone-insulin-like growth factor-I axis in patients with gastrointestinal cancer: related to tumour type and nutritional status. (United States)

    Huang, Qi; Nai, Yong-Jun; Jiang, Zhi-Wei; Li, Jie-Shou


    Changes in the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis, especially acquired GH resistance, develop in many severe illnesses, including cachexia. To study changes in the GH-IGF-I axis in patients with cancer cachexia, biochemical markers and body composition parameters were measured in eighty-eight gastric cancer patients, thirty colorectal cancer patients (subclassified according to the presence or absence of cachexia) and twenty-four healthy control subjects. Fifty-nine patients were defined as cachectic, based on the percentage of weight loss compared with their previous normal weight. The remaining fifty-nine patients were defined as non-cachectic. Measurements were repeated in twenty-seven patients (sixteen with gastric cancer and eleven with colorectal cancer) 3 months after radical operation. Compared with the controls, the cachectic gastric cancer patients had high GH levels (1.36 v. 0.32 ng/ml; P=0.001), a trend towards high IGF-I levels (223.74 v. 195.15 ng/ml; P=0.128 compared with non-cachectic patients) and a low log IGF-I/GH ratio (2.55 and 2.66 v. 3.00; P=0.002), along with a decreased BMI; the cachectic colorectal cancer patients showed the biochemical characteristics of acquired GH resistance: high GH (0.71 v. 0.32 ng/ml; P=0.016), a trend towards decreased IGF-I levels (164.18 v. 183.24 ng/ml; P=0.127) and a low log IGF-I/GH ratio (2.54 v. 2.99; P=0.005), with increased IGF-I levels following radical surgery (200.49 v. 141.91 ng/ml; P=0.046). These findings suggest that normal GH reaction and sensitivity occur in gastric cancer patients, controlled by nutritional status, whereas acquired GH resistance develops in cachectic colorectal cancer patients, which may be caused by tumour itself.

  16. Diagnostic challenges and management of a patient with acromegaly due to ectopic growth hormone-releasing hormone secretion from a bronchial carcinoid tumour

    Directory of Open Access Journals (Sweden)

    Nikolaos Kyriakakis


    Full Text Available A male patient presented at the age of 30 with classic clinical features of acromegaly and was found to have elevated growth hormone levels, not suppressing during an oral glucose tolerance test. His acromegaly was originally considered to be of pituitary origin, based on a CT scan, which was interpreted as showing a pituitary macroadenoma. Despite two trans-sphenoidal surgeries, cranial radiotherapy and periods of treatment with bromocriptine and octreotide, his acromegaly remained active clinically and biochemically. A lung mass was discovered incidentally on a chest X-ray performed as part of a routine pre-assessment for spinal surgery 5 years following the initial presentation. This was confirmed to be a bronchial carcinoid tumour, which was strongly positive for growth hormone-releasing hormone (GHRH and somatostatin receptor type 2 by immunohistochemistry. The re-examination of the pituitary specimens asserted the diagnosis of pituitary GH hyperplasia. Complete resolution of the patient’s acromegaly was achieved following right lower and middle lobectomy. Seventeen years following the successful resection of the bronchial carcinoid tumour the patient remains under annual endocrine follow-up for monitoring of the hypopituitarism he developed after the original interventions to his pituitary gland, while there has been no evidence of active acromegaly or recurrence of the carcinoid tumour. Ectopic acromegaly is extremely rare, accounting for <1% of all cases of acromegaly. Our case highlights the diagnostic challenges differentiating between ectopic acromegaly and acromegaly of pituitary origin and emphasises the importance of avoiding unnecessary pituitary surgery and radiotherapy. The role of laboratory investigations, imaging and histology as diagnostic tools is discussed.

  17. Combined zoledronic acid and meloxicam reduced bone loss and tumour growth in an orthotopic mouse model of bone-invasive oral squamous cell carcinoma. (United States)

    Martin, C K; Dirksen, W P; Carlton, M M; Lanigan, L G; Pillai, S P; Werbeck, J L; Simmons, J K; Hildreth, B E; London, C A; Toribio, R E; Rosol, T J


    Oral squamous cell carcinoma (OSCC) is common in cats and humans and invades oral bone. We hypothesized that the cyclooxygenase (COX)-2 inhibitor, meloxicam, with the bisphosphonate, zoledronic acid (ZOL), would inhibit tumour growth, osteolysis and invasion in feline OSCC xenografts in mice. Human and feline OSCC cell lines expressed COX-1 and COX-2 and the SCCF2 cells had increased COX-2 mRNA expression with bone conditioned medium. Luciferase-expressing feline SCCF2Luc cells were injected beneath the perimaxillary gingiva and mice were treated with 0.1 mg kg(-1) ZOL twice weekly, 0.3 mg kg(-1) meloxicam daily, combined ZOL and meloxicam, or vehicle. ZOL inhibited osteoclastic bone resorption at the tumour-bone interface. Meloxicam was more effective than ZOL at reducing xenograft growth but did not affect osteoclastic bone resorption. Although a synergistic effect of combined ZOL and meloxicam was not observed, combination therapy was well-tolerated and may be useful in the clinical management of bone-invasive feline OSCC.

  18. Growth-Blocking Peptides As Nutrition-Sensitive Signals for Insulin Secretion and Body Size Regulation.

    Directory of Open Access Journals (Sweden)

    Takashi Koyama


    Full Text Available In Drosophila, the fat body, functionally equivalent to the mammalian liver and adipocytes, plays a central role in regulating systemic growth in response to nutrition. The fat body senses intracellular amino acids through Target of Rapamycin (TOR signaling, and produces an unidentified humoral factor(s to regulate insulin-like peptide (ILP synthesis and/or secretion in the insulin-producing cells. Here, we find that two peptides, Growth-Blocking Peptide (GBP1 and CG11395 (GBP2, are produced in the fat body in response to amino acids and TOR signaling. Reducing the expression of GBP1 and GBP2 (GBPs specifically in the fat body results in smaller body size due to reduced growth rate. In addition, we found that GBPs stimulate ILP secretion from the insulin-producing cells, either directly or indirectly, thereby increasing insulin and insulin-like growth factor signaling activity throughout the body. Our findings fill an important gap in our understanding of how the fat body transmits nutritional information to the insulin producing cells to control body size.

  19. Diagnostic challenges and management of a patient with acromegaly due to ectopic growth hormone-releasing hormone secretion from a bronchial carcinoid tumour (United States)

    Kyriakakis, Nikolaos; Trouillas, Jacqueline; Dang, Mary N; Lynch, Julie; Belchetz, Paul; Korbonits, Márta


    Summary A male patient presented at the age of 30 with classic clinical features of acromegaly and was found to have elevated growth hormone levels, not suppressing during an oral glucose tolerance test. His acromegaly was originally considered to be of pituitary origin, based on a CT scan, which was interpreted as showing a pituitary macroadenoma. Despite two trans-sphenoidal surgeries, cranial radiotherapy and periods of treatment with bromocriptine and octreotide, his acromegaly remained active clinically and biochemically. A lung mass was discovered incidentally on a chest X-ray performed as part of a routine pre-assessment for spinal surgery 5 years following the initial presentation. This was confirmed to be a bronchial carcinoid tumour, which was strongly positive for growth hormone-releasing hormone (GHRH) and somatostatin receptor type 2 by immunohistochemistry. The re-examination of the pituitary specimens asserted the diagnosis of pituitary GH hyperplasia. Complete resolution of the patient’s acromegaly was achieved following right lower and middle lobectomy. Seventeen years following the successful resection of the bronchial carcinoid tumour the patient remains under annual endocrine follow-up for monitoring of the hypopituitarism he developed after the original interventions to his pituitary gland, while there has been no evidence of active acromegaly or recurrence of the carcinoid tumour. Ectopic acromegaly is extremely rare, accounting for <1% of all cases of acromegaly. Our case highlights the diagnostic challenges differentiating between ectopic acromegaly and acromegaly of pituitary origin and emphasises the importance of avoiding unnecessary pituitary surgery and radiotherapy. The role of laboratory investigations, imaging and histology as diagnostic tools is discussed. Learning points: Ectopic acromegaly is rare, accounting for less than 1% of all cases of acromegaly. Ectopic acromegaly is almost always due to extra-pituitary GHRH secretion

  20. Clinical utility of KRAS status in circulating plasma DNA compared to archival tumour tissue from patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy

    DEFF Research Database (Denmark)

    Spindler, Karen-Lise Garm; Pallisgaard, Niels; Appelt, Ane Lindegaard


    by an in-house qPCR method. Results are presented according to REMARK. RESULTS: One-hundred-and-forty patients were included. Thirty-four percent had detectable KRAS mutations in the tumour, compared to 23% in plasma. KRAS detection in archival tumour tissue showed no correlation to survival, whereas...... in patients from metastatic colorectal cancer (mCRC) prior to anti-epidermal growth factor receptor (anti-EGFR) therapy. Secondly, we investigated the concentration of total cfDNA in relation to clinical outcome. PATIENTS AND METHODS: Patients were resistant to 5-FU, oxaliplatin and irinotecan and treated......BACKGROUND: Circulating cell-free DNA (cfDNA) in plasma is a mixture of DNA from malignant and normal cells, and can be used as a liquid biopsy to detect and quantify tumour specific mutations e.g. KRAS. We investigated the clinical value of KRAS mutations when detected in plasma compared to tumour...

  1. Blocking transforming growth factor- receptor signaling down-regulates transforming growth factor-β1 autoproduction in keloid fibroblasts

    Institute of Scientific and Technical Information of China (English)

    刘伟; 蔡泽浩; 王丹茹; 武小莉; 崔磊; 商庆新; 钱云良; 曹谊林


    Objective: To study transforming growth factor-β1(TGF-β1) autoproduction in keloid fibroblasts and theregulation effect of blocking TGF-β intracellular signalingon rhTGF-β1 autoproduction.Methods: Keloid fibroblasts cultured in vitro weretreated with either rhTGF-β1 (5 ng/ml ) or recombinantadenovirus containing a truncated type II TGF-β receptorgene (50 pfu/cell ). Their effects of regulating geneexpression of TGF-β1 and its receptor I and II wereobserved with Northern blot.Results: rhTGF-β1 up-regulated the gene expressionof TGF-β1 and receptor I, but not receptor II. Over-expression of the truncated receptor II down-regulated thegene expression of TGF-β1 and its receptor I, but notreceptor II.Conclusions: TGF-β1 autoproduction was observed inkeloid fibroblasts. Over-expression of the truncated TGF-βreceptor H decreased TGF-β1 autoproduction via blockingTGF-β receptor signaling.

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

    DEFF Research Database (Denmark)

    Simonsen, L; Bülow, J; Sengeløv, H


    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...

  3. Expression of a glycosylphosphatidylinositol-anchored ligand, growth hormone, blocks receptor signalling. (United States)

    Guesdon, François; Kaabi, Yahia; Riley, Aiden H; Wilkinson, Ian R; Gray, Colin; James, David C; Artymiuk, Peter J; Sayers, Jon R; Ross, Richard J


    We have investigated the interaction between GH (growth hormone) and GHR (GH receptor). We previously demonstrated that a truncated GHR that possesses a transmembrane domain but no cytoplasmic domain blocks receptor signalling. Based on this observation we investigated the impact of tethering the receptor's extracellular domain to the cell surface using a native lipid GPI (glycosylphosphatidylinositol) anchor. We also investigated the effect of tethering GH, the ligand itself, to the cell surface and demonstrated that tethering either the ecGHR (extracellular domain of GHR) or the ligand itself to the cell membrane via a GPI anchor greatly attenuates signalling. To elucidate the mechanism for this antagonist activity, we used confocal microscopy to examine the fluorescently modified ligand and receptor. GH-GPI was expressed on the cell surface and formed inactive receptor complexes that failed to internalize and blocked receptor activation. In conclusion, contrary to expectation, tethering an agonist to the cell surface can generate an inactive hormone receptor complex that fails to internalize.

  4. Combined therapy using suicide gef gene and paclitaxel enhances growth inhibition of multicellular tumour spheroids of A-549 human lung cancer cells. (United States)

    Prados, Jose; Melguizo, Consolacion; Rama, Ana; Ortiz, Raul; Boulaiz, Houria; Rodriguez-Serrano, Fernando; Caba, Octavio; Rodriguez-Herva, Jose Juan; Ramos, Juan Luis; Aranega, Antonia


    The low efficiency of conventional therapies in achieving long-term survival of lung cancer patients calls for development of novel options. The potential use of combined gene therapy is under intensive study. One approach uses the expression of genes encoding cytotoxic proteins that affect cellular viability. The gef gene from E. coli, identified as a member of a gene family encoding homologous cell-killing functions, encodes for a membrane protein with a toxic domain which leads to a decrease in the rate of tumour cell growth. To improve the antitumoral effect of the paclitaxel in lung cancer cells, we investigated a combined suicide gene therapy using this drug and gef gene in vitro, using A-549 lung cancer cells in culture and forming multicellular tumour spheroids (MTS). Our results showed that gef expression in A-549 cells led to an ultrastructural changes, including dilated mitochondria with clear matrices and disrupted cristae and cell surface alterations such as reduction in length and number of microvilli and cytoplasmic membrane evaginations. The use of paclitaxel in A-549 lung cancer cells transfected with gef gene enhanced the chemotherapeutic effect of this drug. Volume analyses showed an 87.4% decrease in the A-549 MTS growth after 96 h in comparison with control MTS. This inhibition was greater than that obtained using the gene therapy or chemotherapy alone. In conclusion, gef gene has a cytotoxic effect in lung cancer cells and enhances cell growth inhibition when used with paclitaxel. These results indicate that this combined therapy may be of potential therapeutic value in lung cancer.

  5. Growth-inhibitory effects of the chemopreventive agent indole-3-carbinol are increased in combination with the polyamine putrescine in the SW480 colon tumour cell line

    Directory of Open Access Journals (Sweden)

    Gescher Andreas


    Full Text Available Abstract Background Many tumours undergo disregulation of polyamine homeostasis and upregulation of ornithine decarboxylase (ODC activity, which can promote carcinogenesis. In animal models of colon carcinogenesis, inhibition of ODC activity by difluoromethylornithine (DFMO has been shown to reduce the number and size of colon adenomas and carcinomas. Indole-3-carbinol (I3C has shown promising chemopreventive activity against a range of human tumour cell types, but little is known about the effect of this agent on colon cell lines. Here, we investigated whether inhibition of ODC by I3C could contribute to a chemopreventive effect in colon cell lines. Methods Cell cycle progression and induction of apoptosis were assessed by flow cytometry. Ornithine decarboxylase activity was determined by liberation of CO2 from 14C-labelled substrate, and polyamine levels were measured by HPLC. Results I3C inhibited proliferation of the human colon tumour cell lines HT29 and SW480, and of the normal tissue-derived HCEC line, and at higher concentrations induced apoptosis in SW480 cells. The agent also caused a decrease in ODC activity in a dose-dependent manner. While administration of exogenous putrescine reversed the growth-inhibitory effect of DFMO, it did not reverse the growth-inhibition following an I3C treatment, and in the case of the SW480 cell line, the effect was actually enhanced. In this cell line, combination treatment caused a slight increase in the proportion of cells in the G2/M phase of the cell cycle, and increased the proportion of cells undergoing necrosis, but did not predispose cells to apoptosis. Indole-3-carbinol also caused an increase in intracellular spermine levels, which was not modulated by putrescine co-administration. Conclusion While indole-3-carbinol decreased ornithine decarboxylase activity in the colon cell lines, it appears unlikely that this constitutes a major mechanism by which the agent exerts its antiproliferative

  6. Gastric Calcifying Fibrous Tumour

    Directory of Open Access Journals (Sweden)

    Tan Attila


    Full Text Available Intramucosal gastric tumours are most commonly found to be gastrointestinal stromal tumours or leiomyomas (smooth muscle tumours; however, a variety of other uncommon mesenchymal tumours can occur in the stomach wall. A rare benign calcifying fibrous tumour is reported and the endoscopic appearance, ultrasound findings and morphology are documented. A review of the literature found only two similar cases.

  7. Population Blocks. (United States)

    Smith, Martin H.


    Describes an educational game called "Population Blocks" that is designed to illustrate the concept of exponential growth of the human population and some potential effects of overpopulation. The game material consists of wooden blocks; 18 blocks are painted green (representing land), 7 are painted blue (representing water); and the remaining…

  8. MicroRNA-199a-5p promotes tumour growth by dual-targeting PIAS3 and p27 in human osteosarcoma (United States)

    Wang, Chen; Ba, Ximing; Guo, Yu; Sun, Defang; Jiang, Haoyang; Li, Wentao; Huang, Zhen; Zhou, Guangxin; Wu, Sujia; Zhang, Junfeng; Chen, Jiangning


    Osteosarcoma (OS) is the most common primary bone malignancy and remains a leading cause of cancer-related deaths in adolescents. Emerging evidence indicates that microRNAs (miRNAs) are correlated with clinical and biological characteristics of OS. However, the involvement of miR-199a-5p in OS development remains unclear. In this study, we examined the function of miR-199a-5p in vitro and in vivo. The results showed that miR-199a-5p was significantly up-regulated in OS patient tissues and cells. The inhibition of miR-199a-5p led to a significant decrease in cell proliferation and tumour growth. We further demonstrated that miR-199a-5p could directly bind to the 3′UTRs of the mRNA of both PIAS3 and p27 and mediate a decrease in the protein levels of PIAS3 and p27, thereby stimulating STAT3 activation and cell cycle progression in OS cells. Rescue experiments of PIAS3 and p27 further revealed that PIAS3 and p27 were functional targets of miR-199a-5p. Moreover, enhancing the expressions of both PIAS3 and p27 using miR-199a-5p-targeted inhibitors in an OS xenograft model was shown to be a promising approach for OS clinical therapy. Our findings indicate that the pathway of miR-199a-5p targeting both PIAS3 and p27 is a possible mechanism that contributes to tumour growth in OS. PMID:28120918

  9. Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3

    Institute of Scientific and Technical Information of China (English)

    Fang-Ming Gu; Quan-Lin Li; Qiang Gao; Jia-Hao Jiang; Xiao-Yong Huang; Jin-Feng Pan; Jia Fan; Jian Zhou


    AIM: To investigate the inhibitory role and the underlying mechanisms of sorafenib on signal transducer and activator of transcription 3 (STAT3) activity in hepatocellular carcinoma (HCC). METHODS: Human and rat HCC cell lines were treated with sorafenib. Proliferation and STAT3 dephosphorylation were assessed. Potential molecular mechanisms of STAT3 pathway inhibition by sorafenib were evaluated. In vivo antitumor action and STAT3 inhibition were investigated in an immunocompetent orthotopic rat HCC model. RESULTS: Sorafenib decreased STAT3 phosphorylation at the tyrosine and serine residues (Y705 and S727), but did not affect Janus kinase 2 (JAK2) and phospha-tase shatterproof 2 (SHP2), which is associated with growth inhibition in HCC cells. Dephosphorylation of S727 was associated with attenuated extracellular signal-regulated kinase (ERK) phosphorylation, similar to the effects of a mitogen-activated protein kinase (MEK) inhibitor U0126, suggesting that sorafenib induced S727 dephosphorylation by inhibiting MEK/ERK signaling. Meanwhile, sorafenib could also inhibit Akt phosphorylation, and both the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and Akt knockdown resulted in Y705 dephosphorylation, indicating that Y705 dephosphorylation by sorafenib was mediated by inhibiting the PI3K/Akt pathway. Finally, in the rat HCC model, sorafenib significantly inhibited STAT3 activity, reducing tumor growth and metastasis. CONCLUSION: Sorafenib inhibits growth and metastasis of HCC in part by blocking the MEK/ERK/STAT3 and PI3K/Akt/STAT3 signaling pathways, but independent of JAK2 and SHP2 activation.

  10. ING1 and 5-azacytidine act synergistically to block breast cancer cell growth.

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    Satbir Thakur

    Full Text Available BACKGROUND: Inhibitor of Growth (ING proteins are epigenetic "readers" that recognize trimethylated lysine 4 of histone H3 (H3K4Me3 and target histone acetyl transferase (HAT and histone deacetylase (HDAC complexes to chromatin. METHODS AND PRINCIPAL FINDINGS: Here we asked whether dysregulating two epigenetic pathways with chemical inhibitors showed synergistic effects on breast cancer cell line killing. We also tested whether ING1 could synergize better with chemotherapeutics that target the same epigenetic mechanism such as the HDAC inhibitor LBH589 (Panobinostat or a different epigenetic mechanism such as 5-azacytidine (5azaC, which inhibits DNA methyl transferases. Simultaneous treatment of breast cancer cell lines with LBH589 and 5azaC did not show significant synergy in killing cells. However, combination treatment of ING1 with either LBH589 or 5azaC did show synergy. The combination of ING1b with 5azaC, which targets two distinct epigenetic mechanisms, was more effective at lower doses and enhanced apoptosis as determined by Annexin V staining and cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP. ING1b plus 5azaC also acted synergistically to increase γH2AX staining indicating significant levels of DNA damage were induced. Adenoviral delivery of ING1b with 5azaC also inhibited cancer cell growth in a murine xenograft model and led to tumor regression when viral concentration was optimized in vivo. CONCLUSIONS: These data show that targeting distinct epigenetic pathways can be more effective in blocking cancer cell line growth than targeting the same pathway with multiple agents, and that using viral delivery of epigenetic regulators can be more effective in synergizing with a chemical agent than using two chemotherapeutic agents. This study also indicates that the ING1 epigenetic regulator may have additional activities in the cell when expressed at high levels.

  11. [Biotherapy of neuroendocrine tumours of the gastrointestinal tract and pancreas

    DEFF Research Database (Denmark)

    Hansen, C.P.; Knigge, U.


    Biotherapy of hormonal symptoms and tumour growth is a mainstay in the therapy of metastatic neuroendocrine tumours of the gastrointestinal tract and pancreas. Symptomatic relief can be achieved by somatostatin analogues and interferon, either alone or in combination. The effect on tumour growth...... is less convincing although a stabilization of disease is recorded in almost 50% of patients. Interferon treatment should mainly be considered for tumours with a low proliferation index Udgivelsesdato: 2008/6/9...

  12. Effect of an anti-human Co-029/tspan8/Tspan8 mouse monoclonal antibody on tumour growth in a nude mouse model

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    Naouel eAilane


    Full Text Available New therapeutic agents are needed in digestive tract tumours. Co-029/tspan8 is a tetraspanin frequently expressed on human colorectal tumours, In this work, we report the effects of the monoclonal antibody Ts29.2, targeting Co-029/tspan8, on colorectal tumor cells in vitro and after implantation in nude mice. HT29, Isreco1 and SW480 colorectal tumor cell lines were used for this study. HT29 has a strong endogenous expression of Co-029/tspan8, whereas Isreco1 cells don’t express Co-029/tspan8 and SW480 has only a weak expression. Isreco1 and SW480 were transduced to express Co-029/tspan8 at the same level as HT29. In order to check the specificity of the effect of monoclonal antibody Ts29.2, low Co029/tspan8 expressing SW480 cells were injected simultaneously with transduced cells in the back, on the left and right sides of the mice. With an early treatment, Ts29.2 mAb inhibited growth of tumors expressing Co-029/tspan8 up to 70%, whereas a delayed treatment was less efficient. No effect of the antibody on cell proliferation or apoptosis induction was detected in vitro. No increase of activated caspase 3 labeling was observed in vivo and areas occupied by vessels were not significantly different between treated mice and controls. This suggests that the action of Ts29.2 is linked neither to cellular toxicity nor to the inhibition of the previously reported angiogenic properties of Co-029/tspan8. An inhibition of cell proliferation in vivo is demonstrated by a reduction of the mitotic index in HT29 tumors of Ts29.2 treated mice. The discrepancy between in vitro and in vivo data on cell proliferation suggests that the binding of Ts29.2 to tumour cells may modify their response to signals issued from the microenvironment. Given the restricted pattern of tissue expression of the tetraspanin Co-029/tspan8, these preliminary results put forth for consideration the antibody targeting of this tetraspanin in further investigations for therapeutic

  13. MRI characteristics of midbrain tumours

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    Sun, B. [Chinese Academy of Medical Science, Beijing (China). Neurosurgical Inst.]|[Department of Neuroradiology, Beijing Tiantan Hospital (China); Wang, C.C.; Wang, J. [Chinese Academy of Medical Science, Beijing (China). Neurosurgical Inst.


    We diagnosed 60 cases of midbrain tumours by MRI between 1993 to 1997. There were 39 males and 21 females, aged 2-64 years, mean 25.6 years. We found 38 patients with true intramedullary midbrain tumours, 11 predominantly in the tectum, 20 in the tegmentum and 7 with a downward extension to the pons; there were 7 within the cerebral aqueduct. There were 22 patients with infiltrating midbrain tumours extending from adjacent structures, 11 cases each from the thalamus and pineal region. All patients received surgical treatment. Gross total resection was achieved in 42 cases, subtotal (> 75 %) resection in 18. Pathological diagnoses included 16 low-grade and 15 high-grade astrocytomas; 5 oligodendroastrocytomas; 2 ependymomas; 11 glioblastomas; and 11 pineal parenchymal or germ-cell tumours. Midbrain tumours are a heterogeneous group of neoplasms, with wide variation in clinical and MRI features, related to the site and type of tumour. MRI not only allows precise analysis of their growth pattern, but also can lead to a correct preoperative diagnosis in the majority of cases. (orig.) (orig.) With 3 figs., 3 tabs., 19 refs.

  14. A high-fat diet containing whole walnuts (Juglans regia) reduces tumour size and growth along with plasma insulin-like growth factor 1 in the transgenic adenocarcinoma of the mouse prostate model. (United States)

    Davis, Paul A; Vasu, Vihas T; Gohil, Kishorchandra; Kim, Hyunsook; Khan, Imran H; Cross, Carroll E; Yokoyama, Wallace


    Prostate cancer (PCa) has been linked to fat intake, but the effects of both different dietary fat levels and types remain inconsistent and incompletely characterised. The effects on PCa in the transgenic adenocarcinoma of the mouse prostate (TRAMP) cancer model of an elevated fat (20 % of energy as fat) diet containing 155 g of whole walnuts were compared to those of an elevated fat (20 % of energy as soyabean oil) diet with matched macronutrients, tocopherols as well as a low-fat (8 % of energy as soyabean oil) diet. Mice, starting at 8 weeks of age, consumed one of the three different diets ad libitum; and prostates, livers and blood were obtained after 9, 18 or 24 weeks of feeding. No differences were observed in whole animal growth rates in either high-fat (HF) diet group, but prostate tumour weight and growth rate were reduced in the walnut diet group. Walnut diet group prostate weight, plasma insulin-like growth factor 1, resistin and LDL were lower at 18 weeks, while no statistically significant prostate weight differences by diet were seen at 9 or 24 weeks. Multiple metabolites in the livers differed by diet at 9 and 18 weeks. The walnut diet's beneficial effects probably represent the effects of whole walnuts' multiple constituents and not via a specific fatty acid or tocopherols. Moreover, as the two HF diets had dissimilar effects on prostate tumour growth rate and size, and yet had the same total fat and tocopherol composition and content, this suggests that these are not strongly linked to PCa growth.

  15. A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK- and PI3K-induced malignant growth

    Directory of Open Access Journals (Sweden)

    Marie Mayrhofer


    Full Text Available Somatic mutations activating MAPK and PI3K signalling play a pivotal role in both tumours and brain developmental disorders. We developed a zebrafish model of brain tumours based on somatic expression of oncogenes that activate MAPK and PI3K signalling in neural progenitor cells and found that HRASV12 was the most effective in inducing both heterotopia and invasive tumours. Tumours, but not heterotopias, require persistent activation of phospho (p-ERK and express a gene signature similar to the mesenchymal glioblastoma subtype, with a strong YAP component. Application of an eight-gene signature to human brain tumours establishes that YAP activation distinguishes between mesenchymal glioblastoma and low grade glioma in a wide The Cancer Genome Atlas (TCGA sample set including gliomas and glioblastomas (GBMs. This suggests that the activation of YAP might be an important event in brain tumour development, promoting malignant versus benign brain lesions. Indeed, co-expression of dominant-active YAP (YAPS5A and HRASV12 abolishes the development of heterotopias and leads to the sole development of aggressive tumours. Thus, we have developed a model proving that neurodevelopmental disorders and brain tumours might originate from the same activation of oncogenes through somatic mutations, and established that YAP activation is a hallmark of malignant brain tumours.

  16. A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK- and PI3K-induced malignant growth (United States)

    Mayrhofer, Marie; Gourain, Victor; Reischl, Markus; Affaticati, Pierre; Jenett, Arnim; Joly, Jean-Stephane; Benelli, Matteo; Demichelis, Francesca; Poliani, Pietro Luigi; Sieger, Dirk


    ABSTRACT Somatic mutations activating MAPK and PI3K signalling play a pivotal role in both tumours and brain developmental disorders. We developed a zebrafish model of brain tumours based on somatic expression of oncogenes that activate MAPK and PI3K signalling in neural progenitor cells and found that HRASV12 was the most effective in inducing both heterotopia and invasive tumours. Tumours, but not heterotopias, require persistent activation of phospho (p)-ERK and express a gene signature similar to the mesenchymal glioblastoma subtype, with a strong YAP component. Application of an eight-gene signature to human brain tumours establishes that YAP activation distinguishes between mesenchymal glioblastoma and low grade glioma in a wide The Cancer Genome Atlas (TCGA) sample set including gliomas and glioblastomas (GBMs). This suggests that the activation of YAP might be an important event in brain tumour development, promoting malignant versus benign brain lesions. Indeed, co-expression of dominant-active YAP (YAPS5A) and HRASV12 abolishes the development of heterotopias and leads to the sole development of aggressive tumours. Thus, we have developed a model proving that neurodevelopmental disorders and brain tumours might originate from the same activation of oncogenes through somatic mutations, and established that YAP activation is a hallmark of malignant brain tumours. PMID:27935819

  17. CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth. (United States)

    Strock, Christopher J; Park, Jong-In; Rosen, Mark; Dionne, Craig; Ruggeri, Bruce; Jones-Bolin, Susan; Denmeade, Samuel R; Ball, Douglas W; Nelkin, Barry D


    All of the cases of medullary thyroid carcinoma (MTC) express the RET receptor tyrosine kinase. In essentially all of the hereditary cases and approximately 40% of the sporadic cases of MTC, the RET kinase is constitutively activated by mutation. This suggests that RET may be an effective therapeutic target for treatment of MTC. We show that the indolocarbazole derivatives, CEP-701 and CEP-751, inhibit RET in MTC cells. These compounds effectively inhibit RET phosphorylation in a dose-dependent manner at concentrations <100 nM in 0.5% serum and at somewhat higher concentrations in the presence of 16% serum. They also blocked the growth of these MTC cells in culture. CEP-751 and its prodrug, CEP-2563, also inhibited tumor growth in MTC cell xenografts. These results show that inhibiting RET can block the growth of MTC cells and may have a therapeutic benefit in MTC.

  18. p53 status determines the role of autophagy in pancreatic tumour development (United States)

    Rosenfeldt, Mathias T.; O'Prey, Jim; Morton, Jennifer P.; Nixon, Colin; Mackay, Gillian; Mrowinska, Agata; Au, Amy; Rai, Taranjit Singh; Zheng, Liang; Ridgway, Rachel; Adams, Peter D.; Anderson, Kurt I.; Gottlieb, Eyal; Sansom, Owen J.; Ryan, Kevin M.


    Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation. Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease. The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles. Here we show, in a humanized genetically-modified mouse model of pancreatic ductal adenocarcinoma (PDAC), that autophagy's role in tumour development is intrinsically connected to the status of the tumour suppressor p53. Mice with pancreases containing an activated oncogenic allele of Kras (also called Ki-Ras)--the most common mutational event in PDAC--develop a small number of pre-cancerous lesions that stochastically develop into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 or Atg7 accumulate low-grade, pre-malignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC is blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocks tumour progression, but actually accelerates tumour onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumour growth. These findings provide considerable insight into the role of autophagy in cancer and have important implications for autophagy inhibition in cancer therapy. In this regard, we also show that treatment of mice with the autophagy inhibitor hydroxychloroquine, which is currently being used in several clinical trials, significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53.

  19. Specific chalone inhibition of the regeneration of the JB-1 ascites tumour studied by flow microfluorometry. (United States)

    Bichel, P; Barfod, N M


    The variation in the DNA distribution in the JB-1 and the Lla2 ascites tumour was investigated by means of flow microfluorometry (FMF) in the plateau stage and during the initiation of the regenerative growth induced by percutaneous aspiration. The study showed that a considerable influx of cells with G1DNA content into the S phase occurred in both tumours about 10 hr after aspiration. In the JB-1 tumour, these initial regenerative changes could be reversibly blocked by injections of cell-free plateau JB-1 ascitic fluid or an ultrafiltrate of this ascites. In contrast to these observations no delay in the regenerative changes was observed in the L1a2 tumour after treatment with JB-1 ascites or the ultrafiltrate. The study supports the assumption of a specific growth regulation of the JB-1 ascites tumour and emphasizes the suitability of FMF analyses in cell-kinetic studies in which short-term fluctuations take place in the distribution of cells with different DNA content.

  20. Anti-inflammatory effects of tumour necrosis factor (TNF)-alpha are mediated via TNF-R2 (p75) in tolerogenic transforming growth factor-beta-treated antigen-presenting cells. (United States)

    Masli, Sharmila; Turpie, Bruce


    Exposure of macrophages to transforming growth factor (TGF)-beta is known to alter their functional phenotype such that antigen presentation by these cells leads to tolerance rather than an inflammatory immune response. Typically, eye-derived antigen-presenting cells (APCs) exposed to TGF-beta in the local environment are known to induce a form of peripheral tolerance and protect the eye from inflammatory immune effector-mediated damage. In response to TGF-beta, APCs increase their expression of tumour necrosis factor (TNF)-alpha and TNF receptor 2 (TNF-R2). Although TNF-alpha has been implicated in tolerance and the associated regulation of the inflammatory immune response, its source and the receptors involved remain unclear. In this report we determined the contribution of TNF-alpha and TNF-R2 expressed by TGF-beta-treated APCs to their anti-inflammatory tolerogenic effect. Our results indicate that APC-derived TNF-alpha is essential for the ability of APCs to regulate the immune response and their IL-12 secretion. Moreover, in the absence of TNF-R2, APCs exposed to TGF-beta failed to induce tolerance or regulatory cells known to participate in this tolerance. Also, blocking of TNF-R1 signalling enhanced the ability of the APCs to secrete increased TGF-beta in response to TGF-beta exposure. Together our results support an anti-inflammatory role of TNF-alpha in regulation of an immune response by TGF-beta-treated APCs and suggest that TNF-R2 contributes significantly to this role.

  1. Interaction between three subpopulations of Ehrlich carcinoma in mixed solid tumours in nude mice: evidence of contact domination

    DEFF Research Database (Denmark)

    Aabo, K; Vindeløv, L L; Spang-Thomsen, M


    Clonal interaction between three subpopulations of Ehrlich carcinoma were studied during growth as mixed solid tumours and as ascites tumours in immune-incompetent nude NMRI mice. The tumour cell lines differed in DNA content as determined by DNA flow cytometry (FCM). Tumour growth was evaluated...... by tumour growth curves including calculation of tumour volume doubling times, tumour weight on day 14, cell cycle times (per cent labelled mitoses) and cell cycle distributions (FCM). Two subpopulations (E1.15 and E1.95) showed nearly identical growth characteristics during both solid and ascites tumour...


    Directory of Open Access Journals (Sweden)



    Full Text Available Phosphaturic mesenchymal tumour is a tumour that can involve bone or soft tissue. This is a rare tumour and is known to be associated with osteomalasia. This is caused by tumour induced expression of fibroblastic growth factor (FGF23. We present a case of PMT in a 72 year old female patient who was diagnosed with osteomalasia due to nutritional deficiency of vitamin D and was appropriately treated but later presented with a mass in her foot.

  3. A multifactorial approach including tumoural epidermal growth factor receptor, p53, thymidylate synthase and dihydropyrimidine dehydrogenase to predict treatment outcome in head and neck cancer patients receiving 5-fluorouracil


    Etienne, M. C.; Pivot, X; Formento, J. L.; Bensadoun, R J; Formento, P.; Dassonville, O; Francoual, M.; Poissonnet, G.; Fontana, X; Schneider, M.; Demard, F.; Milano, G


    The prognostic value of tumoural epidermal growth factor receptor (EGFR), p53, thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) was analysed on 82 advanced head and neck cancer patients (71 men, 11 women; mean age 59). Induction treatment was cisplatin–5-FU ± folinic acid (61 patients, Chem group) or concomitant cisplatin–5-FU–radiotherapy (21 patients, RChem group). EGFR (binding assay), p53 protein (Sangtec immunoluminometric assay), TS and DPD activities (radioenzymatic ...

  4. Targeting tumour Cell Plasticity

    Institute of Scientific and Technical Information of China (English)

    Elizabeth D. WILLIAMS


    @@ Her research is focused on understanding the mechanisms of tumour progression and metastasis, particularly in uro-logical carcinomas (bladder and prostate). Tumour cell plasticity, including epithelial-mesenchymal transition, is a cen-tral theme in Dr Williams' work.

  5. The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth. (United States)

    Ehnman, M; Li, H; Fredriksson, L; Pietras, K; Eriksson, U


    Members of the platelet-derived growth factor (PDGF) family are mitogens for cells of mesenchymal origin and have important functions during embryonic development, blood vessel maturation, fibrotic diseases and cancer. In contrast to the two classical PDGFs, the novel and less well-characterized members, PDGF-CC and PDGF-DD, are latent factors that need to be processed extracellularly by activating proteases, before they can mediate PDGF receptor activation. Here, we elucidate the structural requirements for urokinase plasminogen activator (uPA)-mediated activation of PDGF-DD, as well as the intricate interplay with uPA receptor (uPAR) signalling. Furthermore, we show that activated PDGF-DD, in comparison to latent, more potently transforms NIH/3T3 cells in vitro. Conversely, xenograft studies in nude mice demonstrate that cells expressing latent PDGF-DD are more tumorigenic than those expressing activated PDGF-DD. These findings imply that a fine-tuned proteolytic activation, in the local milieu, controls PDGF-DD bioavailability. Moreover, we suggest that proteolytic activation of PDGF-DD reveals a retention motif mediating interactions with pericellular components. Our proposed mechanism, where uPA not only generates active PDGF-DD, but also regulates its spatial distribution, provides novel insights into the biological function of PDGF-DD.

  6. Growth of Theileria annulata and Theileria parva macroschizont-infected bovine cells in immunodeficient mice: effect of irradiation and tumour load on lymphocyte subsets

    Energy Technology Data Exchange (ETDEWEB)

    Fell, A.H.; Preston, P.M. (Edinburgh Univ. (United Kingdom))


    Bovine cells infected with macroschizonts of the protozoan parasites Theileria annulata and Theileria parva formed solid tumours when injected into irradiated Balb/c and irradiated Balb/c nude mice. T. annulata tumours grew more vigorously than T. parva tumours, when initiated with similar doses of infected cells in mice exposed to the same doses of gamma-irradiation. In irradiated Balb/c mice, tumours of both species of parasites began to regress 2-3 weeks after injection of cells but grew without regression in irradiated Balb/c nude mice. Haemorrhage and necrosis of tumours, induced by macrophages and neutrophils, were seen in both mouse strains but were insufficient to cause regression in Balb/c nude mice. Theileria-infected bovine cells failed to establish in C57 beige mice, which lack functional natural killer (NK) cells. Flow cytometry, using monoclonal antibodies to murine leukocyte/lymphocyte antigens, showed that the radiation dose required to allow establishment of T. annulata tumours in Balb/c mice caused a severe depletion of splenic lymphocytes. B cells, helper T and cytotoxic T cells showed differing levels of susceptibility to irradiation. (Author).

  7. Use of ultrasonic back-reflection intensity for predicting the onset of crack growth due to low-cycle fatigue in stainless steel under block loading. (United States)

    Islam, Md Nurul; Arai, Yoshio; Araki, Wakako


    The present study proposes the use of ultrasonic back-reflected waves for evaluating low cycle fatigue crack growth from persistent slip bands (PSBs) of stainless steel under block loading. Fatigue under high-low block loading changes the back-reflected intensity of the ultrasonic wave that emanates from the surface. Measuring the change in ultrasonic intensity can predict the start of crack growth with reasonable accuracy. The present study also proposes a modified constant cumulative plastic strain method and a PSB damage evolution model to predict the onset of crack growth under block loads.

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

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    Bremmer Felix


    Full Text Available 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:

  9. Thermal resistance in a spontaneous murine tumour. (United States)

    Maher, J; Urano, M; Rice, L; Suit, H D


    Resistance to subsequent hyperthermia as a result of prior heating was investigated using a spontaneous murine tumour implanted into the feet of C3H/Sed mice. Tumours were treated by immersing the tumour-bearing foot into a constant-temperature hot water bath set at 45.5 degrees C and were given single and split doses of heat. Response was assessed using a tumour-growth time assay. Three aspects of thermally-induced resistance were particularly considered: the time course of development and decay; the importance of the magnitude of the priming dose and the influence of the size of the tumour at the time of treatment. Substantial resistance was induced in this tumour by short priming doses at 45.5 degrees C, rising rapidly 1-2 days after the first treatment and then starting to decay. There was no significant difference in the kinetics of thermal resistance induced in tumours treated at 4mm and those treated at 8 mm in size, although the large tumours were more sensitive to single doses of heat. Increasing the magnitude of the priming dose of heat resulted in an increase in the magnitude of resistance to the second dose. The results of this study are compared with results of similar studies in this and other laboratories using murine normal tissues and cells in culture. Possible clinical implications are considered.

  10. Oncogenic extracellular vesicles in brain tumour progression

    Directory of Open Access Journals (Sweden)

    Esterina eD'Asti


    Full Text Available The brain is a frequent site of neoplastic growth, including both primary and metastatic tumours. The clinical intractability of many brain tumours and their distinct biology are implicitly linked to the unique microenvironment of the central nervous system (CNS and cellular interactions within. Among the most intriguing forms of cellular interactions is that mediated by membrane-derived extracellular vesicles (EVs. Their biogenesis (vesiculation and uptake by recipient cells serves as a unique mechanism of intercellular trafficking of complex biological messages including the exchange of molecules that cannot be released through classical secretory pathways, or that are prone to extracellular degradation. Tumour cells produce EVs containing molecular effectors of several cancer-related processes such as growth, invasion, drug resistance, angiogenesis, and coagulopathy. Notably, tumour-derived EVs (oncosomes also contain oncogenic proteins, transcripts, DNA and microRNA (miR. Uptake of this material may change properties of the recipient cells and impact the tumour microenvironment. Examples of transformation-related molecules found in the cargo of tumour-derived EVs include the oncogenic epidermal growth factor receptor (EGFRvIII, tumour suppressors (PTEN and oncomirs (miR-520g. It is postulated that EVs circulating in blood or cerebrospinal fluid (CSF of brain tumour patients may be used to decipher molecular features (mutations of the underlying malignancy, reflect responses to therapy or molecular subtypes of primary brain tumours (e.g. glioma or medulloblastoma. It is possible that metastases to the brain may also emit EVs with clinically relevant oncogenic signatures. Thus EVs emerge as a novel and functionally important vehicle of intercellular communication that can mediate multiple biological effects. In addition, they provide a unique platform to develop molecular biomarkers in brain malignancies.

  11. Mechanisms of tumour escape from immune surveillance

    Directory of Open Access Journals (Sweden)

    Lisiecka Urszula


    Full Text Available The progressive growth and spread of tumour cells in the form of metastases requires an interaction of healthy host cells, such as endothelial cells, fibroblasts, and other cells of mesenchymal origin with immune cells taking part in innate and adaptive responses within the tumour lesion and entire body. The host cells interact with tumour cells to create a dynamic tumour microenvironment, in which healthy cells can both positively and negatively influence the growth and spread of the tumour. The balance of cellular homeostasis and the effect of substances they secrete on the tumour microenvironment determine whether the tumour has a tendency to grow or disappear, and whether the cells remain within the lesion or are capable of metastasis to other regions of the body. Intercellular interactions also determine the tumour’s susceptibility to radiation or other types of cancer treatment. They may also be a rational explanation for differences in treatment outcomes, in which some metastases regress and others progress in response to the same treatment method.

  12. mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis. (United States)

    Roy, Debasmita; Sin, Sang-Hoon; Lucas, Amy; Venkataramanan, Raman; Wang, Ling; Eason, Anthony; Chavakula, Veenadhari; Hilton, Isaac B; Tamburro, Kristen M; Damania, Blossom; Dittmer, Dirk P


    Kaposi sarcoma originates from endothelial cells and it is one of the most overt angiogenic tumors. In Sub-Saharan Africa, where HIV and the Kaposi sarcoma-associated herpesvirus (KSHV) are endemic, Kaposi sarcoma is the most common cancer overall, but model systems for disease study are insufficient. Here, we report the development of a novel mouse model of Kaposi sarcoma, where KSHV is retained stably and tumors are elicited rapidly. Tumor growth was sensitive to specific allosteric inhibitors (rapamycin, CCI-779, and RAD001) of the pivotal cell growth regulator mTOR. Inhibition of tumor growth was durable up to 130 days and reversible. mTOR blockade reduced VEGF secretion and formation of tumor vasculature. Together, the results show that mTOR inhibitors exert a direct anti-Kaposi sarcoma effect by inhibiting angiogenesis and paracrine effectors, suggesting their application as a new treatment modality for Kaposi sarcoma and other cancers of endothelial origin.

  13. Determination of the Critical Concentration of Neutrophils Required to Block Bacterial Growth in Tissues


    Li, Yongmei; Karlin, Arthur; Loike, John D.; Silverstein, Samuel C


    We showed previously that the competition between bacterial killing by neutrophils and bacterial growth in stirred serum-containing suspensions could be modeled as the competition between a first-order reaction (bacterial growth) and a second-order reaction (bacterial killing by neutrophils). The model provided a useful parameter, the critical neutrophil concentration (CNC), below which bacterial concentration increased and above which it decreased, independent of the initial bacterial concen...

  14. Sorafenib inhibits tumor growth and vascularization of rhabdomyosarcoma cells by blocking IGF-1R-mediated signaling

    Directory of Open Access Journals (Sweden)

    Wessen Maruwge


    Full Text Available Wessen Maruwge1, Pádraig D’Arcy1, Annika Folin1,2, Slavica Brnjic1, Johan Wejde1, Anthony Davis1, Fredrik Erlandsson3, Jonas Bergh1,2, Bertha Brodin11Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; 2Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden; 3Bayer Pharmaceutical Corporation, SwedenAbstract: The growth of many soft tissue sarcomas is dependent on aberrant growth factor signaling, which promotes their proliferation and motility. With this in mind, we evaluated the effect of sorafenib, a receptor tyrosine kinase inhibitor, on cell growth and apoptosis in sarcoma cell lines of various histological subtypes. We found that sorafenib effectively inhibited cell proliferation in rhabdomyosarcoma, synovial sarcoma and Ewing’s sarcoma with IC50 values <5 µM. Sorafenib effectively induced growth arrest in rhabdomyosarcoma cells, which was concurrent with inhibition of Akt and Erk signaling. Studies of ligand-induced phosphorylation of Erk and Akt in rhabdomyosarcoma cells showed that insulin-like growth factor-1 is a potent activator, which can be blocked by treatment with sorafenib. In vivo sorafenib treatment of rhabdomyosarcoma xenografts had a significant inhibitory effect on tumor growth, which was associated with inhibited vascularization and enhanced necrosis in the adjacent tumor stroma. Our results demonstrate that in vitro and in vivo growth of rhabdomyosarcoma can be suppressed by treatment with sorafenib, and suggests the possibilities of using sorafenib as a potential adjuvant therapy for the treatment of rhabdomyosarcoma.Keywords: soft tissue sarcoma, kinase inhibitors, targeted therapy, vascularization

  15. Imaging of sacral tumours

    Energy Technology Data Exchange (ETDEWEB)

    Gerber, S.; Ollivier, L.; Brisse, H.; Neuenschwander, S. [Institut Curie, Department of Radiology, Paris (France); Leclere, J. [Institut Gustave Roussy, Department of Radiology, Villejuif (France); Vanel, D. [The Rizzoli Institute, Department of Radiology, Bologna (Italy); Missenard, G. [Institut Gustave Roussy, Comite de pathologie tumorale de l' appareil locomoteur, Villejuif (France); Pinieux, G. de [CHRU de Tours, Department of Pathology, Hopital Trousseau, Tours (France)


    All components of the sacrum (bone, cartilage, bone marrow, meninges, nerves, notochord remnants, etc.) can give rise to benign or malignant tumours. Bone metastases and intraosseous sites of haematological malignancies, lymphoma and multiple myeloma are the most frequent aetiologies, while primary bone tumours and meningeal or nerve tumours are less common. Some histological types have a predilection for the sacrum, especially chordoma and giant cell tumour. Clinical signs are usually minor, and sacral tumours are often discovered in the context of nerve root or pelvic organ compression. The roles of conventional radiology, CT and MRI are described and compared with the histological features of the main tumours. The impact of imaging on treatment decisions and follow-up is also reviewed. (orig.)

  16. Blocking tumor growth by targeting autophagy and SQSTM1 in vivo. (United States)

    Wei, Huijun; Guan, Jun-Lin


    Autophagy is a highly conserved cellular process for degradation of bulk cytoplasmic materials in response to starvation and maintenance of cellular homeostasis. Dysfunction of autophagy is implicated in a variety of diseases including cancer. In a recent study, we devised a system for inducible deletion of an essential autophagy gene Rb1cc1/Fip200 in established tumor cells in vivo and showed that Rb1cc1 is required for maintaining tumor growth. We further investigated the role of the accumulated SQSTM1 in Rb1cc1-null autophagy-deficient tumor cells. To our surprise, the increased SQSTM1 was not responsible for the inhibition of tumor growth, but rather supported the residual growth of tumors (i.e., partially compensated for the defective growth caused by Rb1cc1 deletion). Further analysis indicated that SQSTM1 promoted tumor growth in autophagy-deficient cells at least partially through its activation of the NFKB signaling pathway. A working model is proposed to account for our findings, which suggest that targeting both autophagy and the consequently increased SQSTM1 may be exploited for developing more effective cancer therapies.

  17. Perinatal tumours: the contribution of radiology to management

    Energy Technology Data Exchange (ETDEWEB)

    Donoghue, Veronica; Ryan, Stephanie; Twomey, Eilish [Children' s University Hospital, Radiology Department, Dublin (Ireland)


    A formal classification does not exist and they are probably best classified by their location. Overall the most common neoplasms are - Extracranial teratoma - Neuroblastoma - Soft-tissue tumours - Brain tumours - Leukaemia - Renal tumours - Liver tumours - Retinoblastoma. The prognosis is generally poor, although there are some exceptions such as congenital neuroblastoma and hepatoblastoma. These tumours have a tendency to regress and have a benign clinical course despite a clear malignant histological picture. Other tumours, though histologically benign, may be fatal because of their size and location. Large benign masses may cause airway or cardiovascular compromise and death. Others may cause significant mass effect preventing normal organ development. As normal embryonic cells have a high mitotic rate it is not surprising that perinatal tumours may have a rapid growth rate and become enormous in size. (orig.)

  18. Growth of block copolymer stabilized metal nanoparticles probed simultaneously by in situ XAS and UV-Vis spectroscopy. (United States)

    Nayak, C; Bhattacharyya, D; Jha, S N; Sahoo, N K


    The growth of Au and Pt nanoparticles from their respective chloride precursors using block copolymer-based reducers has been studied by simultaneous in situ measurement of XAS and UV-Vis spectroscopy at the energy-dispersive EXAFS beamline (BL-08) at INDUS-2 SRS at RRCAT, Indore, India. While the XANES spectra of the precursor give real-time information on the reduction process, the EXAFS spectra reveal the structure of the clusters formed at the intermediate stages of growth. The growth kinetics of both types of nanoparticles are found to be almost similar and are found to follow three stages, though the first stage of nucleation takes place earlier in the case of Au than in the case of Pt nanoparticles due to the difference in the reduction potential of the respective precursors. The first two stages of the growth of Au and Pt nanoparticles as obtained by in situ XAS measurements could be corroborated by simultaneous in situ measurement of UV-Vis spectroscopy also.

  19. The Antituberculosis Drug Ethambutol Selectively Blocks Apical Growth in CMN Group Bacteria (United States)

    Schubert, Karin; Sieger, Boris; Meyer, Fabian; Giacomelli, Giacomo; Böhm, Kati; Rieblinger, Angela; Lindenthal, Laura; Sachs, Nadja; Wanner, Gerhard


    ABSTRACT Members of the genus Mycobacterium are the most prevalent cause of infectious diseases. Mycobacteria have a complex cell envelope containing a peptidoglycan layer and an additional arabinogalactan polymer to which a mycolic acid bilayer is linked; this complex, multilayered cell wall composition (mAGP) is conserved among all CMN group bacteria. The arabinogalactan and mycolic acid synthesis pathways constitute effective drug targets for tuberculosis treatment. Ethambutol (EMB), a classical antituberculosis drug, inhibits the synthesis of the arabinose polymer. Although EMB acts bacteriostatically, its underlying molecular mechanism remains unclear. Here, we used Corynebacterium glutamicum and Mycobacterium phlei as model organisms to study the effects of EMB at the single-cell level. Our results demonstrate that EMB specifically blocks apical cell wall synthesis, but not cell division, explaining the bacteriostatic effect of EMB. Furthermore, the data suggest that members of the family Corynebacterineae have two dedicated machineries for cell elongation (elongasome) and cytokinesis (divisome). PMID:28174310

  20. Nanoparticle-blood interactions: the implications on solid tumour targeting. (United States)

    Lazarovits, James; Chen, Yih Yang; Sykes, Edward A; Chan, Warren C W


    Nanoparticles are suitable platforms for cancer targeting and diagnostic applications. Typically, less than 10% of all systemically administered nanoparticles accumulate in the tumour. Here we explore the interactions of blood components with nanoparticles and describe how these interactions influence solid tumour targeting. In the blood, serum proteins adsorb onto nanoparticles to form a protein corona in a manner dependent on nanoparticle physicochemical properties. These serum proteins can block nanoparticle tumour targeting ligands from binding to tumour cell receptors. Additionally, serum proteins can also encourage nanoparticle uptake by macrophages, which decreases nanoparticle availability in the blood and limits tumour accumulation. The formation of this protein corona will also increase the nanoparticle hydrodynamic size or induce aggregation, which makes nanoparticles too large to enter into the tumour through pores of the leaky vessels, and prevents their deep penetration into tumours for cell targeting. Recent studies have focused on developing new chemical strategies to reduce or eliminate serum protein adsorption, and rescue the targeting potential of nanoparticles to tumour cells. An in-depth and complete understanding of nanoparticle-blood interactions is key to designing nanoparticles with optimal physicochemical properties with high tumour accumulation. The purpose of this review article is to describe how the protein corona alters the targeting of nanoparticles to solid tumours and explains current solutions to solve this problem.

  1. Enhanced inhibition of tumour growth and metastasis, and induction of antitumour immunity by IL-2-IgG2b fusion protein. (United States)

    Budagian, V; Nanni, P; Lollini, P L; Musiani, P; Di Carlo, E; Bulanova, E; Paus, R; Bulfone-Paus, S


    Cytokine-immunoglobulin (Ig)-fusion proteins have attracted increasing interest as antitumour agents. Here, we have investigated the antimetastatic and antitumour responses elicited in vivo by mammary adenocarcinoma cells (TS/A) engineered to secrete interleukin (IL)-2-IgG fusion proteins. TS/A cells were transfected with DNA coding for IL-2-IgG2b, IgG2b or IL-2, and injected subcutaneously into syngeneic mice. Animals injected with TS/A-IL-2 or TS/A-IL-2-IgG2b both efficiently rejected tumours, whereas treatment with parental cells or TS/A-IgG2b was lethal. Interestingly, only mice vaccinated with IL-2-IgG2b fusion protein-secreting cells showed a long-lasting protective immunity against a later challenge with parental tumour cells. Moreover, the metastatic potential of TS/A-IL-2-IgG2b-transfected cells was dramatically decreased compared with TS/A-IL-2-cells, with a virtual absence of lung metastases after intravenous injection. Adenocarcinomas secreting IL-2-IgG2b exhibited a more prominent, early and persistent infiltration of CD4+, CD8+ and natural killer (NK) cells than TS/A-IL-2 cells. Therefore, upon transfection into adenocarcinoma cells, the IgG2b part of IL-2 fusion protein exerts intriguing added antitumour properties over IL-2 alone, thus contributing to a long-lasting tumour immunity, probably by the recruitment of specific immune effector cells. These findings suggest a promising new oncotherapeutic strategy for poorly immunogenic tumours: vaccination with tumour cells engineered to secrete IL-2-IgG2b fusion protein.

  2. Inflammatory myofibroblastic tumour of maxilla

    Directory of Open Access Journals (Sweden)

    Deshingkar S


    Full Text Available Inflammatory myofibroblastic tumour (IMT is a biologically controversial entity that was originally described as non-neoplastic lesion in the lungs and designated initially as inflammatory pseudotumour. The lesion has recently been recognized to occur at various sites but rarely affects head and neck region. Controversies still exist regarding its reactive versus neoplastic nature. The lesion has a potential for recurrence, persistent local growth, progression to frank sarcoma and metastasis. Hence IMT can best be regarded as a low-grade sarcoma. A case of a 30-year-old female with swelling in the right maxilla and associated ophthalmic manifestations is discussed here. Contribution of immunohistochemistry for diagnosis of IMT is emphasized. Additional cytogenetic studies of this highly enigmatic and minimally studied tumour are warranted.

  3. Small interfering RNA targeted to secretory clusterin blocks tumor growth, motility, and invasion in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Zhaohe Niu; Xinhui Li; Bin Hu; Rong Li; Ligang Wang; Lilin Wu; Xingang Wang


    Clusterin/apolipoprotein J (Clu) is a ubiquitously expressed secreted heterodimeric glycoprotein that is implicated in several physiological processes.It has been reported that the elevated level of secreted clusterin (sClu) protein is associated with poor survival in breast cancer patients and can induce metastasis in rodent models.In this study,we investigated the effects of sClu inhibition with small interfering RNAs (siRNAs) on cell motility,invasion,and growth in vitro and in vivo.MDA-MB-231 cells were transfected with pSuper-siRNA/sClu.Cell survival and proliferation were examined by 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and clonogenic survival assay.The results showed that sClu silencing significantly inhibited the proliferation of MDA-MB-231 cells.The invasion and migration ability were also dramatically decreased,which was detected by matrigel assays.TUNEL staining and caspase-3 activity assay demonstrated that sClu silencing also could increase the apoptosis rate of cells,resulting in the inhibition of cell growth.We also determined the effects of sClu silencing on tumor growth and metastatic progression in an orthotopic breast cancer model.The results showed that orthotopic primary tumors derived from MDA-MB-231/pSuper sClu siRNA cells grew significantly slower than tumors derived from parental MDA-MB-231 or MDA-MB-231/pSuper scramble siRNA cells,and metastasize less to the lungs.These data suggest that secretory clusterin plays a significant role in tumor growth and metastatic progression.Knocking-down sClu gene expression may provide a valuable method for breast cancer therapy.

  4. Platycodin D inhibits tumor growth by antiangiogenic activity via blocking VEGFR2-mediated signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Luan, Xin; Gao, Yun-Ge; Guan, Ying-Yun; Xu, Jian-Rong; Lu, Qin [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China); Zhao, Mei [Department of Pharmacy, Shanghai Institute of Health Sciences and Health School Attached to SJTU-SM, 279 Zhouzhu Road, Shanghai 201318 (China); Liu, Ya-Rong; Liu, Hai-Jun [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China); Fang, Chao, E-mail: [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China); Chen, Hong-Zhuan, E-mail: [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China)


    Platycodin D (PD) is an active component mainly isolated from the root of Platycodon grandiflorum. Recent studies proved that PD exhibited inhibitory effect on proliferation, migration, invasion and xenograft growth of diverse cancer cell lines. However, whether PD is suppressive for angiogenesis, an important hallmark in cancer development, remains unknown. Here, we found that PD could dose-dependently inhibit human umbilical vein endothelial cell (HUVEC) proliferation, motility, migration and tube formation. PD also significantly inhibited angiogenesis in the chick embryo chorioallantoic membrane (CAM). Moreover, the antiangiogenic activity of PD contributed to its in vivo anticancer potency shown in the decreased microvessel density and delayed growth of HCT-15 xenograft in mice with no overt toxicity. Western blot analysis indicated that PD inhibited the phosphorylation of VEGFR2 and its downstream protein kinase including PLCγ1, JAK2, FAK, Src, and Akt in endothelial cells. Molecular docking simulation showed that PD formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. The present study firstly revealed the high antiangiogenic activity and the underlying molecular basis of PD, suggesting that PD may be a potential antiangiogenic agent for angiogenesis-related diseases. - Highlights: • Platycodin D inhibits HUVEC proliferation, motility, migration and tube formation. • Platycodin D inhibits the angiogenesis in chick embryo chorioallantoic membrane. • Platycodin D suppresses the angiogenesis and growth of HCT-15 xenograft in mice. • Platycodin D inhibits the phosphorylation of VEGFR2 and downstream kinases in HUVEC.

  5. A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth in vivo

    Directory of Open Access Journals (Sweden)

    Powers David


    Full Text Available Abstract Background Integrins are important adhesion molecules that regulate tumor and endothelial cell survival, proliferation and migration. The integrin α5β1 has been shown to play a critical role during angiogenesis. An inhibitor of this integrin, volociximab (M200, inhibits endothelial cell growth and movement in vitro, independent of the growth factor milieu, and inhibits tumor growth in vivo in the rabbit VX2 carcinoma model. Although volociximab has already been tested in open label, pilot phase II clinical trials in melanoma, pancreatic and renal cell cancer, evaluation of the mechanism of action of volociximab has been limited because this antibody does not cross-react with murine α5β1, precluding its use in standard mouse xenograft models. Methods We generated a panel of rat-anti-mouse α5β1 antibodies, with the intent of identifying an antibody that recapitulated the properties of volociximab. Hybridoma clones were screened for analogous function to volociximab, including specificity for α5β1 heterodimer and blocking of integrin binding to fibronectin. A subset of antibodies that met these criteria were further characterized for their capacities to bind to mouse endothelial cells, inhibit cell migration and block angiogenesis in vitro. One antibody that encompassed all of these attributes, 339.1, was selected from this panel and tested in xenograft models. Results A panel of antibodies was characterized for specificity and potency. The affinity of antibody 339.1 for mouse integrin α5β1 was determined to be 0.59 nM, as measured by BIAcore. This antibody does not significantly cross-react with human integrin, however 339.1 inhibits murine endothelial cell migration and tube formation and elicits cell death in these cells (EC50 = 5.3 nM. In multiple xenograft models, 339.1 inhibited the growth of established tumors by 40–60% (p Conclusion The results herein demonstrate that 339.1, like volociximab, exhibits potent anti-α5β1

  6. Suppression of β3-integrin in mice triggers a neuropilin-1-dependent change in focal adhesion remodelling that can be targeted to block pathological angiogenesis

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    Tim S. Ellison


    Full Text Available Anti-angiogenic treatments against αvβ3-integrin fail to block tumour growth in the long term, which suggests that the tumour vasculature escapes from angiogenesis inhibition through αvβ3-integrin-independent mechanisms. Here, we show that suppression of β3-integrin in mice leads to the activation of a neuropilin-1 (NRP1-dependent cell migration pathway in endothelial cells via a mechanism that depends on NRP1's mobilisation away from mature focal adhesions following VEGF-stimulation. The simultaneous genetic targeting of both molecules significantly impairs paxillin-1 activation and focal adhesion remodelling in endothelial cells, and therefore inhibits tumour angiogenesis and the growth of already established tumours. These findings provide a firm foundation for testing drugs against these molecules in combination to treat patients with advanced cancers.

  7. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression. (United States)

    Li, Dan; Williams, Jon I; Pietras, Richard J


    Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural antiangiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene overexpression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene overexpression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 overexpression were grown as subcutaneous xenografts in nude mice. Animals were treated by intraperitoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status.

  8. Biochemistry of neuroendocrine tumours. (United States)

    de Herder, Wouter W


    Several circulating or urinary tumour markers can be used for the diagnosis and follow-up of functioning and clinically non-functioning neuroendocrine tumours of the pancreatic islet cells and intestinal tract. Among the specific tumour markers are serotonin and its metabolites--e.g. 5-hydroxyindoleacetic acid (5-HIAA)--in carcinoid tumours and the carcinoid syndrome, insulin and its precursors or breakdown products in insulinoma, and gastrin in gastrinoma. Plasma vasointestinal polypeptide (VIP) determinations have been used in the diagnosis of VIPoma, plasma glucagon for glucagonoma, and serum somatostatin for somatostatinoma. Among the tumour-non-specific markers are: chromogranins, neuron-specific enolase (NSE), alpha-subunits of the glycoprotein hormones, catecholamines, pancreatic polypeptide (PP), ghrelin and adrenomedullin.

  9. Brain hyaluronan binding protein inhibits tumor growth

    Institute of Scientific and Technical Information of China (English)

    高锋; 曹曼林; 王蕾


    Background Great efforts have been made to search for the angiogenic inhibitors in avascular tissues. Several proteins isolated from cartilage have been proved to have anti-angiogenic or anti-tumour effects. Because cartilage contains a great amount of hyaluronic acid (HA) oligosaccharides and abundant HA binding proteins (HABP), therefore, we speculated that HABP might be one of the factors regulating vascularization in cartilage or anti-angiogenesis in tumours. The purpose of this research was to evaluale the effects of hyaluronan binding protein on inhibiting tumour growth both in vivo and vitro. Methods A unique protein termed human brain hyaluronan (HA) binding protein (b-HABP) was cloned from human brain cDNA library. MDA-435 human breast cancer cell line was chosen as a transfectant. The in vitro underlying mechanisms were investigated by determining the possibilities of MDA-435/b-HABP colony formation on soft agar, the effects of the transfectant on the proliferation of endothelial cells and the expression levels of caspase 3 and FasL from MDA-435/b-HABP. The in vivo study included tumour growth on the chorioallantoic membrane (CAM) of chicken embryos and nude mice. Results Colony formation assay revealed that the colonies formed by MDA-435/b-HABP were greatly reduced compared to mock transfectants. The conditioned media from MDA-435/b-HABP inhibited the growth of endothelial cells in culture. Caspase 3 and FasL expressions were induced by MDA-435/b-HABP. The size of tumours of MDA-435/b-HABP in both CAM and nude mice was much smaller than that of MDA-435 alone. Conclusions Human brain hyaluronan binding protein (b-HABP) may represent a new kind of naturally existing anti-tumour substance. This brain-derived glycoprotein may block tumour growth by inducing apoptosis of cancer cells or by decreasing angiogenesis in tumour tissue via inhibiting proliferation of endothelial cells.

  10. Hydrophilic block copolymer-directed growth of lanthanum hydroxide nano-particles

    Energy Technology Data Exchange (ETDEWEB)

    Bouyer, F.; Sanson, N.; Gerardin, C. [Laboratoire de Materiaux Catalytiques et Catalyse en Chimie Organique, UMR 5618 CNRS-ENSCM-UM1, FR 1878, Institut Gerhardt, 34 - Montpellier (France); Destarac, M. [Centre de Recherches Rhodia Aubervilliers, 93 - Aubervilliers (France)


    Stable hairy lanthanum hydroxide nano-particles were synthesized in water by performing hydrolysis and condensation reactions of lanthanum cations in the presence of double hydrophilic poly-acrylic acid-b-polyacrylamide block copolymers (PAA-b-PAM). In the first step, the addition of asymmetric PAA-b-PAM copolymers (M{sub w,PAA} {<=} M{sub w,PAM}) to lanthanum salt solutions, both at pH = 5.5, induces the formation of monodispersed micellar aggregates, which are predominantly isotropic. The core of the hybrid aggregates is constituted of a lanthanum polyacrylate complex whose formation is due to bidentate coordination bonding between La{sup 3+} and acrylate groups, as shown by ATR-FTIR experiments and pH measurements. The size of the micellar aggregates depends on the molecular weight of the copolymer but is independent of the copolymer to metal ratio in solution. In the second step, the hydrolysis of lanthanum ions is induced by addition of a strong base such as sodium hydroxide. Either flocculated suspensions or stable anisotropic or spherical nano-particles of lanthanum hydrolysis products were obtained depending on the metal complexation ratio [acrylate]/[La]. The variation of that parameter also enables the control of the size of the core-corona nano-particles obtained by lanthanum hydroxylation. The asymmetry degree of the copolymer was shown to influence both the size and the shape of the particles. Elongated particles with a high aspect ratio, up to 10, were obtained with very asymmetric copolymers (M{sub w,PAM}/M{sub w,PAA}{>=}10) while shorter rice grain-like particles were obtained with a less asymmetric copolymer. The asymmetry degree also influences the value of the critical metal complexation degree required to obtain stable colloidal suspensions of polymer-stabilized lanthanum hydroxide. (authors)

  11. Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

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    Kaylani, Samer Z. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Xu, Jianmin; Srivastava, Ritesh K. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda (United States); Pressey, Joseph G. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Athar, Mohammad, E-mail: [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)


    Graphical abstract: Intervention of poorly differentiated RMS by rapamycin: In poorly differentiated RMS, rapamycin blocks mTOR and Hh signaling pathways concomitantly. This leads to dampening in cell cycle regulation and induction of apoptosis. This study provides a rationale for the therapeutic intervention of poorly differentiated RMS by treating patients with rapamycin alone or in combination with other chemotherapeutic agents. -- Highlights: •Rapamycin abrogates RMS tumor growth by modulating proliferation and apoptosis. •Co-targeting mTOR/Hh pathways underlie the molecular basis of effectiveness. •Reduction in mTOR/Hh pathways diminish EMT leading to reduced invasiveness. -- Abstract: Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis

  12. The role of long-chain polyunsaturated fatty acids in the treatment of cancer Cachexia and tumour growth in patients with malignant diseases: A review

    Directory of Open Access Journals (Sweden)

    Elizabeth A Symington


    Full Text Available Recent studies show that ω-3 polyunsaturated fatty acids (PUFAs have the capacity to modulate cancer outcomes. The body responds to cancer in the same way that it responds to inflammation and wound healing. Nutrients with anti-inflammatory effects could therefore be expected to play a role in cancer treatment. This review focuses on the role of ω-3 PUFAs in tumourigenesis and cancer cachexia. Studies indicate that eicosapentaenoic acid (EPA supplementation may promote arrest of tumour growth and reduce cell proliferation. Patients need to consume at least 2 g of EPA per day for it to have a therapeutic effect. Positive outcomes related to cachexia include diminished weight loss, increased appetite, improved quality of life and prolonged survival, although there is controversy regarding these clinical outcomes. The effects of ω-3 PUFAs on tumourigenesis and cachexia are viewed in the context of altered lipid and protein metabolism. This altered metabolism usually experienced by cancer patients results in increased formation of proinflammatory eicosanoids and cytokines. Cytokines play an indirect role by stimulating the production of arachidonic acid-derived eicosanoids, which support inflammation, cell proliferation and angiogenesis, and inhibit apoptosis. It can be concluded that ω-3 PUFA supplementation offers a means of augmenting cancer therapy, inhibiting tumourigenesis and possibly contributing to cachexia alleviation. Opsomming Onlangse studies toon dat ω-3-poli-onversadigde vetsure (POVSe oor die vermoë beskik om kankeruitkomste te moduleer. Die liggaam reageer op kanker op dieselfde wyse as wat dit op inflammasie en wondgenesing reageer. Daar kan dus verwag word dat voedingstowwe met ‘n anti-inflammatoriese uitwerking ‘n rol in die behandeling van kanker kan speel. In hierdie oorsig word daar op die rol van ω-3-POVSe in tumorigenese en kankerkageksie gefokus. Studies dui daarop dat eikosapentanoënsuur- (EPS

  13. Targeting the tumour microenvironment in ovarian cancer. (United States)

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


    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.

  14. Effects of continuous peripheral nerve block by tetrodotoxin on growth associated protein-43 expression during neuropathic pain development

    Institute of Scientific and Technical Information of China (English)

    Chen Wang; Xiaoyu Huang


    BACKGROUND: Peripheral nerve injury may lead to neuropathic pain and cause a markedly increase expression of growth associated protein-43 (GAP-43) in the spinal cord and dorsal root ganglion, local anesthetics blocking electrical impulse propagation of nerve fibers may also affect the expression of GAP-43 in the spinal cord and dorsal root ganglion.OBJECTIVE: To determine the effects of continuous peripheral nerve block by tetrodotoxin before and after nerve injury on GAP-43 expression in the dorsal root ganglion during the development of neuropathic pain.DESIGN: A randomized controlled animal experiment.SETTINGS: Department of Anesthesiology, the Second Hospital of Xiamen City; Department of Anesthesiology, the Second Affiliated Hospital of Shantou University Medical College. MATERIALS: Thirty-five Sprague Dawley (SD) rats, weighing 200 - 250 g, were randomly divided into four groups: control group (n =5), simple sciatic nerve transection group (n =10), peripheral nerve block before and after sciatic nerve transection groups (n =10). All the sciatic nerve transection groups were divided into two subgroups according to the different postoperative survival periods: 3 and 7 days (n =5) respectively. Mouse anti-GAP-43 monoclonal antibody (Sigma Co., Ltd.), supervision TM anti-mouse reagent (HRP, Changdao antibody diagnosis reagent Co., Ltd., Shanghai), and HMIAS-100 image analysis system (Qianping Image Engineering Company, Tongji Medical University) were employed in this study. METHODS: This experiment was carried out hi the Department of Surgery and Pathological Laboratory, the Second Affiliated Hospital of Shantou University Medical College from April 2005 to April 2006.①The animals were anesthetized and the right sciatic nerve was exposed and transected at 1 cm distal to sciatic notch.②Tetrodotoxin 10 μg/kg was injected percutaneously between the greater trochanter and the posterior superior iliac spine of right hind limb to block the sciatic nerve proximally

  15. Oridonin inhibits tumor growth and metastasis through anti-angiogenesis by blocking the Notch signaling.

    Directory of Open Access Journals (Sweden)

    Yanmin Dong

    Full Text Available While significant progress has been made in understanding the anti-inflammatory and anti-proliferative effects of the natural diterpenoid component Oridonin on tumor cells, little is known about its effect on tumor angiogenesis or metastasis and on the underlying molecular mechanisms. In this study, Oridonin significantly suppressed human umbilical vascular endothelial cells (HUVECs proliferation, migration, and apillary-like structure formation in vitro. Using aortic ring assay and mouse corneal angiogenesis model, we found that Oridonin inhibited angiogenesis ex vivo and in vivo. In our animal experiments, Oridonin impeded tumor growth and metastasis. Immunohistochemistry analysis further revealed that the expression of CD31 and vWF protein in xenografts was remarkably decreased by the Oridonin. Furthermore, Oridonin reinforced endothelial cell-cell junction and impaired breast cancer cell transendothelial migration. Mechanistically, Oridonin not only down-regulated Jagged2 expression and Notch1 activity but also decreased the expression of their target genes. In conclusion, our results demonstrated an original role of Oridonin in inhibiting tumor angiogenesis and propose a mechanism. This study also provides new evidence supporting the central role of Notch in tumor angiogenesis and suggests that Oridonin could be a potential drug candidate for angiogenesis related diseases.

  16. Inhibition of the Flavin-Dependent Monooxygenase Siderophore A (SidA) Blocks Siderophore Biosynthesis and Aspergillus fumigatus Growth. (United States)

    Martín Del Campo, Julia S; Vogelaar, Nancy; Tolani, Karishma; Kizjakina, Karina; Harich, Kim; Sobrado, Pablo


    Aspergillus fumigatus is an opportunistic fungal pathogen and the most common causative agent of fatal invasive mycoses. The flavin-dependent monooxygenase siderophore A (SidA) catalyzes the oxygen and NADPH dependent hydroxylation of l-ornithine (l-Orn) to N(5)-l-hydroxyornithine in the biosynthetic pathway of hydroxamate-containing siderophores in A. fumigatus. Deletion of the gene that codes for SidA has shown that it is essential in establishing infection in mice models. Here, a fluorescence polarization high-throughput assay was used to screen a 2320 compound library for inhibitors of SidA. Celastrol, a natural quinone methide, was identified as a noncompetitive inhibitor of SidA with a MIC value of 2 μM. Docking experiments suggest that celastrol binds across the NADPH and l-Orn pocket. Celastrol prevents A. fumigatus growth in blood agar. The addition of purified ferric-siderophore abolished the inhibitory effect of celastrol. Thus, celastrol inhibits A. fumigatus growth by blocking siderophore biosynthesis through SidA inhibiton.

  17. Prograde and retrograde growth of monazite in migmatites:An example from the Nagercoil Block, southern India

    Institute of Scientific and Technical Information of China (English)

    Tim E. Johnson; Chris Clark; Richard J.M. Taylor; M. Santosh; Alan S. Collins


    Data from a migmatised metapelite raft enclosed within charnockite provide quantitative constraints on the pressureetemperatureetime (PeTet) evolution of the Nagercoil Block at the southernmost tip of peninsular India. An inferred peak metamorphic assemblage of garnet, K-feldspar, sillimanite, plagioclase, magnetite, ilmenite, spinel and melt is consistent with peak metamorphic pressures of 6e8 kbar and temperatures in excess of 900 ?C. Subsequent growth of cordierite and biotite record high-temperature retrograde decompression to around 5 kbar and 800 ?C. SHRIMP UePb dating of magmatic zircon cores suggests that the sedimentary protoliths were in part derived from felsic igneous rocks with Palae-oproterozoic crystallisation ages. New growth of metamorphic zircon on the rims of detrital grains con-strains the onset of melt crystallisation, and the minimum age of the metamorphic peak, to around 560 Ma. The data suggest two stages of monazite growth. The first generation of REE-enriched monazite grew during partial melting along the prograde path at around 570 Ma via the incongruent breakdown of apatite. Relatively REE-depleted rims, which have a pronounced negative europium anomaly, grew during melt crystallisation along the retrograde path at around 535 Ma. Our data show the rocks remained at suprasolidus temperatures for at least 35 million years and probably much longer, supporting a long-lived high-grade metamorphic history. The metamorphic conditions, timing and duration of the implied clockwise PeTet path are similar to that previously established for other regions in peninsular India during the Ediacaran to Cambrian assembly of that part of the Gondwanan supercontinent.

  18. Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan. (United States)

    Pfefferkorn, E R


    Treatment of human fibroblasts with human recombinant gamma interferon blocked the growth of Toxoplasma gondii, an obligate intracellular protozoan parasite. Growth of the parasite was measured by a plaque assay 7 days after infection or by the incorporation of [3H]uracil 1 or 2 days after infection. The antitoxoplasma activity induced in the host cells by gamma interferon was strongly dependent upon the tryptophan concentration of the medium. Progressively higher minimal inhibitory concentrations of gamma interferon were observed as the tryptophan concentration in the culture medium was increased. Treatment with gamma interferon did not make the cells impermeable to tryptophan. The kinetics of [3H]tryptophan uptake into the acid-soluble pools of control and gamma interferon-treated cultures were identical during the first 48 sec. Thereafter uptake of [3H]tryptophan into the acid-soluble pool of control fibroblasts reached the expected plateau after 96 sec. In contrast, uptake of [3H]tryptophan continued for at least 12 min in the gamma interferon-treated cultures. At that time, the acid-soluble pool of the gamma interferon-treated cultures contained 8 times the radioactivity of the control cultures. This continued accumulation was the result of rapid intracellular degradation of [3H]tryptophan into kynurenine and N-formylkynurenine that leaked slowly from the cells. These two metabolites were also recovered from the medium of cultures treated for 1 or 2 days with gamma interferon. Human recombinant alpha and beta interferons, which have no antitoxoplasma activity, did not induce any detectable degradation of tryptophan. Several hypotheses are presented to explain how the intracellular degradation of tryptophan induced by gamma interferon could restrict the growth of an obligate intracellular parasite. Images PMID:6422465

  19. Prograde and retrograde growth of monazite in migmatites: An example from the Nagercoil Block, southern India

    Directory of Open Access Journals (Sweden)

    Tim E. Johnson


    Full Text Available Data from a migmatised metapelite raft enclosed within charnockite provide quantitative constraints on the pressure–temperature–time (P–T–t evolution of the Nagercoil Block at the southernmost tip of peninsular India. An inferred peak metamorphic assemblage of garnet, K-feldspar, sillimanite, plagioclase, magnetite, ilmenite, spinel and melt is consistent with peak metamorphic pressures of 6–8 kbar and temperatures in excess of 900 °C. Subsequent growth of cordierite and biotite record high-temperature retrograde decompression to around 5 kbar and 800 °C. SHRIMP U–Pb dating of magmatic zircon cores suggests that the sedimentary protoliths were in part derived from felsic igneous rocks with Palaeoproterozoic crystallisation ages. New growth of metamorphic zircon on the rims of detrital grains constrains the onset of melt crystallisation, and the minimum age of the metamorphic peak, to around 560 Ma. The data suggest two stages of monazite growth. The first generation of REE-enriched monazite grew during partial melting along the prograde path at around 570 Ma via the incongruent breakdown of apatite. Relatively REE-depleted rims, which have a pronounced negative europium anomaly, grew during melt crystallisation along the retrograde path at around 535 Ma. Our data show the rocks remained at suprasolidus temperatures for at least 35 million years and probably much longer, supporting a long-lived high-grade metamorphic history. The metamorphic conditions, timing and duration of the implied clockwise P–T–t path are similar to that previously established for other regions in peninsular India during the Ediacaran to Cambrian assembly of that part of the Gondwanan supercontinent.

  20. Pulsation-limited oxygen diffusion in the tumour microenvironment (United States)

    Milotti, Edoardo; Stella, Sabrina; Chignola, Roberto


    Hypoxia is central to tumour evolution, growth, invasion and metastasis. Mathematical models of hypoxia based on reaction-diffusion equations provide seemingly incomplete descriptions as they fail to predict the measured oxygen concentrations in the tumour microenvironment. In an attempt to explain the discrepancies, we consider both the inhomogeneous distribution of oxygen-consuming cells in solid tumours and the dynamics of blood flow in the tumour microcirculation. We find that the low-frequency oscillations play an important role in the establishment of tumour hypoxia. The oscillations interact with consumption to inhibit oxygen diffusion in the microenvironment. This suggests that alpha-blockers–a class of drugs used to treat hypertension and stress disorders, and known to lower or even abolish low-frequency oscillations of arterial blood flow –may act as adjuvant drugs in the radiotherapy of solid tumours by enhancing the oxygen effect.

  1. Bilateral Malignant Brenner Tumour

    Directory of Open Access Journals (Sweden)

    Nasser D Choudhary, S.Manzoor Kadri, Ruby Reshi, S. Besina, Mansoor A. Laharwal, Reyaz tasleem, Qurrat A. Chowdhary


    Full Text Available Bilateral malignant Brenner tumour ofovary is extremely rate. A case ofmalignant Brenner tumourinvolving both the ovaries with mctastasis to mesentery in a 48 year femalc is presented. Grosslyo'arian masses were firm with soft areas, encapsulated and having bosselated external surfaces.Cut sections showed yellowish white surface with peripheral cysts (in both tumours. Microscopyrevealed transitional cell carcinoma with squamoid differentiation at places. Metastatic deposits werefound in the mesentery. Endometrium showed cystic glandular hyperplasia.

  2. Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: in vivo evaluation of anti-cancer activity. (United States)

    Batrakova, E V; Dorodnych, T Y; Klinskii, E Y; Kliushnenkova, E N; Shemchukova, O B; Goncharova, O N; Arjakov, S A; Alakhov, V Y; Kabanov, A V


    The chemosensitising effects of poly(ethylene oxide)-poly(propylene oxide)-poly-(ethylene oxide) (PEO-PPO-PEO) block copolymers (Pluronic) in multidrug-resistant cancer cells has been described recently (Alakhov VY, Moskaleva EY, Batrakova EV, Kabanov AV 1996, Biocon. Chem., 7, 209). This paper presents initial studies on in vivo evaluation of Pluronic copolymers in the treatment of cancer. The anti-tumour activity of epirubicin (EPI) and doxorubicin (DOX), solubilised in micelles of Pluronic L61, P85 and F108, was investigated using murine leukaemia P388 and daunorubicin-sensitive Sp2/0 and -resistant Sp2/0(DNR) myeloma cells grown subcutaneously (s.c.). The study revealed that the lifespan of the animals and inhibition of tumour growth were considerably increased in mice treated with drug/copolymer compositions compared with animals treated with the free drugs. The anti-tumour activity of the drug/copolymer compositions depends on the concentration of the copolymer and its hydrophobicity, as determined by the ratio of the lengths of hydrophilic PEO and hydrophobic PPO segments. The data suggest that higher activity is associated with more hydrophobic copolymers. In particular, a significant increase in lifespan (T/C> 150%) and tumour growth inhibition (> 90%) was observed in animals with Sp2/0 tumours with EPI/P85 and DOX/L61 compositions. The effective doses of these compositions caused inhibition of Sp2/0 tumour growth and complete disappearance of tumour in 33-50% of animals. Future studies will focus on the evaluation of the activity of Pluronic-based compositions against human drug-resistant tumours.

  3. [{sup 99m}Tc(CO){sub 3}]{sup +}-(HE){sub 3}-Z{sub IGF1R:4551}, a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours

    Energy Technology Data Exchange (ETDEWEB)

    Orlova, Anna; Varasteh, Zohreh [Uppsala University, Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala (Sweden); Hofstroem, Camilla; Graeslund, Torbjoern [Royal Institute of Technology, Division of Molecular Biotechnology, School of Biotechnology, Stockholm (Sweden); Strand, Joanna [Uppsala University, Division of Biomedical Radiation Sciences, Uppsala (Sweden); Sandstrom, Mattias [Uppsala University Hospital, Medical Physics, Department of Oncology, Uppsala (Sweden); Andersson, Karl [Uppsala University, Division of Biomedical Radiation Sciences, Uppsala (Sweden); Ridgeview Instruments AB, Uppsala (Sweden); Tolmachev, Vladimir [Uppsala University, Division of Biomedical Radiation Sciences, Uppsala (Sweden); Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden)


    Radionuclide imaging of insulin-like growth factor type 1 receptor (IGF-1R) expression in tumours might be used for selection of patients who would benefit from IGF-1R-targeted therapy. We have previously shown the feasibility of IGF-1R imaging using the Affibody molecule {sup 111}In-DOTA-His{sub 6}-Z{sub IGF1R:4551}. The use of {sup 99m}Tc instead of {sup 111}In should improve sensitivity and resolution of imaging, and reduce the dose burden to patients. We hypothesized that inclusion of a HEHEHE tag instead of a His{sub 6} tag in Z{sub IGF1R:4551} would permit its convenient purification using IMAC, enable labelling with [{sup 99m}Tc(CO){sub 3}]{sup +}, and improve its biodistribution. Z{sub IGF1R:4551} was expressed with a HEHEHE tag in the N terminus. The resulting (HE){sub 3}-Z{sub IGF1R:4551} construct was labelled with [{sup 99m}Tc(CO){sub 3}]{sup +}. Targeting of IGF-1R-expressing cells using [{sup 99m}Tc(CO){sub 3}]{sup +}-(HE){sub 3}-Z{sub IGF1R:4551} was evaluated in vitro and in vivo. (HE){sub 3}-Z{sub IGF1R:4551} was stably labelled with {sup 99m}Tc with preserved specific binding to IGF-1R-expressing DU-145 prostate cancer cells in vitro. In mice, [{sup 99m}Tc(CO){sub 3}]{sup +}-(HE){sub 3}-Z{sub IGF1R:4551} accumulated in IGF-1R-expressing organs (pancreas, stomach, lung and salivary gland). [{sup 99m}Tc(CO){sub 3}]{sup +}-(HE){sub 3}-Z{sub IGF1R:4551} demonstrated 3.6-fold lower accumulation in the liver and spleen than {sup 111}In-DOTA-Z{sub IGF1R:4551}. In NMRI nu/nu mice with DU-145 prostate cancer xenografts, the tumour uptake was 1.32 {+-} 0.11 %ID/g and the tumour-to-blood ratio was 4.4 {+-} 0.3 at 8 h after injection. The xenografts were visualized using a gamma camera 6 h after injection. [{sup 99m}Tc(CO){sub 3}]{sup +}-(HE){sub 3}-Z{sub IGF1R:4551} is a promising candidate for visualization of IGF-1R expression in malignant tumours. (orig.)

  4. The natural history of disappearing bone tumours and tumour-like conditions

    Energy Technology Data Exchange (ETDEWEB)

    Yanagawa, Takashi; Watanabe, Hideomi; Shinozaki, Tetsuya; Ahmed, Adel Refaat; Shirakura, Kenji; Takagishi, Kenji


    We describe 27 cases of bone tumours or tumour-like lesions where there was spontaneous regression. The follow-up period was 2.8-16.7 years (average, 7.0 years). Fourteen of these cases were no longer visible on plain radiographs. Histological diagnosis included exostosis, eosinophilic granuloma, fibrous dysplasia, fibrous cortical defect, non-ossifying fibroma, osteoid osteoma and bone island. Most cases began to reduce in adolescence or earlier, although sclerotic type lesions showed their regression in older patients. All lesions thought to be eosinophilic granuloma began to regress after periods of less than 3 months, while the duration of the other lesions showed wide variation (1-74 months). As resolution of the lesions took between 2 and 79 months (mean, 25.0 {+-} 20.3 months) we consider that the most likely mechanism was recovery of normal skeletal growth control. In exostosis with fracture, alteration of vascular supply may contribute to growth arrest, but not to subsequent remodelling stage. In inflammatory-related lesions such as eosinophilic granuloma, cessation of inflammation may be the mechanism of growth arrest, whilst temporary inflammation may stimulate osteogenic cells engaged in remodeling. In the sclerotic type, growth arrest is a less probable mechanism. Necrosis within the tumour and/or local changes in hormonal control, plus remodelling of the sclerotic area takes longer. Knowledge of the potential for spontaneous resolution may help in management of these tumour and tumour-like lesions of bone. Yanagawa, T. et al. (2001)

  5. Analysis of the progression of fibroepithelial tumours of the breast by PCR-based clonality assay

    NARCIS (Netherlands)

    Kuijper, Arno; Buerger, H.; Simon, R.; Schaefer, K-L.; Croonen, A.; Boecker, W.; Wall, E. van der; Diest, P.J. van


    Fibroadenoma and phyllodes tumour of the breast are both fibroepithelial tumours. Although progression to epithelial malignancy has been described, the behaviour of most fibroadenomas is benign. Phyllodes tumours, on the other hand, can display locally destructive growth and can even metastasize. A

  6. First experiences with genetic counselling based on predictive DNA diagnosis in hereditary glomus tumours (paragangliomas)

    NARCIS (Netherlands)

    Oosterwijk, JC; Jansen, JC; vanSchothorst, EM; Oosterhof, AW; Devilee, P; Bakker, E; Zoeteweij, MW; vanderMey, AGL


    Hereditary glomus tumour (MIM 168000) or paraganglioma (PGL) is a slowly progressive disorder causing benign tumour growth predominantly in the head and neck region. Though benign in nature the tumours can lead to severe morbidity. Inheritance of PGL is autosomal dominant and is strongly modified by

  7. Midkine, heparin-binding growth factor, blocks kainic acid-induced seizure and neuronal cell death in mouse hippocampus

    Directory of Open Access Journals (Sweden)

    Lim In J


    Full Text Available Abstract Background Midkine (MK, a member of the heparin-binding growth factor family, which includes MK and pleiotrophin, is known to possess neurotrophic and neuroprotective properties in the central nervous system. Previous studies have shown that MK is an effective neuroprotective agent in reducing retinal degeneration caused by excessive light and decreasing hippocampal neuronal death in ischemic gerbil brain. The present study was undertaken to investigate whether MK acts as an anticonvulsant in kainic acid (KA-induced seizure in mouse and blocks KA-mediated neuronal cell death in hippocampus. Results Increased expression of MK was found in hippocampus of mouse following seizures induced by intracerebroventricular injection of KA, and MK expression was found in glial fibrillary acidic protein (GFAP-positive astrocytes. Concurrent injection of MK and KA attenuated KA-induced seizure activity and cell death of hippocampal neurons including pyramidal cells and glutamic acid decarboxylase 67 (GAD67-positive GABAergic interneurons in the CA3 and hilar area. Conclusion The results of the present study indicate that MK functions as an anticonvulsant and neuroprotective agent in hippocampus during KA-induced seizures.

  8. Blocking TNF-α inhibits angiogenesis and growth of IFIT2-depleted metastatic oral squamous cell carcinoma cells. (United States)

    Lai, Kuo-Chu; Liu, Chung-Ji; Lin, Tsung-Jen; Mar, Ai-Chung; Wang, Hsiu-Hua; Chen, Chi-Wei; Hong, Zi-Xuan; Lee, Te-Chang


    Our previous study demonstrated that the depletion of interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) promoted metastasis and was associated with a poor prognosis in patients with oral squamous cell carcinoma (OSCC). Our current study explores the major downstream signaling involved in IFIT2 depletion-induced OSCC metastasis. To this end, we used two cell lines (designated sh-control-xeno and sh-IFIT2-xeno) derived from human OSCC xenografts expressing sh-control and sh-IFIT2, respectively, and one metastatic OSCC subline (sh-IFIT2-meta) from an IFIT2-depleted metastatic tumor. We found that the sh-IFIT2-meta cells proliferated more slowly than the sh-control-xeno cells but exhibited higher migration and chemoresistance. Using microarray technology and Ingenuity Pathway Analysis, we found that TNF-α was one of the major downstream targets in IFIT2-depleted OSCC cells. Quantitative real-time PCR, western blotting, and ELISA results confirmed that TNF-α was upregulated in the sh-IFIT2-meta cells. Blocking TNF-α abolished the angiogenic activity induced by the sh-IFIT2-meta cells. Furthermore, the human-specific TNF-α antibody golimumab significantly inhibited in vivo angiogenesis, tumor growth and metastasis of sh-IFIT2-meta cells. These results demonstrate that IFIT2 depletion results in TNF-α upregulation, leading to angiogenesis and metastasis of OSCC cells.

  9. A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth (United States)

    Rane, Chetan; Senapedis, William; Baloglu, Erkan; Landesman, Yosef; Crochiere, Marsha; Das-Gupta, Soumyasri; Minden, Audrey


    Breast cancer is a heterogeneous disease consisting of several subtypes. Among these subtypes, triple negative breast cancer is particularly difficult to treat. This is due to a lack of understanding of the mechanisms behind the disease, and consequently a lack of druggable targets. PAK4 plays critical roles in cell survival, proliferation, and morphology. PAK4 protein levels are high in breast cancer cells and breast tumors, and the gene is often amplified in basal like breast cancers, which are frequently triple negative. PAK4 is also overexpressed in other types of cancer, making it a promising drug target. However, its inhibition is complicated by the fact that PAK4 has both kinase-dependent and -independent functions. Here we investigate a new clinical compound KPT-9274, which has been shown to inhibit PAK4 and NAMPT. We find that KPT-9274 (and its analog, KPT-8752) can reduce the steady state level of PAK4 protein in triple negative breast cancer cells. These compounds also block the growth of the breast cancer cells in vitro, and stimulate apoptosis. Most importantly, oral administration of KPT-9274 reduces tumorigenesis in mouse models of human triple negative breast cancer. Our results indicate that KPT-9274 is a novel therapeutic option for triple negative breast cancer therapy. PMID:28198380

  10. An imaging-based computational model for simulating angiogenesis and tumour oxygenation dynamics (United States)

    Adhikarla, Vikram; Jeraj, Robert


    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 analysing

  11. [Surgical treatment of children with hepatic tumours

    DEFF Research Database (Denmark)

    Rasmussen, A.; Kvist, N.; Kirkegaard, P.;


    INTRODUCTION: In this paper we review the results of surgical treatment of children with hepatic tumours. MATERIALS AND METHODS: The study comprises 33 children who have undergone lever resection or liver transplantation since 1990. 26 patients had hepatoblastoma, 3 had hepatocellular carcinoma, 2......%). There was no difference in survival dependent on the type of resection, and there was no impact of the extension of tumour growth at the time of diagnosis. CONCLUSION: The combination of neoadjuvant chemotherapy followed by liver resection or liver transplantation is the treatment of choice in all children...

  12. Carcino-embryonic antigen in monitoring the growth of human colon adenocarcinoma tumour cells SK-CO-1 and HT-29 in vitro and in nude mice

    DEFF Research Database (Denmark)

    Sölétormos, G; Fogh, J M; Sehested-Hansen, B;


    A set of experimental model systems were designed to investigate (a) the inter-relationship between growth of two human cancer cell lines (SK-CO-1, HT-29) and carcino-embryonic antigen (CEA) kinetics; and (b) whether neoplastic growth or CEA concentration is modulated by human growth hormone (h...

  13. Anti-interleukin-10R1 monoclonal antibody in combination with bacillus Calmette--Guérin is protective against bladder cancer metastasis in a murine orthotopic tumour model and demonstrates systemic specific anti-tumour immunity. (United States)

    Newton, M R; Askeland, E J; Andresen, E D; Chehval, V A; Wang, X; Askeland, R W; O'Donnell, M A; Luo, Y


    Effective treatment of bladder cancer with bacillus Calmette-Guérin (BCG) depends on the induction of a T helper type (Th) 1 immune response. Interleukin (IL)-10 down-regulates the Th1 response and is associated with BCG failure. In this study, we investigated whether blocking IL-10 signalling could enhance the BCG-induced Th1 response and anti-tumour immunity in a murine orthotopic tumour model. Treatment with BCG and anti-IL-10 receptor 1 monoclonal antibody (anti-IL-10R1 mAb) increased the interferon (IFN)-γ to IL-10 ratio in both splenocyte cultures and urine. Mice bearing luciferase-expressing MB49 (MB49-Luc) tumours were treated and followed for tumour growth by bioluminescent imaging, bladder weight and histology. Mice treated with phosphate-buffered saline (PBS) (group 1), BCG plus control immunoglobulin (Ig)G1 (group 2) or BCG plus anti-IL-10R1 mAb (group 3) showed 0, 6 and 22% tumour regression, respectively. The mean bladder weight of group 3 mice was substantially lower than those of groups 1 and 2 mice. Remarkably, 36% of group 1 and 53% of group 2 mice but no group 3 mice developed lung metastasis (P = 0·02). To investigate the mechanisms underlying the effect of combination therapy, splenocytes were stimulated with S12 peptide (serine mutation at codon 12 of the K-ras oncogene) known to be expressed in MB49-Luc cells. Induction of ras mutation-specific IFN-γ and cytotoxicity was observed in mice treated with combination therapy. These observations indicate that BCG, in combination with anti-IL-10R1 mAb, induces enhanced anti-tumour immunity that is protective against lung metastasis. Anti-IL-10R1 mAb demonstrates systemic effects and may prove useful in clinical practice for treating bladder cancer in high-risk patients.

  14. Anti-interleukin-10R1 monoclonal antibody in combination with bacillus Calmette–Guérin is protective against bladder cancer metastasis in a murine orthotopic tumour model and demonstrates systemic specific anti-tumour immunity (United States)

    Newton, M R; Askeland, E J; Andresen, E D; Chehval, V A; Wang, X; Askeland, R W; O'Donnell, M A; Luo, Y


    Effective treatment of bladder cancer with bacillus Calmette–Guérin (BCG) depends on the induction of a T helper type (Th) 1 immune response. Interleukin (IL)-10 down-regulates the Th1 response and is associated with BCG failure. In this study, we investigated whether blocking IL-10 signalling could enhance the BCG-induced Th1 response and anti-tumour immunity in a murine orthotopic tumour model. Treatment with BCG and anti-IL-10 receptor 1 monoclonal antibody (anti-IL-10R1 mAb) increased the interferon (IFN)-γ to IL-10 ratio in both splenocyte cultures and urine. Mice bearing luciferase-expressing MB49 (MB49-Luc) tumours were treated and followed for tumour growth by bioluminescent imaging, bladder weight and histology. Mice treated with phosphate-buffered saline (PBS) (group 1), BCG plus control immunoglobulin (Ig)G1 (group 2) or BCG plus anti-IL-10R1 mAb (group 3) showed 0, 6 and 22% tumour regression, respectively. The mean bladder weight of group 3 mice was substantially lower than those of groups 1 and 2 mice. Remarkably, 36% of group 1 and 53% of group 2 mice but no group 3 mice developed lung metastasis (P = 0·02). To investigate the mechanisms underlying the effect of combination therapy, splenocytes were stimulated with S12 peptide (serine mutation at codon 12 of the K-ras oncogene) known to be expressed in MB49-Luc cells. Induction of ras mutation-specific IFN-γ and cytotoxicity was observed in mice treated with combination therapy. These observations indicate that BCG, in combination with anti-IL-10R1 mAb, induces enhanced anti-tumour immunity that is protective against lung metastasis. Anti-IL-10R1 mAb demonstrates systemic effects and may prove useful in clinical practice for treating bladder cancer in high-risk patients. PMID:24593764

  15. A reproducible brain tumour model established from human glioblastoma biopsies

    Directory of Open Access Journals (Sweden)

    Li Xingang


    Full Text Available Abstract Background Establishing clinically relevant animal models of glioblastoma multiforme (GBM remains a challenge, and many commonly used cell line-based models do not recapitulate the invasive growth patterns of patient GBMs. Previously, we have reported the formation of highly invasive tumour xenografts in nude rats from human GBMs. However, implementing tumour models based on primary tissue requires that these models can be sufficiently standardised with consistently high take rates. Methods In this work, we collected data on growth kinetics from a material of 29 biopsies xenografted in nude rats, and characterised this model with an emphasis on neuropathological and radiological features. Results The tumour take rate for xenografted GBM biopsies were 96% and remained close to 100% at subsequent passages in vivo, whereas only one of four lower grade tumours engrafted. Average time from transplantation to the onset of symptoms was 125 days ± 11.5 SEM. Histologically, the primary xenografts recapitulated the invasive features of the parent tumours while endothelial cell proliferations and necrosis were mostly absent. After 4-5 in vivo passages, the tumours became more vascular with necrotic areas, but also appeared more circumscribed. MRI typically revealed changes related to tumour growth, several months prior to the onset of symptoms. Conclusions In vivo passaging of patient GBM biopsies produced tumours representative of the patient tumours, with high take rates and a reproducible disease course. The model provides combinations of angiogenic and invasive phenotypes and represents a good alternative to in vitro propagated cell lines for dissecting mechanisms of brain tumour progression.

  16. Anti-tumour immune effect of oral administration of Lactobacillus plantarum to CT26 tumour-bearing mice

    Indian Academy of Sciences (India)

    Jingtao Hu; Chunfeng Wang; Liping Ye; Wentao Yang; Haibin Huang; Fei Meng; Shaohua Shi; Zhuang Ding


    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- (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.

  17. Blocking the NOTCH pathway can inhibit the growth of CD133-positive A549 cells and sensitize to chemotherapy. (United States)

    Liu, Juntao; Mao, Zhangfan; Huang, Jie; Xie, Songping; Liu, Tianshu; Mao, Zhifu


    Cancer stem cells (CSCs) are believed to play an important role in tumor growth and recurrence. These cells exhibit self-renewal and proliferation properties. CSCs also exhibit significant drug resistance compared with normal tumor cells. Finding new treatments that target CSCs could significantly enhance the effect of chemotherapy and improve patient survival. Notch signaling is known to regulate the development of the lungs by controlling the cell-fate determination of normal stem cells. In this study, we isolated CSCs from the human lung adenocarcinoma cell line A549. CD133 was used as a stem cell marker for fluorescence-activated cell sorting (FACS). We compared the expression of Notch signaling in both CD133+ and CD133- cells and blocked Notch signaling using the γ-secretase inhibitor DAPT (GSI-IX). The effect of combining GSI and cisplatin (CDDP) was also examined in these two types of cells. We observed that both CD133+ and CD133- cells proliferated at similar rates, but the cells exhibited distinctive differences in cell cycle progression. Few CD133+ cells were observed in the G2/M phase, and there were half as many cells in S phase compared with the CD133- cells. Furthermore, CD133+ cells exhibited significant resistance to chemotherapy when treated with CDDP. The expression of Notch signaling pathway members, such as Notch1, Notch2 and Hes1, was lower in CD133+ cells. GSI slightly inhibited the proliferation of both cell types and exhibited little effect on the cell cycle. The inhibitory effects of DPP on these two types of cells were enhanced when combined with GSI. Interestingly, this effect was especially significant in CD133+ cells, suggesting that Notch pathway blockade may be a useful CSC-targeted therapy in lung cancer.

  18. Parallel evolution of tumour subclones mimics diversity between tumours. (United States)

    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


    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.

  19. Blocking the NOTCH pathway can inhibit the growth of CD133-positive A549 cells and sensitize to chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Juntao; Mao, Zhangfan; Huang, Jie; Xie, Songping; Liu, Tianshu; Mao, Zhifu, E-mail:


    Highlights: • Notch signaling pathway members are expressed lower levels in CD133+ cells. • CD133+ cells are not as sensitive as CD133− cells to chemotherapy. • GSI could inhibit the growth of both CD133+ and CD133− cells. • Blockade of Notch signaling pathway enhanced the effect of chemotherapy with CDDP. • DAPT/CDDP co-therapy caused G2/M arrest and elimination in CD133+ cells. - Abstract: Cancer stem cells (CSCs) are believed to play an important role in tumor growth and recurrence. These cells exhibit self-renewal and proliferation properties. CSCs also exhibit significant drug resistance compared with normal tumor cells. Finding new treatments that target CSCs could significantly enhance the effect of chemotherapy and improve patient survival. Notch signaling is known to regulate the development of the lungs by controlling the cell-fate determination of normal stem cells. In this study, we isolated CSCs from the human lung adenocarcinoma cell line A549. CD133 was used as a stem cell marker for fluorescence-activated cell sorting (FACS). We compared the expression of Notch signaling in both CD133+ and CD133− cells and blocked Notch signaling using the γ-secretase inhibitor DAPT (GSI-IX). The effect of combining GSI and cisplatin (CDDP) was also examined in these two types of cells. We observed that both CD133+ and CD133− cells proliferated at similar rates, but the cells exhibited distinctive differences in cell cycle progression. Few CD133+ cells were observed in the G{sub 2}/M phase, and there were half as many cells in S phase compared with the CD133− cells. Furthermore, CD133+ cells exhibited significant resistance to chemotherapy when treated with CDDP. The expression of Notch signaling pathway members, such as Notch1, Notch2 and Hes1, was lower in CD133+ cells. GSI slightly inhibited the proliferation of both cell types and exhibited little effect on the cell cycle. The inhibitory effects of DPP on these two types of cells were

  20. Small peripheral lung carcinomas with five-year post-surgical follow-up: assessment by semi-automated volumetric measurement of tumour size, CT value and growth rate on TSCT

    Energy Technology Data Exchange (ETDEWEB)

    Sone, Shusuke [JA Nagano Azumi General Hospital, Ikeda, Nagano (Japan); Nagano Health Promotion Corporation, Inasato, Nagano (Japan); Hanaoka, Takaomi [JA Nagano Azumi General Hospital, Department of Chest Surgery, Ikeda, Nagano (Japan); Ogata, Hiroyuki [JA Nagano Azumi General Hospital, Division of Clinical Laboratory and Pathology, Ikeda, Nagano (Japan); Takayama, Fumiyoshi [JA Nagano Azumi General Hospital, Department of Radiology, Ikeda, Nagano (Japan); Ichinose Neurosurgery Hospital, Matsumoto, Nagano (Japan); Watanabe, Tomofumi [Iida Municipal Hospital, Iida, Nagano (Japan); Haniuda, Masayuki [Aichi Medical University, Division of Chest Surgery, Aichi (Japan); Kaneko, Kazuhiko [Shinshu University School of Medicine, Department of Surgery, Matsumoto (Japan); Okaya-Enrei Hospital, Okaya, Nagano (Japan); Kondo, Ryoichi [National Chushin Matsumoto Hospital, Matsumoto (Japan); Yoshida, Kazuo [Shinshu University School of Medicine, Department of Surgery, Matsumoto (Japan); Honda, Takayuki [Shinshu University School of Medicine, Department of Laboratory Medicine, Matsumoto (Japan)


    To retrospectively assess the utility of semi-automated measurements by stratification of CT values of tumour size, CT value and doubling time (DT) using thin-section computed tomography (CT) images. The post-surgical outcomes of favourable and problematic tumours (more advanced p stage than IA, post-surgical recurrence or mortality from lung cancer) were compared using the measured values. The computed DTs were compared with manually measured values. The study subjects comprised 85 patients (aged 33-80 years, 48 women, 37 men), followed-up for more than 5 years postoperatively, with 89 lung lesions, including 17 atypical adenomatous hyperplasias and 72 lung cancers. DTs were determined in 45 lesions. For problematic lesions, whole tumour diameter and density were >18 mm and >-400 HU, respectively. The respective values for the tumour core (with CT values of -350 to 150 HU) were >15 mm and >-70 HU. Analysis of tumour core DTs showed interval tumour progression even if little progress was seen by standard tumour volume DT (TVDT). Software-based volumetric measurements by stratification of CT values provide valuable information on tumour core and help estimate tumour aggressiveness and interval tumour progression better than standard manually measured 2D-VDTs. (orig.)

  1. Inhibition of Wnt signalling and breast tumour growth by the multi-purpose drug suramin through suppression of heterotrimeric G proteins and Wnt endocytosis. (United States)

    Koval, Alexey; Ahmed, Kamal; Katanaev, Vladimir L


    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.

  2. Percutaneous renal tumour biopsy. (United States)

    Delahunt, Brett; Samaratunga, Hemamali; Martignoni, Guido; Srigley, John R; Evans, Andrew J; Brunelli, Matteo


    The use of percutaneous renal tumour biopsy (RTB) as a diagnostic tool for the histological characterization of renal masses has increased dramatically within the last 30 years. This increased utilization has paralleled advances in imaging techniques and an evolving knowledge of the clinical value of nephron sparing surgery. Improved biopsy techniques using image guidance, coupled with the use of smaller gauge needles has led to a decrease in complication rates. Reports from series containing a large number of cases have shown the non-diagnostic rate of RTB to range from 4% to 21%. Re-biopsy has been shown to reduce this rate, while the use of molecular markers further improves diagnostic sensitivity. In parallel with refinements of the biopsy procedure, there has been a rapid expansion in our understanding of the complexity of renal cell neoplasia. The 2013 Vancouver Classification is the current classification for renal tumours, and contains five additional entities recognized as novel forms of renal malignancy. The diagnosis of tumour morphotype on RTB is usually achievable on routine histology; however, immunohistochemical studies may be of assistance in difficult cases. The morphology of the main tumour subtypes, based upon the Vancouver Classification, is described and differentiating features are discussed.

  3. Imaging biomarkers in primary brain tumours

    Energy Technology Data Exchange (ETDEWEB)

    Lopci, Egesta; Chiti, Arturo [Humanitas Clinical and Research Center, Nuclear Medicine Department, Rozzano, MI (Italy); Franzese, Ciro; Navarria, Pierina; Scorsetti, Marta [Humanitas Clinical and Research Center, Radiosurgery and Radiotherapy, Rozzano, MI (Italy); Grimaldi, Marco [Humanitas Clinical and Research Center, Radiology, Rozzano, MI (Italy); Zucali, Paolo Andrea; Simonelli, Matteo [Humanitas Clinical and Research Center, Medical Oncology, Rozzano, MI (Italy); Bello, Lorenzo [Humanitas Clinical and Research Center, Neurosurgery, Rozzano, MI (Italy)


    We are getting used to referring to instrumentally detectable biological features in medical language as ''imaging biomarkers''. These two terms combined reflect the evolution of medical imaging during recent decades, and conceptually comprise the principle of noninvasive detection of internal processes that can become targets for supplementary therapeutic strategies. These targets in oncology include those biological pathways that are associated with several tumour features including independence from growth and growth-inhibitory signals, avoidance of apoptosis and immune system control, unlimited potential for replication, self-sufficiency in vascular supply and neoangiogenesis, acquired tissue invasiveness and metastatic diffusion. Concerning brain tumours, there have been major improvements in neurosurgical techniques and radiotherapy planning, and developments of novel target drugs, thus increasing the need for reproducible, noninvasive, quantitative imaging biomarkers. However, in this context, conventional radiological criteria may be inappropriate to determine the best therapeutic option and subsequently to assess response to therapy. Integration of molecular imaging for the evaluation of brain tumours has for this reason become necessary, and an important role in this setting is played by imaging biomarkers in PET and MRI. In the current review, we describe most relevant techniques and biomarkers used for imaging primary brain tumours in clinical practice, and discuss potential future developments from the experimental context. (orig.)

  4. Expression of Robo protein in bladder cancer tissues and its effect on the growth of cancer cells by blocking Robo protein. (United States)

    Li, Yang; Cheng, Hepeng; Xu, Weibo; Tian, Xin; Li, Xiaodong; Zhu, Chaoyang


    This study aimed to detect the expression of Slit signaling protein ligand Robo protein in human bladder cancer and para-carcinoma tissue, and observe the tumor cell survival and growth by inoculating the bladder cancer cells with the blocked signaling protein into the subcutaneous tissue of nude mice. The expression of Robo protein was detected in T24 cells in human bladder uroepithelium carcinoma and cultivated human bladder uroepithelium carcinoma confirmed by pathological diagnosis. The cultivated T24 cells were coated by the protein antibody and human bladder uroepithelium carcinoma T24 tumor-bearing mice model was established. The tumor cell survival and growth were observed in the antibody coating group and non-coating group. The tumor body size was measured. The immunohistochemical detection showed that Robo protein isoforms Robo1 and Robo 4 were expressed in T24 cells of cancer tissues, paracarcinoma tissues and cultured human uroepithelium carcinoma. The expression of Robo1 was significantly higher than that of Robo4 (PRobo4 antibody coating group and non-coating group (P>0.05); The difference was statistically significant compared with the anti-Robo1 antibody coating group (PRobo protein isoforms Robo1 and Robo4 were expressed in human bladder cancer T24 cells. To block Robo4 signal protein had little effect on the survival and growth of the transplantation tumor and to block Robo1 signal protein would seriously affect the survival and growth of the transplantation tumor, suggesting that Robo1 might play an important role in the growth and metastasis of bladder cancer, and might become a new target for the treatment of human bladder cancer and drug research.

  5. Fabrication of honeycomb-structured poly(ethylene glycol)-block-poly(lactic acid) porous films and biomedical applications for cell growth

    Energy Technology Data Exchange (ETDEWEB)

    Yao, Bingjian [Key Laboratory of Special Functional Aggregated Materials, Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250199 (China); College of chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Normal University, Jinan 250014 (China); Zhu, Qingzeng, E-mail: [Key Laboratory of Special Functional Aggregated Materials, Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250199 (China); Yao, Linli [Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, 250012 Jinan (China); Hao, Jingcheng [Key Laboratory of Special Functional Aggregated Materials, Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250199 (China)


    Graphical abstract: - Highlights: • Honeycomb-structured PEG-PLA porous films were fabricated. • The organization of pores depends on molecular weight ratio of PEG-to-PLA block. • The pores in the film were internally decorated with a layer of PEG. • The honeycomb-structured PEG-PLA film was suitable as a substrate for cell growth. - Abstract: A series of poly(ethylene glycol)-block-poly(lactic acid) (PEG-PLA) copolymers with a hydrophobic PLA block of different molecular weights and a fixed length hydrophilic PEG were synthesized successfully and characterized. These amphiphilic block copolymers were used to fabricate honeycomb-structured porous films using the breath figure (BF) templating technique. The surface topology and composition of the highly ordered pattern film were further characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and fluorescence microscopy. The results indicated that the PEG-to-PLA block molecular weight ratio influenced the BF film surface topology. The film with the best ordered pores was obtained with a PEG-to-PLA ratio of 2.0 × 10{sup 3}:3.0 × 10{sup 4}. The self-organization of the hydrophilic PEG chains within the pores was confirmed by XPS and fluorescence labeled PEG. A model is proposed to elucidate the stabilization process of the amphiphilic PEG-PLA aggregated architecture on the water droplet-based templates. In addition, GFP-U87 cell viability has been investigated by MTS test and the cell morphology on the honeycomb-structured PEG-PLA porous film has been evaluated using phase-contrast microscope. This porous film is shown to be suitable as a matrix for cell growth.

  6. Malignant salivary gland tumours

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, S.H. (University of the Witwatersrand, Johannesburg (South Africa). Dept. of Oral Pathology)


    The most frequent malignant salivary gland tumours are the mucoepidermoid tumour, adenoid cystic carcinoma and adenocarcinoma. The major salivary glands and the minor glands of the mouth and upper respiratory tract may potentially develop any of these malignant lesions. Malignant lesions most frequently present as a palpable mass and tend to enlarge more rapidly than benign neoplasms. Pain, paresthesia, muscle paralysis and fixation to surrounding tissue are all ominous signs and symptoms. The only reliable means of differential diagnosis of these lesions is biopsy and histologic analysis. Therapy involves surgery or a combination of surgery and radiation therapy. The ultimate prognosis is governed by the intrinsic biologic behaviour of the neoplasms, the extent of disease and adequate clinical therapy.

  7. Skull base tumours

    Energy Technology Data Exchange (ETDEWEB)

    Borges, Alexandra [Instituto Portugues de Oncologia Francisco Gentil, Servico de Radiologia, Rua Professor Lima Basto, 1093 Lisboa Codex (Portugal)], E-mail:


    With the advances of cross-sectional imaging radiologists gained an increasing responsibility in the management of patients with skull base pathology. As this anatomic area is hidden to clinical exam, surgeons and radiation oncologists have to rely on imaging studies to plan the most adequate treatment. To fulfil these endeavour radiologists need to be knowledgeable about skull base anatomy, about the main treatment options available, their indications and contra-indications and needs to be aware of the wide gamut of pathologies seen in this anatomic region. This article will provide a radiologists' friendly approach to the central skull base and will review the most common central skull base tumours and tumours intrinsic to the bony skull base.

  8. Synthesis, biodistribution and effects of farnesyltransferase inhibitor therapy on tumour uptake in mice of 99mTc labelled epidermal growth factor.

    NARCIS (Netherlands)

    Cornelissen, B.; Kersemans, V.; Burvenich, I.; Oltenfreiter, R.; Heyden, J.L. van der; Boerman, O.C.; Wiele, C. van de; Slegers, G.


    OBJECTIVE: The goal of this study was to develop a 99mTc labelled human epidermal growth factor (hEGF) for the in-vivo prediction of cancer cell response to farnesyltransferase inhibitor (FTI) therapy. This is based on the observation that internalization of EGF receptors is inhibited by FTIs. METHO

  9. Prostacyclin Inhibits Non-Small Cell Lung Cancer Growth by a Frizzled 9-Dependent Pathway That Is Blocked by Secreted Frizzled-Related Protein 1

    Directory of Open Access Journals (Sweden)

    Meredith A. Tennis


    Full Text Available The goal of this study was to assess the ability of iloprost, an orally active prostacyclin analog, to inhibit transformed growth of human non-small cell lung cancer (NSCLC and to define the mechanism of iloprost's tumor suppressive effects. In a panel of NSCLC cell lines, the ability of iloprost to inhibit transformed cell growth was not correlated with the expression of the cell surface receptor for prostacyclin, but instead was correlated with the presence of Frizzled 9 (Fzd 9 and the activation of peroxisome proliferator-activated receptor-γ (PPARγ. Silencing of Fzd 9 blocked PPARγ activation by iloprost, and expression of Fzd 9 in cells lacking the protein resulted in iloprost's activation of PPARγ and inhibition of transformed growth. Interestingly, soluble Frizzled-related protein-1, a well-known inhibitor of Wnt/Fzd signaling, also blocked the effects of iloprost and Fzd 9. Moreover, mice treated with iloprost had reduced lung tumors and increased Fzd 9 expression. These studies define a novel paradigm, linking the eicosanoid pathway and Wnt signaling. In addition, these data also suggest that prostacyclin analogs may represent a new class of therapeutic agents in the treatment of NSCLC where the restoration of noncanonical Wnt signaling maybe important for the inhibition of transformed cell growth.

  10. Computer aided diagnosis of bone tumours and tumour-like skeletal abnormalities: Critical evaluation of its clinical use

    Energy Technology Data Exchange (ETDEWEB)

    Fotter, R.; Gell, G.; Melzer, G.; Kopp, W.; Lehnert, M.; Weybora, W.


    Thirty-four patients with bone tumours and tumour-like abnormalities of the skeleton, of varying ages, were examined by a computer-aided diagnostic programm; the accuracy, clinical usefullness and specific advantages and disadvantages of the programm have been evaluated. This was done by two statistical methods, both with showed high accuracy and reliability of the system (97% and 88,2%). In addition to the diagnostic results, the growth rate of the lesion could be estimated. This indicates the biological behaviour of the tumour independently of the histological diagnosis.

  11. Perturbation of blood flow as a mechanism of anti-tumour action of direct current electrotherapy. (United States)

    Jarm, Tomaz; Cemazar, Maja; Steinberg, Fritz; Streffer, Christian; Sersa, Gregor; Miklavcic, Damijan


    Anti-tumour effects of direct current electrotherapy are attributed to different mechanisms depending on the electrode configuration and on the parameters of electric current. The effects mostly arise from the electrochemical products of electrolysis. Direct toxicity of these products to tumour tissue is, however, not a plausible explanation for the observed tumour growth retardation in the case when the electrodes are placed into healthy tissue surrounding the tumour and not into the tumour itself. The hypothesis that the anti-tumour effectiveness of electrotherapy could result from disturbed blood flow in tumours was tested by the measurement of changes in blood perfusion and oxygenation in tumours with three different methods (in vivo tissue staining with Patent Blue Violet dye, polarographic oximetry, near-infrared spectroscopy). The effects induced by electrotherapy were evaluated in two experimental tumour models: Sa-1 fibrosarcoma in A/J mice and LPB fibrosarcoma in C57B1/6 mice. We found that perfusion and oxygenation were significantly decreased after electrotherapy. Good agreement between the results of different methods was observed. The effect of electrotherapy on local perfusion of tumours is probably the prevalent mechanism of anti-tumour action for the particular type of electrotherapy used in the study. The importance of this effect should be considered for the optimization of electrotherapy protocols in experimental and clinical trials. The non-invasive technique of near-infrared spectroscopy proved to be a reliable method for detecting perfusion and oxygenation changes in small solid tumours.

  12. Development of luciferase tagged brain tumour models in mice for chemotherapy intervention studies. (United States)

    Kemper, E M; Leenders, W; Küsters, B; Lyons, S; Buckle, T; Heerschap, A; Boogerd, W; Beijnen, J H; van Tellingen, O


    The blood-brain barrier (BBB) is considered one of the major causes for the low efficacy of cytotoxic compounds against primary brain tumours. The aim of this study was to develop intracranial tumour models in mice featuring intact or locally disrupted BBB properties, which can be used in testing chemotherapy against brain tumours. These tumours were established by intracranial injection of suspensions of different tumour cell lines. All cell lines had been transfected with luciferase to allow non-invasive imaging of tumour development using a super-cooled CCD-camera. Following their implantation, tumours developed which displayed the infiltrative, invasive or expansive growth patterns that are also found in primary brain cancer or brain metastases. Contrast-enhanced magnetic resonance imaging showed that the Mel57, K1735Br2 and RG-2 lesions grow without disruption of the BBB, whereas the BBB was leaky in the U87MG and VEGF-A-transfected Mel57 lesions. This was confirmed by immunohistochemistry. Bioluminescence measurements allowed the visualisation of tumour burden already within 4 days after injection of the tumour cells. The applicability of our models for performing efficacy studies was demonstrated in an experiment using temozolomide as study drug. In conclusion, we have developed experimental brain tumour models with partly disrupted, or completely intact BBB properties. In vivo imaging by luciferase allows convenient follow-up of tumour growth and these models will be useful for chemotherapeutic intervention studies.

  13. Multimodal therapy for synergic inhibition of tumour cell invasion and tumour-induced angiogenesis

    Directory of Open Access Journals (Sweden)

    Muehlenweg Bernd


    Full Text Available Abstract Background Squamous cell carcinoma of the head and neck (SCCHN are highly invasive tumours with frequent local and distant recurrence. Metastasis formation requires degradation of the extracellular matrix, which is fulfilled by membrane-associated proteases such as the urokinase plasminogen activator (uPA. WX-UK1 is a competitive active site inhibitor of the protease function of uPA that impairs on the capacity of tumour cells to invade in vitro. Methods In the present study, effects of combinations of WX-UK1 with matrix metalloprotease inhibitors (MMP, galardin® and cyclooxygenase-2 (COX-2, celecoxib® inhibitors on tumour cell proliferation, invasion, and angiogenesis induction were evaluated. Matrigel invasion chambers and a spheroid co-cultivation model with human fibroblast served to determine the invasive potential of both FaDu (SCCHN and HeLa (cervical carcinoma cells, each treated with combinations of Celecoxib®, Galardin®, and WX-UK1. Results Blocking of single protease systems resulted in a significant 50% reduction of tumour cell invasion using WX-UK1, while the triple combination was even more effective with 80% reduction of invasion. Additionally, a sprouting assay with HUVEC was used to test the anti-angiogenetic potential of the triple combination, resulting in a 40% decrease in the sprouting rate. Conclusions A combined approach targeting different families of proteases and cyclooxygenases represents a promising adjuvant therapy.

  14. Evidence for Existence of Immunoglobulins that Block Ovarian Granulosa Cell Growth in Vitro. A Putative Role in Resistant Ovary Syndrome?

    NARCIS (Netherlands)



    The sera of 26 patients with premature ovarian failure were examined in order to detect immunoglobulin-G (IgGs) that can block FSH-induced in vitro granulosa cell DNA synthesis via, a Feulgen cytochemical bioassay system. The IgGs of four patients with polycystic ovary-like disease, five postmenopau

  15. Vaginal haemangioendothelioma: an unusual tumour.

    LENUS (Irish Health Repository)

    Mohan, H


    Vaginal tumours are uncommon and this is a particularly rare case of a vaginal haemangioendothelioma in a 38-year-old woman. Initial presentation consisted of symptoms similar to uterovaginal prolapse with "something coming down". Examination under anaesthesia demonstrated a necrotic anterior vaginal wall tumour. Histology of the lesion revealed a haemangioendothelioma which had some features of haemangiopericytoma. While the natural history of vaginal haemangioendothelioma is uncertain, as a group, they have a propensity for local recurrence. To our knowledge this is the third reported case of a vaginal haemangioendothelioma. Management of this tumour is challenging given the paucity of literature on this tumour. There is a need to add rare tumours to our "knowledge bank" to guide management of these unusual tumours.

  16. Rock blocks


    Turner, W.


    Consider representation theory associated to symmetric groups, or to Hecke algebras in type A, or to q-Schur algebras, or to finite general linear groups in non-describing characteristic. Rock blocks are certain combinatorially defined blocks appearing in such a representation theory, first observed by R. Rouquier. Rock blocks are much more symmetric than general blocks, and every block is derived equivalent to a Rock block. Motivated by a theorem of J. Chuang and R. Kessar in the case of sym...

  17. Primary bone tumours in infants

    Energy Technology Data Exchange (ETDEWEB)

    Kozlowski, K.; Beluffi, G.; Cohen, D.H.; Padovani, J.; Tamaela, L.; Azouz, M.; Bale, P.; Martin, H.C.; Nayanar, V.V.; Arico, M.


    Ten cases of primary bone tumours in infants (1 osteosarcoma, 3 Ewing's sarcoma, 1 chondroblastoma and 5 angiomastosis) are reported. All cases of angiomatosis showed characteristic radiographic findings. In all the other tumours the X-ray appearances were different from those usually seen in older children and adolescents. In the auhtors' opinion the precise diagnosis of malignant bone tumours in infancy is very difficult as no characteristic X-ray features are present in this age period.

  18. LET-painting increases tumour control probability in hypoxic tumours. (United States)

    Bassler, Niels; Toftegaard, Jakob; Lühr, Armin; Sørensen, Brita Singers; Scifoni, Emanuele; Krämer, Michael; Jäkel, Oliver; Mortensen, Lise Saksø; Overgaard, Jens; Petersen, Jørgen B


    LET-painting was suggested as a method to overcome tumour hypoxia. In vitro experiments have demonstrated a well-established relationship between the oxygen enhancement ratio (OER) and linear energy transfer (LET), where OER approaches unity for high-LET values. However, high-LET radiation also increases the risk for side effects in normal tissue. LET-painting attempts to restrict high-LET radiation to compartments that are found to be hypoxic, while applying lower LET radiation to normoxic tissues. Methods. Carbon-12 and oxygen-16 ion treatment plans with four fields and with homogeneous dose in the target volume, are applied on an oropharyngeal cancer case with an identified hypoxic entity within the tumour. The target dose is optimised to achieve a tumour control probability (TCP) of 95% when assuming a fully normoxic tissue. Using the same primary particle energy fluence needed for this plan, TCP is recalculated for three cases assuming hypoxia: first, redistributing LET to match the hypoxic structure (LET-painting). Second, plans are recalculated for varying hypoxic tumour volume in order to investigate the threshold volume where TCP can be established. Finally, a slight dose boost (5-20%) is additionally allowed in the hypoxic subvolume to assess its impact on TCP. Results. LET-painting with carbon-12 ions can only achieve tumour control for hypoxic subvolumes smaller than 0.5 cm(3). Using oxygen-16 ions, tumour control can be achieved for tumours with hypoxic subvolumes of up to 1 or 2 cm(3). Tumour control can be achieved for tumours with even larger hypoxic subvolumes, if a slight dose boost is allowed in combination with LET-painting. Conclusion. Our findings clearly indicate that a substantial increase in tumour control can be achieved when applying the LET-painting concept using oxygen-16 ions on hypoxic tumours, ideally with a slight dose boost.

  19. Immunology of cancer stem cells in solid tumours. A review. (United States)

    Maccalli, Cristina; Volontè, Andrea; Cimminiello, Carolina; Parmiani, Giorgio


    Cancer stem cells (CSCs) represent a minor subpopulation of tumour cells that share some features with the normal stem cells of the tissue from which tumour derives and have the properties of self-renewal, multiple differentiation and tumour initiation (tumour-initiating cells, TICs). Thus CSCs/TICs need to survive cancer therapies in order to provide new, more differentiated, metastatic-prone tumour cells. This occurs through different signals delivered within the tumour microenvironment. The immune system of cancer patients may recognise CSCs/TICs and kill them though it is unclear whether this may occur in vivo during spontaneous tumour growth. This review summarises findings on the immunological profile of CSCs/TICs as compared with neoplastic non-stem cells and discusses the possible antigens recognised by the patients' immune system, the in vitro and the potential in vivo immunogenicity of such antigens and the ability of human CSCs/TICs to down-regulate the immune response by the release of a variety of suppressive factors. We conclude that available data on immunological characterisation of CSCs/TICs may be useful in the perspective of designing new translational immunotherapy protocols targeting CSCs/TICs.

  20. VIP induces NF-κB1-nuclear localisation through different signalling pathways in human tumour and non-tumour prostate cells. (United States)

    Fernández-Martínez, Ana B; Carmena, María J; Bajo, Ana M; Vacas, Eva; Sánchez-Chapado, Manuel; Prieto, Juan C


    The nuclear factor κB (NF-κB) is a powerful activator of angiogenesis, invasion and metastasis. Transactivation and nuclear localisation of NF-κB is an index of recurrence in prostate cancer. Vasoactive intestinal peptide (VIP) exerts similar effects in prostate cancer models involving increased expression of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) which are related to NF-κB transactivation. Here we studied differential mechanisms of VIP-induced NF-κB transactivation in non-tumour RWPE-1 and tumour LNCaP and PC3 human prostate epithelial cells. Immunofluorescence studies showed that VIP increases translocation of the p50 subunit of NF-κB1 to the nucleus, an effect that was inhibited by curcumin. The signalling transduction pathways involved are different depending on cell transformation degree. In control cells (RWPE1), the effect is mediated by protein kinase A (PKA) activation and does not implicate extracellular signal-regulated kinase (ERK) or phosphoinositide 3-kinase (PI3-K) pathways whereas the opposite is true in tumour LNCaP and PC3 cells. Exchange protein directly activated by cAMP (EPAC) pathway is involved in transformed cells but not in control cells. Curcumin blocks the activating effect of VIP on COX-2 promoter/prostaglandin E2 (PGE2) production and VEGF expression and secretion. The study incorporates direct observation on COX-2 promoter and suggests that VIP effect on VEGF may be indirectly mediated by PGE2 after being synthesised by COX-2, thus amplifying the initial signal. We show that the signalling involved in VIP effects on VEGF is cAMP/PKA in non-tumour cells and cAMP/EPAC/ERK/PI3K in tumour cells which coincides with pathways mediating p50 nuclear translocation. Thus, VIP appears to use different pathways for NF-κB1 (p50) transactivation in prostate epithelial cells depending on whether they are transformed or not. Transformed cells depend on pro-survival and pro-proliferative signalling pathways

  1. Endocrine disorders following treatment of childhood brain tumours.


    Livesey, E A; Hindmarsh, P C; Brook, C G; Whitton, A. C.; Bloom, H. J.; Tobias, J. S.; Godlee, J. N.; Britton, J.


    We have studied the long-term endocrine effects of treatment on 144 children treated for brain tumours. All received cranial irradiation, 86 also received spinal irradiation and 34 chemotherapy. Almost all patients (140 of 144) had evidence of growth hormone insufficiency. Treatment with growth hormone was effective in maintaining normal growth but could not restore a deficit incurred by delay in instituting treatment. The effect of spinal irradiation on spinal growth was not corrected by gro...

  2. Effects of Continuous Sciatic Nerve Block by Tetrodotoxin on Growth Associated Protein-43 Expression in Dorsal Root Ganglions of Normal and Sciatic Nerve Injury Rats

    Institute of Scientific and Technical Information of China (English)

    Chen Wang; Yong-fa Zhang; Xiao-yu Huang


    @@ Growth associated protein-43 (GAP-43) is considered to be one of the most useful molecular markers for the neural development, nerve regeneration, and neuroplasticity. In most mature neurons, the expression of GAP-43 is at very low or negative level; its expression is triggered in response to the interruption of axonal transport. The purpose of this study was to examine whether continuous sciatic nerve block by tetrodotoxin (TTX) affects GAP-43 expression in the dorsal root ganglion (DRG) of normal and sciatic nerve injury rats.

  3. Blood vessel hyperpermeability and pathophysiology in human tumour xenograft models of breast cancer: a comparison of ectopic and orthotopic tumours

    Directory of Open Access Journals (Sweden)

    Ho Karyn S


    in vivo. A more predictable growth profile and the absence of ulcerated skin lesions further point to the MFP model as a strong choice for long term treatment studies that initiate after a target tumour size has been reached.

  4. Antimicrobial Activity, Growth Inhibition of Human Tumour Cell Lines, and Phytochemical Characterization of the Hydromethanolic Extract Obtained from Sapindus saponaria L. Aerial Parts

    Directory of Open Access Journals (Sweden)

    Khaled N. Rashed


    Full Text Available 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.

  5. Tumours in the Small Bowel

    Directory of Open Access Journals (Sweden)

    N. Kurniawan


    Full Text Available Small bowel tumours are rare and originate from a wide variety of benign and malignant entities. Adenocarcinomas are the most frequent primary malignant small bowel tumours. Submucosal tumours like gastrointestinal stromal tumours (GIST or neuroendocrine tumours (NET may show a central umbilication, pathologic vessels, bridging folds or an ulceration of the overlying mucosa. These signs help to differentiate them from harmless bulges caused by impression from outside, e.g. from other intestinal loops. Sarcomas of the small bowel are rare neoplasias with mesenchymal origin, sometimes presenting as protruding masses. Benign tumours like lipoma, fibrolipoma, fibroma, myoma, and heterotopias typically present as submucosal masses. They cannot be differentiated endoscopically from those with malignant potential as GIST or NET. Neuroendocrine carcinomas may present with diffuse infiltration, which may resemble other malignant tumours. The endoscopic appearance of small bowel lymphomas has a great variation from mass lesions to diffuse infiltrative changes. Melanoma metastases are the most frequent metastases to the small bowel. They may be hard to distinguish from other tumours when originating from an amelanotic melanoma.

  6. Anatomical and biochemical investigation of primary brain tumours

    Energy Technology Data Exchange (ETDEWEB)

    Del Sole, A. [Univ. di Milano (Italy); Falini, A. [Univ. Vita e Salute (Italy). IRCCS; Ravasi, L.; Ottobrini, L.; Lucignani, G. [Univ. di Milano (Italy). Ist. di Scienze Radiologiche; De Marchis, D. [Univ. di Milano-Bicocca (Italy); Bombardieri, E. [Istituto Nazionale dei Tumori, Milano (Italy)


    Cancerous transformation entails major biochemical changes including modifications of the energy metabolism of the cell, e.g. utilisation of glucose and other substrates, protein synthesis, and expression of receptors and antigens. Tumour growth also leads to heterogeneity in blood flow owing to focal necrosis, angiogenesis and metabolic demands, as well as disruption of transport mechanisms of substrates across cell membranes and other physiological boundaries such as the blood-brain barrier. All these biochemical, histological and anatomical changes can be assessed with emission tomography, X-ray computed tomography (CT), magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Whereas anatomical imaging is aimed at the diagnosis of brain tumours, biochemical imaging is better suited for tissue characterisation. The identification of a tumoural mass and the assessment of its size and vascularisation are best achieved with X-ray CT and MRI, while biochemical imaging can provide additional information that is crucial for tumour classification, differential diagnosis and follow-up. As the assessment of variables such as water content, appearance of cystic lesions and location of the tumour are largely irrelevant for tissue characterisation, a number of probes have been employed for the assessment of the biochemical features of tumours. Since biochemical changes may be related to the growth rate of cancer cells, they can be thought of as markers of tumour cell proliferation. Biochemical imaging with radionuclides of processes that occur at a cellular level provides information that complements findings obtained by anatomical imaging aimed at depicting structural, vascular and histological changes. This review focusses on the clinical application of anatomical brain imaging and biochemical assessment with positron emission tomography, single-photon emission tomography and MRS in the diagnosis of primary brain tumours, as well as in follow-up. (orig.)

  7. In vivo 31P magnetic resonance spectroscopy and 1H magnetic resonance imaging of human bladder carcinoma on nude mice: effects of tumour growth and treatment with cis-dichloro-diamine platinum

    DEFF Research Database (Denmark)

    De Certaines, J D; Albrectsen, J; Larsen, V A;


    phosphate and phosphomonoesters and a decrease of phosphocreatine. Fast growing tumours and early stage of regrowth after treatment presented a higher phosphocreatine/beta NTP ratio. Following CDDP treatment, 31P metabolite ratios and pH were significantly altered compared with age-matched controls......, as early as 6 hours after treatment. Although necrotic area was clearly visible in MRI, no treatment effect could be detected on the images of treated tumours....

  8. In vivo 31P magnetic resonance spectroscopy and 1H magnetic resonance imaging of human bladder carcinoma on nude mice: effects of tumour growth and treatment with cis-dichloro-diamine platinum

    DEFF Research Database (Denmark)

    De Certaines, J D; Albrectsen, J; Larsen, V A;


    phosphate and phosphomonoesters and a decrease of phosphocreatine. Fast growing tumours and early stage of regrowth after treatment presented a higher phosphocreatine/beta NTP ratio. Following CDDP treatment, 31P metabolite ratios and pH were significantly altered compared with age-matched controls......, as early as 6 hours after treatment. Although necrotic area was clearly visible in MRI, no treatment effect could be detected on the images of treated tumours....

  9. Neutrophil-induced transmigration of tumour cells treated with tumour-conditioned medium is facilitated by granulocyte-macrophage colony-stimulating factor.

    LENUS (Irish Health Repository)

    Wu, Q D


    OBJECTIVE: To investigate the effect of different cytokines that are present in tumour-conditioned medium on human neutrophil (PMN)-induced tumour cell transmigration. DESIGN: Laboratory study. SETTING: University hospital, Ireland. MATERIAL: Isolated human PMN and cultured human breast tumour cell line, MDA-MB-231. Interventions: Human PMN treated with either tumour-conditioned medium or different media neutralised with monoclonal antibodies (MoAb), and MDA-MB-231 cells were plated on macrovascular and microvascular endothelial monolayers in collagen-coated transwells to assess migration of tumour cells. MAIN OUTCOME MEASURES: Cytokines present in tumour-conditioned medium, PMN cytocidal function and receptor expression, and tumour cell transmigration. RESULTS: tumour-conditioned medium contained high concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8), but not granulocyte colony-stimulating factor (G-CSF) and interleukin 3 (IL-3). Anti-GM-CSF MoAb significantly reduced PMN-induced transmigration of tumour cells treated with tumour-conditioned medium (p < 0.05), whereas anti-VEGF and anti-IL-8 MoAbs did not affect their migration. In addition, anti-GM-CSF MoAb, but not anti-VEGF or anti-IL-8 MoAb, reduced PMN CD11b and CD18 overexpression induced by tumour-conditioned medium (p < 0.05). CONCLUSION: These results indicate that the GM-CSF that is present in tumour-conditioned medium may be involved, at least in part, in alterations in PMN function mediated by the medium and subsequently PMN-induced transmigration of tumour cells.

  10. Intraspinal tumours in the Kenya African. (United States)

    Ruberti, R F; Carmagnani, A L


    Thirty-one cases of intraspinal tumours in the African have been described, with age, sex incidence, frequency, site and histopathology shown. Intraspinal tumours in this series are compared with the larger series. Extradural and intramedullary tumours together with cervical spine tumours appear to be more frequent in this series. There is a high incidence of dumbell tumours in the neurinomas. Sarcomas are the most common type of tumours and mainly affect the thoracic spine.

  11. Unusual tumours of the lung. (United States)

    Wright, E S; Pike, E; Couves, C M


    Unusual lung tumors are not simply pathological curiosities. They demonstrate features of major significance in diagnosis, treatment, and prognosis. Six of these tumours are discussed: (1) Carcinosarcoma is rarely found in the lung. The histogenis of the lesion is unclear and the prognosis is poor. (2) Only three cases of pleomorphic adenoma have previously been described. Differentiation from other "mixed tumours" of the lung is essential. (3) A rare case of bronchial adenoma producing ectopic ACTH is described. Early recognition of these polypeptide hormone-secreting tumours is stressed. (4) Oat cell carcinoma with the myasthenic (Eaton-Lambert) syndrome shows the clinical features which should permit early tumour diagnosis. The hazards of muscle relaxants must be recognized. (5) Prostatic carcinoma with endobronchial metastases is is discussed. The importance of localization of the primary tumour is emphasized. (6) An example of double primary carcinoma is presented. The rarity of this finding may be related to the poor prognosis of patients with bronchogenesis carcinoma.

  12. Defect blocking via laterally induced growth of semipolar (1 0 1̅ 1) GaN on patterned substrates (United States)

    Khoury, Michel; Vennéguès, Philippe; Leroux, Mathieu; Delaye, Vincent; Feuillet, Guy; Zúñiga-Pérez, Jesus


    Semipolar (1 0 \\overline{1}  1) GaN thin films with state-of-the-art optical and structural quality have been obtained on silicon substrates by metal organic chemical vapor deposition using a novel defect reduction method. We initially apply a classical patterning approach on Si (0 0 1) {{7}\\circ} off substrates to reveal the Si (1 1 1) facets over which the subsequent inclined epitaxy will be carried out. After the growth of AlN, the sample is etched with \\text{S}{{\\text{F}}6} before the GaN growth is done on the same structure. The process has shown to induce the spontaneous formation of a defect blocking layer that substantially reduces the presence of threading dislocations and basal stacking faults. This is confirmed by correlated optical and structural characterizations. Further, a simple model explaining the origin and working-principle of the blocking layer will be discussed.

  13. Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours

    Directory of Open Access Journals (Sweden)

    Brown Allison


    Full Text Available Abstract 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

  14. Cushing syndrome associated with an adrenal tumour. (United States)

    Vieira, Helena; Brain, Caroline


    Cushing syndrome (CS) in children is a rare disorder that is most frequently caused by an adrenal tumour or a pituitary corticotrophin-secreting adenoma. The management is challenging and requires an individualised approach and multidisciplinary care. We present the case of a 23-month-old female child with a history of excessive weight gain, growth failure, hirsutism, acne and behavioural difficulties. Investigations revealed elevated serum midnight cortisol and 24 h urinary free cortisol. Overnight dexamethasone suppression testing showed no suppression of cortisol levels. Abdominal imaging revealed a right-sided suprarenal mass. She underwent right adrenalectomy and the histology showed an adrenal cortical carcinoma. There was clinical improvement with catch-up growth and weight normalisation. Despite being rare in clinical practice, in a child with weight gain, hirsuitism and growth failure the diagnosis must be considered. The overall prognosis of CS in childhood is good, but challenges remain to ensure normal growth and body composition.

  15. Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo.

    Directory of Open Access Journals (Sweden)

    Masami Suzuki

    Full Text Available The dormancy of tumor cells is a major problem in chemotherapy, since it limits the therapeutic efficacy of anti-tumor drugs that only target dividing cells. One potential way to overcome chemo-resistance is to "wake up" these dormant cells. Here we show that the opioid antagonist methylnaltrexone (MNTX enhances the effect of docetaxel (Doc by blocking a cell growth-suppressive pathway. We found that PENK, which encodes opioid growth factor (OGF and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs. The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc. In comparison with the use of Doc alone, the combined use of Doc and MNTX significantly prolongs survival, alleviates abdominal pain, and diminishes Doc-resistant spheroids on the peritoneal membrane in model mice. These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.

  16. The Mechanism of Action of Unique Small Molecules that Inhibit the Pim Protein Kinase Blocking Prostate Cancer Cell Growth (United States)


    purified from insect cells (39) andmixedwith in vitro-translated 35S-labeled p27 that had previously been incubatedwith cyclin E/Cdk2 alongwithmeth...phosphorylation, mTORC1 activity, 5′-cap-dependent translation, and ultimately cell growth (Fig. 5C). Discussion The combined approach of genetic knockout, RNAi

  17. Imatinib treatment for gastrointestinal stromal tumour (GIST). (United States)

    Lopes, Lisandro F; Bacchi, Carlos E


    Gastrointestinal stromal tumour (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. GISTs are believed to originate from intersticial cells of Cajal (the pacemaker cells of the gastrointestinal tract) or related stem cells, and are characterized by KIT or platelet-derived growth factor receptor alpha (PDGFRA) activating mutations. The use of imatinib has revolutionized the management of GIST and altered its natural history, substantially improving survival time and delaying disease progression in many patients. The success of imatinib in controlling advanced GIST led to interest in the neoadjuvant and adjuvant use of the drug. The neoadjuvant (preoperative) use of imatinib is recommended to facilitate resection and avoid mutilating surgery by decreasing tumour size, and adjuvant therapy is indicated for patients at high risk of recurrence. The molecular characterization (genotyping) of GISTs has become an essential part of the routine management of the disease as KIT and PDGFRA mutation status predicts the likelihood of achieving response to imatinib. However, the vast majority of patients who initially responded to imatinib will develop tumour progression (secondary resistance). Secondary resistance is often related to secondary KIT or PDGFRA mutations that interfere with drug binding. Multiple novel tyrosine kinase inhibitors may be potentially useful for the treatment of imatinib-resistant GISTs as they interfere with KIT and PDGFRA receptors or with the downstream-signalling proteins.

  18. Primary vertebral tumours in children

    Energy Technology Data Exchange (ETDEWEB)

    Kozlowski, K.; Beluffi, G.; Masel, J.; Diard, F.; Ferrari-Ciboldi, F.; Le Dosseur, P.; Labatut, J.


    20 cases of primary benign and malignant bone tumours in children were reported. The most common tumours were Ewing's sarcoma, aneurismal bone cyst, benign osteoblastoma and osteoid osteoma. Some rare primary bone tumours in children (osteochondroma, chondroblastoma 6F, primary lymphoma of bone and neurofibromatosis with unusual cervical spinal changes) were also reported. The authors believe that radiographic findings together with clinical history and clinical examination may yield a high percentage of accurate diagnoses. Although microscopy is essential in the final diagnosis, the microscopic report should be also accepted with caution.

  19. Low grade epithelial stromal tumour of the seminal vesicle

    Directory of Open Access Journals (Sweden)

    Pozzoli Gianluigi


    Full Text Available Abstract Background The mixed epithelial stromal tumour is morphologically characterised by a mixture of solid and cystic areas consisting of a biphasic proliferation of glands admixed with solid areas of spindle cells with variable cellularity and growth patterns. In previous reports the seminal vesicle cystoadenoma was either considered a synonym of or misdiagnosed as mixed epithelial stromal tumour. The recent World Health Organisation Classification of Tumours considered the two lesions as two distinct neoplasms. This work is aimed to present the low-grade epithelial stromal tumour case and the review of the literature to the extent of establishing the true frequency of the neoplasm. Case presentation We describe a low-grade epithelial stromal tumour of the seminal vesicle in a 50-year-old man. Computed tomography showed a 9 × 4.5 cm pelvic mass in the side of the seminal vesicle displacing the prostate and the urinary bladder. Magnetic resonance was able to define tissue planes between the lesion and the adjacent structures and provided useful information for an accurate conservative laparotomic surgical approach. The histology revealed biphasic proliferation of benign glands admixed with stromal cellularity, with focal atypia. After 26 months after the excision the patient is still alive with no evidence of disease. Conclusion Cystoadenoma and mixed epithelial stromal tumour of seminal vesicle are two distinct pathological entities with different histological features and clinical outcome. Due to the unavailability of accurate prognostic parameters, the prediction of the potential biological evolution of mixed epithelial stromal tumour is still difficult. In our case magnetic resonance imaging was able to avoid an exploratory laparotomy and to establish an accurate conservative surgical treatment of the tumour.

  20. MET is required for the recruitment of anti-tumoural neutrophils. (United States)

    Finisguerra, Veronica; Di Conza, Giusy; Di Matteo, Mario; Serneels, Jens; Costa, Sandra; Thompson, A A Roger; Wauters, Els; Walmsley, Sarah; Prenen, Hans; Granot, Zvi; Casazza, Andrea; Mazzone, Massimiliano


    Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours, which rely on the constitutive engagement of this pathway for their growth and survival. However, MET is expressed not only by cancer cells but also by tumour-associated stromal cells, although its precise role in this compartment is not well characterized. Here we show that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor (HGF). Met deletion in mouse neutrophils enhances tumour growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumour and metastatic sites. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash or peritonitis. Mechanistically, Met is induced by tumour-derived tumour necrosis factor (TNF)-α or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and for inducible nitric oxide synthase production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumour growth and metastasis. After systemic administration of a MET kinase inhibitor, we prove that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoural effect arising from MET blockade in neutrophils. Our work identifies an unprecedented role of MET in neutrophils, suggests a potential 'Achilles' heel' of MET-targeted therapies in cancer, and supports the rationale for evaluating anti-MET drugs in certain inflammatory diseases.

  1. Anaesthetic management for caesarean section in a case of previously operated with residual pituitary tumour

    Directory of Open Access Journals (Sweden)

    Prerana N Shah


    Full Text Available 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.

  2. Statin suppresses Hippo pathway-inactivated malignant mesothelioma cells and blocks the YAP/CD44 growth stimulatory axis. (United States)

    Tanaka, Kosuke; Osada, Hirotaka; Murakami-Tonami, Yuko; Horio, Yoshitsugu; Hida, Toyoaki; Sekido, Yoshitaka


    Malignant mesothelioma (MM) frequently exhibits Hippo signaling pathway inactivation (HPI) mainly due to NF2 and/or LATS2 mutations, which leads to the activation of YAP transcriptional co-activator. Here, we show antitumor effects of statin on MM cells with HPI, through the interplay of the mevalonate and Hippo signaling pathways. Statin attenuated proliferation and migration of MM cells harboring NF2 mutation by accelerating YAP phosphorylation/inactivation. CD44 expression was decreased by statin, in parallel with YAP phosphorylation/inactivation. Importantly, we discovered that YAP/TEAD activated CD44 transcription by binding to the CD44 promoter at TEAD-binding sites. On the other hand, CD44 regulated Merlin phosphorylation according to cell density and sequentially promoted YAP transcriptional co-activator, suggesting that CD44 plays two pivotal functional roles as an upstream suppressor of the Hippo pathway and one of downstream targets regulated by YAP/TEAD. Moreover, the YAP/CD44 axis conferred cancer stem cell (CSC)-like properties in MM cells leading to chemoresistance, which was blocked by statin. Together, our findings suggest that YAP mediates CD44 up-regulation at the transcriptional level, conferring CSC-like properties in MM cells, and statin represents a potential therapeutic option against MM by inactivating YAP.

  3. Effects of blocking androgen receptor expression with specific hammerhead ribozyme on in vitro growth of prostate cancer cell line

    Institute of Scientific and Technical Information of China (English)

    童强松; 赵军; 陈朝晖; 曾甫清; 鲁功成


    Objective To study the possibility of gene therapy for prostate cancer by blocking androgen receptor (AR) gene expression using a specific hammerhead ribozyme (RZ).Methods The hammerhead ribozyme expression vector pcDNA-hAR-RZ, specific to AR mRNA, was constructed and transfected into the prostate cancer cell line LNCaP by using lipofectamine. Androgen receptor expression was measured by RT-PCR and immunohistochemical methods. Cellular proliferation activities were assayed using the tetrazolium bromide colorimetry method; cell cycle changes were observed by flow cytometry; and cell apoptosis was detected by the TdT-mediated dUTP-biotin nick end labeling method. Results One to seven days after transfection with the ribozyme expression vector, AR mRNA expression at molecular and protein levels in LNCaP cells decreased by 32.6%-40.7% (P<0.05) and 21.0%-87.64% (P<0.05) respectively, and cell proliferation was inhibited by 18.28%-35.34% (P<0.05). Meanwhile, the cell cycle was arrested at the G2/M stage, and apoptotic morphological changes occurred with an apoptosis rate of 25.17% (P<0.01).Conclusion Ribozyme specific against AR mRNA is capable of inhibiting the expression AR and inducing the apoptosis in prostate cancer cells.


    Jenson, Lacey J; Bloomquist, Jeffrey R


    A neuronal morphological phenotype can be induced in cultured Spodoptera frugiperda insect cells (Sf21) by supplementing serum-containing media with 20-hydroxyecdysone (20-HE) and/or insulin. In this study, the primary objectives were to determine any role of ion channels in mediating the morphological change in cells treated with 20-HE and insulin, and whether serum was required to observe this effect. Results showed serum-free media also induced growth of processes in Sf21 cells, but at a lower percentage than that found previously in cells bathed in serum-containing media. Veratridine, a sodium channel activator, increased cell survival when applied in combination with 20-HE to Sf21 cells, and the effect was blocked by tetrodotoxin (1 μM) a known sodium channel blocker. Cobalt, a calcium channel blocker, showed significant inhibition of cell process growth when applied in combination with both 20-HE and 20-HE plus veratridine. Cobalt also showed significant inhibition of cell process growth when applied in combination with insulin. Thus, some type of sodium channel, as well as a mechanism for transmembrane calcium ion movement, are apparently expressed in Sf21 cells and are involved in the differentiation process. These cell lines may be used in a wide variety of endeavors, including the screening of insecticides, as well as foster basic studies of neurodevelopment and ecdysone action.

  5. [Molecular genetics of familial tumour syndromes of the central nervous system]. (United States)

    Murnyák, Balázs; Szepesi, Rita; Hortobágyi, Tibor


    Although most of the central nervous system tumours are sporadic, rarely they are associated with familial tumour syndromes. These disorders usually present with an autosomal dominant inheritance and neoplasia develops at younger age than in sporadic cases. Most of these tumours are bilateral, multiplex or multifocal. The causative mutations occur in genes involved in cell cycle regulation, cell growth, differentiation and DNA repair. Studying these hereditary cancer predisposition syndromes associated with nervous system tumours can facilitate the deeper understanding of the molecular background of sporadic tumours and the development of novel therapeutic agents. This review is an update on hereditary tumour syndromes with nervous system involvement with emphasis on molecular genetic characteristics and their clinical implications.

  6. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. (United States)

    Zhang, Xiaonan; Fryknäs, Mårten; Hernlund, Emma; Fayad, Walid; De Milito, Angelo; Olofsson, Maria Hägg; Gogvadze, Vladimir; Dang, Long; Påhlman, Sven; Schughart, Leoni A Kunz; Rickardson, Linda; D'Arcy, Padraig; Gullbo, Joachim; Nygren, Peter; Larsson, Rolf; Linder, Stig


    Abnormal vascularization of solid tumours results in the development of microenvironments deprived of oxygen and nutrients that harbour slowly growing and metabolically stressed cells. Such cells display enhanced resistance to standard chemotherapeutic agents and repopulate tumours after therapy. Here we identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to bioenergetic catastrophe and tumour cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Importantly, VLX600 displays tumour growth inhibition in vivo. Our findings suggest that tumour cells in metabolically compromised microenvironments have a limited ability to respond to decreased mitochondrial function, and suggest a strategy for targeting the quiescent populations of tumour cells for improved cancer treatment.

  7. A dominant negative erythropoietin (EPO) receptor inhibits EPO-dependent growth and blocks F-gp55-dependent transformation.


    Barber, D L; DeMartino, J C; Showers, M O; D'Andrea, A D


    The erythropoietin receptor (EPO-R), a member of the cytokine receptor superfamily, can be activated to signal cell growth by binding either EPO or F-gp55, the Friend spleen focus-forming virus glycoprotein. Activation by F-gp55 results in constitutive EPO-R signalling and the first stage of Friend virus-induced erythroleukemia. We have generated a truncated form of the EPO-R polypeptide [EPO-R(T)] which lacks the critical cytoplasmic signal-transducing domain of the EPO-R required for EPO- o...

  8. The Heidelberg classification of renal cell tumours

    NARCIS (Netherlands)

    Kovacs, G; Akhtar, M; Beckwith, BJ; Bugert, P; Cooper, CS; Delahunt, B; Eble, JN; Fleming, S; Ljungberg, B; Medeiros, LJ; Moch, H; Reuter, VE; Ritz, E; Roos, G; Schmidt, D; Srigley, [No Value; Storkel, S; VandenBerg, E; Zbar, B


    This paper presents the conclusions of a workshop entitled 'Impact of Molecular Genetics on the Classification of Renal Cell Tumours', which was held in Heidelberg in October 1996, The focus on 'renal cell tumours' excludes any discussion of Wilms' tumour and its variants, or of tumours metastatic t

  9. Modelling of Anti-Tumour Immune Response: Immunocorrective Effect of Weak Centimetre Electromagnetic Waves

    Directory of Open Access Journals (Sweden)

    O. G. Isaeva


    Full Text Available We formulate the dynamical model for the anti-tumour immune response based on intercellular cytokine-mediated interactions with the interleukin-2 (IL-2 taken into account. The analysis shows that the expression level of tumour antigens on antigen presenting cells has a distinct influence on the tumour dynamics. At low antigen presentation, a progressive tumour growth takes place to the highest possible value. At high antigen presentation, there is a decrease in tumour size to some value when the dynamical equilibrium between the tumour and the immune system is reached. In the case of the medium antigen presentation, both these regimes can be realized depending on the initial tumour size and the condition of the immune system. A pronounced immunomodulating effect (the suppression of tumour growth and the normalization of IL-2 concentration is established by considering the influence of low-intensity electromagnetic microwaves as a parametric perturbation of the dynamical system. This finding is in qualitative agreement with the recent experimental results on immunocorrective effects of centimetre electromagnetic waves in tumour-bearing mice.

  10. Soft tissue tumours: imaging strategy

    Energy Technology Data Exchange (ETDEWEB)

    Brisse, Herve J. [Institute Curie, Department of Radiology, Paris (France); Orbach, Daniel [Institute Curie, Department of Paediatric Oncology, Paris (France); Klijanienko, Jerzy [Institute Curie, Department of Pathology, Paris (France)


    Vascular tumours and malformations, fibrous and fibrohistiocytic tumours and pseudotumours are the most common benign soft-tissue masses observed in children, and can be treated conservatively. Rhabdomyosarcomas are the most frequent malignant tumours, accounting for about half of soft tissue sarcomas. A child referred for a soft-tissue mass should ideally be managed by a multidisciplinary team and primary excision should be proscribed until a definite diagnosis has been established. Clinical examination, conventional radiography and US with Doppler represent the first-line examinations and are sometimes sufficient to make a diagnosis. In all other situations, MRI is mandatory to establish the aggressiveness and extension of the tumour. This technique provides the relevant data to guide the decision regarding tissue sampling. (orig.)

  11. Tumour markers in gastrointestinal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lamerz, R.


    For non-endocrine gastrointestinal tumours the following tumour markers are of clinical interest: For esophageal cancer CEA (sensitivity, s: 40-60%) and SCC (squamous cell carcinoma antigen, x: 20-50%); for gastric cancer CEA (s: 30-40%) as well as CA 19-9 (s: 30-40%) because of complementary results (additive s: 50-60); for hepatocellular cancer AFP (first choice, s: 70-90%; second choice CA 19-9, s: 50-70%); for cholangiocellular cancer CA 19-9 (s: 40-70%); for secondary liver cancer in general CEA; for biliary tract cancer CA 19-9 (s: 40-70%) as well as for excretory pancreatic cancer (s: 70-90%); for colorectal cancer CEA (s: 40-70%) as a first choice marker, and CA 19-9 (s: 20-60%) as a second choice marker, and for anal cancer SCC. The frequency of tumour marker determinations depends on follow-up care recommendations for different tumour diseases (e.g. 1-3 monthly during the 1st and 2nd postoperative year, following chemotherapy courses, on change of therapy, on restaging and at unclear alteration of the clinical state). Tumour markers are only valuable adjuncts to the medical care of tumour patients and therefore useless as solitary findings or on missing therapeutic consequence.

  12. Sodium hyaluronate enhances colorectal tumour cell metastatic potential in vitro and in vivo.

    LENUS (Irish Health Repository)

    Tan, B


    BACKGROUND: Sodium hyaluronate has been used intraperitoneally to prevent postoperative adhesions. However, the effect of sodium hyaluronate on tumour growth and metastasis in vitro and in vivo is still unknown. METHODS: Human colorectal tumour cell lines SW480, SW620 and SW707 were treated with sodium hyaluronate (10-500 microg\\/ml) and carboxymethylcellulose (0.125-1 per cent), and tumour cell proliferation and motility were determined in vitro. For the in vivo experiments male BD IX rats were randomized to a sodium hyaluronate group (n = 11; intraperitoneal administration of 0.5 x 10(6) DHD\\/K12 tumour cells and 5 ml 0.4 per cent sodium hyaluronate) or a phosphate-buffered saline group (n = 11; 0.5 x 10(6) DHD\\/K12 tumour cells and 5 ml phosphate-buffered saline intraperitoneally). Four weeks later the intraperitoneal tumour load was visualized directly. RESULTS: In vitro sodium hyaluronate increased tumour cell proliferation and motility significantly. Sodium hyaluronate-induced tumour cell motility appeared to be CD44 receptor dependent, whereas sodium hyaluronate-induced tumour cell proliferation was CD44 receptor independent. In vivo there was a significantly higher total tumour nodule count in the peritoneal cavity of the sodium hyaluronate-treated group compared with the control (P = 0.016). CONCLUSION: Sodium hyaluronate enhances tumour metastatic potential in vitro and in vivo, which suggests that use of sodium hyaluronate to prevent adhesions in colorectal cancer surgery may also potentiate intraperitoneal tumour growth. Presented to the Patey Prize Session of the Surgical Research Society and the annual scientific meeting of the Association of Surgeons of Great Britain and Ireland, Brighton, UK, 4-7 May 1999

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

    Directory of Open Access Journals (Sweden)

    Robert Hermes

    Full Text Available 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.

  14. Reproductive tract tumours: the scourge of woman reproduction ails Indian rhinoceroses. (United States)

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


    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.

  15. Tumour metastasis as an adaptation of tumour cells to fulfil their phosphorus requirements. (United States)

    de Carvalho, Carla C C R; Caramujo, Maria José


    Inorganic phosphate (Pi) is a vital component of nucleotides, membrane phospholipids, and phosphorylated intermediates in cellular signalling. The Growth Rate Hypothesis (GRH) states that fast growing organisms should be richer in phosphorus (relatively low C:P and N:P cell content) than slow developing organisms as a result of high ribosome biogenesis. Cells that proliferate rapidly, such as cancer cells, require a high amount of ribosomes and other P-rich RNA components that are necessary to manufacture proteins. The GRH hypothesis may be applied to cancer predicting that tumour cells are richer in phosphorus than the surrounding tissue, and that they resort to metastasis in order to meet their nutrient demands. Considering that the cells most P-deprived should be located in the inner parts of the tumour we propose that changes in the membrane of these cells favour the detachment of the more peripheral cells.

  16. Analysis of the local kinetics and localization of interleukin-1 alpha, tumour necrosis factor-alpha and transforming growth factor-beta, during the course of experimental pulmonary tuberculosis. (United States)

    Hernandez-Pando, R; Orozco, H; Arriaga, K; Sampieri, A; Larriva-Sahd, J; Madrid-Marina, V


    A mouse model of pulmonary tuberculosis induced by the intratracheal instillation of live and virulent mycobacteria strain H37-Rv was used to examine the relationship of the histopathological findings with the local kinetics production and cellular distribution of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) and transforming growth factor-beta (TGF-beta). The histopathological and immunological studies showed two phases of the disease: acute or early and chronic or advanced. The acute phase was characterized by inflammatory infiltrate in the alveolar-capillary interstitium, blood vessels and bronchial wall with formation of granulomas. During this acute phase, which lasted from 1 to 28 days, high percentages of TNF-alpha and IL-1 alpha immunostained activated macrophages were observed principally in the interstium-intralveolar inflammatory infiltrate and in granulomas. Electron microscopy studies of these cells, showed extensive rough endoplasmic reticulum, numerous lysosomes and occasional mycobacteria. Double labelling with colloid gold showed that TNF-alpha and IL-1 alpha were present in the same cells, but were confined to separate vacuoles near the Golgi area, and mixed in larger vacuoles near to cell membrane. The concentration of TNF-alpha and IL-1 alpha as well as their respective mRNAs were elevated in the early phase, particularly at day 3 when the bacillary count decreased. A second peak was seen at days 14 and 21-28 when granulomas appeared and evolved to full maturation. In contrast, TGF-beta production and numbers of immunoreactive cells were low in comparison with the advanced phase of the disease. The chronic phase was characterized by histopathological changes indicative of more severity (i.e. pneumonia, focal necrosis and extensive interstitial fibrosis) with a decrease in the TNF-alpha and IL-1 alpha production that coincided with the highest level of TGF-beta. The bacillary counts were highest as the macrophages

  17. Single-domain antibodies that compete with the natural ligand fibroblast growth factor block the internalization of the fibroblast growth factor receptor 1

    Energy Technology Data Exchange (ETDEWEB)

    Veggiani, Gianluca; Ossolengo, Giuseppe; Aliprandi, Marisa; Cavallaro, Ugo [IFOM-IEO Campus, Via Adamello 16, 20139 Milano (Italy); Marco, Ario de, E-mail: [IFOM-IEO Campus, Via Adamello 16, 20139 Milano (Italy); Dept. Environmental Sciences, University of Nova Gorica (UNG), Vipavska 13, P.O. Box 301-SI-5000, Rozna Dolina, Nova Gorica (Slovenia)


    Highlights: {yields} Recombinant antibodies for FGFR1 were isolated from a llama naive library in VHH format. {yields} These antibodies compete with the natural ligand FGF-2 for the same epitope on FGFR1. {yields} The antibody competition inhibits the FGF-2-dependent internalization of FGFR1. -- Abstract: Single-domain antibodies in VHH format specific for fibroblast growth factor receptor 1 (FGFR1) were isolated from a phage-display llama naive library. In particular, phage elution in the presence of the natural receptor ligand fibroblast growth factor (FGF) allowed for the identification of recombinant antibodies that compete with FGF for the same region on the receptor surface. These antibodies posses a relatively low affinity for FGFR1 and were never identified when unspecific elution conditions favoring highly affine binders were applied to panning procedures. Two populations of competitive antibodies were identified that labeled specifically the receptor-expressing cells in immunofluorescence and recognize distinct epitopes. Antibodies from both populations effectively prevented FGF-dependent internalization and nuclear accumulation of the receptor in cultured cells. This achievement indicates that these antibodies have a capacity to modulate the receptor physiology and, therefore, constitute powerful reagents for basic research and a potential lead for therapeutic applications.

  18. Zitongdong Block

    Institute of Scientific and Technical Information of China (English)


    @@ The Zitongdong Block (Eastern Zitong Block) is located in the northwest of the Sichuan Basin. Tectonically, it is situated in the east part of Zitong Depression, southeast of mid-Longmenshan folded and faulted belt( as shown on Fig. 8 ), covering an area of 1 730 km2. The traffic is very convenient, the No. 108 national highway passes through the north of the block. Topographically, the area belongs to low hilly land at the elevation of 500-700 m.

  19. Involvement of formyl peptide receptors in the stimulatory effect of crotoxin on macrophages co-cultivated with tumour cells. (United States)

    Costa, E S; Faiad, O J; Landgraf, R G; Ferreira, A K; Brigatte, P; Curi, R; Cury, Y; Sampaio, S C


    Crotoxin (CTX) is the main neurotoxic component of Crotalus durissus terrificus snake venom. It inhibits tumour growth and modulates the function of macrophages, which are essential cells in the tumour microenvironment. The present study investigated the effect of CTX on the secretory activity of monocultured macrophages and macrophages co-cultivated with LLC-WRC 256 cells. The effect of the macrophage secretory activities on tumour cell proliferation was also evaluated. Macrophages pre-treated with CTX (0.3 μg/mL) for 2 h were co-cultivated with LLC-WRC 256 cells, and the secretory activity of the macrophages was determined after 12, 24 and 48 h. The co-cultivation of CTX-treated macrophages with the tumour cells caused a 20% reduction in tumour cell proliferation. The production of both H2O2 and NO was increased by 41% and 29% after 24 or 48 h of co-cultivation, respectively, compared to the values for the co-cultures of macrophages of control. The level of secreted IL-1β increased by 3.7- and 3.2-fold after 12 h and 24 h of co-cultivation, respectively. Moreover, an increased level of LXA4 (25%) was observed after 24 h of co-cultivation, and a 2.3- and 2.1-fold increased level of 15-epi-LXA4 was observed after 24 h and 48 h, respectively. Boc-2, a selective antagonist of formyl peptide receptors, blocked both the stimulatory effect of CTX on the macrophage secretory activity and the inhibitory effect of these cells on tumour cell proliferation. Taken together, these results indicate that CTX enhanced the secretory activity of macrophages, which may contribute to the antitumour activity of these cells, and that activation of formyl peptide receptors appears to play a major role in this effect.


    Directory of Open Access Journals (Sweden)

    Senthilvel Arumugam


    Full Text Available Wilms’ tumour also called as nephroblastoma is a malignant renal neoplasm of childhood that arises from remnant of immature kidney. About 80% of Wilms’ tumour cases occur before age 5 with a median age of 3.5 years. But adult Wilms’ tumour can occur at any age from 16 to 70 years, the median age in young adult is around 24. CASE REPORT A 16-year-old girl came with history of mass right abdomen, which she noticed for 1 week duration; no urinary symptoms. Her recent blood pressure was 140/90 mmHg. Per abdomen a 10 x 9 cm mass palpable in the right lumbar region, surface smooth, firmto-hard in consistency, non-tender, well defined, no bruit. Urine routine examination was normal; urine culture was sterile; renal and liver function tests were within normal limits; Sr. calcium 9.5 mg/dL. CT abdomen plain and contrast showed a 10 x 9 cm heterodense lesion equivocal with renal cell carcinoma and angiomyolipoma. MR angiogram was done. It showed well-defined encapsulated heterointense mass of size 12 x 8 x 7cm, IVC and bilateral renal vein normal. Since findings were inconclusive, we did a CT-guided biopsy and report came as feature positive for small round cell tumour. Hence, proceeded with right radical nephrectomy. The final histopathology report came as Wilms’ tumour spindle cell variant. Margins clear and ureter not involved. She was then started on adjuvant chemotherapy Inj. Vincristine 2 mg weekly for 27 weeks. She is on regular followup now. CONCLUSION Wilms’ tumour should be considered in a patient who presents with a renal mass with or without loin pain, haematuria especially in young adults. Every attempt should be made to differentiate it from renal cell carcinoma. The outcome for adult Wilms’ tumour is steadily improving with current multimodality treatment approach.

  1. The Role of CD10 Immunohistochemistry in the Grading of Phyllodes Tumour of The Breast

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    Huzlinda Hussin,Jayalakshmi Pailoor


    Full Text Available Objective: To determine the relationship between the degree of CD10 expression in the stromal cells of phyllodes tumour and tumour grading. Methods: A total of 61 cases of mammary phyllodes tumours over the past 11 years were searched from histopathology files, University Malaya Medical Centre. The paraffin blocks were retrieved and 4 μm thick slides were prepared and stained using an antibody against CD10 with the envision method. Fibroadenoma case was used as a control slide and breast myoepithelium as the internal control. Each stained slides was independantly and semiquantitatively analysed for the intensity and percentage of the stromal cells stained. The staining intensity was graded as negative (no staining, mild, moderate and strong if the staining was much weaker, slightly weaker and same intensity as that of the myoepithelium, respectively. The tumour was considered positive for CD10 if the staining intensity is moderate to strong in 20% or more of the stromal cells. Results: 21 (44.7% of 47 benign phyllodes tumour, 5 (83.3% of 6 borderline phyllodes tumour and all 8 cases (100% of malignant phyllodes tumour showed positive expression for CD10 immunostain. Conclusions: There was a significant increase in CD10 expression in the stromal cells as the lesions progressed from benign to borderline and malignant phyllodes tumour. [J Interdiscipl Histopathol 2013; 1(4.000: 195-203

  2. S100A7-downregulation inhibits epidermal growth factor-induced signaling in breast cancer cells and blocks osteoclast formation.

    Directory of Open Access Journals (Sweden)

    Vikram Paruchuri

    Full Text Available S100A7 is a small calcium binding protein, which has been shown to be differentially expressed in psoriatic skin lesions, as well as in squamous cell tumors of the skin, lung and breast. Although its expression has been correlated to HER+ high-grade tumors and to a high risk of progression, the molecular mechanisms of these S100A7-mediated tumorigenic effects are not well known. Here, we showed for the first time that epidermal growth factor (EGF induces S100A7 expression in both MCF-7 and MDA-MB-468 cell lines. We also observed a decrease in EGF-directed migration in shRNA-downregulated MDA-MB-468 cell lines. Furthermore, our signaling studies revealed that EGF induced simultaneous EGF receptor phosphorylation at Tyr1173 and HER2 phosphorylation at Tyr1248 in S100A7-downregulated cell lines as compared to the vector-transfected controls. In addition, reduced phosphorylation of Src at tyrosine 416 and p-SHP2 at tyrosine 542 was observed in these downregulated cell lines. Further studies revealed that S100A7-downregulated cells had reduced angiogenesis in vivo based on matrigel plug assays. Our results also showed decreased tumor-induced osteoclastic resorption in an intra-tibial bone injection model involving SCID mice. S100A7-downregulated cells had decreased osteoclast number and size as compared to the vector controls, and this decrease was associated with variations in IL-8 expression in in vitro cell cultures. This is a novel report on the role of S100A7 in EGF-induced signaling in breast cancer cells and in osteoclast formation.

  3. Nonlinear modelling of cancer: bridging the gap between cells and tumours. (United States)

    Lowengrub, J S; Frieboes, H B; Jin, F; Chuang, Y-L; Li, X; Macklin, P; Wise, S M; Cristini, V


    Despite major scientific, medical and technological advances over the last few decades, a cure for cancer remains elusive. The disease initiation is complex, and including initiation and avascular growth, onset of hypoxia and acidosis due to accumulation of cells beyond normal physiological conditions, inducement of angiogenesis from the surrounding vasculature, tumour vascularization and further growth, and invasion of surrounding tissue and metastasis. Although the focus historically has been to study these events through experimental and clinical observations, mathematical modelling and simulation that enable analysis at multiple time and spatial scales have also complemented these efforts. Here, we provide an overview of this multiscale modelling focusing on the growth phase of tumours and bypassing the initial stage of tumourigenesis. While we briefly review discrete modelling, our focus is on the continuum approach. We limit the scope further by considering models of tumour progression that do not distinguish tumour cells by their age. We also do not consider immune system interactions nor do we describe models of therapy. We do discuss hybrid-modelling frameworks, where the tumour tissue is modelled using both discrete (cell-scale) and continuum (tumour-scale) elements, thus connecting the micrometre to the centimetre tumour scale. We review recent examples that incorporate experimental data into model parameters. We show that recent mathematical modelling predicts that transport limitations of cell nutrients, oxygen and growth factors may result in cell death that leads to morphological instability, providing a mechanism for invasion via tumour fingering and fragmentation. These conditions induce selection pressure for cell survivability, and may lead to additional genetic mutations. Mathematical modelling further shows that parameters that control the tumour mass shape also control its ability to invade. Thus, tumour morphology may serve as a predictor of

  4. Gene expression profiling of tumours derived from rasV12/E1A-transformed mouse embryonic fibroblasts to identify genes required for tumour development

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    Dagorn Jean


    Full Text Available Abstract Background In cancer, cellular transformation is followed by tumour development. Knowledge on the mechanisms of transformation, involving activation of proto-oncogenes and inactivation of tumour-suppressor genes has considerably improved whereas tumour development remains poorly understood. An interesting way of gaining information on tumour progression mechanisms would be to identify genes whose expression is altered during tumour formation. We used the Affymetrix-based DNA microarray technology to analyze gene expression profiles of tumours derived from rasV12/E1A-transformed mouse embryo fibroblasts in order to identify the genes that could be involved in tumour development. Results Among the 12,000 genes analyzed in this study, only 489 showed altered expression during tumour development, 213 being up-regulated and 276 down-regulated. The genes differentially expressed are involved in a variety of cellular functions, including control of transcription, regulation of mRNA maturation and processing, regulation of protein translation, activation of interferon-induced genes, intracellular signalling, apoptosis, cell growth, angiogenesis, cytoskeleton, cell-to-cell interaction, extracellular matrix formation, metabolism and production of secretory factors. Conclusions Some of the genes identified in this work, whose expression is altered upon rasV12/E1A transformation of MEFs, could be new cancer therapeutic targets.

  5. Tumour banking: the Spanish design. (United States)

    Morente, M M; de Alava, E; Fernandez, P L


    In the last decade the technical advances in high throughput techniques to analyze DNA, RNA and proteins have had a potential major impact on prevention, diagnosis, prognosis and treatment of many human diseases. Key pieces in this process, mainly thinking about the future, are tumour banks and tumour bank networks. To face these challenges, diverse suitable models and designs can be developed. The current article presents the development of a nationwide design of tumour banks in Spain based on a network of networks, specially focusing on its harmonization efforts mainly regarding technical procedures, ethical requirements, unified quality control policy and unique sample identification. We also describe our most important goals for the next years. This model does not correspond to a central tumour bank, but to a cooperative and coordinated network of national and regional networks. Independently from the network in which it is included, sample collections reside in their original institution, where it can be used for further clinical diagnosis, teaching and research activities of each independent hospital. The herein described 'network of networks' functional model could be useful for other countries and/or international tumour bank activities.

  6. Tumour homing peptide-functionalized porous silicon nanovectors for cancer therapy. (United States)

    Kinnari, Päivi J; Hyvönen, Maija L K; Mäkilä, Ermei M; Kaasalainen, Martti H; Rivinoja, Antti; Salonen, Jarno J; Hirvonen, Jouni T; Laakkonen, Pirjo M; Santos, Hélder A


    Tumour targeting nanoparticles (NPs) have demonstrated great potential for enhancing anticancer drug delivery to tumour sites and for reducing the side effects of chemotherapy. However, many nanoparticulate delivery systems still lack efficient tumour accumulation. In this work, we present a porous silicon (PSi) nanovector functionalized with a tumour-homing peptide, which targets the mammary-derived growth inhibitor (MDGI) expressing cancer cells both in vitro and in vivo, thereby enhancing the accumulation of the NPs in the tumours. We demonstrated that the tumour homing peptide (herein designated as CooP) functionalized thermally hydrocarbonized PSi (THCPSi) NPs homed specifically to the subcutaneous MDGI-expressing xenograft tumours. The THCPSi-CooP NPs were stable in human plasma and their uptake by MDGI-expressing cancer cells measured by confocal microscopy and flow cytometry was significantly increased compared to the non-functionalized THCPSi NPs. After intravenous injections into nude mice bearing MDGI-expressing tumours, effective targeting was detected and THCPSi-CooP NPs showed ~9-fold higher accumulation in the tumour site compared to the control THCPSi NPs. Accumulation of both NPs in the vital organs was negligible.

  7. Pitfalls in colour photography of choroidal tumours. (United States)

    Schalenbourg, A; Zografos, L


    Colour imaging of fundus tumours has been transformed by the development of digital and confocal scanning laser photography. These advances provide numerous benefits, such as panoramic images, increased contrast, non-contact wide-angle imaging, non-mydriatic photography, and simultaneous angiography. False tumour colour representation can, however, cause serious diagnostic errors. Large choroidal tumours can be totally invisible on angiography. Pseudogrowth can occur because of artefacts caused by different methods of fundus illumination, movement of reference blood vessels, and flattening of Bruch's membrane and sclera when tumour regression occurs. Awareness of these pitfalls should prevent the clinician from misdiagnosing tumours and wrongfully concluding that a tumour has grown.

  8. Pitfalls in colour photography of choroidal tumours (United States)

    Schalenbourg, A; Zografos, L


    Colour imaging of fundus tumours has been transformed by the development of digital and confocal scanning laser photography. These advances provide numerous benefits, such as panoramic images, increased contrast, non-contact wide-angle imaging, non-mydriatic photography, and simultaneous angiography. False tumour colour representation can, however, cause serious diagnostic errors. Large choroidal tumours can be totally invisible on angiography. Pseudogrowth can occur because of artefacts caused by different methods of fundus illumination, movement of reference blood vessels, and flattening of Bruch's membrane and sclera when tumour regression occurs. Awareness of these pitfalls should prevent the clinician from misdiagnosing tumours and wrongfully concluding that a tumour has grown. PMID:23238442

  9. Preoperative shunts in thalamic tumours.

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    Goel A


    Full Text Available Thirty one patients with thalamic glioma underwent a pre-tumour resection shunt surgery. The procedure was uneventful in 23 patients with relief from symptoms of increased intracranial pressure. Eight patients worsened after the procedure. The level of sensorium worsened from excessively drowsy state to unconsciousness in seven patients. Three patients developed hemiparesis, 4 developed paresis of extra-ocular muscles and altered pupillary reflexes, and 1 developed incontinence of urine and persistent vomiting. Alteration in the delicately balanced intracranial pressure and movements in the tumour and vital adjacent brain areas could be the probable cause of the worsening in the neurological state in these 8 patients. On the basis of these observations and on review of literature, it is postulated that the ventricular dilatation following an obstruction in the path of the cerebrospinal fluid flow by a tumour could be a natural defense phenomenon of the brain.

  10. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan (United States)

    Maishi, Nako; Ohba, Yusuke; Akiyama, Kosuke; Ohga, Noritaka; Hamada, Jun-ichi; Nagao-Kitamoto, Hiroko; Alam, Mohammad Towfik; Yamamoto, Kazuyuki; Kawamoto, Taisuke; Inoue, Nobuo; Taketomi, Akinobu; Shindoh, Masanobu; Hida, Yasuhiro; Hida, Kyoko


    Tumour blood vessels are gateways for distant metastasis. Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts. We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells. However, the contribution of TECs to metastasis has not been elucidated. Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs. Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours. Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal–regulated kinase 1/2. Biglycan expression was upregulated by DNA demethylation in TECs. Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis. PMID:27295191

  11. Zitongxi Block

    Institute of Scientific and Technical Information of China (English)


    @@ Zitongxi Block (Western Zitong Block), is located in Zitong County, northwest of Sichuan Province (as shown on Fig. 8 ). Geologically. it is situated in the Zitong Depression, southwest of the middle Longmenshan faulted and folded belt, covering an area of 1 830 km2. Transportation is very convenient. A crisscross network of highways run through the block and the Baocheng railway is nearby. The climate is moderate. Most area belongs to hilly land with the elevation of 500-600 m.The Tongjiang River runs across the area.

  12. Influencia del sitio de inoculación sobre el crecimiento, morfología y metástasis espontáneas del cáncer de mama en un modelo murino (Effect of tumour host microenvironment on growth, morphology and spontaneous metastases in a breast cancer mouse model

    Directory of Open Access Journals (Sweden)

    Fuentes-Morales, Dasha


    mouse breast tumor model. For experimental purpose we compared the growth, morphology and metastatic spontaneous spread of F3II mammary carcinoma cells subsequent to breast (orthotopic or subcutaneous (ectopic implantations in young females BALB/c mice. All animals were sacrificed after 35 days followed by macroscopical and histological evaluation of local invasion or regional or distant metastasis. In all animals, tumour histology and spontaneous metastases became similar, however orthotopic F3II tumour showed faster growth as compared withsubcutaneous tumours. These data suggest that injection of F3II breast ancer cells in both sites (orthotopic or ectopic into the BALB/c mouse may provide a valuable model to study the biology and therapy of human breast cancer.

  13. Tumour angiogenesis regulation by the miR-200 family (United States)

    Pecot, Chad V.; Ivan, Cristina; Lu, Chunhua; Wu, Sherry; Han, Hee-Dong; Shah, Maitri Y.; Rodriguez-Aguayo, Cristian; Bottsford-Miller, Justin; Liu, Yuexin; Kim, Sang Bae; Unruh, Anna; Gonzalez-Villasana, Vianey; Huang, Li; Zand, Behrouz; Moreno-Smith, Myrthala; Mangala, Lingegowda S.; Taylor, Morgan; Dalton, Heather J.; Sehgal, Vasudha; Wen, Yunfei; Kang, Yu; Baggerly, Keith A.; Lee, Ju-Seog; Ram, Prahlad T.; Ravoori, Murali K.; Kundra, Vikas; Zhang, Xinna; Ali-Fehmi, Rouba; Gonzalez-Angulo, Ana-Maria; Massion, Pierre P.; Calin, George A.; Lopez-Berestein, Gabriel; Zhang, Wei; Sood, Anil K.


    The miR-200 family is well known to inhibit the epithelial–mesenchymal transition, suggesting it may therapeutically inhibit metastatic biology. However, conflicting reports regarding the role of miR-200 in suppressing or promoting metastasis in different cancer types have left unanswered questions. Here we demonstrate a difference in clinical outcome based on miR-200's role in blocking tumour angiogenesis. We demonstrate that miR-200 inhibits angiogenesis through direct and indirect mechanisms by targeting interleukin-8 and CXCL1 secreted by the tumour endothelial and cancer cells. Using several experimental models, we demonstrate the therapeutic potential of miR-200 delivery in ovarian, lung, renal and basal-like breast cancers by inhibiting angiogenesis. Delivery of miR-200 members into the tumour endothelium resulted in marked reductions in metastasis and angiogenesis, and induced vascular normalization. The role of miR-200 in blocking cancer angiogenesis in a cancer-dependent context defines its utility as a potential therapeutic agent. PMID:24018975

  14. Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice (United States)

    Lau, Janet; Cheung, Jeanne; Navarro, Armando; Lianoglou, Steve; Haley, Benjamin; Totpal, Klara; Sanders, Laura; Koeppen, Hartmut; Caplazi, Patrick; McBride, Jacqueline; Chiu, Henry; Hong, Rebecca; Grogan, Jane; Javinal, Vincent; Yauch, Robert; Irving, Bryan; Belvin, Marcia; Mellman, Ira; Kim, Jeong M.; Schmidt, Maike


    Expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1, is one key immunosuppressive mechanism by which cancer avoids eradication by the immune system. Therapeutic use of blocking antibodies to PD-L1 or its receptor PD-1 has produced unparalleled, durable clinical responses, with highest likelihood of response seen in patients whose tumour or immune cells express PD-L1 before therapy. The significance of PD-L1 expression in each cell type has emerged as a central and controversial unknown in the clinical development of immunotherapeutics. Using genetic deletion in preclinical mouse models, here we show that PD-L1 from disparate cellular sources, including tumour cells, myeloid or other immune cells can similarly modulate the degree of cytotoxic T-cell function and activity in the tumour microenvironment. PD-L1 expression in both the host and tumour compartment contribute to immune suppression in a non-redundant fashion, suggesting that both sources could be predictive of sensitivity to therapeutic agents targeting the PD-L1/PD-1 axis. PMID:28220772

  15. Chengzikou Block

    Institute of Scientific and Technical Information of China (English)


    @@ Chengzikou Block is located in the north of Hekou district, Dongying City, Shandong Province, adjacent to Bohai Bay. It can be geographically divided into three units: onshore, transitional zone and offshore ultrashallow zone, totally covering an area of 470 km2. The southern onshore area is low and gentle in topography;the northern shallow sea is at water depths of 2-8 m below sea level, and the transitional zone occupies more than 60% of the whole block. The climate belongs to temperate zone with seasonal wind. Highways are welldeveloped here, and the traffic is very convenient. The Chengzikou Block is about 80 km away from Dongying City and 290 km from Jinan City in the south. The northern offshore area of the block is 160 km away from Longkou port in the east and only 38 km away in the west from Zhuangxi port.

  16. Longmenshan Block

    Institute of Scientific and Technical Information of China (English)


    @@ Longmenshan Block is located in Jiange County of Jiangyou City in the northwest of Sichuan Basin. covering an area of 2 628 km2. Geologically, it is situated in the Mid-Longmenshan fault and fold belt, neighbouring Zitong Depression in its southeast. There are mountains surrounding its northwest , the rest area being hilly land,with the elevation of 500-700 m. The BaoCheng railway and the No. 108 highway run through the block, the traffic is very convenient.


    Directory of Open Access Journals (Sweden)

    Krishna Bharathi Yarlagadda


    Full Text Available BACKGROUND Ovarian tumours being second most common gynaecological cancer in India account for 30% of all cancers of female genital tract. Study conducted to determine relative frequencies of various histological types based on WHO classification and their age distribution with particular emphasis on surface epithelial tumours. This study is undertaken to find out the frequency of incidence of different histopathological subtypes with particular emphasis on surface epithelial tumours and age distribution of ovarian tumours in our institute located in coastal Andhra Pradesh. METHODS This is a retrospective study of 100 cases of ovarian neoplasms collected during a period of 3 years from June 2013 to May 2016 from the Department of Pathology, Katuri Medical College and Hospital, Chinakondrupadu, Guntur, A. P, India. The patients attending our hospital are mostly from rural areas around. Paraffin blocks of all 100 ovarian neoplasms retrieved. Complete clinical and radiological findings analysed from our records. RESULTS The tumours are grouped according to the nature of tumour whether benign or borderline or malignant according to cell of origin, histological subtyping, and age group. Surface epithelial tumours are the most common. Benign tumours outnumber the malignant tumours. Benign ovarian tumours showed a peak in 21-40 Yrs. age group and malignant in the age group of 41- 60 Yrs. Results of our study compared with other studies. CONCLUSION Because of the geographic location, poverty, and illiteracy, patients seek medical advice late. So, awareness among public by health education, passive surveillance, and community screening facility will be helpful in early detection of ovarian neoplasms.

  18. AAV2-mediated in vivo immune gene therapy of solid tumours

    LENUS (Irish Health Repository)

    Collins, Sara A


    Abstract Background Many strategies have been adopted to unleash the potential of gene therapy for cancer, involving a wide range of therapeutic genes delivered by various methods. Immune therapy has become one of the major strategies adopted for cancer gene therapy and seeks to stimulate the immune system to target tumour antigens. In this study, the feasibility of AAV2 mediated immunotherapy of growing tumours was examined, in isolation and combined with anti-angiogenic therapy. Methods Immune-competent Balb\\/C or C57 mice bearing subcutaneous JBS fibrosarcoma or Lewis Lung Carcinoma (LLC) tumour xenografts respectively were treated by intra-tumoural administration of AAV2 vector encoding the immune up-regulating cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) and the co-stimulatory molecule B7-1 to subcutaneous tumours, either alone or in combination with intra-muscular (IM) delivery of AAV2 vector encoding Nk4 14 days prior to tumour induction. Tumour growth and survival was monitored for all animals. Cured animals were re-challenged with tumourigenic doses of the original tumour type. In vivo cytotoxicity assays were used to investigate establishment of cell-mediated responses in treated animals. Results AAV2-mediated GM-CSF, B7-1 treatment resulted in a significant reduction in tumour growth and an increase in survival in both tumour models. Cured animals were resistant to re-challenge, and induction of T cell mediated anti-tumour responses were demonstrated. Adoptive transfer of splenocytes to naïve animals prevented tumour establishment. Systemic production of Nk4 induced by intra-muscular (IM) delivery of Nk4 significantly reduced subcutaneous tumour growth. However, combination of Nk4 treatment with GM-CSF, B7-1 therapy reduced the efficacy of the immune therapy. Conclusions Overall, this study demonstrates the potential for in vivo AAV2 mediated immune gene therapy, and provides data on the inter-relationship between tumour

  19. Cytotoxic macrophage-released tumour necrosis factor-alpha (TNF-α) as a killing mechanism for cancer cell death after cold plasma activation (United States)

    Kaushik, Nagendra Kumar; Kaushik, Neha; Min, Booki; Choi, Ki Hong; Hong, Young June; Miller, Vandana; Fridman, Alexander; Choi, Eun Ha


    The present study aims at studying the anticancer role of cold plasma-activated immune cells. The direct anti-cancer activity of plasma-activated immune cells against human solid cancers has not been described so far. Hence, we assessed the effect of plasma-treated RAW264.7 macrophages on cancer cell growth after co-culture. In particular, flow cytometer analysis revealed that plasma did not induce any cell death in RAW264.7 macrophages. Interestingly, immunofluorescence and western blot analysis confirmed that TNF-α released from plasma-activated macrophages acts as a tumour cell death inducer. In support of these findings, activated macrophages down-regulated the cell growth in solid cancer cell lines and induced cell death in vitro. Together our findings suggest plasma-induced reactive species recruit cytotoxic macrophages to release TNF-α, which blocks cancer cell growth and can have the potential to contribute to reducing tumour growth in vivo in the near future.

  20. Myeloblastic leukemia cells conditionally blocked by myc-estrogen receptor chimeric transgenes for terminal differentiation coupled to growth arrest and apoptosis. (United States)

    Selvakumaran, M; Liebermann, D; Hoffman-Liebermann, B


    Conditional mutants of the myeloblastic leukemic M1 cell line, expressing the chimeric mycer transgene, have been established. It is shown that M1 mycer cells, like M1, undergo terminal differentiation coupled to growth arrest and programmed cell death (apoptosis) after treatment with the physiologic differentiation inducer interleukin-6. However, when beta-estradiol is included in the culture medium, M1 mycer cells respond to differentiation inducers like M1 myc cell lines, where the differentiation program is blocked at an intermediate stage. By manipulating the function of the mycer transgene product, it is shown that there is a 10-hour window during myeloid differentiation, from 30 to 40 hours after the addition of the differentiation inducer, when the terminal differentiation program switches from being dependent on c-myc suppression to becoming c-myc suppression independent, where activation of c-myc has no apparent effect on mature macrophages. M1 mycer cell lines provide a powerful tool to increase our understanding of the role of c-myc in normal myelopoiesis and in leukemogenesis, also providing a strategy to clone c-myc target genes.

  1. Growth-dissolution-regrowth transitions of Fe3O4 nanoparticles as building blocks for 3D magnetic nanoparticle clusters under hydrothermal conditions. (United States)

    Lin, Mouhong; Huang, Haoliang; Liu, Zuotao; Liu, Yingju; Ge, Junbin; Fang, Yueping


    Magnetic nanoparticle clusters (MNCs) are a class of secondary structural materials that comprise chemically defined nanoparticles assembled into clusters of defined size. Herein, MNCs are fabricated through a one-pot solvothermal reaction featuring self-limiting assembly of building blocks and the controlled reorganization process. Such growth-dissolution-regrowth fabrication mechanism overcomes some limitations of conventional solvothermal fabrication methods with regard to restricted available feature size and structural complexity, which can be extended to other oxides (as long as one can be chelated by EDTA-2Na). Based on this method, the nanoparticle size of MNCs is tuned between 6.8 and 31.2 nm at a fixed cluster diameter of 120 nm, wherein the critical size for superparamagnetic-ferromagnetic transition is estimated from 13.5 to 15.7 nm. Control over the nature and secondary structure of MNCs gives an excellent model system to understand the nanoparticle size-dependent magnetic properties of MNCs. MNCs have potential applications in many different areas, while this work evaluates their cytotoxicity and Pb(2+) adsorption capacity as initial application study.

  2. Targeted therapy of gastrointestinal stromal tumours

    Institute of Scientific and Technical Information of China (English)

    Ashish Jakhetiya; Pankaj Kumar Garg; Gaurav Prakash; Jyoti Sharma; Rambha Pandey; Durgatosh Pandey


    Gastrointestinal stromal tumours(GISTs) are mesen-chymal neoplasms originating in the gastrointestinal tract, usually in the stomach or the small intestine, and rarely elsewhere in the abdomen. The malignant potential of GISTs is variable ranging from small lesions with a benign behaviour to fatal sarcomas. The majo-rity of the tumours stain positively for the CD-117(KIT) and discovered on GIST-1(DOG-1 or anoctamin 1) expression, and they are characterized by the presence of a driver kinase-activating mutation in either KIT or platelet-derived growth factor receptor α. Although surgery is the primary modality of treatment, almost half of the patients have disease recurrence following surgery, which highlights the need for an effective adjuvant therapy. Traditionally, GISTs are considered chemotherapy and radiotherapy resistant. With the advent of targeted therapy(tyrosine kinase inhibitors), there has been a paradigm shift in the management of GISTs in the last decade. We present a comprehensive review of targeted therapy in the management of GISTs.

  3. Computer-aided hepatic tumour ablation

    CERN Document Server

    Voirin, D; Amavizca, M; Leroy, A; Letoublon, C; Troccaz, J; Voirin, David; Payan, Yohan; Amavizca, Miriam; Leroy, Antoine; Letoublon, Christian; Troccaz, Jocelyne


    Surgical resection of hepatic tumours is not always possible. Alternative techniques consist in locally using chemical or physical agents to destroy the tumour and this may be performed percutaneously. It requires a precise localisation of the tumour placement during ablation. Computer-assisted surgery tools may be used in conjunction to these new ablation techniques to improve the therapeutic efficiency whilst benefiting from minimal invasiveness. This communication introduces the principles of a system for computer-assisted hepatic tumour ablation.

  4. Primary brain tumours in adults. (United States)

    Ricard, Damien; Idbaih, Ahmed; Ducray, François; Lahutte, Marion; Hoang-Xuan, Khê; Delattre, Jean-Yves


    Important advances have been made in the understanding and management of adult gliomas and primary CNS lymphomas--the two most common primary brain tumours. Progress in imaging has led to a better analysis of the nature and grade of these tumours. Findings from large phase 3 studies have yielded some standard treatments for gliomas, and have confirmed the prognostic value of specific molecular alterations. High-throughput methods that enable genome-wide analysis of tumours have improved the knowledge of tumour biology, which should lead to a better classification of gliomas and pave the way for so-called targeted therapy trials. Primary CNS lymphomas are a group of rare non-Hodgkin lymphomas. High-dose methotrexate-based regimens increase survival, but the standards of care and the place of whole-brain radiotherapy remain unclear, and are likely to depend on the age of the patient. The focus now is on the development of new polychemotherapy regimens to reduce or defer whole-brain radiotherapy and its delayed complications.

  5. Intraoral myxoid nerve sheath tumour

    NARCIS (Netherlands)

    Schortinghuis, J; Hille, JJ; Singh, S


    A case of an intraoral myxoid nerve sheath tumour of the dorsum of the tongue in a 73-year-old Caucasian male is reported. This case describes the oldest patient with this pathology to date. Immunoperoxidase staining for neuronspecific enolase (NSE) and epithelial membrane antigen (EMA) expression d

  6. CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment. (United States)

    Zhang, Tao; Tseng, Chieh; Zhang, Yan; Sirin, Olga; Corn, Paul G; Li-Ning-Tapia, Elsa M; Troncoso, Patricia; Davis, John; Pettaway, Curtis; Ward, John; Frazier, Marsha L; Logothetis, Christopher; Kolonin, Mikhail G


    White adipose tissue (WAT) overgrowth in obesity is linked with increased aggressiveness of certain cancers. Adipose stromal cells (ASCs) can become mobilized from WAT, recruited by tumours and promote cancer progression. Mechanisms underlying ASC trafficking are unclear. Here we demonstrate that chemokines CXCL1 and CXCL8 chemoattract ASC by signalling through their receptors, CXCR1 and CXCR2, in cell culture models. We further show that obese patients with prostate cancer have increased epithelial CXCL1 expression. Concomitantly, we observe that cells with ASC phenotype are mobilized and infiltrate tumours in obese patients. Using mouse models, we show that the CXCL1 chemokine gradient is required for the obesity-dependent tumour ASC recruitment, vascularization and tumour growth promotion. We demonstrate that αSMA expression in ASCs is induced by chemokine signalling and mediates the stimulatory effects of ASCs on endothelial cells. Our data suggest that ASC recruitment to tumours, driven by CXCL1 and CXCL8, promotes prostate cancer progression.

  7. VEGF concentrations in tumour arteries and veins from patients with rectal cancer

    DEFF Research Database (Denmark)

    Werther, Kim; Bülow, Steffen; Hesselfeldt, Peter;


    , automated complete white cell and platelet counts were performed. In serum and EDTA plasma, no significant differences in VEGF concentrations were observed (p = 0.1 and p = 0.5), respectively) between tumour arteries and tumour veins. However, in supernatants from lysed blood, VEGF concentrations were......This pilot study investigated the hypothesis that the tumour itself is the source of the elevated vascular endothelial growth factor (VEGF) concentrations which are often observed in peripheral blood from patients with rectal cancer. Twenty-four consecutive patients with primary rectal cancer were...... included. Blood samples were drawn preoperatively from peripheral veins (I) and intraoperatively from peripheral veins (II), tumour arteries (III), and tumour veins (IV). In the four compartments, VEGF concentrations were measured in serum, EDTA plasma, and supernatants from lysed whole blood. Additionally...

  8. FDG uptake, a surrogate of tumour hypoxia?

    NARCIS (Netherlands)

    Dierckx, Rudi Andre; de Wiele, Christophe Van


    Introduction Tumour hyperglycolysis is driven by activation of hypoxia-inducible factor-1 (HIF-1) through tumour hypoxia. Accordingly, the degree of 2-fluro-2-deoxy-D-glucose (FDG) uptake by tumours might indirectly reflect the level of hypoxia, obviating the need for more specific radiopharmaceutic

  9. Melanotic neuroectodermal tumour of the pineal region

    Energy Technology Data Exchange (ETDEWEB)

    Gorhan, C.; Soto-Ares, G.; Pruvo, J.P. [Dept. of Neuroradiology, Hopital Roger Salengro, CHRU Lille, Lille (France); Ruchoux, M.M. [Dept. of Neuropathology, Hopital Roger Salengro, CHRU Lille (France); Blond, S. [Dept. of Neurosurgery, Hopital Roger Salengro, CHRU Lille (France)


    We describe CT and MR findings in a 23-month-old infant with a melanotic neuroectodermal tumour of the pineal gland. The tumour has been stereotactically biopsied and surgically resected. The pathological diagnosis was made on the resected piece. Embryology of the pineal gland and the histology of melanotic neuroectodermal tumour of infancy are discussed. (orig.)

  10. Imaging of salivary gland tumours

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Y.Y.P.; Wong, K.T.; King, A.D. [Department of Diagnostic Radiology and Organ Imaging, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong (Hong Kong); Ahuja, A.T. [Department of Diagnostic Radiology and Organ Imaging, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong (Hong Kong)], E-mail:


    Salivary gland neoplasms account for <3% of all tumors. Most of them are benign and parotid gland is the commonest site. As a general rule, the smaller the involved salivary gland, the higher is the possibility of the tumor being malignant. The role of imaging in assessment of salivary gland tumour is to define intra-glandular vs. extra-glandular location, detect malignant features, assess local extension and invasion, detect nodal metastases and systemic involvement. Image guided fine needle aspiration cytology provides a safe means to obtain cytological confirmation. For lesions in the superficial parotid and submandibular gland, ultrasound is an ideal tool for initial assessment. These are superficial structures accessible by high resolution ultrasound and FNAC which provides excellent resolution and tissue characterization without a radiation hazard. Nodal involvement can also be assessed. If deep tissue extension is suspected or malignancy confirmed on cytology, an MRI or CT is mandatory to evaluate tumour extent, local invasion and perineural spread. For all tumours in the sublingual gland, MRI should be performed as the risk of malignancy is high. For lesions of the deep lobe of parotid gland and the minor salivary glands, MRI and CT are the modalities of choice. Ultrasound has limited visualization of the deep lobe of parotid gland which is obscured by the mandible. Minor salivary gland lesions in the mucosa of oral cavity, pharynx and tracheo-bronchial tree, are also not accessible by conventional ultrasound. Recent study suggests that MR spectroscopy may differentiate malignant and benign salivary gland tumours as well as distinguishing Warthin's tumor from pleomorphic adenoma. However, its role in clinical practice is not well established. Similarly, the role of nuclear medicine and PET scan, in imaging of parotid masses is limited. Sialography is used to delineate the salivary ductal system and has limited role in assessment of tumour extent.

  11. Bilateral disease and new trends in Wilms tumour

    Energy Technology Data Exchange (ETDEWEB)

    Owens, Catherine M.; Olsen, Oeystein E. [Great Ormond Street Hospital for Children NHS Trust, Department of Radiology, London (United Kingdom); Brisse, Herve J. [Institut Curie, Service de Radiodiagnostic, Paris (France); Begent, Joanna [University College Hospital, Paediatric Oncology, London (United Kingdom); Smets, Anne M. [Academic Medical Center Amsterdam, Department of Radiology, Amsterdam (Netherlands)


    Wilms tumour is a great therapeutic success story within paediatric oncology; its prognosis is excellent. Although mainly sporadic, occurring in otherwise well children, it occurs in a small number of genetically predisposed children. Thus regular surveillance imaging is performed in predisposed children in parts of the USA and Europe. The risks and benefits of surveillance are unclear, as the existing ad-hoc surveillance protocols are lacking in consistency of practice and equity of provision. We present guidelines for Wilms tumour surveillance based on a review of current practice and available evidence, outlined by a multidisciplinary working group in the UK. Wilms tumours are bilateral in 4-13% of affected children. Bilateral synchronous nephroblastomas are observed in 5% of affected children and are usually associated with the presence of nephrogenic rests, congenital malformations and predisposing syndromes. The major challenge in bilateral disease is to achieve a cure and at the same time to preserve sufficient functional renal tissue for normal growth and development. The association among Wilms tumour, nephrogenic rests and nephroblastomatosis makes detection and characterization of renal lesions with imaging extremely important. We discuss the relative strengths and weaknesses of the different modalities used for diagnosis and follow-up in bilateral renal disease. We also discuss newly emerging diagnostic imaging tests such as {sup 18}F-fluorodeoxyglucose positron emission tomography (FDG-PET). This technique, when fused with CT (PET-CT), allows accelerated metabolic activity to be accurately anatomically localised and so is potentially useful for staging, assessment of treatment response, and for surgical and radiotherapy planning. In addition, quantitative MRI techniques have been proved to be valuable in intracranial tumours, but no such role has been validated in abdominal disease. Diffusion-weighted imaging with calculation of ADC maps is feasible in

  12. Tumour cell recruitment of the JB-1 and L 1210 ascites tumour determined directly by double labelling with [14C]- and [3H]-thymidine. (United States)

    Maurer-Schultze, B; Kondziella, U; Böswald, M


    Tumour cell recruitment of the JB-1 and L 1210 ascites tumour has been demonstrated directly by a double-labelling method with [14C]- and [3H]-thymidine (TdR). After [14C]-labelling of all proliferating tumour cells by multiple injections of [14C]TdR, recruitment of resting cells was stimulated by removal of the majority of tumour cells, i.e. by maximum aspiration of ascitic fluid. The number of recruited resting cells in the remaining tumour that re-enter the cell cycle after stimulation was demonstrated directly by a single injection of [3H]TdR given at different times after stimulation. The increase in the percentage of purely [3H]-labelled cells, i.e. recruited cells, with increasing time after stimulation, shows that recruitment is not a synchronous but a continuous process, the maximum of which occurs earlier in the case of the L 1210 than the JB-1 tumour. This suggests that there seems to be a relationship between the time required for maximum recruitment and the corresponding cell cycle parameters of the unperturbed tumour. There is a transitory increase of the growth fraction to about 100% and a considerable shortening of the cycle time at the maximum of recruitment.

  13. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. (United States)

    Iozzo, Renato V; Sanderson, Ralph D


    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.

  14. Tumours of the fetal body: a review

    Energy Technology Data Exchange (ETDEWEB)

    Avni, Fred E.; Massez, Anne; Cassart, Marie [University Clinics of Brussels - Erasme Hospital, Department of Medical Imaging, Brussels (Belgium)


    Tumours of the fetal body are rare, but lesions have been reported in all spaces, especially in the mediastinum, the pericardial space, the adrenals, the kidney, and the liver. Lymphangioma and teratoma are the commonest histological types encountered, followed by cardiac rhabdomyoma. Adrenal neuroblastoma is the commonest malignant tumour. Imaging plays an essential role in the detection and work-up of these tumours. In addition to assisting clinicians it also helps in counselling parents. Most tumours are detected by antenatal US, but fetal MRI is increasingly used as it brings significant additional information in terms of tumour extent, composition and complications. (orig.)

  15. Chadong Block

    Institute of Scientific and Technical Information of China (English)


    @@ The Chadong Block, located in the east of Qaidam Basin, Qinghai Province, covers an area of 12 452 km2. It is bounded by Kunlum Mountains in the south and the northwest is closely adjacent to Aimunike Mountain.Rivers are widely distributed, which always run in NWSE direction, including the Sulunguole, Qaidam and Haluwusu Rivers. The traffic condition is good, the Qinghai-Tibet highway stretching through the whole area and the Lan-Qing railway, 20-50 km away from the block, passing from north to west. A lot of Mongolia minority people have settled there, of which herdsmen always live nearby the Qaidam River drainage area.

  16. Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade.

    Directory of Open Access Journals (Sweden)

    Sylwia Libard

    Full Text Available Human cytomegalovirus (HCMV has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, low-grade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.

  17. GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment. (United States)

    Podar, Klaus; Catley, Laurence P; Tai, Yu-Tzu; Shringarpure, Reshma; Carvalho, Pedro; Hayashi, Toshiaki; Burger, Renate; Schlossman, Robert L; Richardson, Paul G; Pandite, Lini N; Kumar, Rakesh; Hideshima, Teru; Chauhan, Dharminder; Anderson, Kenneth C


    Previous studies have shown that the multiple myeloma (MM) cell line and MM patient cells express high-affinity vascular endothelial growth factor (VEGF) receptor-1 or Fms-like tyrosine kinase-1 (Flt-1) but not VEGF receptor-2 or Flk-1/kinase insert domain-containing receptor (Flk-1/KDR) and that VEGF triggers MM cell proliferation through a mitogen-activated protein kinase (MAPK)-dependent pathway and migration through a protein kinase C (PKC)-dependent pathway. The present study evaluates the efficacy of the small molecule tyrosine-kinase inhibitor GW654652, which inhibits all 3 VEGF receptors with similar potency. We show that GW654652 acts directly on MM cells and in the bone marrow microenvironment. Specifically, GW654652 (1-10 microg/mL) inhibits, in a dose-dependent fashion, VEGF-triggered migrational activity and cell proliferation of MM cell lines that are sensitive and resistant to conventional therapy. As expected from our previous studies of VEGF-induced signaling and sequelae in MM cells, GW654652 blocked VEGF-induced Flt-1 phosphorylation and downstream activation of AKT-1 and MAPK-signaling cascades. Importantly, GW654652 also inhibits interleukin-6 and VEGF secretion and proliferation of MM cells induced by tumor cell binding to bone marrow (BM) stromal cells. The activity of a pan-VEGF receptor inhibitor against MM cells in the BM milieu, coupled with its lack of major toxicity in preclinical mouse models, provides the framework for clinical trials of this drug class to improve patient outcome in MM.

  18. The selective adhesion molecule inhibitor Natalizumab decreases multiple myeloma cell growth in the bone marrow microenvironment: therapeutic implications. (United States)

    Podar, Klaus; Zimmerhackl, Alexander; Fulciniti, Mariateresa; Tonon, Giovanni; Hainz, Ursula; Tai, Yu-Tzu; Vallet, Sonia; Halama, Niels; Jäger, Dirk; Olson, Dian L; Sattler, Martin; Chauhan, Dharminder; Anderson, Kenneth C


    Recent advances regarding the introduction of anti-adhesion strategies as a novel therapeutic concept in oncology hold great promise. Here we evaluated the therapeutic potential of the new-in-class-molecule selective-adhesion-molecule (SAM) inhibitor Natalizumab, a recombinant humanized IgG4 monoclonal antibody, which binds integrin-α4, in multiple myeloma (MM). Natalizumab, but not a control antibody, inhibited adhesion of MM cells to non-cellular and cellular components of the microenvironment as well as disrupted the binding of already adherent MM cells. Consequently, Natalizumab blocked both the proliferative effect of MM-bone marrow (BM) stromal cell interaction on tumour cells, and vascular endothelial growth factor (VEGF)-induced angiogenesis in the BM milieu. Moreover, Natalizumab also blocked VEGF- and insulin-like growth factor 1 (IGF-1)-induced signalling sequelae triggering MM cell migration. In agreement with our in vitro results, Natalizumab inhibited tumour growth, VEGF secretion, and angiogenesis in a human severe combined immunodeficiency murine model of human MM in the human BM microenvironment. Importantly, Natalizumab not only blocked tumour cell adhesion, but also chemosensitized MM cells to bortezomib, in an in vitro therapeutically representative human MM-stroma cell co-culture system model. Our data therefore provide the rationale for the clinical evaluation of Natalizumab, preferably in combination with novel agents (e.g. bortezomib) to enhance MM cytotoxicity and improve patient outcome.

  19. Tumour targeting with systemically administered bacteria.

    LENUS (Irish Health Repository)

    Morrissey, David


    Challenges for oncology practitioners and researchers include specific treatment and detection of tumours. The ideal anti-cancer therapy would selectively eradicate tumour cells, whilst minimising side effects to normal tissue. Bacteria have emerged as biological gene vectors with natural tumour specificity, capable of homing to tumours and replicating locally to high levels when systemically administered. This property enables targeting of both the primary tumour and secondary metastases. In the case of invasive pathogenic species, this targeting strategy can be used to deliver genes intracellularly for tumour cell expression, while non-invasive species transformed with plasmids suitable for bacterial expression of heterologous genes can secrete therapeutic proteins locally within the tumour environment (cell therapy approach). Many bacterial genera have been demonstrated to localise to and replicate to high levels within tumour tissue when intravenously (IV) administered in rodent models and reporter gene tagging of bacteria has permitted real-time visualisation of this phenomenon. Live imaging of tumour colonising bacteria also presents diagnostic potential for this approach. The nature of tumour selective bacterial colonisation appears to be tumour origin- and bacterial species- independent. While originally a correlation was drawn between anaerobic bacterial colonisation and the hypoxic nature of solid tumours, it is recently becoming apparent that other elements of the unique microenvironment within solid tumours, including aberrant neovasculature and local immune suppression, may be responsible. Here, we consider the pre-clinical data supporting the use of bacteria as a tumour-targeting tool, recent advances in the area, and future work required to develop it into a beneficial clinical tool.

  20. Prevalance and pathology of gastric tumours in Indian oil sardine (Sardinella longiceps) from Parangipettai coastal waters, southeast coast of India

    Institute of Scientific and Technical Information of China (English)

    Vijayapoopathi Singaravel; Ayyaru Gopalakrishnan; RamalingamVijayakumar; Kuzhanthaivel Raja


    Objective: To carry out the survey of prevalence of gastric tumour in Sardinella longiceps of Parangipettai coastal waters, south east coast of India for a period of one year. Methods: Fish samples were directly collected from fishermen and also from auction yard. The prevalence of gastric tumour, gross pathology, radiography, histopathology, morphometric and meristic characters were investigated. Results: A total of 31 stomach tumour infected individuals were collected during the study period. The gross morphology showed distended abdomen and the radiograph exhibited enlargement of stomach. Autopsy of the infected fish exhibited reddish multilobed tumourous growth on the stomach. Histologically, the tumour lesions were characterized by the differential rate of glandular epitheloid and mesenchymal cells, polymorphic and hyperchromatic nuclei and mitotic activity. No evidence of local invasion and distinct metastases were observed in these cases. Conclusions: The tumours were diagnosed as gastric adenoma, myofibroblastoma, lipoma and fibrosarcoma. Among them myofibroblastoma is highly prevalent.

  1. Glioblastoma brain tumours: estimating the time from brain tumour initiation and resolution of a patient survival anomaly after similar treatment protocols. (United States)

    Murray, J D


    A practical mathematical model for glioblastomas (brain tumours), which incorporates the two key parameters of tumour growth, namely the cancer cell diffusion and the cell proliferation rate, has been shown to be clinically useful and predictive. Previous studies explain why multifocal recurrence is inevitable and show how various treatment scenarios have been incorporated in the model. In most tumours, it is not known when the cancer started. Based on patient in vivo parameters, obtained from two brain scans, it is shown how to estimate the time, after initial detection, when the tumour started. This is an input of potential importance in any future controlled clinical study of any connection between cell phone radiation and brain tumour incidence. It is also used to estimate more accurately survival times from detection. Finally, based on patient parameters, the solution of the model equation of the tumour growth helps to explain why certain patients live longer than others after similar treatment protocols specifically surgical resection (removal) and irradiation.

  2. Desmoplastic small round cell tumour

    Energy Technology Data Exchange (ETDEWEB)

    Tan, T.H.L. [North District Hospital, Fanling, Kowloon (Hong Kong). Radiology Department; Ong, K.L. [Prince of Wales Hospital, Shatin, Kowloon (Hong Kong). Accident and Emergency Department; Au, Y.M.C. [Princess Margarete Hospital, Kowloon, (Hong Kong). Department of Radiology


    The present report describes a rare case of primary desmoplastic small cell tumour of the recto-sigmoid colon with hepatic metastases and lymphadenopathy. There are no pathognomonic radiological features and often their features overlap with other diseases including lymphoma. Histology is necessary to confirm this diagnosis. Unfortunately despite aggressive therapy, the prognosis for this disease is poor. Copyright (1998) Blackwell Science Pty Ltd 8 refs., 1 fig.

  3. Reconstructive options in pelvic tumours

    Directory of Open Access Journals (Sweden)

    Mayilvahanan N


    Full Text Available Background: Pelvic tumours present a complex problem. It is difficult to choose between limb salvage and hemipelvectomy. Method: Forty three patients of tumours of pelvis underwent limb salvage resection with reconstruction in 32 patients. The majority were chondrosarcomas (20 cases followed by Ewing sarcoma. Stage II B was the most common stage in malignant lesions and all the seven benign lesions were aggressive (B3. Surgical margins achieved were wide in 31 and marginal in 12 cases. Ilium was involved in 51% of cases and periacetabular involvement was seen in 12 patients. The resections done were mostly of types I &II of Enneking′s classification of pelvic resection. Arthrodesis was attempted in 24 patients. Customized Saddle prosthesis was used in seven patients and no reconstruction in 12 patients. Adjuvant chemotherapy was given to all high-grade malignant tumours, combined with radiotherapy in 7 patients. Results: With a mean follow up of 48.5 months and one patient lost to follow up, the recurrence rate among the evaluated cases was 16.6%. Oncologically, 30 patients were continuously disease free with 7 local recurrences and 4 deaths due to disseminated disease and 2 patients died of other causes. During the initial years, satisfactory functional results were achieved with prosthetic replacement. Long-term functional result of 36 patients who were alive at the time of latest follow up was satisfactory in 75% who underwent arthrodesis and in those where no reconstruction was used. We also describe a method of new classification of pelvic resections that clarifies certain shortcomings of the previous systems of classification. Conclusion: Selection of a procedure depends largely on the patient factors, the tumour grade, the resultant defect and the tissue factors. Resection with proper margins gives better functional and oncological results

  4. Putting tumours in context

    Energy Technology Data Exchange (ETDEWEB)

    Bissell, Mina J.; Radisky, Derek


    The interactions between cancer cells and their micro- and macroenvironment create a context that promotes tumor growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets. Under normal conditions, ORGANS are made up of TISSUES that exchange information with other cell types via cell-cell contact, cytokines and the EXTRACELLULAR MATRIX (ECM). The ECM, which is produced by collaboration between STROMAL fibroblasts and EPITHELIAL cells, provides structural scaffolding for cells, as well as contextual information. The endothelial vasculature provides nutrients and oxygen, and cells of the immune system combat pathogens and remove apoptotic cells. Epithelial cells associate into intact, polarized sheets. These tissues communicate through a complex network of interactions: physically, through direct contact or through the intervening ECM, and biochemically, through both soluble and insoluble signalling molecules. In combination, these interactions provide the information that is necessary to maintain cellular differentiation and to create complex tissue structures. Occasionally, the intercellular signals that define the normal context become disrupted. Alterations in epithelial tissues can lead to movement of epithelial sheets and proliferation - for example, after activation of mesenchymal fibroblasts due to wounding.Normally, these conditions are temporary and reversible, but when inflammation is sustained, an escalating feedback loop ensues.Under persistent inflammatory conditions, continual upregulation of enzymes such as matrix metalloproteinases (MMPs) by stromal fibroblasts can disrupt the ECM, and invading immune cells can overproduce factors that promote abnormal proliferation. As this process

  5. Notch as a tumour suppressor. (United States)

    Nowell, Craig S; Radtke, Freddy


    The Notch signalling cascade is an evolutionarily conserved pathway that has a crucial role in regulating development and homeostasis in various tissues. The cellular processes and events that it controls are diverse, and continued investigation over recent decades has revealed how the role of Notch signalling is multifaceted and highly context dependent. Consistent with the far-reaching impact that Notch has on development and homeostasis, aberrant activity of the pathway is also linked to the initiation and progression of several malignancies, and Notch can in fact be either oncogenic or tumour suppressive depending on the tissue and cellular context. The Notch pathway therefore represents an important target for therapeutic agents designed to treat many types of cancer. In this Review, we focus on the latest developments relating specifically to the tumour-suppressor activity of Notch signalling and discuss the potential mechanisms by which Notch can inhibit carcinogenesis in various tissues. Potential therapeutic strategies aimed at restoring or augmenting Notch-mediated tumour suppression will also be highlighted.

  6. Association of primary tumour FDG uptake with clinical, histopathological and molecular characteristics in breast cancer patients scheduled for neoadjuvant chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Koolen, B.B.; Aukema, T.S. [Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Department of Nuclear Medicine, Amsterdam (Netherlands); Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Department of Surgical Oncology, Amsterdam (Netherlands); Vrancken Peeters, M.J.T.F.D.; Rutgers, E.J.T. [Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Department of Surgical Oncology, Amsterdam (Netherlands); Wesseling, J.; Lips, E.H. [Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Department of Pathology and Experimental Therapy, Amsterdam (Netherlands); Vogel, W.V.; Valdes Olmos, R.A. [Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Department of Nuclear Medicine, Amsterdam (Netherlands); Werkhoven, E. van [Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Department of Biometrics, Amsterdam (Netherlands); Gilhuijs, K.G.A. [Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Department of Radiology, Amsterdam (Netherlands); University Medical Centre Utrecht, Department of Radiology, Utrecht (Netherlands); Rodenhuis, S. [Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Department of Medical Oncology, Amsterdam (Netherlands)


    The aim of this study was to evaluate the association of primary tumour {sup 18}F-fluorodeoxyglucose (FDG) uptake with clinical, histopathological and molecular characteristics of breast cancer patients scheduled for neoadjuvant chemotherapy. Second, we wished to establish for which patients pretreatment positron emission tomography (PET)/CT could safely be omitted because of low FDG uptake. PET/CT was performed in 214 primary stage II or III breast cancer patients in the prone position with hanging breasts. Tumour FDG uptake was qualitatively evaluated to determine the possibility of response monitoring with PET/CT and was quantitatively assessed using maximum standardized uptake values (SUV{sub max}). FDG uptake was compared with age, TNM stage, histology, hormone and human epidermal growth factor receptor 2 status, grade, Ki-67 and molecular subtype in univariable and multivariable analyses. In 203 tumours (95 %) FDG uptake was considered sufficient for response monitoring. No subgroup of patients with consistently low tumour FDG uptake could be identified. In a univariable analysis, SUV{sub max} was significantly higher in patients with distant metastases at staging examination, non-lobular carcinomas, tumours with negative hormone receptors, triple negative tumours, grade 3 tumours, and in tumours with a high proliferation index (Ki-67 expression). After multiple linear regression analysis, triple negative and grade 3 tumours were significantly associated with a higher SUV{sub max}. Primary tumour FDG uptake in breast cancer patients scheduled for neoadjuvant chemotherapy is significantly higher in tumours with prognostically unfavourable characteristics. Based on tumour characteristics associated with low tumour FDG uptake, this study was unable to identify a subgroup of patients unlikely to benefit from pretreatment PET/CT. (orig.)

  7. Pharmacokinetic and anti-cancer properties of high dose ascorbate in solid tumours of ascorbate-dependent mice. (United States)

    Campbell, Elizabeth J; Vissers, Margreet C M; Wohlrab, Christina; Hicks, Kevin O; Strother, R Matthew; Bozonet, Stephanie M; Robinson, Bridget A; Dachs, Gabi U


    Despite recent evidence for an anti-tumour role for high-dose ascorbate, potential mechanisms of action are still unclear. At mM concentrations that are achieved with high-dose intravenous administration, autoxidation of ascorbate can generate cytotoxic levels of H2O2. Ascorbate is also a required co-factor for the hydroxylases that suppress the transcription factor hypoxia-inducible factor (HIF-1). HIF-1 supports an aggressive tumour phenotype and is associated with poor prognosis, and previous studies have shown that optimizing intracellular ascorbate levels down-regulates HIF-1 activation. In this study we have simultaneously measured ascorbate concentrations and the HIF-1 pathway activity in tumour tissue following high dose ascorbate administration, and have studied tumour growth and physiology. Gulo(-/-) mice, a model of the human ascorbate dependency condition, were implanted with syngeneic Lewis lung tumours, 1g/kg ascorbate was administered into the peritoneum, and ascorbate concentrations were monitored in plasma, liver and tumours. Ascorbate levels peaked within 30min, and although plasma and liver ascorbate returned to baseline within 16h, tumour levels remained elevated for 48h, possibly reflecting increased stability in the hypoxic tumour environment. The expression of HIF-1 and its target proteins was down-regulated with tumour ascorbate uptake. Elevated tumour ascorbate levels could be maintained with daily administration, and HIF-1 and vascular endothelial growth factor protein levels were reduced in these conditions. Increased tumour ascorbate was associated with slowed tumour growth, reduced tumour microvessel density and decreased hypoxia. Alternate day administration of ascorbate resulted in lower tumour levels and did not consistently decrease HIF-1 pathway activity. Levels of sodium-dependent vitamin C transporters 1 and 2 were not clearly associated with ascorbate accumulation by murine tumour cells in vitro or in vivo. Our results support

  8. Tumour tissue microenvironment can inhibit dendritic cell maturation in colorectal cancer.

    LENUS (Irish Health Repository)

    Michielsen, Adriana J


    Inflammatory mediators in the tumour microenvironment promote tumour growth, vascular development and enable evasion of anti-tumour immune responses, by disabling infiltrating dendritic cells. However, the constituents of the tumour microenvironment that directly influence dendritic cell maturation and function are not well characterised. Our aim was to identify tumour-associated inflammatory mediators which influence the function of dendritic cells. Tumour conditioned media obtained from cultured colorectal tumour explant tissue contained high levels of the chemokines CCL2, CXCL1, CXCL5 in addition to VEGF. Pre-treatment of monocyte derived dendritic cells with this tumour conditioned media inhibited the up-regulation of CD86, CD83, CD54 and HLA-DR in response to LPS, enhancing IL-10 while reducing IL-12p70 secretion. We examined if specific individual components of the tumour conditioned media (CCL2, CXCL1, CXCL5) could modulate dendritic cell maturation or cytokine secretion in response to LPS. VEGF was also assessed as it has a suppressive effect on dendritic cell maturation. Pre-treatment of immature dendritic cells with VEGF inhibited LPS induced upregulation of CD80 and CD54, while CXCL1 inhibited HLA-DR. Interestingly, treatment of dendritic cells with CCL2, CXCL1, CXCL5 or VEGF significantly suppressed their ability to secrete IL-12p70 in response to LPS. In addition, dendritic cells treated with a combination of CXCL1 and VEGF secreted less IL-12p70 in response to LPS compared to pre-treatment with either cytokine alone. In conclusion, tumour conditioned media strongly influences dendritic cell maturation and function.

  9. Interphase cytogenetics of multicentric renal cell tumours confirm associations of specific aberrations with defined cytomorphologies (United States)

    Amo-Takyi, B K; Mittermayer, C; Günther, K; Handt, S


    To demonstrate associations of certain chromosomal aberrations with defined renal cell tumour (RCT) subtypes, we analysed 239 tumour nephrectomy cases for specimens with multicentric tumours. Chromosomal in situ hybridization was then performed on 15 cases with 34 foci (16 conventional renal cell carcinomas (RCCs), and 18 papillary RCTs (11 carcinomas and seven adenomas) for specific chromosomal aberrations, using α-satellite probes for chromosomes 3, 7 or 17. Particular preference was given to cases which had separate foci with different cytomorphologies. Furthermore, we compared aberrations in relation to tumour size, stage, grade and between different foci in a specimen. Thirty-four cases had multiple tumours. Forty-seven per cent of the multicentric tumours were conventional RCCs and 53% papillary RCTs (against 83% solitary conventional RCCs and 5% solitary papillary RCTs). Three conventional RCCs sized 8 mm (G3), 13 cm (pT2, G2) and 15 cm (pT3b, G3), respectively, revealed monosomy 3, and 13 were disomic. Seventeen papillary RCTs (11 carcinomas and six adenomas) displayed trisomy 17, irrespective of size or grade. Four papillary carcinomas and six papillary adenomas had trisomy 7, and the rest (seven papillary carcinomas and one papillary adenoma) revealed disomy 7. In conclusion, papillary RCTs were tendentially multicentric. Although specific for conventional RCCs heedless of size, monosomy 3 was only observed in high-grade and/or advanced tumours. Trisomy 17 was only detectable in papillary RCTs irrespective of tumour state, showing increased copies with tumour growth. Papillary RCTs also appeared to lose some copies of chromosome 7 with tumour progress, possibly reflecting malignancy. © 2000 Cancer Research Campaign PMID:10780519

  10. Molecular characterization of c-Abl/c-Src kinase inhibitors targeted against murine tumour progenitor cells that express stem cell markers.

    Directory of Open Access Journals (Sweden)

    Thomas Kruewel

    Full Text Available BACKGROUND: The non-receptor tyrosine kinases c-Abl and c-Src are overexpressed in various solid human tumours. Inhibition of their hyperactivity represents a molecular rationale in the combat of cancerous diseases. Here we examined the effects of a new family of pyrazolo [3,4-d] pyrimidines on a panel of 11 different murine lung tumour progenitor cell lines, that express stem cell markers, as well as on the human lung adenocarcinoma cell line A549, the human hepatoma cell line HepG2 and the human colon cancer cell line CaCo2 to obtain insight into the mode of action of these experimental drugs. METHODOLOGY/PRINCIPAL FINDINGS: Treatment with the dual kinase inhibitors blocked c-Abl and c-Src kinase activity efficiently in the nanomolar range, induced apoptosis, reduced cell viability and caused cell cycle arrest predominantly at G0/G1 phase while western blot analysis confirmed repressed protein expression of c-Abl and c-Src as well as the interacting partners p38 mitogen activated protein kinase, heterogenous ribonucleoprotein K, cyclin dependent kinase 1 and further proteins that are crucial for tumour progression. Importantly, a significant repression of the epidermal growth factor receptor was observed while whole genome gene expression analysis evidenced regulation of many cell cycle regulated genes as well integrin and focal adhesion kinase (FAK signalling to impact cytoskeleton dynamics, migration, invasion and metastasis. CONCLUSIONS/SIGNIFICANCE: Our experiments and recently published in vivo engraftment studies with various tumour cell lines revealed the dual kinase inhibitors to be efficient in their antitumour activity.

  11. Nimotuzumab enhances radiation sensitivity of NSCLC H292 cells in vitro by blocking epidermal growth factor receptor nuclear translocation and inhibiting radiation-induced DNA damage repair

    Directory of Open Access Journals (Sweden)

    Teng K


    Full Text Available Kai Teng,1,2,* Yong Zhang,1,* Xiaoyan Hu,1 Yihui Ding,1 Rui Gong,1 Li Liu1,* 1Department of Thoracic Oncology, Cancer Center of Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Department of Radiation Oncology, Hainan Cancer Hospital, Haikou, Hainan, People’s Republic of China *These authors contributed equally to this work Background: The epidermal growth factor receptor (EGFR signaling pathway plays a significant role in radiation resistance. There is evidence that EGFR nuclear translocation is associated with DNA double-strand breaks (DSB repair. Nimotuzumab has shown the effect of radiosensitization in various cancer cells, but little is known about the relationship between nimotuzumab and EGFR nuclear translocation in non-small cell lung cancer (NSCLC cell lines. In this study, we selected two NSCLC cell lines, namely, H292 (with high EGFR expression and H1975 (with low EGFR expression and explored the mechanisms underlying radiation sensitivity.Methods: MTT assay, clonogenic survival assay, and flow cytometry were performed separately to test cell viability, radiation sensitivity, cell cycle distribution, and apoptosis. Protein γ-H2AX, DNA-PK/p-DNA-PK, and EGFR/p-EGFR expression were further compared both in the cytoplasm and the nucleus with the western blot.Results: Nimotuzumab reduced the viability of H292 cells and sensitized H292 cells to ionizing radiation. The radiation sensitivity enhancement ratio (SER was 1.304 and 1.092 for H292 and H1975 cells, respectively. H292 cells after nimotuzumab administration were arrested at the G0/G1 phase in response to radiation. Apoptosis was without statistical significance in both cell lines. γ-H2AX formation in the combination group (nimotuzumab and radiation increased both in the cytoplasm and the nucleus along with the decreased expression of nuclear EGFR/p-EGFR and p-DNA-PK in H292 cells (P<0.05 that

  12. Malignant tumours of the kidney: imaging strategy

    Energy Technology Data Exchange (ETDEWEB)

    Smets, Anne M. [Academic Medical Center, Department of Radiology G1, Amsterdam (Netherlands); Kraker, Jan de [Paediatric Oncology-Academic Medical Center, Amsterdam (Netherlands)


    Primitive malignant renal tumours comprise 6% of all childhood cancers. Wilms tumour (WT) or nephroblastoma is the most frequent type accounting for more than 90%. Imaging alone cannot differentiate between these tumours with certainty but it plays an important role in screening, diagnostic workup, assessment of therapy response, preoperative evaluation and follow-up. The outcome of WT after therapy is excellent with an overall survival around 90%. In tumours such as those where the outcome is extremely good, focus can be shifted to a risk-based stratification to maintain excellent outcome in children with low risk tumours while improving quality of life and decreasing toxicity and costs. This review will discuss the imaging issues for WT from the European perspective and briefly discuss the characteristics of other malignant renal tumours occurring in children and new imaging techniques with potential in this matter. (orig.)

  13. Movement disorders caused by brain tumours.

    Directory of Open Access Journals (Sweden)

    Bhatoe H


    Full Text Available Movement disorders are uncommon presenting features of brain tumours. Early recognition of such lesions is important to arrest further deficit. We treated seven patients with movement disorders secondary to brain tumours over a period of seven years. Only two of these were intrinsic thalamic tumours (astrocytomas while the rest were extrinsic tumours. The intrinsic tumours were accompanied by hemichorea. Among the extrinsic tumours, there was one pituitary macroadenoma with hemiballismus and four meningiomas with parkinsonism. Symptoms were unilateral in all patients except one with anterior third falcine meningioma who had bilateral rest tremors. There was relief in movement disorders observed after surgery. Imaging by computed tomography or magnetic resonance imaging is mandatory in the evaluation of movement disorders, especially if the presentation is atypical, unilateral and/or accompanied by long tract signs.

  14. [Adenomatoid tumour of the adrenal gland]. (United States)

    Bandier, Philippe Claus; Hansen, Alastair; Thorelius, Lars


    An adenomatoid tumour in the right suprarenal gland was discovered during clinical cancer staging of a 73-year-old woman. Adenomatoid tumours in the suprarenal glands are rare and are most often found incidentally. A definitive diagnosis is made on the basis of histology since imaging methods are non-specific. Differential diagnoses comprise malignant vascular neoplasm or adenocarcinoma. Immunohistochemistry or electron microscopy allows uncomplicated distinction between these tumours. In general, it is recommended to obtain biopsies from suprarenal processes.

  15. An unusual presentation of a glomus tumour.

    LENUS (Irish Health Repository)

    Nugent, N


    Glomus tumours are benign, soft tissue tumours, usually of fingertips. Classically they present with severe pain, temperature sensitivity and localised tenderness. The diagnosis is often delayed due to sometimes non-specific symptoms and rarity of the disorder. While usually a clinical diagnosis, imaging may be necessary for diagnosis and localisation. We present a case of glomus tumour of the fingertip with an unusual history.

  16. Ex-vivo HRMAS of adult brain tumours: metabolite quantification and assignment of tumour biomarkers.

    NARCIS (Netherlands)

    Wright, A.J.; Fellows, G.A.; Griffiths, J.R.; Wilson, M.; Bell, B.A.; Howe, F.A.


    BACKGROUND: High-resolution magic angle spinning (HRMAS) NMR spectroscopy allows detailed metabolic analysis of whole biopsy samples for investigating tumour biology and tumour classification. Accurate biochemical assignment of small molecule metabolites that are "NMR visible" will improve our inter

  17. Bax/bcl-2: cellular modulator of apoptosis in feline skin and basal cell tumours. (United States)

    Madewell, B R; Gandour-Edwards, R; Edwards, B F; Matthews, K R; Griffey, S M


    Bcl-2 and bax are two members of the BCL-2 gene family that play a prominent role in the regulation of apoptosis. Bax and bcl-2 expression were examined immunohistochemically in normal (healthy) feline skin and in 24 benign feline cutaneous basal cell tumours. The tumours were also examined for cellular proliferation by measurement of reactivity for the proliferation marker Ki-67, and for apoptosis by in-situ labelling for fragmented DNA. Bcl-2 was detected in normal basal epithelium and in 23 of 24 basal cell tumours. Bax was detected in both basal and suprabasal epithelium, but in only seven of 24 tumours. For tumours that expressed both bax and bcl-2, the bax:bcl-2 ratio was low. Neither bax nor bcl-2 expression was detected in 14 feline cutaneous squamous cell carcinomas. Basal cell tumours showed modest cellular proliferation (median, 17.5% Ki-67- reactive cells), but few (less than 1%) apoptotic cells. The slow, indolent growth of feline cutaneous basal cells in these benign skin tumours may be a response, at least in part, to opposing regulatory expressions of bcl-2 and bax.

  18. Prognosis of Brain Tumours with Epilepsy



    The prognosis of 560 patients with a clinical and CT diagnosis of intrinsic supratentorial brain tumour was examined retrospectively at the Department of Neurosciences, Walton Hospital, Liverpool, England.

  19. Elevated tumour marker: an indication for imaging?

    LENUS (Irish Health Repository)

    McMahon, Colm J


    INTRODUCTION: The purpose of this study was to evaluate the utility of imaging examinations in patients with elevated tumour markers when (a) the tumour marker is not validated for as a primary diagnostic test; (b) the patient had no personal history of cancer and (c) the patient had no other imaging indication. MATERIALS AND METHODS: Patients without known cancer who had abnormal carcinoembryonic antigen, CA19-9, CA125 and\\/or CA15-3 serology over a one-year period were included. A retrospective medical record review was performed to assess the number of these cases who underwent imaging because of \\'elevated tumour marker\\' in the absence of a clinical indication for imaging. The number and result of these imaging studies were evaluated. RESULTS: Eight hundred and nineteen patients were included. Of those, 25 patients (mean age: 67.8 [range 41-91] y), were imaged to evaluate: \\'elevated tumour marker\\'. They underwent 29 imaging studies (mean [+\\/-standard deviation (SD)] per patient = 1.2 [+\\/-0.4]), and had 42 elevated tumour marker serology tests (mean [+\\/-SD] per patient = 1.7 [+\\/-0.7]). Four patients had >1 imaging test. No patient had an imaging study which diagnosed a malignancy or explained the elevated tumour marker. CONCLUSION: The non-judicious use of tumour markers can prompt further unnecessary investigations including imaging. In this study, there was no positive diagnostic yield for imaging performed for investigation of \\'elevated tumour marker\\'. \\'Elevated tumour marker\\

  20. Paediatric solid tumours in Nigerian children: A changing pattern?

    Directory of Open Access Journals (Sweden)

    Tanko Na′anlep


    Full Text Available Background: Childhood cancer is fast becoming an important paediatric problem in Nigeria and several parts of Africa, with the progressive decline of infectious and nutritional diseases. The following study was a 5-year retrospective review of paediatric solid tumours as seen at the Jos University Teaching Hospital, Nigeria. Objective: To determine the relative frequencies of childhood solid malignant tumours in Jos, Central Nigeria and compare with reports of previous studies both locally and abroad. Materials and Methods: Cancer registers and medical records of patients were used to extract demographic data, specimen number and/or codes. Archival materials were retrieved from the histopathology laboratory and sections were made from paraffin embedded blocks of these specimens. Slides of these histological sections were reviewed and reclassified where necessary. The relative frequencies were then determined. Results: One hundred and eighty one solid tumours of children were diagnosed within the study period. Ninety-four (51% were benign and 87 (49% malignant. Male: Female ratio was 1.3:1. The commonest malignant tumour diagnosed was rhabdomyosarcoma which accounted for 27 (31%, comprising of 15 (55.6%, 11 (40.7% and 1 (3.7% embryonal, alveolar and pleomorphic rhabdomyosarcomas, respectively. Non Hodgkin lymphoma and Burkitt lymphoma accounted for 17 (19.5% and 12 (13.8%, respectively. Conclusion: Based on the result of our study, we conclude that the commonest solid malignancy of childhood in Jos, Nigeria is rhabdomyosarcoma. This has implications for diagnosis, management and prognosis of theses soft tissue sarcomas in our paediatric population.

  1. Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation.

    LENUS (Irish Health Repository)

    Whelan, M C


    Obstacles to effective immunotherapeutic anti-cancer approaches include poor immunogenicity of the tumour cells and the presence of tolerogenic mechanisms in the tumour microenvironment. We report an effective immune-based treatment of weakly immunogenic, growing solid tumours using a locally delivered immunogene therapy to promote development of immune effector responses in the tumour microenvironment and a systemic based T regulatory cell (Treg) inactivation strategy to potentiate these responses by elimination of tolerogenic or immune suppressor influences. As the JBS fibrosarcoma is weakly immunogenic and accumulates Treg in its microenvironment with progressive growth, we used this tumour model to test our combined immunotherapies. Plasmids encoding GM-CSF and B7-1 were electrically delivered into 100 mm(3) tumours; Treg inactivation was accomplished by systemic administration of anti-CD25 antibody (Ab). Using this approach, we found that complete elimination of tumours was achieved at a level of 60% by immunogene therapy, 25% for Treg inactivation and 90% for combined therapies. Moreover, we found that these responses were immune transferable, systemic, tumour specific and durable. Combined gene-based immune effector therapy and Treg inactivation represents an effective treatment for weakly antigenic solid growing tumours and that could be considered for clinical development.

  2. Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNalpha

    DEFF Research Database (Denmark)

    Brender, C; Lovato, P; Sommer, V H;


    Signal transducer and activator of transcription (Stat)3 is constitutively activated in cutaneous T-cell lymphoma (CTCL), where it protects tumour cells against apoptosis. The constitutive activation of Stat3 leads to a constitutive expression of suppressor of cytokine signalling (SOCS)-3....... In healthy cells, SOCS-3 is transiently expressed following cytokine stimulation and functions as a negative feedback inhibitor of the Stat3-activating kinases. Here, we attempt to resolve the apparent paradox of a simultaneous SOCS-3 expression and Stat3 activation in the same cells. We show that (i) SOCS-3...... expression in tumour cells is equal to or higher than in cytokine-stimulated nonmalignant T cells, (ii) SOCS-3 is not mutated in CTCL, (iii) overexpression of SOCS-3 blocks IFNalpha-mediated growth inhibition without affecting Stat3 activation, growth, and apoptosis, and (iv) inhibition of SOCS-3...

  3. Granular cell tumour of the neurohypophysis: a rare sellar tumour with specific radiological and operative features.

    LENUS (Irish Health Repository)

    Aquilina, K


    Symptomatic granular cell tumours of the neurohypophysis are rare sellar lesions. Preoperative prediction of the diagnosis on the basis of radiological appearance is useful as these tumours carry specific surgical difficulties. This is possible when the tumour arises from the pituitary stalk, rostral to a normal pituitary gland. This has not been emphasized previously.

  4. Combined micro-PET/micro-CT imaging of lung tumours in SPC-raf and SPC-myc transgenic mice.

    Directory of Open Access Journals (Sweden)

    Thomas Rodt

    Full Text Available INTRODUCTION: SPC-raf and SPC-myc transgenic mice develop disseminated and circumscribed lung adenocarcinoma respectively, allowing for assessment of carcinogenesis and treatment strategies. The purpose of this study was to investigate the technical feasibility, the correlation of initial findings to histology and the administered radiation dose of combined micro-PET/micro-CT in these animal models. MATERIAL AND METHODS: 14 C57BL/6 mice (4 nontransgenic, 4 SPC-raf transgenic, 6 SPC-myc transgenic were examined using micro-CT and (18F-Fluoro-deoxyglucose micro-PET in-vivo. Micro-PET data was corrected for random events and scatter prior to reconstruction with a 3D-FORE/2D-OSEM iterative algorithm. Rigid micro-PET/micro-CT registration was performed. Tumour-to-non-tumour ratios were calculated for different lung regions and focal lesions. Diffuse tumour growth was quantified using a semiautomated micro-CT segmentation routine reported earlier. Regional histologic tumour load was assessed using a 4-point rating scale. Gamma radiation dose was determined using thermoluminescence dosimeters. RESULTS: Micro-CT allowed visualisation of diffuse and circumscribed tumours in SPC-raf and SPC-myc transgenic animals along with morphology, while micro-PET provided information on metabolism, but lacked morphologic detail. Mean tumour-to-non-tumour ratio was 2.47 for circumscribed lesions. No significant correlation could be shown between histological tumour load and tumour-to-nontumour ratio for diffuse tumours in SPC-raf transgenic animals. Calculation of the expected dose based on gamma dosimetry yielded approximately 140 mGy/micro-PET examination additional to approximately 200 mGy due to micro-CT. CONCLUSIONS: Combined micro-PET/micro-CT imaging allows for in-vivo assessment of lung tumours in SPC-raf and SPC-myc transgenic mice. The technique has potential for the evaluation of carcinogenesis and treatment strategies in circumscribed lung tumours.

  5. An imaging study using laminin peptide 99mTc-YIGSR in mice bearing Ehrlich ascites tumour

    Institute of Scientific and Technical Information of China (English)

    HU Jia; ZHANG Yong-xue; LAN Xiao-li; QIN Guang-ming; ZHANG Jun; HU Zhi-hong


    Background The YIGSR is a pentapeptide, from the laminin-1 of the β1 chain, which can mediate cell adhesion and bind the 67 kD laminin receptor. The purpose is to evaluate the usefulness of 99mTc-YIGSR, a novel tumour radiotracer, in the receptor imaging of Ehrlich ascites tumour.Methods Using S-Acetly-NH3-MAG3 as chelate, YIGSR, a pentapeptide from laminin, was tagged with 99mTc. 99mTc-YIGSR was detected in the tumour group bearing Ehrlich ascites tumour and blocked group. Tumour, normal, inflammatory and blocked groups were imaged. Results Through reverse phase Sep-Pak C18 chromatogram, it was revealed that YIGSR could conjugate with S-Acetly-NH3-MAG3, and be radiolabelled at room temperature and neutral pH with a radiolabelling yield of 62%, and of 4% without chelate. 99mTc-YIGSR was rapidly cleared from kidney, then liver. The imaging findings showed tumour tissue accumulated initial radioactivity at fifteen minutes after injection in the tumour group, and the uptake increased to peak at three hours with a tumour/muscle ratio (T/M) of 11.36, then cleared slowly to a T/M of 7.50 at eight hours. The tumour uptake of radiotracer in blocked group was significantly lower with T/M of 4.61 at three hours and 0.89 at eight hours. The T/M was only 3.72 at three hours and 1.29 at eight hours after injection in inflammatory group. Compared with inflammatory group and control obstructive group, the ratio of T/M in tumour group was significantly different (P<0.001). Conclusions Using S-Acetly-NH3-MAG3, we radiolabelled YIGSR with 99mTc. 99mTc-YIGSR possesses many merits of tumour imaging: rapid visualization, high sensitivity and specificity, and satisfactory target/nontarget ratio. Our data suggest 99mTc-YIGSR is a promising tumour radiotracer.

  6. A study on the antitumour effect of total flavonoids from Pteris multifida Poir in H22 tumour-bearing mice. (United States)

    Yu, Canqiu; Chen, Jinwei; Huang, Li


    The objective of this paper was to investigate the inhibitory effect of total flavonoids from Pteris multifida Poir on growth of transplanted H22 tumour in mice. H22 tumour-bearing mice model was established; the experimental animals were divide/d into the model group, Pteris multifida Poir total flavonoids high-, low-dose groups, and CTX group. Pteris multifida Poir groups were administered continuously for 10d, and CTX group was administered every other day. Tumour inhibition rate, thymus index and spleen index were calculated. Serum levels of TNF-α and IL-2 were determined, as well as total antioxidant capacity (T-AOC) and malondialdehyde (MDA) levels in serum. Compared with the model group, the total flavonoids of Pteris multifida Poir can significantly inhibit tumour growth, with tumour inhibition rates of high-and low-dose groups 49.36% and 33.97%, respectively. They can also evidently increase the spleen and thymus indices of tumour-bearing mice, elevate serum TNF-α and IL-2 levels increase serum T-AOC level and reduce serum MDA level in tumour-bearing mice. The study concluded that total flavonoids from Pteris multifida Poir has an obvious inhibitory effect on transplanted H22 tumours; its mechanism of action may be associated with the improvement of immune function and enhancement of antioxidant capacity in mice.

  7. Modulation of Acid Sphingomyelinase in Melanoma Reprogrammes the Tumour Immune Microenvironment

    Directory of Open Access Journals (Sweden)

    Emma Assi


    Full Text Available The inflammatory microenvironment induces tumours to acquire an aggressive and immunosuppressive behaviour. Since acid sphingomyelinase (A-SMase downregulation in melanoma was shown to determine a malignant phenotype, we aimed here to elucidate the role of A-SMase in the regulation of tumour immunogenic microenvironment using in vivo melanoma models in which A-SMase was either downregulated or maintained at constitutively high levels. We found high levels of inflammatory factors in low A-SMase expressing tumours, which also displayed an immunosuppressive/protumoural microenvironment: high levels of myeloid-derived suppressor cells (MDSCs and regulatory T lymphocytes (Tregs, as well as low levels of dendritic cells (DCs. In contrast, the restoration of A-SMase in melanoma cells not only reduced tumour growth and immunosuppression, but also induced a high recruitment at tumour site of effector immune cells with an antitumoural function. Indeed, we observed a poor homing of MDSCs and Tregs and the increased recruitment of CD8+ and CD4+ T lymphocytes as well as the infiltration of DCs and CD8+/CD44high T lymphocytes. This study demonstrates that change of A-SMase expression in cancer cells is sufficient per se to tune in vivo melanoma growth and that A-SMase levels modulate immune cells at tumour site. This may be taken into consideration in the setting of therapeutic strategies.

  8. Neuroblastoma patient-derived orthotopic xenografts retain metastatic patterns and geno- and phenotypes of patient tumours. (United States)

    Braekeveldt, Noémie; Wigerup, Caroline; Gisselsson, David; Mohlin, Sofie; Merselius, My; Beckman, Siv; Jonson, Tord; Börjesson, Anna; Backman, Torbjörn; Tadeo, Irene; Berbegall, Ana P; Ora, Ingrid; Navarro, Samuel; Noguera, Rosa; Påhlman, Sven; Bexell, Daniel


    Neuroblastoma is a childhood tumour with heterogeneous characteristics and children with metastatic disease often have a poor outcome. Here we describe the establishment of neuroblastoma patient-derived xenografts (PDXs) by orthotopic implantation of viably cryopreserved or fresh tumour explants of patients with high risk neuroblastoma into immunodeficient mice. In vivo tumour growth was monitored by magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography. Neuroblastoma PDXs retained the undifferentiated histology and proliferative capacity of their corresponding patient tumours. The PDXs expressed neuroblastoma markers neural cell adhesion molecule, chromogranin A, synaptophysin and tyrosine hydroxylase. Whole genome genotyping array analyses demonstrated that PDXs retained patient-specific chromosomal aberrations such as MYCN amplification, deletion of 1p and gain of chromosome 17q. Thus, neuroblastoma PDXs recapitulate the hallmarks of high-risk neuroblastoma in patients. PDX-derived cells were cultured in serum-free medium where they formed free-floating neurospheres, expressed neuroblastoma gene markers MYCN, CHGA, TH, SYP and NPY, and retained tumour-initiating and metastatic capacity in vivo. PDXs showed much higher degree of infiltrative growth and distant metastasis as compared to neuroblastoma SK-N-BE(2)c cell line-derived orthotopic tumours. Importantly, the PDXs presented with bone marrow involvement, a clinical feature of aggressive neuroblastoma. Thus, neuroblastoma PDXs serve as clinically relevant models for studying and targeting high-risk metastatic neuroblastoma.

  9. Exploitation of pleiotropic actions of statins by using tumour-targeted delivery systems. (United States)

    Licarete, Emilia; Sesarman, Alina; Banciu, Manuela


    Statins are drugs traditionally used to lower cholesterol levels in blood. At concentrations 100- to 500-fold higher than those needed for reaching cholesterol lowering activity, they have anti-tumour activity. This anti-tumour activity is based on statins pleiotropic effects derived from their ability to inhibit the mevalonate synthesis and include anti-proliferative, pro-apoptotic, anti-angiogenic, anti-inflammatory, anti-metastatic actions and modulatory effects on intra-tumour oxidative stress. Thus, in this review, we summarise the possible pleiotropic actions of statins involved in tumour growth inhibition. Since the administration of these high doses of statins is accompanied by severe side effects, targeted delivery of statins seems to be the appropriate strategy for efficient application of statins in oncology. Therefore, we also present an overview of the current status of targeted delivery systems for statins with possible utilisation in oncology.

  10. Spatiotemporally restricted arenavirus replication induces immune surveillance and type I interferon-dependent tumour regression (United States)

    Kalkavan, Halime; Sharma, Piyush; Kasper, Stefan; Helfrich, Iris; Pandyra, Aleksandra A.; Gassa, Asmae; Virchow, Isabel; Flatz, Lukas; Brandenburg, Tim; Namineni, Sukumar; Heikenwalder, Mathias; Höchst, Bastian; Knolle, Percy A.; Wollmann, Guido; von Laer, Dorothee; Drexler, Ingo; Rathbun, Jessica; Cannon, Paula M.; Scheu, Stefanie; Bauer, Jens; Chauhan, Jagat; Häussinger, Dieter; Willimsky, Gerald; Löhning, Max; Schadendorf, Dirk; Brandau, Sven; Schuler, Martin; Lang, Philipp A.; Lang, Karl S.


    Immune-mediated effector molecules can limit cancer growth, but lack of sustained immune activation in the tumour microenvironment restricts antitumour immunity. New therapeutic approaches that induce a strong and prolonged immune activation would represent a major immunotherapeutic advance. Here we show that the arenaviruses lymphocytic choriomeningitis virus (LCMV) and the clinically used Junin virus vaccine (Candid#1) preferentially replicate in tumour cells in a variety of murine and human cancer models. Viral replication leads to prolonged local immune activation, rapid regression of localized and metastatic cancers, and long-term disease control. Mechanistically, LCMV induces antitumour immunity, which depends on the recruitment of interferon-producing Ly6C+ monocytes and additionally enhances tumour-specific CD8+ T cells. In comparison with other clinically evaluated oncolytic viruses and to PD-1 blockade, LCMV treatment shows promising antitumoural benefits. In conclusion, therapeutically administered arenavirus replicates in cancer cells and induces tumour regression by enhancing local immune responses. PMID:28248314

  11. Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells. (United States)

    Bagci-Onder, Tugba; Du, Wanlu; Figueiredo, Jose-Luiz; Martinez-Quintanilla, Jordi; Shah, Khalid


    Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications.

  12. Size Matters: Developing Design Rules to Engineer Nanoparticles for Solid Tumour Targeting (United States)

    Sykes, Edward Alexander

    Nanotechnology enables the design of highly customizable platforms for producing minimally invasive and programmable strategies for cancer diagnosis and treatment. Advances in this field have demonstrated that nanoparticles can enhance specificity of anti-cancer agents, respond to tumour-specific cues, and direct the visualization of biological targets in vivo. . Nanoparticles can be synthesized within the 1 to 100 nm range to achieve different electromagnetic properties and specifically interact with biological tissues by tuning their size, shape, and surface chemistry. However, it remains unclear which physicochemical parameters are critical for delivering nanomaterials to the tumour site. With less than 5% of administered nanoparticles reaching the tumour, engineering of nanoparticles for effective delivery to solid tumours remains a critical challenge to cancer nanomedicine. A more comprehensive understanding of the interplay between the nanomaterial physicochemical properties and biological systems is necessary to enhance the efficacy of nanoparticle tumour targeting. This thesis explores how nanoparticle size and functionalization with cancer cell specific agents impact nanoparticle delivery to tumours. Furthermore, this doctoral work (i) discusses how tumour structure evolves with growth, (ii) elucidates how such changes modulate nanoparticle accumulation, and (iii) identifies how the skin serves as a significant off-target site for nanoparticle uptake. This thesis also demonstrates the utility of empirically-derived parametric models, Monte Carlo simulations, and decision matrices for mechanistically understanding and predicting the impact of nanomaterial features and tumour biology on nanoparticle fate in vivo. These topics establish key design considerations to tailor nanoparticles for enhanced tumour targeting. Collectively, the concepts presented herein form a fundamental framework for the development of personalized nanomedicine and nano


    NARCIS (Netherlands)



    The sera of 26 patients with premature ovarian failure were examined in order to detect immunoglobulin-G (IgGs) that can block FSH-induced in vitro granulosa cell DNA synthesis via, a Feulgen cytochemical bioassay system. The IgGs of four patients with polycystic ovary-like disease, five postmenopau

  14. Epithelial tumours of the lacrimal gland

    DEFF Research Database (Denmark)

    von Holstein, Sarah Linéa; Coupland, Sarah E; Briscoe, Daniel;


    Epithelial tumours of the lacrimal gland represent a large spectrum of lesions with similarities in clinical signs and symptoms but with different biological behaviour and prognosis. They are rare, but with aggressive malignant potential. Tumours of the lacrimal gland may present with swelling of...

  15. Percutaneously implanted markers in peripheral lung tumours

    DEFF Research Database (Denmark)

    Persson, G.F.; Josipovic, Mirjana; Nygaard, Ditte Eklund;


    A letter to the editor is presented which is concerned with research which investigated percutaneously implanted markers in peripheral lung tumours and their complications.......A letter to the editor is presented which is concerned with research which investigated percutaneously implanted markers in peripheral lung tumours and their complications....

  16. Skull metastasis from rectal gastrointestinal stromal tumours. (United States)

    Gil-Arnaiz, Irene; Martínez-Trufero, Javier; Pazo-Cid, Roberto Antonio; Felipo, Francesc; Lecumberri, María José; Calderero, Verónica


    Gastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasm of the gastrointestinal tract. Rectum localisation is infrequent for these neoplasms, accounting for about 5% of all cases. Distant metastases of GIST are also rare. We present a patient with special features: the tumour is localised in rectum and it has an uncommon metastatic site, the skull, implying a complex differential diagnosis approach.

  17. Occurrence studies of intracranial tumours

    Energy Technology Data Exchange (ETDEWEB)

    Larjavaara, S.


    Intracranial tumours are a histopathologically heterogeneous group of tumours. This thesis focused on three types of intracranial tumours; gliomas, meningiomas and vestibular schwannomas (VS). The main objectives of the dissertation were to estimate the occurrence of intracranial tumours by different subtypes, and to assess the validity and completeness of the cancer registry data. The specific aims of the publications were to evaluate the validity of reported incidence rates of meningioma cases, to describe the trends of VS incidence in four Nordic countries, and to define the anatomic distribution of gliomas and to investigate their location in relation to mobile phone use. Completeness of meningioma registration was examined by comparing five separate sources of information, and by defining the frequencies of cases reported to the Finnish Cancer Registry (FCR). Incidence trends of VS were assessed in the four Nordic countries over a twenty-one-year period (1987 - 2007) using cancer registry data. The anatomic site of gliomas was evaluated using both crude locations in the cerebral lobes and, in more detail, a three-dimensional (3D) distribution in the brain. In addition, a study on specific locations of gliomas in relation to the typical position of mobile phones was conducted using two separate approaches: a case-case and a case-specular analysis. The thesis was based on four sets of materials. Data from the international Interphone study were used for the studies on gliomas, while the two other studies were register-based. The dataset for meningiomas included meningioma cases from the FCR and four clinical data sources in Tampere University Hospital (neurosurgical clinic, pathology database, hospital discharge register and autopsy register). The data on VS were obtained from the national cancer registries of Denmark, Finland, Norway and Sweden. The coverage of meningiomas was not comprehensive in any of the data sources. The completeness of FCR was

  18. Immunohistochemical detection of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 in formalin-fixed breast carcinoma cell block preparations: correlation of results to corresponding tissue block (needle core and excision) samples. (United States)

    Kinsella, Mary D; Birdsong, George G; Siddiqui, Momin T; Cohen, Cynthia; Hanley, Krisztina Z


    Evaluation of ER, PR and Her 2 are routinely performed on breast carcinomas. For accurate detection of these markers, compliance with the ASCO/CAP guidelines is recommended. Our previous study showed that alcohol fixation did not affect ER results when alcohol-fixed cell block (CB) sections were compared to formalin-fixed tissue sections, while PR and Her2 showed less concordance. The aim of this study was to evaluate and to compare ER, PR and Her2 IHC results on formalin-fixed CB sections to those observed on subsequent surgical (needle core or resection) specimens (SS). Fifty cases of formalin fixed CB samples obtained from primary (18%) and metastatic (82%) breast carcinomas were studied, all of which had subsequent SS available. ER, PR, and Her2 IHC studies were done on all samples and results were compared. ER results on formalin-fixed CB samples showed excellent correlation with SS (correlation coefficient cc = 0.82). While there was minimal improvement in PR results (cc = 0.433), Her2 detection did not improve by formalin fixation (cc = 0.439). Formalin fixation for CB preparations does not significantly improve the already good detection of ER positive breast tumors. The concordance rate in PR and IHC results between formalin-fixed CB and SS samples showed improvement as compared with the alcohol-fixed CB results. However, there was no improvement in detection of Her2 overexpression by using formalin fixation on cytology specimens.

  19. TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study

    Directory of Open Access Journals (Sweden)

    Papadopoulos Thomas


    Full Text Available Abstract Background Histological phenotype and clinical behaviour of malignant tumours are not only dependent on alterations in the epithelial cell compartment, but are affected by their interaction with inflammatory cells and tumour-associated stroma. Studies in animal models have shown influence of tumour-associated macrophages (TAM on histological grade of differentiation in colon carcinoma. Disruption of transforming growth factor beta (TGF-beta signalling in tumour cells is related to more aggressive clinical behaviour. Expression data of components of this pathway in tumour-associated stroma is limited. Methods Tissue micro arrays of 310 colon carcinomas from curatively resected patients in UICC stage II and III were established. In a first step we quantified amount of CD68 positive TAMs and expression of components of TGF-beta signalling (TGF-beta1, TGF-beta receptors type 1 and 2, Smad 3 and 4 in tumour and associated stroma. Further we analyzed correlation to histological and clinical parameters (histological grade of differentiation (low-grade (i.e. grade 1 and 2 vs. high-grade (i.e. grade 3 and 4, lymph node metastasis, distant metastasis, 5 year cancer related survival using Chi-square or Fisher's exact test, when appropriate, to compare frequencies, Kaplan-Meier method to calculate 5-year rates of distant metastases and cancer-related survival and log rank test to compare the rates of distant metastases and survival. To identify independent prognostic factors Cox regression analysis including lymph node status and grading was performed. Results High-grade tumours and those with lymph node metastases showed higher rates of TAMs and lower expression of TGF-beta1. Loss of nuclear Smad4 expression in tumor was associated with presence of lymph node metastasis, but no influence on prognosis could be demonstrated. Decrease of both TGF-beta receptors in tumour-associated stroma was associated with increased lymph node metastasis and

  20. A flow cytometric in vivo chalone assay using retransplanted old murine JB-1 ascites tumour cells. (United States)

    Barfod, N M


    A flow cytometric in vivo chalone assay is described. Transplantation of old JB-1 ascites tumour cells to new hosts induced an influx of tumour cells, with G1 DNA content, to the S phase. This induction could be reversibly and specifically blocked by injections of an ultrafiltrate of old JB-1 ascites fluid. The method described is superior to a previously published in vivo chalone assay using regenerating ascites tumours. Owing to a reduced variability in time of onset of DNA synthesis, a smaller scatter of observations is achieved and thus the number of mice per group may be reduced using the new method. In contrast to the older technique, the present one does not necessitate killing of mice during the observation period.

  1. The ‘Pantie' Tumour

    Directory of Open Access Journals (Sweden)

    Silada Kanokrungsee


    Full Text Available We present a case of radiation-associated angiosarcoma. A 67-year-old Thai woman was diagnosed with endometrium carcinoma stage IC and was treated with surgery and radiations. Ten years later, she presented with a gradually enlarging mass on the pubic area, in the shape of a pair of panties. Skin biopsy of lesions confirmed angiosarcoma. The diagnosis was radiation-associated angiosarcoma. She was treated with chemotherapy due to unresectable tumour. The chemotherapy was started with paclitaxel 70 mg/m2 every 2 weeks. After completing the fifth cycle of paclitaxel, the lesion was markedly decreased in size and the symptoms previously described were also completely resolved.

  2. Geographical mapping of a multifocal thyroid tumour using genetic alteration analysis & miRNA profiling

    Directory of Open Access Journals (Sweden)

    Li Jing


    Full Text Available Abstract Background Papillary thyroid carcinoma (PTC frequently presents as multiple tumour-foci within a single thyroid gland or pluriform, with synchronous tumours comprising different histological variants, raising questions regarding its clonality. Among the genetic aberrations described in PTC, the BRAF V600E mutation and ret/PTC activation occur most commonly. Several studies have investigated the genetic alteration status of multifocal thyroid tumours, with discordant results. To address the question of clonality this study examined disparate geographical and morphological areas from a single PTC (classic PTC, insular and anaplastic foci, and tumour cells adjacent to vascular invasion and lymphocytic infiltrate for the presence of ret/PTC 1 or BRAF mutations. Moreover, we wanted to investigate the consistency of miRNA signatures within disparate areas of a tumour, and geographical data was further correlated with expression profiles of 330 different miRNAs. Putative miRNA gene targets were predicted for differentially regulated miRNAs and immunohistochemistry was performed on tissue sections in an effort to investigate phenotypic variations in microvascular density (MVD, and cytokeratin and p53 protein expression levels. Results All of the morphological areas proved negative for ret/PTC 1 rearrangement. Two distinct foci with classic morphology harboured the BRAF mutation. All other regions, including the insular and anaplastic areas were negative for the mutation. MiRNA profiles were found to distinguish tumours containing the BRAF mutation from the other tumour types, and to differentiate between the more aggressive insular & anaplastic tumours, and the classic variant. Our data corroborated miRNAs previously discovered in this carcinoma, and additional miRNAs linked to various processes involved in tumour growth and proliferation. Conclusion The initial genetic alteration analysis indicated that pluriform PTC did not necessarily evolve

  3. Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune tolerance. (United States)

    Lee, K J; Moon, J Y; Choi, H K; Kim, H O; Hur, G Y; Jung, K H; Lee, S Y; Kim, J H; Shin, C; Shim, J J; In, K H; Yoo, S H; Kang, K H; Lee, S Y


    Statins are potent inhibitors of hydroxyl-3-methylglutaryl co-enzyme A (HMG-CoA) reductase, and have emerged as potential anti-cancer agents based on preclinical evidence. In particular, compelling evidence suggests that statins have a wide range of immunomodulatory properties. However, little is known about the role of statins in tumour immune tolerance. Tumour immune tolerance involves the production of immunosuppressive molecules, such as interleukin (IL)-10, transforming growth factor (TGF)-beta and indoleamine-2,3-dioxygenase (IDO) by tumours, which induce a regulatory T cell (T(reg)) response. In this study, we investigated the effect of simvastatin on the production of IL-10, TGF-beta and IDO production and the proliferation of T(regs) using several cancer cell lines, and Lewis lung cancer (3LL) cells-inoculated mouse tumour model. Simvastatin treatment resulted in a decrease in the number of cancer cells (3LL, A549 and NCI-H292). The production of the immune regulatory markers IL-10, TGF-beta in 3LL and NCI-H292 cells increased after treatment with simvastatin. The expression of IDO and forkhead box P3 (FoxP3) transcription factor was also increased in the presence of simvastatin. In a murine 3LL model, there were no significant differences in tumour growth rate between untreated and simvastatin-treated mice groups. Therefore, while simvastatin had an anti-proliferative effect, it also exhibited immune tolerance-promoting properties during tumour development. Thus, due to these opposing actions, simvastatin had no net effect on tumour growth.

  4. Omentum and bone marrow: how adipocyte-rich organs create tumour microenvironments conducive for metastatic progression (United States)

    Gusky, H. Chkourko; Diedrich, J.; MacDougald, O. A.; Podgorski, I.


    Summary A number of clinical studies have linked adiposity with increased cancer incidence, progression and metastasis, and adipose tissue is now being credited with both systemic and local effects on tumour development and survival. Adipocytes, a major component of benign adipose tissue, represent a significant source of lipids, cytokines and adipokines, and their presence in the tumour microenvironment substantially affects cellular trafficking, signalling and metabolism. Cancers that have a high predisposition to metastasize to the adipocyte-rich host organs are likely to be particularly affected by the presence of adipocytes. Although our understanding of how adipocytes influence tumour progression has grown significantly over the last several years, the mechanisms by which adipocytes regulate the meta-static niche are not well-understood. In this review, we focus on the omentum, a visceral white adipose tissue depot, and the bone, a depot for marrow adipose tissue, as two distinct adipocyte-rich organs that share common characteristic: they are both sites of significant metastatic growth. We highlight major differences in origin and function of each of these adipose depots and reveal potential common characteristics that make them environments that are attractive and conducive to secondary tumour growth. Special attention is given to how omental and marrow adipocytes modulate the tumour microenvironment by promoting angiogenesis, affecting immune cells and altering metabolism to support growth and survival of metastatic cancer cells. PMID:27432523

  5. Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways

    NARCIS (Netherlands)

    Meel, van der Roy; Oliveira, Sabrina; Altintas, Isil; Heukers, Raimond; Pieters, Ebel H.E.; Bergen en Henegouwen, van Paul M.P.; Storm, Gert; Hennink, Wim E.; Kok, Robbert J.; Schiffelers, Raymond M.


    The clinical efficacy of epidermal growth factor receptor (EGFR)-targeted inhibitors is limited due to resistance mechanisms of the tumor such as activation of compensatory pathways. Crosstalk between EGFR and insulin-like growth factor 1 (IGF-1R) signaling has been frequently described to be involv

  6. Dual role of Sp3 transcription factor as an inducer of apoptosis and a marker of tumour aggressiveness.

    Directory of Open Access Journals (Sweden)

    Khadija Essafi-Benkhadir

    Full Text Available BACKGROUND: The ambiguous role of transcription factor Sp3 for tumour progression is still debated since it was described as a transcriptional repressor or activator. Here we tried to decipher the molecular mechanisms implicated in Sp3 accumulation observed in aggressive tumours. METHODOLOGY: We generated normal and tumour cell lines conditionally expressing Sp3. Cell growth was analyzed in vitro and after inoculation in nude mice. Apoptosis was assessed by pan- caspase activity assays, by counting fragmented nuclei and by determination of caspase 9 cleavage. Gene expression was determined by quantitative PCR. Cleavage by different caspases was performed after in vitro translation of the Sp3 cDNA in the presence of [S(35] labelled methionine. Different tumour cell lines and head and neck tumour samples were tested for the presence of Sp3 by western blots. Correlation between Sp3 expression and overall survival has been statistically determined. PRINCIPAL FINDINGS: Conditional over-expression of Sp3 induces apoptosis and modifies expression of genes implicated in the regulation of cell cycle and pro and anti apoptotic genes. Sp3 over-expression strongly reduces the development of tumours in nude mice confirming its pro-apoptotic potential in vivo. However, cells can survive to apoptosis through selective Sp3 cleavage by caspase. Sp3 induction in established tumours resulted in transient regression then progression. Progression coincides with re-accumulation of the full length form of Sp3. Sp3 is over-expressed in tumour cell lines of different origins. The presence of high levels of the full-length form of Sp3 indicates a poor prognosis for overall survival of patients with head and neck tumours. CONCLUSIONS: Full length Sp3 accumulation highlights bypass of tumour cell apoptotic capacities and is indicative of head and neck tumours aggressiveness.

  7. Targeting the tumour vasculature: exploitation of low oxygenation and sensitivity to NOS inhibition by treatment with a hypoxic cytotoxin. (United States)

    Baker, Jennifer H E; Kyle, Alastair H; Bartels, Kirsten L; Methot, Stephen P; Flanagan, Erin J; Balbirnie, Andrew; Cran, Jordan D; Minchinton, Andrew I


    Many cancer research efforts focus on exploiting genetic-level features that may be targeted for therapy. Tissue-level features of the tumour microenvironment also represent useful therapeutic targets. Here we investigate the presence of low oxygen tension and sensitivity to NOS inhibition of tumour vasculature as potential tumour-specific features that may be targeted by hypoxic cytotoxins, a class of therapeutics currently under investigation. We have previously demonstrated that tirapazamine (TPZ) mediates central vascular dysfunction in tumours. TPZ is a hypoxic cytotoxin that is also a competitive inhibitor of NOS. Here we further investigated the vascular-targeting activity of TPZ by combining it with NOS inhibitor L-NNA, or with low oxygen content gas breathing. Tumours were analyzed via multiplex immunohistochemical staining that revealed irreversible loss of perfusion and enhanced tumour cell death when TPZ was combined with either low oxygen or a NOS inhibitor. Tumour growth rate was reduced by TPZ + NOS inhibition, and tumours previously resistant to TPZ-mediated vascular dysfunction were sensitized by low oxygen breathing. Additional mapping analysis suggests that tumours with reduced vascular-associated stroma may have greater sensitivity to these effects. These results indicate that poorly oxygenated tumour vessels, also being abnormally organized and with inadequate smooth muscle, may be successfully targeted for significant anti-cancer effects by inhibition of NOS and hypoxia-activated prodrug toxicity. This strategy illustrates a novel use of hypoxia-activated cytotoxic prodrugs as vascular targeting agents, and also represents a novel mechanism for targeting tumour vessels.

  8. Mitogenesis of Vascular Smooth Muscle Cell Stimulated by Platelet-Derived Growth Factor-bb Is Inhibited by Blocking of Intracellular Signaling by Epigallocatechin-3-O-Gallate

    Directory of Open Access Journals (Sweden)

    Mi Hee Lee


    Full Text Available Epigallocatechin gallate (EGCG is known to exhibit antioxidant, antiproliferative, and antithrombogenic effects and reduce the risk of cardiovascular diseases. Key events in the development of cardiovascular disease are hypertrophy and hyperplasia according to vascular smooth muscle cell proliferation. In this study, we investigated whether EGCG can interfere with PDGF-bb stimulated proliferation, cell cycle distribution, and the gelatinolytic activity of MMP and signal transduction pathways on RAOSMC when it was treated in two different ways—cotreatment with PDGF-bb and pretreatment of EGCG before addition of PDGF-bb. Both cotreated and pretreated EGCG significantly inhibited PDGF-bb induced proliferation, cell cycle progression of the G0/G1 phase, and the gelatinolytic activity of MMP-2/9 on RAOSMC. Also, EGCG blocked PDGF receptor-β (PDGFR-β phosphorylation on PDGF-bb stimulated RAOSMC under pretreatment with cells as well as cotreatment with PDGF-bb. The downstream signal transduction pathways of PDGFR-β, including p42/44 MAPK, p38 MAPK, and Akt phosphorylation, were also inhibited by EGCG in a pattern similar to PDGFR-β phosphorylation. These findings suggest that EGCG can inhibit PDGF-bb stimulated mitogenesis by indirectly and directly interrupting PDGF-bb signals and blocking the signaling pathway via PDGFR-β phosphorylation. Furthermore, EGCG may be used for treatment and prevention of cardiovascular disease through blocking of PDGF-bb signaling.

  9. MRI of pineal region tumours: relationship between tumours and adjacent structures

    Energy Technology Data Exchange (ETDEWEB)

    Satoh, H. [Hiroshima University, School of Medicine (Japan). Dept. of Neurosurgery; Uozumi, T. [Hiroshima University, School of Medicine (Japan). Dept. of Neurosurgery; Kiya, K. [Dept. of Neurosurgery, Hiroshima Prefectural Hospital, Hiroshima (Japan); Kurisu, K. [Hiroshima University, School of Medicine (Japan). Dept. of Neurosurgery; Arita, K. [Hiroshima University, School of Medicine (Japan). Dept. of Neurosurgery; Sumida, M. [Hiroshima University, School of Medicine (Japan). Dept. of Neurosurgery; Ikawa, F. [Dept. of Neurosurgery, Hiroshima Prefectural Hospital, Hiroshima (Japan)


    A variety of tumours may arise in the pineal region; accurate diagnosis is important in the selection of treatment and prognosis. A retrospective analysis of the MRI studies of 25 patients with pathologically proven pineal region tumours was performed, focused on the relationship between the tumour and neighbouring structures. Compression of the tectal plate was classified as expansive or invasive, and compression of the corpus callosum as inferior, anterior or posterior. In 10 of the 14 patients (71 %) with germ cell tumours tectal compression was of the invasive type; 8 patients (57 %) had multiple tumours and in 13 (93 %) the tumour margins were irregular. Teratomas were readily diagnosed because of characteristic heterogeneous signal intensity. Pineal cell tumours were differentiated from germ cell tumours by their rounded shape, solid nature, sharp margins, and expansive type of tectal compression. Meningiomas were characterised by their falcotentorial attachments, posterior callosal compression, and a low-intensity rim on T2-weighted images. Gd-DTPA injection enabled clear demonstration of the site and extent of tumour spread and was useful in differentiating cystic and solid components. The appearances described, while not pathognomonic, are helpful in the differential diagnosis of pineal region tumours, and valuable in planning appropriate treatment. (orig.). With 4 figs., 6 tabs.

  10. Acute Pancreatitis Secondary to Pancreatic Neuroendocrine Tumours

    Directory of Open Access Journals (Sweden)

    Grinó P


    Full Text Available CONTEXT: Pancreatic neoplasms are an uncommon aetiology of acute pancreatitis. Pancreatic neuroendocrine tumours are a rare subgroup of pancreatic neoplasms. CASE REPORT: We report on three patients having acute pancreatitis secondary to pancreatic neuroendocrine tumours, one of them with severe pancreatitis, and review the published cases up to now. Only 22 patients with acute pancreatitis secondary to pancreatic neuroendocrine tumours have been reported (including the present cases. Most of these cases were of non-functioning neoplasms and the course of the pancreatitis tended to be mild. In the most recent reports and in the present cases, the initial diagnostic method was CT scan. Less than half had metastases when the tumour was diagnosed and mortality from these neoplasms reached approximately 50%. CONCLUSIONS: Pancreatic neuroendocrine tumours can cause acute pancreatitis even in patients under 50 years of age. On many occasions, the tumours are non-functioning; therefore, acute pancreatitis may be the first clinical symptom. Consequently, faced with acute pancreatitis of unknown origin, a non-functioning neuroendocrine tumour should be ruled out.

  11. Climacostol reduces tumour progression in a mouse model of melanoma via the p53-dependent intrinsic apoptotic programme (United States)

    Perrotta, Cristiana; Buonanno, Federico; Zecchini, Silvia; Giavazzi, Alessio; Proietti Serafini, Francesca; Catalani, Elisabetta; Guerra, Laura; Belardinelli, Maria Cristina; Picchietti, Simona; Fausto, Anna Maria; Giorgi, Simone; Marcantoni, Enrico; Clementi, Emilio; Ortenzi, Claudio; Cervia, Davide


    Climacostol, a compound produced by the ciliated protozoan Climacostomum virens, displayed cytotoxic properties in vitro. This study demonstrates that it has anti-tumour potential. Climacostol caused a reduction of viability/proliferation of B16-F10 mouse melanoma cells, a rapidly occurring DNA damage, and induced the intrinsic apoptotic pathway characterised by the dissipation of the mitochondrial membrane potential, the translocation of Bax to the mitochondria, the release of Cytochrome c from the mitochondria, and the activation of Caspase 9-dependent cleavage of Caspase 3. The apoptotic mechanism of climacostol was found to rely on the up-regulation of p53 and its targets Noxa and Puma. In vivo analysis of B16-F10 allografts revealed a persistent inhibition of tumour growth rate when melanomas were treated with intra-tumoural injections of climacostol. In addition, it significantly improved the survival of transplanted mice, decreased tumour weight, induced a remarkable reduction of viable cells inside the tumour, activated apoptosis and up-regulated the p53 signalling network. Importantly, climacostol toxicity was more selective against tumour than non-tumour cells. The anti-tumour properties of climacostol and the molecular events associated with its action indicate that it is a powerful agent that may be considered for the design of pro-apoptotic drugs for melanoma therapy. PMID:27271364

  12. MEG3: a novel long noncoding potentially tumour-suppressing RNA in meningiomas. (United States)

    Balik, Vladimir; Srovnal, Josef; Sulla, Igor; Kalita, Ondrej; Foltanova, Tatiana; Vaverka, Miroslav; Hrabalek, Lumir; Hajduch, Marian


    Meningiomas represent one of the most common types of primary intracranial tumours. However, the specific molecular mechanisms underlying their pathogenesis remain uncertain. Loss of chromosomes 22q, 1p, and 14q have been implicated in most meningiomas. Inactivation of the NF2 gene at 22q12 has been identified as an early event in their pathogenesis, whereas abnormalities of chromosome 14 have been reported in higher-grade as well as recurrent tumours. It has long been supposed that chromosome 14q32 contains a tumour suppressor gene. However, the identity of the potential 14q32 tumour suppressor remained elusive until the Maternally Expressed Gene 3 (MEG3) was recently suggested as an ideal candidate. MEG3 is an imprinted gene located at 14q32 that encodes a non-coding RNA (ncRNA). In meningiomas, loss of MEG3 expression, its genomic DNA deletion and degree of promoter methylation have been found to be associated with aggressive tumour growth. These findings indicate that MEG3 may have a significant role as a novel long noncoding RNA tumour suppressor in meningiomas.

  13. Re-programming tumour cell metabolism to treat cancer: no lone target for lonidamine (United States)

    Bhutia, Yangzom D.; Babu, Ellappan; Ganapathy, Vadivel


    Tumour cell metabolism is very different from normal cell metabolism; cancer cells re-programme the metabolic pathways that occur in normal cells in such a manner that it optimizes their proliferation, growth and survival. Although this metabolic re-programming obviously operates to the advantage of the tumour, it also offers unique opportunities for effective cancer therapy. Molecules that target the tumour cell-specific metabolic pathways have potential as novel anti-cancer drugs. Lonidamine belongs to this group of molecules and is already in use in some countries for cancer treatment. It has been known for a long time that lonidamine interferes with energy production in tumour cells by inhibiting hexokinase II (HKII), a glycolytic enzyme. However, subsequent studies have uncovered additional pharmacological targets for the drug, which include the electron transport chain and the mitochondrial permeability transition pore, thus expanding the pharmacological effects of the drug on tumour cell metabolism. A study by Nancolas et al. in a recent issue of the Biochemical Journal identifies two additional new targets for lonidamine: the pyruvate transporter in the mitochondria and the H+-coupled monocarboxylate transporters in the plasma membrane (PM). It is thus becoming increasingly apparent that the anti-cancer effects of lonidamine do not occur through a single target; the drug works at multiple sites. Irrespective of the molecular targets, what lonidamine does in the end is to undo what the tumour cells have done in terms of re-programming cellular metabolism and mitochondrial function. PMID:27234586

  14. Re-programming tumour cell metabolism to treat cancer: no lone target for lonidamine. (United States)

    Bhutia, Yangzom D; Babu, Ellappan; Ganapathy, Vadivel


    Tumour cell metabolism is very different from normal cell metabolism; cancer cells re-programme the metabolic pathways that occur in normal cells in such a manner that it optimizes their proliferation, growth and survival. Although this metabolic re-programming obviously operates to the advantage of the tumour, it also offers unique opportunities for effective cancer therapy. Molecules that target the tumour cell-specific metabolic pathways have potential as novel anti-cancer drugs. Lonidamine belongs to this group of molecules and is already in use in some countries for cancer treatment. It has been known for a long time that lonidamine interferes with energy production in tumour cells by inhibiting hexokinase II (HKII), a glycolytic enzyme. However, subsequent studies have uncovered additional pharmacological targets for the drug, which include the electron transport chain and the mitochondrial permeability transition pore, thus expanding the pharmacological effects of the drug on tumour cell metabolism. A study by Nancolas et al. in a recent issue of the Biochemical Journal identifies two additional new targets for lonidamine: the pyruvate transporter in the mitochondria and the H(+)-coupled monocarboxylate transporters in the plasma membrane (PM). It is thus becoming increasingly apparent that the anti-cancer effects of lonidamine do not occur through a single target; the drug works at multiple sites. Irrespective of the molecular targets, what lonidamine does in the end is to undo what the tumour cells have done in terms of re-programming cellular metabolism and mitochondrial function.

  15. N-cadherin expression in malignant germ cell tumours of the testis

    Directory of Open Access Journals (Sweden)

    Bremmer Felix


    Full Text Available Abstract Background Testicular germ cell tumours (TGCTs are the most common malignancy in young men aged 18–35 years. They are clinically and histologically subdivided into seminomas and non-seminomas. Cadherins are calcium-dependent transmembrane proteins of the group of adhesion proteins. They play a role in the stabilization of cell-cell contacts, the embryonic morphogenesis, in the maintenance of cell polarity and signal transduction. N-cadherin (CDH2, the neuronal cadherin, stimulates cell-cell contacts during migration and invasion of cells and is able to suppress tumour cell growth. Methods Tumour tissues were acquired from 113 male patients and investigated by immunohistochemistry, as were the three TGCT cell lines NCCIT, NTERA-2 and Tcam2. A monoclonal antibody against N-cadherin was used. Results Tumour-free testis and intratubular germ cell neoplasias (unclassified (IGCNU strongly expressed N-cadherin within the cytoplasm. In all seminomas investigated, N-cadherin expression displayed a membrane-bound location. In addition, the teratomas and yolk sac tumours investigated also differentially expressed N-cadherin. In contrast, no N-cadherin could be detected in any of the embryonal carcinomas and chorionic carcinomas examined. This expression pattern was also seen in the investigated mixed tumours consisting of seminomas, teratomas, and embryonal carcinoma. Conclusions N-cadherin expression can be used to differentiate embryonal carcinomas and chorionic carcinomas from other histological subtypes of TGCT.

  16. Carcinoid tumour of the middle ear

    LENUS (Irish Health Repository)

    Baig, Salman


    A case of middle ear mass in a young female from Ireland is described, who presented with left ear hearing loss and intermittent bloody discharge from the same ear. Examination under microscope revealed occlusive polyp in the left ear and a biopsy had been taken under general anaesthesia. Histopathology report described an adenoma \\/ carcinoid tumour of the middle ear confirmed by positive immunohistochemical staining. CT temporal bones revealed the extension of the disease. The patient underwent left tympanotomy and excision of the tumour. In general, these tumours are regarded as benign but may be mistaken for adenocarcinomas because of their histological heterogenecity.

  17. Thallium uptake and biological behaviour in childhood brain tumours

    Energy Technology Data Exchange (ETDEWEB)

    Bernard, E.J.; Howman-Giles, R.; Kellie, S.; Uren, R.F. [Royal Alexandra Hospital for Children, Sydney, NSW (Australia)


    Full text: The histopathological grade and radiological appearance of the diverse cerebral neoplasms in childhood frequently poorly reflect their biological behaviour. We examined thallium accumulation prior to treatment (and in several cases, at intervals there after) in 13 children to determine its usefulness as a tumour marker. 23 SPECT studies were acquired 20 minutes after the injection of 1-3 mCi of {sup 201}TI. Thallium index (TI), the ratio of counts in tumour/normal brain, was calculated. No uptake was seen in two patients (pts) with a Grade 1 cerebellar astrocytomas (disease free at 4/12 f/u). Three pts with medulloblastomas were studied. One pt showed intense uptake (Tl =12). His tumour (proliferative antigen stain Ki67 = 50%) recurred early after debulking surgery (Tl +ve prior to CT or MRI changes). The second pt was imaged at relapse (Ki67 = 60%) and showed intense uptake, Tl = 17. The third pt showed lower level uptake (Tl = 2), Ki67 = 5%, and is disease-free at 5/12 (as per {sup 201}TI and MRI). One pt with a Grade 1 brainstem glioma showed Tl = 5 and has progressed rapidly despite low grade histology. Four pts with chiasmatic-hypothalamic gliomas have been studied. Although these neoplasms are usually low grade histologically, their growth properties vary greatly. Two pts with Tl<2.5 have been conservatively managed because of slow tumour growth. The other two pts have Tl>3.5 and have required aggressive treatment for rapid disease progression. One pt with a large pilocytic astrocytoma of the optic chiasm showed Tl = 9.5. Active treatment was not undertaken. One pt with a pineal germ cell tumour showed avid {sup 201}TI uptake (Tl not performed) and has had two normal studies, and is clinically well, since BMT. Avid {sup 201}TI uptake also seen in one pt with cerebral neuroblastoma. (Died at 8/12 after Dx.) Thus, {sup 201}TI accumulates in histologically diverse paediatric neoplasms. The Tl appears to reflect biological behaviour in the limited

  18. Morphological, functional and metabolic imaging biomarkers: assessment of vascular-disrupting effect on rodent liver tumours

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Huaijun; Li, Junjie; Keyzer, Frederik De; Yu, Jie; Feng, Yuanbo; Marchal, Guy; Ni, Yicheng [University Hospitals, University of Leuven, Department of Radiology, Leuven (Belgium); Chen, Feng [University Hospitals, University of Leuven, Department of Radiology, Leuven (Belgium); Southeast University, Department of Radiology, Zhongda Hospital, Nanjing (China); Nuyts, Johan [University Hospitals, University of Leuven, Department of Nuclear Medicine, Leuven (Belgium)


    To evaluate effects of a vascular-disrupting agent on rodent tumour models. Twenty rats with liver rhabdomyosarcomas received ZD6126 intravenously at 20 mg/kg, and 10 vehicle-treated rats were used as controls. Multiple sequences, including diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) with the microvascular permeability constant (K), were acquired at baseline, 1 h, 24 h and 48 h post-treatment by using 1.5-T MRI. [{sup 18}F]fluorodeoxyglucose micro-positron emission tomography ({sup 18}F-FDG {mu}PET) was acquired pre- and post-treatment. The imaging biomarkers including tumour volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC) and K from MRI, and maximal standardised uptake value (SUV{sub max}) from FDG {mu}PET were quantified and correlated with postmortem microangiography and histopathology. In the ZD6126-treated group, tumours grew slower with higher necrosis ratio at 48 h (P < 0.05), corresponding well to histopathology; tumour K decreased from 1 h until 24 h, and partially recovered at 48 h (P < 0.05), parallel to the evolving enhancement ratios (P < 0.05); ADCs varied with tumour viability and perfusion; and SUV{sub max} dropped at 24 h (P < 0.01). Relative K of tumour versus liver at 48 h correlated with relative vascular density on microangiography (r = 0.93, P < 0.05). The imaging biomarkers allowed morphological, functional and metabolic quantifications of vascular shutdown, necrosis formation and tumour relapse shortly after treatment. A single dose of ZD6126 significantly diminished tumour blood supply and growth until 48 h post-treatment. (orig.)

  19. Detection and assessment of human tumours producing granulocyte-macrophage colony-stimulating factor (GM-CSF) by heterotransplantation into nude mice.



    Production of granulocyte-macrophage colony-stimulating factor(s) (GM-CSF) by human tumours was investigated using heterotransplantation of a number of different tumours in nude mice. An increase in granulocyte numbers (> 20,000/mm3) in the peripheral blood of nude mice accompanied the growth of 9 of the 25 transplanted tumours. GM-CSF activity tested against normal human marrow cells was relatively high in 6 of these 9 tumours. Moreover there was either weak activity or none at all in 14 of ...

  20. Palisaded encapsulated neuroma: an uncommon tumour at uncommon location

    Directory of Open Access Journals (Sweden)

    Anup Kumar Tiwary


    Full Text Available Palisaded encapsulated neuroma (PEN is an uncommon, sporadic, benign, intraneural tumour presenting as an asymptomatic, solitary, sessile, immobile, skin-coloured papule or nodule, commonly affecting the “butterfly area” of face in middle-aged person. Other less commonly involved sites are trunk, shoulder and distal part of extremities. We herein report a 45 years old male presenting with a painless, firm, nodular growth over the posteromedial aspect of right knee which was further confirmed to be the case of PEN on histopathological examination.

  1. Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy (United States)

    Park, Jason; Wrzesinski, Stephen H.; Stern, Eric; Look, Michael; Criscione, Jason; Ragheb, Ragy; Jay, Steven M.; Demento, Stacey L.; Agawu, Atu; Licona Limon, Paula; Ferrandino, Anthony F.; Gonzalez, David; Habermann, Ann; Flavell, Richard A.; Fahmy, Tarek M.


    The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-β (TGF-β), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-β inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.

  2. Inhibition of angiopoietin 2 attenuates lumen formation of tumour-associated vessels in vivo. (United States)

    Suzuki, Rei; Yamamoto, Hirofumi; Ngan, Chew Yee; Ohtsuka, Masahisa; Kitani, Kotaro; Uemura, Mamoru; Nishimura, Junichi; Takemasa, Ichiro; Mizushima, Tsunekazu; Sekimoto, Mitsugu; Minamoto, Toshinari; Doki, Yuichiro; Mori, Masaki


    Anti-angiogenic therapy, inhibition of a co-operative process with vascular endothelial cells and pericytes could be an effective strategy to treat malignant tumours. Apart from vascular endothelial growth factor (VEGF), angiopoietin 2 (Ang2) is a promising target of anti-angiogenic therapy. Although inhibition of Ang2 has been shown to decrease tumour size in preclinical and phase I trials, its mechanisms of action remain largely unknown. To elucidate the mechanisms of Ang2 inhibition, we have focused on differentiation of the vessels as well as on growth of the vessels, especially in vivo. L1-10, a selective Ang2 inhibitor was used. The in vitro effects of Ang2 inhibition or addition of Ang2 using HUVECs were also examined. Growth and differentiation of tumour-associated vessels were investigated in xenografts derived from a colon cancer treated by L1-10. Effects of VEGF inhibition were also examined to discriminate Ang2-specific action on the tumour-associated vessels. In vitro studies showed that VEGF enhanced proliferation and tube formation of HUVECs, and caused a significant increase in Rac1 and CDC42 expression when cultured in the collagen matrix gel, whereas neither Ang2 nor L1-10 affected in vitro behaviour of HUVECs or levels of the proteins. In vivo, on the other hand, we found that Ang2 inhibition with treatment of L1-10 dose‑dependently decreased tumour growth. Furthermore, we found that L1-10 treatment extends the tumour-associated vessels whilst it suppressed a sound lumen formation. Histological analysis on xenografts suggests that Ang2 inhibition could have disturbed in vivo vascular differentiation. Our data provide a novel aspect that Ang2 may play an essential role in in vivo vascular differentiation, thus supporting a rationale for Ang2-targeted therapy against colon cancer.

  3. Regional tumour glutamine supply affects chromatin and cell identity. (United States)

    Højfeldt, Jonas W; Helin, Kristian


    Limited perfusion of solid tumours produces a nutrient-deprived tumour core microenvironment. Low glutamine levels in the tumour core are now shown to lead to reduced levels of α-ketoglutarate and decreased histone demethylase activity, thereby promoting a less differentiated and more therapy-resistant state of the tumour cells.

  4. Symptoms and time to diagnosis in children with brain tumours

    DEFF Research Database (Denmark)

    Klitbo, Ditte Marie; Nielsen, Rine; Illum, Niels Ove;


    Clinical symptoms in brain tumours in children are variable at onset and diagnosis is often delayed. Symptoms were investigated with regard to brain tumour localisation, prediagnostic symptomatic intervals and malignancy.......Clinical symptoms in brain tumours in children are variable at onset and diagnosis is often delayed. Symptoms were investigated with regard to brain tumour localisation, prediagnostic symptomatic intervals and malignancy....

  5. Interactions of human monocytes with TMVs (tumour-derived microvesicles). (United States)

    Baj-Krzyworzeka, Monika; Baran, Jarosław; Szatanek, Rafał; Mytar, Bożenna; Siedlar, Maciej; Zembala, Marek


    The tumour microenvironment represents a dynamic complex milieu, which includes tumour cells, cells of the immune system and other (cellular and non-cellular) components. The role of these particular 'puzzle pieces' may change substantially due to their mutual interactions. The present review concerns different opinions on interactions that occur between monocytes, tumour cells and TMVs (tumour-derived microvesicles).

  6. Epstein-Barr Virus-Induced Gene 3 (EBI3) Blocking Leads to Induce Antitumor Cytotoxic T Lymphocyte Response and Suppress Tumor Growth in Colorectal Cancer by Bidirectional Reciprocal-Regulation STAT3 Signaling Pathway (United States)

    Liang, Yanfang; Chen, Qianqian; Du, Wenjing; Chen, Can; Li, Feifei; Yang, Jingying; Peng, Jianyu; Kang, Dongping; Lin, Bihua; Chai, Xingxing; Zhou, Keyuan; Zeng, Jincheng


    Epstein-Barr virus-induced gene 3 (EBI3) is a member of the interleukin-12 (IL-12) family structural subunit and can form a heterodimer with IL-27p28 and IL-12p35 subunit to build IL-27 and IL-35, respectively. However, IL-27 stimulates whereas IL-35 inhibits antitumor T cell responses. To date, little is known about the role of EBI3 in tumor microenvironment. In this study, firstly we assessed EBI3, IL-27p28, IL-12p35, gp130, and p-STAT3 expression with clinicopathological parameters of colorectal cancer (CRC) tissues; then we evaluated the antitumor T cell responses and tumor growth with a EBI3 blocking peptide. We found that elevated EBI3 may be associated with IL-12p35, gp130, and p-STAT3 to promote CRC progression. EBI3 blocking peptide promoted antitumor cytotoxic T lymphocyte (CTL) response by inducing Granzyme B, IFN-γ production, and p-STAT3 expression and inhibited CRC cell proliferation and tumor growth to associate with suppressing gp130 and p-STAT3 expression. Taken together, these results suggest that EBI3 may mediate a bidirectional reciprocal-regulation STAT3 signaling pathway to assist the tumor escape immune surveillance in CRC. PMID:27247488

  7. Pineal anlage tumour - a rare entity with divergent histology. (United States)

    Ahuja, Arvind; Sharma, Mehar Chand; Suri, Vaishali; Sarkar, Chitra; Sharma, B S; Garg, Ajay


    Pineal anlage tumour is a rare tumour of the pineal gland that is not listed in the 2007 World Health Organization classification of tumours of the central nervous system. Pineal anlage has been defined as a primary pineal tumour with both neuroepithelial and ectomesenchymal differentiation but without endodermal differentiation. We report a pineal anlage tumour in a 4-month-old boy, the youngest patient reported with this rare tumour, with a brief review of the literature. Clinicians and neuropathologists should be aware of this entity as it is likely to be misdiagnosed as a teratoma or a melanocytic tumour of the central nervous system.

  8. Serum tumour markers in malignant mesothelioma

    Directory of Open Access Journals (Sweden)

    Rao Pallavi


    Full Text Available Malignant mesothelioma is a rare malignancy of the body cavities with dismal prognosis. It has been a diagnostic dilemma for years with many clinical and pathological mimics. Discovery of a reliable tumour marker will definitely be of value in screening individuals with a history of asbestos exposure, diagnosis, treatment and follow up of malignant mesothelioma. Many tumour markers have been studied and speculatively associated with the malignant mesothelioma, but much still needs to be proven.

  9. Diagnosis and treatment of bronchopulmonary neuroendocrine tumours

    DEFF Research Database (Denmark)

    Tabaksblat, Elizaveta Mitkina; Langer, Seppo W; Knigge, Ulrich;


    Bronchopulmonary neuroendocrine tumours (BP-NET) are a heterogeneous population of neoplasms with different pathology, clinical behaviour and prognosis compared to the more common lung cancers. The management of BP-NET patients is largely based on studies with a low level of evidence and extrapol...... and extrapolation of data obtained from more common types of neuroendocrine tumours. This review reflects our view of the current state of the art of diagnosis and treatment of patients with BP-NET....

  10. 'Pseudo-Alzheimer's' and primary brain tumour.


    O'Mahony, D; Walsh, J. B.; Coakley, D.


    Primary brain tumour may present in the elderly purely as a dementing illness before the onset or detection of sensorimotor neurological symptoms or signs. Although neurological examination may indicate no definite signs, close attention to accepted DSM-IIIR and NINCDS-ADRDA diagnostic criteria for primary degenerative dementia and 'probable' Alzheimer's disease respectively will suggest a process other than a degenerative one. This was the case in two patients with primary brain tumour prese...

  11. Effects of pigment epithelium derived factor (PEDF) on malignant peripheral nerve sheath tumours (MPNSTs). (United States)

    Demestre, Maria; Terzi, Menderes Yusuf; Mautner, Victor; Vajkoczy, Peter; Kurtz, Andreas; Piña, Ana Luisa


    Neurofibromatosis type 1 (NF1) is an inherited genetic disease affecting 1 in 3,500 individuals. A prominent feature of NF1 is the formation of benign tumours of the peripheral nerve sheath (neurofibromas). However, these can become malignant and form highly metastatic malignant peripheral nerve sheath tumours (MPNST), which are usually fatal despite aggressive surgery, chemotherapy, and radiotherapy. Recent studies have shown that pigment epithelium-derived factor (PEDF) can induce differentiation and inhibit angiogenesis in several kinds of tumours. The present study was designed to determine the in vitro and in vivo effects of PEDF on MPNST angiogenesis and tumour growth. PEDF inhibited proliferation and augmented apoptosis in S462 MPNST cells after 48 h of treatment in culture. In xenografts of S462 MPNST cells in athymic nude mice, PEDF suppressed MPNST tumour burden, due mainly to inhibition of angiogenesis. These results demonstrate for the first time inhibitory effects of PEDF on the growth of human MPNST via induction of anti-angiogenesis and apoptosis. Our results suggest that PEDF could be a novel approach for future therapeutic purposes against MPNST.

  12. Brain tumour-associated status epilepticus. (United States)

    Goonawardena, Janindu; Marshman, Laurence A G; Drummond, Katharine J


    We have reviewed the scant literature on status epilepticus in patients with brain tumours. Patients with brain tumour-associated epilepsy (TAE) appear less likely to develop status epilepticus (TASE) than patients with epilepsy in the general population (EGP) are to develop status epilepticus (SEGP). TASE is associated with lesions in similar locations as TAE; in particular, the frontal lobes. However, in contrast to TAE, where seizures commence early in the course of the disease or at presentation, TASE is more likely to occur later in the disease course and herald tumour progression. In marked contrast to TAE, where epilepsy risk is inversely proportional to Word Health Organization tumour grade, TASE risk appears to be directly proportional to tumour grade (high grade gliomas appear singularly predisposed). Whilst anti-epileptic drug (AED) resistance is more common in TAE than EGP (with resistance directly proportional to tumour grade and frontal location), TASE appears paradoxically more responsive to simple AED regimes than either TAE or SEGP. Although some results suggest that mortality may be higher with TASE than with SEGP, it is likely that (as with SEGP) the major determinant of mortality is the underlying disease process. Because all such data have been derived from retrospective studies, because TASE and SEGP are less common than TAE and EGP, and because TASE and SEGP classification has often been inconsistent, findings can only be considered preliminary: multi-centre, prospective studies are required. Whilst preliminary, our review suggests that TASE has a distinct clinical profile compared to TAE and SEGP.

  13. Consensus on biomarkers for neuroendocrine tumour disease (United States)

    Oberg, Kjell; Modlin, Irvin M; De Herder, Wouter; Pavel, Marianne; Klimstra, David; Frilling, Andrea; Metz, David C; Heaney, Anthony; Kwekkeboom, Dik; Strosberg, Jonathan; Meyer, Timothy; Moss, Steven F; Washington, Kay; Wolin, Edward; Liu, Eric; Goldenring, James


    Management of neuroendocrine neoplasia represents a clinical challenge because of its late presentation, lack of treatment options, and limitations in present imaging modalities and biomarkers to guide management. Monoanalyte biomarkers have poor sensitivity, specificity, and predictive ability. A National Cancer Institute summit, held in 2007, on neuroendocrine tumours noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumours. A multinational consensus meeting of multidisciplinary experts in neuroendocrine tumours assessed the use of current biomarkers and defined the perquisites for novel biomarkers via the Delphi method. Consensus (at >75%) was achieved for 88 (82%) of 107 assessment questions. The panel concluded that circulating multianalyte biomarkers provide the highest sensitivity and specificity necessary for minimum disease detection and that this type of biomarker had sufficient information to predict treatment effectiveness and prognosis. The panel also concluded that no monoanalyte biomarker of neuroendocrine tumours has yet fulfilled these criteria and there is insufficient information to support the clinical use of miRNA or circulating tumour cells as useful prognostic markers for this disease. The panel considered that trials measuring multianalytes (eg, neuroendocrine gene transcripts) should also identify how such information can optimise the management of patients with neuroendocrine tumours. PMID:26370353

  14. Blocking the ZZ Domain of Sequestosome1/p62 Suppresses Myeloma Growth and Osteoclast Formation In Vitro and Induces Dramatic Bone Formation in Myeloma-Bearing Bones In Vivo (United States)

    Teramachi, Jumpei; Silbermann, Rebecca; Yang, Peng; Zhao, Wei; Mohammad, Khalid S.; Guo, Jianxia; Anderson, Judith L.; Zhou, Dan; Feng, Rentian; Myint, Kyaw-Zeyar; Maertz, Nathan; Beumer, Jan H.; Eiseman, Julie L.; Windle, Jolene J.; Xie, Xiang-Qun; Roodman, G. David; Kurihara, Noriyoshi


    We reported that p62 (sequestosome 1) serves as a signaling hub in bone marrow stromal cells (BMSC) for the formation of signaling complexes, including NFκB, p38MAPK, and JNK, that are involved in the increased osteoclastogenesis and multiple myeloma (MM) cell growth induced by BMSC that are key contributors to myeloma bone disease (MMBD), and demonstrated that the ZZ-domain of p62 (p62-ZZ) is required for BMSC enhancement of MMBD. We recently identified a novel p62-ZZ inhibitor, XRK3F2, that inhibits MM cell growth and BMSC growth enhancement of human MM cells. In the current study we evaluate the relative specificity of XRK3F2 for p62-ZZ, characterize XRK3F2’s capacity to inhibit growth of primary MM cells and human MM cell lines, and test the in vivo effects of XRK3F2 in the immunocompetent 5TGM1 MM model. We found that XRK3F2 induces dramatic cortical bone formation that is restricted to MM containing bones and blocked the effects and upregulation of TNFα, an OBL differentiation inhibitor that is increased in the MM bone marrow microenvironment and utilizes signaling complexes formed on p62-ZZ, in BMSC. Interestingly, XRK3F2 had no effect on non-MM bearing bone. These results demonstrate that targeting p62 in MM models has profound effects on MMBD. PMID:26286116

  15. Perfusion imaging of parotid gland tumours: usefulness of arterial spin labeling for differentiating Warthin's tumours

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Hiroki; Watanabe, Haruo [Gifu University School of Medicine, Department of Radiology, Gifu (Japan); Kanematsu, Masayuki [Gifu University School of Medicine, Department of Radiology, Gifu (Japan); Gifu University Hospital, High-level Imaging Diagnosis Center, Gifu (Japan); Kajita, Kimihiro [Gifu University Hospital, High-level Imaging Diagnosis Center, Gifu (Japan); Mizuta, Keisuke; Aoki, Mitsuhiro [Gifu University School of Medicine, Department of Otolaryngology, Gifu (Japan); Okuaki, Tomoyuki [Philips Healthcare, Tokyo (Japan)


    To assess prospectively the efficacy of arterial spin labelling (ASL) against conventional and diffusion-weighted (DW) MR imaging for differentiating parotid gland tumours. We included 10 pleomorphic adenomas, 12 Warthin's tumours, and nine malignant tumours of the parotid glands. Only tumours larger than 10 mm were included in this study. All parotid gland tumours underwent T1-weighted, T2-weighted, DW, and ASL imaging. Tumour-to-parotid gland signal intensity ratios (SIRs) and apparent diffusion coefficients (ADCs) of solid components were correlated with these pathologies. SIRs on T2-weighted images and ADCs were higher in pleomorphic adenomas than in Warthin's tumours (p <.01) and malignant tumours (p <.01). SIRs on ASL were higher in Warthin's tumours than in pleomorphic adenomas (p <.01) and malignant tumours (p <.05). Az value of SIRs on ASL for differentiating Warthin's tumours from the other pathologies was 0.982. The sensitivity, specificity, and accuracy of SIRs on ASL for the diagnosis of Warthin's tumours at an optimal SIR threshold of over 8.70 were 91.7 %, 94.7 %, and 93.5 %, respectively. ASL with SIR measurements could non-invasively evaluate tumour blood flow of parotid gland tumours and differentiate Warthin's tumours from pleomorphic adenomas and malignant tumours. (orig.)

  16. Polysaccharide Agaricus blazei Murill stimulates myeloid derived suppressor cell differentiation from M2 to M1 type, which mediates inhibition of tumour immune-evasion via the Toll-like receptor 2 pathway. (United States)

    Liu, Yi; Zhang, Lingyun; Zhu, Xiangxiang; Wang, Yuehua; Liu, WenWei; Gong, Wei


    Gr-1(+) CD11b(+) myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing animals and play a critical negative role during tumor immunotherapy. Strategies for inhibition of MDSCs are expected to improve cancer immunotherapy. Polysaccharide Agaricus blazei Murill (pAbM) has been found to have anti-cancer activity, but the underlying mechanism of this is poorly understood. Here, pAbM directly activated the purified MDSCs through inducing the expression of interleukin-6 (IL-6), IL-12, tumour necrosis factor and inducible nitric oxide synthase (iNOS), CD86, MHC II, and pSTAT1 of it, and only affected natural killer and T cells in the presence of Gr-1(+) CD11b(+) monocytic MDSCs. On further analysis, we demonstrated that pAbM could selectively block the Toll-like receptor 2 (TLR2) signal of Gr-1(+) CD11b(+) MDSCs and increased their M1-type macrophage characteristics, such as producing IL-12, lowering expression of Arginase 1 and increasing expression of iNOS. Extensive study showed that Gr-1(+) CD11b(+) MDSCs by pAbM treatment had less ability to convert the CD4(+) CD25(-) cells into CD4(+) CD25(+) phenotype. Moreover, result from selective depletion of specific cell populations in xenograft mice model suggested that the anti-tumour effect of pAbM was dependent on Gr-1(+ ) CD11b(+) monocytes, nether CD8(+) T cells nor CD4(+) T cells. In addition to, pAbM did not inhibit tumour growth in TLR2(-/-) mice. All together, these results suggested that pAbM, a natural product commonly used for cancer treatment, was a specific TLR2 agonist and had potent anti-tumour effects through the opposite of the suppressive function of Gr-1(+) CD11b(+) MDSCs.

  17. Exophytic benign mixed epithelial stromal tumour of the kidney: case report of a rare tumour entity

    Directory of Open Access Journals (Sweden)

    Küster Jens


    Full Text Available Abstract Background Mixed epithelial and stromal tumour (MEST represents a recently described benign composite neoplasm of the kidney, which predominantly affects perimenopausal females. Most tumours are benign, although rare malignant cases have been observed. Case report A 47-year-old postmenopausal female presented to the urologist with flank pain. A CT scan of the abdomen showed a 30-mm-in-diameter uniform mass adjacent to the pelvis of the left kidney. Surgical exploration showed a tumour arising from the lower anterior hilus of the left kidney. The tumour could be excised by preserving the kidney. By intraoperative frozen section the tumour showed characteristic features of MEST with epithelial-covered cysts embedded in an "ovarian-like" stroma. Additional immunohistochemistry investigations showed expression for hormone receptors by the stromal component of the tumour. Discussion MEST typically presents in perimenopausal women as a primarily cystic mass. Commonly, the tumour arises from the renal parenchyma or pelvis. The tumour is composed of an admixture of cystic and sometimes more solid areas. The stromal cells typically demonstrate an ovarian-type stroma showing expression for the estrogen and progesterone receptors. Conclusion MEST represents a distinctive benign tumour entity of the kidney, which affects perimenopausal woman. The tumour should be distinguished from other cystic renal neoplasms. By imaging studies it is difficult to distinguish between a benign or malignant nature of the tumour. Thus, intraoperative frozen section is necessary for conservative surgery, since the overall prognosis is favourable and renal function can be preserved in most cases.

  18. Ovarian down Regulation by GnRF Vaccination Decreases Reproductive Tract Tumour Size in Female White and Greater One-Horned Rhinoceroses.

    Directory of Open Access Journals (Sweden)

    Robert Hermes

    Full Text Available Reproductive tract tumours, specifically leiomyoma, are commonly found in female rhinoceroses. Similar to humans, tumour growth in rhinoceroses is thought to be sex hormone dependent. Tumours can form and expand from the onset of ovarian activity at puberty until the cessation of sex-steroid influences at senescence. Extensive tumour growth results in infertility. The aim of this study was to down regulate reproductive function of tumour-diseased and infertile females to stop further tumour growth using a Gonadotropin releasing factor (GnRF vaccine. Four infertile southern white (Ceratotherium simum simum and three Greater one-horned rhinoceroses (rhinoceros unicornis with active ovaries and 2.7 ± 0.9 and 14.0 ± 1.5 reproductive tract tumours respectively were vaccinated against GnRF (Improvac®, Zoetis, Germany at 0, 4 and 16 weeks and re-boostered every 6-8 months thereafter. After GnRF vaccination ovarian and luteal activity was suppressed in all treated females. Three months after vaccination the size of the ovaries, the number of follicles and the size of the largest follicle were significantly reduced (P<0.03. Reproductive tract tumours decreased significantly in diameter (Greater-one horned rhino: P<0.0001; white rhino: P<0.01, presumably as a result of reduced sex-steroid influence. The calculated tumour volumes were reduced by 50.8 ± 10.9% in Greater one-horned and 48.6 ± 12.9% in white rhinoceroses. In conclusion, GnRF vaccine effectively down regulated reproductive function and decreased the size of reproductive tract tumours in female rhinoceros. Our work is the first to use down regulation of reproductive function as a symptomatic treatment against benign reproductive tumour disease in a wildlife species. Nonetheless, full reversibility and rhinoceros fertility following GnRF vaccination warrants further evaluation.

  19. Com-1/p8 acts as a putative tumour suppressor in prostate cancer. (United States)

    Jiang, Wen G; Davies, Gaynor; Martin, Tracey A; Kynaston, Howard; Mason, Malcolm D; Fodstad, Oystein


    Com-1, candidate of metastasis-1, also known as p8, is a recently discovered molecule with a putative role in determining the metastatic nature of cancer cells. We have investigated the expression of Com-1 in normal and malignant human prostate tissues and its molecular interaction within prostate cancer cells. The expression of Com-1 in human prostate tissues and prostate cancer cell lines was assessed at both the mRNA and protein levels, by RT-PCR and immunohistochemistry. The staining intensity of Com-1 was semiquantified using computer assisted image analysis. Full- length Com-1 cDNA was isolated from normal mammary tissues. Ribozyme transgenes that specifically target human Com-1 were constructed using the pEF6/V5-His vector. The growth of prostate cancer cells in vitro and tumour growth in vivo (athymic mice model) following Com-1 overexpression in prostate cancer cells were determined. In normal prostate tissues, the epithelial cells strongly stained Com-1, both in the cytoplasm and in the nucleus. In contrast, prostate cancer cells in tumour tissue showed substantially reduced Com-1 staining levels (p Com-1. Transfection of these cells with hammerhead ribozyme transgenes resulted in the loss of expression of the Com-1 transcript. Using an in vitro invasion assay we found that the loss of Com-1 from prostate cancer cells increased their invasiveness. Knockout of Com-1 also resulted in the accelerated growth of all three cell lines. Forced overexpression of Com-1/ p8 in prostate cancer cells was able to reverse the changes in invasiveness and growth seen with the Com-1 knock-out cells. In a spontaneous tumour model, it was demonstrated that PC-3 cells with forced overexpression of Com-1 (PC-3com1Exp) had a significantly slower rate of growth compared with control cells (tumour size 36.6 +/- 31.2 vs 114.3 +/- 68.1 mm3, for tumours from PC-3com1Exp and control PC-3 cells, respectively, p = 0.0023). In conclusion, Com-1/p8 was expressed at lower levels in human

  20. Role of CD10 Immunoexpression in Grading Phyllodes Tumour of the Breast (United States)

    Khandeparkar, Siddhi Gaurish Sinai; Joshi, Avinash R; Kothikar, Vishakha; Nasare, Anuja; Patil, Sukhada; Niraspatil, Supriya; Dhande, Bhagyashree


    Introduction Fibroepithelial tumours are a heterogeneous group of biphasic neoplasms consisting of a proliferation of both epithelial and stromal components. Fibroadenoma (FA) and Phyllodes Tumour (PT) constitute the major entities. It is crucial to distinguish benign from borderline PT (low grade malignant PT), because the former do not metastasize, have a lesser risk of local recurrence and initial local recurrences are histologically benign in almost all instances. Multiple Immunohistochemical (IHC) markers are being studied to find their utility in grading the PT accurately for planning proper treatment. Aim To study, the IHC expression of CD10 in the stromal cells of a series of PTs and FA, with the aim of determining whether the degree of CD10 expression in the stromal cells is related to the grade of the tumour. Materials and Methods Records of 28 cases of PT and 35 cases of FA received in the Department of Pathology in a tertiary care hospital were obtained. Histopathology reports and slides of all the cases were reviewed and clinical data such as age and histomorphological features such as tumour cellularity, stromal overgrowth, mitotic count and nuclear atypia were noted. Representative block of the tumour with maximum cellularity was subjected to CD10 staining. For FA and benign PT a technique of tissue microarray was used. For borderline and malignant PT, representative section was used. Stromal cell staining was assessed, using cytoplasmic staining of the breast myoepithelium as internal control. Results Present study included 35 cases of FA, 20 cases of benign PT, five cases of borderline PT and three cases of malignant PT. The mean age of the patients increased with the increasing tumour grade of PT and this was also observed for FA and benign PT. The mean age increased with increase in tumour grade of PT and was statistically significant (p<0.05). The mean size did not increase with the increasing tumour grade of PT and was statistically

  1. Ultrasound guided supraclavicular block.

    LENUS (Irish Health Repository)

    Hanumanthaiah, Deepak


    Ultrasound guided regional anaesthesia is becoming increasingly popular. The supraclavicular block has been transformed by ultrasound guidance into a potentially safe superficial block. We reviewed the techniques of performing supraclavicular block with special focus on ultrasound guidance.

  2. Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part II-specific NE tumour types

    DEFF Research Database (Denmark)

    Oberg, Kjell; Astrup, Lone Bording; Eriksson, Barbro;


    Part II of the guidelines contains a description of epidemiology, histopathology, clinical presentation, diagnostic procedure, treatment, and survival for each type of neuroendocrine tumour. We are not only including gastroenteropancreatic tumours but also bronchopulmonary and thymic neuroendocrine...... tumours. These guidelines essentially cover basic knowledge in the diagnosis and management of the different forms of neuroendocrine tumour. We have, however, tried to give more updated information about the epidemiology and histopathology, which is essential for the clinical management of these tumours....

  3. MicroRNA Regulation of Brain Tumour Initiating Cells in Central Nervous System Tumours

    Directory of Open Access Journals (Sweden)

    Neha Garg


    Full Text Available CNS tumours occur in both pediatric and adult patients and many of these tumours are associated with poor clinical outcome. Due to a paradigm shift in thinking for the last several years, these tumours are now considered to originate from a small population of stem-like cells within the bulk tumour tissue. These cells, termed as brain tumour initiating cells (BTICs, are perceived to be regulated by microRNAs at the posttranscriptional/translational levels. Proliferation, stemness, differentiation, invasion, angiogenesis, metastasis, apoptosis, and cell cycle constitute some of the significant processes modulated by microRNAs in cancer initiation and progression. Characterization and functional studies on oncogenic or tumour suppressive microRNAs are made possible because of developments in sequencing and microarray techniques. In the current review, we bring recent knowledge of the role of microRNAs in BTIC formation and therapy. Special attention is paid to two highly aggressive and well-characterized brain tumours: gliomas and medulloblastoma. As microRNA seems to be altered in the pathogenesis of many human diseases, “microRNA therapy” may now have potential to improve outcomes for brain tumour patients. In this rapidly evolving field, further understanding of miRNA biology and its contribution towards cancer can be mined for new therapeutic tools.

  4. Why some tumours trigger neovascularisation andothers don’t:the story thus far

    Institute of Scientific and Technical Information of China (English)

    Omanma Adighibe; Russell DLeek; Marta FernandezMercado; JiangtingHu; Cameron Snell; Kevin CGatter; AdrianLHarris; Francesco Pezzella


    Background:Angiogenesis is not essential for tumours to develop and expand, as cancer can also grow in a non‑angiogenic fashion, but why this type of growth occurs is unknown. Surprisingly, our data from mRNA transcription proifling did not show any differences in the classical angiogenic pathways, but differences were observed in mito‑chondrial metabolic pathways, suggesting a key role for metabolic reprogramming. We then validated these results with mRNA proifling by investigating differential protein expression via immunohistochemistry in angiogenic and non‑angiogenic non‑small cell lung cancers (NSCLCs). Methods:Immunohistochemical staining for 35 angiogenesis‑ and hypoxia‑related biomarkers were performed on a collection of 194 angiogenic and 73 non‑angiogenic NSCLCs arranged on tissue microarrays. Sequencing of P53 was performed with frozen tissue samples of NSCLC. Results:The non‑angiogenic tumours were distinguished from the angiogenic ones by having higher levels of proteins associated with ephrin pathways, mitochondria, cell biogenesis, and hypoxia‑inducible factor 1 (HIF1) regula‑tion by oxygen and transcription of HIF‑controlled genes but lower levels of proteins involved in the stroma, cell–cell signaling and adhesion, integrins, and Delta‑Notch and epidermal growth factor (EGF)‑related signaling. However, proteins classically associated with angiogenesis were present in both types of tumours at very comparable levels. Cytoplasmic expression of P53 was strongly associated with non‑angiogenic tumours. A pilot investigation showed that P53 mutations were observed in 32.0% of angiogenic cases but in 71.4% of non‑angiogenic tumours. Conclusions:Our observations thus far indicate that both angiogenic and non‑angiogenic tumours experience hypoxia/HIF and vascular endothelial growth factor (VEGF) pathway protein expression in a comparable fashion. How‑ever, angiogenesis does not ensue in the non‑angiogenic tumours

  5. Desmoplastic nested spindle cell tumours and nested stromal epithelial tumours of the liver. (United States)

    Misra, Sunayana; Bihari, Chhagan


    Desmoplastic nested spindle cell tumour of liver (DNSTL), nested stromal-epithelial tumour (NSET) and calcifying nested stromal-epithelial tumour (CNSET) are recently described entities with similar morphology, immunohistochemistry and molecular genetics. These are rare entities with only three large case series described till date. These tumours commonly present in the paediatric age group. NSETs, in addition have been described to be associated with ectopic adrenocorticotropic hormone (ACTH) production and Cushingoid features. It is important to discuss this rare group of tumours with a low malignant potential as the most common radiological differential diagnosis is hepatoblastoma, which has a relatively poorer prognosis. Thus, a pathologist needs to keep this entity in mind, so as to offer a correct histological diagnosis.

  6. Blocking Epidermal Growth Factor Receptor Signaling in HTR-8/SVneo First Trimester Trophoblast Cells Results in Dephosphorylation of PKBα/AKT and Induces Apoptosis

    Directory of Open Access Journals (Sweden)

    J. Bolnick


    Full Text Available We identified a major peptide signaling target of EGF/EGFR pathway and explored the consequences of blocking or activating this pathway in the first trimester extravillous trophoblast cells, HTR-8/SVneo. A global analysis of protein phosphorylation was undertaken using novel technology (Kinexus Kinetworks that utilizes SDS-polyacrylamide minigel electrophoresis and multi-lane immunoblotting to permit specific and semiquantitative detection of multiple phosphoproteins. Forty-seven protein phosphorylation sites were queried, and the results reported based on relative phosphorylation at each site. EGF- and Iressa-(gefitinib, ZD1839, an inhibitor of EGFR treated HTR-8/SVneo cells were subjected to immunoblotting and flow cytometry to confirm the phosphoprotein screen and to assess the effects of EGF versus Iressa on cell cycle and apoptosis. EGFR mediates the phosphorylation of important signaling proteins, including PKBα/AKT. This pathway is likely to be central to EGFR-mediated trophoblast survival. Furthermore, EGF treatment induces proliferation and inhibits apoptosis, while Iressa induces apoptosis.

  7. Synergic anti-tumour effect of B7.1 gene modified tumour vaccine combined with allicin for murine bladder tumour

    Institute of Scientific and Technical Information of China (English)

    WANG Jian; LIN Li-guo; LIU Jian-jun; LIU Xin-guang; HE Cheng-wei; HE Hui-juan; WU ping; HUANG Ping-ping; CHEN Xiao-wen; DONG Zhong; WU Xiu-dong


    @@ In the previous study, we found that B7.1 gene transduction failed to induce sufficient anti-tumour response when it is used as a tumour vaccine. It is necessary to develop immunity by a combination of appropriate cytokines to stimulate effective tumour immunity in a therapeutic setting.

  8. Block Cipher Analysis

    DEFF Research Database (Denmark)

    Miolane, Charlotte Vikkelsø

    Block ciphersarecryptographicprimitivesthatoperateon fixed sizetexts(blocks). Mostdesigns aim towards secure andfastencryption oflarge amounts ofdata. Block ciphers also serve as the building block of a number of hash functions and message authentication codes(MAC).Thetask of cryptanalysisisto en...... on small scale variants of AES. In the final part of the thesis we present a new block cipher proposal Present and examine its security against algebraic and differential cryptanalysis in particular.......Block ciphersarecryptographicprimitivesthatoperateon fixed sizetexts(blocks). Mostdesigns aim towards secure andfastencryption oflarge amounts ofdata. Block ciphers also serve as the building block of a number of hash functions and message authentication codes(MAC).Thetask of cryptanalysisisto...... ensurethat no attack violatesthe securitybounds specifiedbygeneric attack namely exhaustivekey search and table lookup attacks. This thesis contains a general introduction to cryptography with focus on block ciphers and important block cipher designs, in particular the Advanced Encryption Standard...

  9. Tumour-host dynamics under radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Placeres Jimenez, Rolando, E-mail: [Departamento de Fi' sica, Universidade Federal de Sao Carlos, Sao Carlos - SP (Brazil); Ortiz Hernandez, Eloy [Centre of Medicine and Complexity, Medical University Carlos J. Finlay, Carretera Central s/n, Camagueey (Cuba)


    Highlight: > Tumour-host interaction is modelled by Lotka-Volterra equations. > A brief review of the motion integral and analysis of linear stability is presented. > Radiotherapy is introduced into the model, using a periodic Dirac delta function. > A two-dimensional logistic map is derived from the modified Lotka-Volterra model. > It is shown that tumour can be controlled by a correct selection of therapy strategy. - Abstract: Tumour-host interaction is modelled by the Lotka-Volterra equations. Qualitative analysis and simulations show that this model reproduces all known states of development for tumours. Radiotherapy effect is introduced into the model by means of the linear-quadratic model and the periodic Dirac delta function. The evolution of the system under the action of radiotherapy is simulated and parameter space is obtained, from which certain threshold of effectiveness values for the frequency and applied doses are derived. A two-dimensional logistic map is derived from the modified Lotka-Volterra model and used to simulate the effectiveness of radiotherapy in different regimens of tumour development. The results show the possibility of achieving a successful treatment in each individual case by employing the correct therapeutic strategy.


    Directory of Open Access Journals (Sweden)



    Full Text Available BACKGROUND Pituitary gland is known as the “Master Gland” of the body as it controls majority of the endocrine glands of the body. Embryologically, they are formed by two parts. There are two types of malignancies encountered namely adenomas and carcinomas. Vast majority of the neoplasms located in the sella turcica are benign pituitary adenomas derived from adenohypophyseal cells. The aim is to study the pituitary malignancies. METHODS The sample size included 100 cases of intra-cranial neoplasms that turned in the Department of Medicine in KVG Medical College, Sullia and different local private hospitals of Sullia and Mangalore. RESULTS Pituitary tumours comprised 6(6% of all the tumour studies. They occurred maximally in the age above 14 years. Tumours showed a male predominance. All the tumours were located in pituitary fossa. Principal presenting complaint was visual disturbance. Microscopically, the tumour was composed of small polyhedral to round cells with a uniform darkly staining round nucleus and scant eosinophilic cytoplasm. The cells formed papillary structures or were arranged in a trabecular pattern. CONCLUSION There is a male predominance in this study and the percentage of cases was found to be less in this region of Karnataka

  11. EGFR antisense RNA blocks expression of the epidermal growth factor receptor and partially reverse the malignant phenotype of human breast cancer MDA—MB—231 cells

    Institute of Scientific and Technical Information of China (English)



    The effects of human EGFR to the malignant phenotype of human breast cancer cell line MDA-MB-231 were investigated experimentally.A retroviral vector containing a 5'1350bp fragment of the human EGFR cDNA in the antisense orientation was transfected into targeted cells by lipofectamine.The effects on cell proliferation,cell cycle and adherent ability to extracellular matrix(ECM) components were studied after the expression of antisense transcripts to EGFR5'1350bp fragment in target cells,In vitro studies showed that the growth ability of the transfected cells was partialy inhibited in comparison to parental cells and to cells transfected with the plasmid containing the neomycin resistance gene only.It was found that EGF(10ng/ml) had an augmenation effect on the growth of transfected MDA-AS10 cells but not MDA-MB-231 cells.Flow cytometric analysis showed that the cell cycle of the transfected cells was abnormal with a decrease of cells in G2/M and S phases and an increase of cells in G1 phase,indicating a blockage in phase G1.Immunofluorescence of EGFR expression in transfectants stained with an antiEGFR antibody was decreased and their growth in soft agarose was also severely imparired.The transfected cells showed less adherence to laminin(LN) and fibronectin (FN).In short,EGFR antisense RNA decreases the expression of EGFR on MDA-MB-231 cells and partially reverses their malignant phenotype as well.

  12. The evolution of carrying capacity in constrained and expanding tumour cell populations. (United States)

    Gerlee, Philip; Anderson, Alexander R A


    Cancer cells are known to modify their micro-environment such that it can sustain a larger population, or, in ecological terms, they construct a niche which increases the carrying capacity of the population. It has however been argued that niche construction, which benefits all cells in the tumour, would be selected against since cheaters could reap the benefits without paying the cost. We have investigated the impact of niche specificity on tumour evolution using an individual based model of breast tumour growth, in which the carrying capacity of each cell consists of two components: an intrinsic, subclone-specific part and a contribution from all neighbouring cells. Analysis of the model shows that the ability of a mutant to invade a resident population depends strongly on the specificity. When specificity is low selection is mostly on growth rate, while high specificity shifts selection towards increased carrying capacity. Further, we show that the long-term evolution of the system can be predicted using adaptive dynamics. By comparing the results from a spatially structured versus well-mixed population we show that spatial structure restores selection for carrying capacity even at zero specificity, which poses a solution to the niche construction dilemma. Lastly, we show that an expanding population exhibits spatially variable selection pressure, where cells at the leading edge exhibit higher growth rate and lower carrying capacity than those at the centre of the tumour.

  13. Src activation by β-adrenoreceptors is a key switch for tumour metastasis. (United States)

    Armaiz-Pena, Guillermo N; Allen, Julie K; Cruz, Anthony; Stone, Rebecca L; Nick, Alpa M; Lin, Yvonne G; Han, Liz Y; Mangala, Lingegowda S; Villares, Gabriel J; Vivas-Mejia, Pablo; Rodriguez-Aguayo, Cristian; Nagaraja, Archana S; Gharpure, Kshipra M; Wu, Zheng; English, Robert D; Soman, Kizhake V; Shahzad, Mian M K; Shazhad, Mian M K; Zigler, Maya; Deavers, Michael T; Zien, Alexander; Soldatos, Theodoros G; Jackson, David B; Wiktorowicz, John E; Torres-Lugo, Madeline; Young, Tom; De Geest, Koen; Gallick, Gary E; Bar-Eli, Menashe; Lopez-Berestein, Gabriel; Cole, Steve W; Lopez, Gustavo E; Lutgendorf, Susan K; Sood, Anil K


    Noradrenaline can modulate multiple cellular functions important for cancer progression; however, how this single extracellular signal regulates such a broad array of cellular processes is unknown. Here we identify Src as a key regulator of phosphoproteomic signalling networks activated in response to beta-adrenergic signalling in cancer cells. These results also identify a new mechanism of Src phosphorylation that mediates beta-adrenergic/PKA regulation of downstream networks, thereby enhancing tumour cell migration, invasion and growth. In human ovarian cancer samples, high tumoural noradrenaline levels were correlated with high pSrc(Y419) levels. Moreover, among cancer patients, the use of beta blockers was significantly associated with reduced cancer-related mortality. Collectively, these data provide a pivotal molecular target for disrupting neural signalling in the tumour microenvironment.

  14. Improvement of Radiation-Mediated Immunosuppression of Human NSCLC Tumour Xenografts in a Nude Rat Model

    Directory of Open Access Journals (Sweden)

    Sergey V. Tokalov


    Full Text Available Human tumour xenografts in a nude rat model have consistently been used as an essential part of preclinical studies for anticancer drugs activity in human. Commonly, these animals receive whole body irradiation to assure immunosuppression. But whole body dose delivery might be inhomogeneous and the resulting incomplete bone marrow depletion may modify tumour behaviour. To improve irradiation-mediated immunosuppression of human non-small cell lung cancer (NSCLC xenografts in a nude rat model irradiation (2 + 2 Gy from opposite sides of animals has been performed using a conventional X-ray tube. The described modification of whole body irradiation improves growth properties of human NSCLC xenografts in a nude rat model. The design of the whole body irradiation mediated immunosuppression described here for NSCLC xenografts may be useful for research applications involving other types of human tumours.

  15. Dislocation blocking by AlGaN hot electron injecting layer in the epitaxial growth of GaN terahertz Gunn diode (United States)

    Li, Liang; Yang, Lin'an; Zhang, Jincheng; Hao, Yue


    This paper reports an efficient method to improve the crystal quality of GaN Gunn diode with AlGaN hot electron injecting layer (HEI). An evident reduction of screw dislocation and edge dislocation densities is achieved by the strain management and the enhanced lateral growth in high temperature grown AlGaN HEI layer. Compared with the top hot electron injecting layer (THEI) structure, the bottom hot electron injecting layer (BHEI) structure enhances the crystal quality of transit region due to the growth sequence modulation of HEI layer. A high Hall mobility of 2934 cm2/Vs at 77 K, a nearly flat downtrend of Hall mobility at the temperature ranging from 300 to 573 K, a low intensity of ratio of yellow luminescence band to band edge emission, a narrow band edge emission line-width, and a smooth surface morphology are observed for the BHEI structural epitaxy of Gunn diode, which indicates that AlGaN BHEI structure is a promising candidate for fabrication of GaN Gunn diodes in terahertz regime.

  16. Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis

    Directory of Open Access Journals (Sweden)

    Zervou Sevasti


    Full Text Available Abstract Background Tumour regression observed in many conditional mouse models following oncogene inactivation provides the impetus to develop, and a platform to preclinically evaluate, novel therapeutics to inactivate specific oncogenes. Inactivating single oncogenes, such as c-Myc, can reverse even advanced tumours. Intriguingly, transient c-Myc inactivation proved sufficient for sustained osteosarcoma regression; the resulting osteocyte differentiation potentially explaining loss of c-Myc's oncogenic properties. But would this apply to other tumours? Results We show that brief inactivation of c-Myc does not sustain tumour regression in two distinct tissue types; tumour cells in pancreatic islets and skin epidermis continue to avoid apoptosis after c-Myc reactivation, by virtue of Bcl-xL over-expression or a favourable microenvironment, respectively. Moreover, tumours progress despite reacquiring a differentiated phenotype and partial loss of vasculature during c-Myc inactivation. Interestingly, reactivating c-Myc in β-cell tumours appears to result not only in further growth of the tumour, but also re-expansion of the accompanying angiogenesis and more pronounced β-cell invasion (adenocarcinoma. Conclusions Given that transient c-Myc inactivation could under some circumstances produce sustained tumour regression, the possible application of this potentially less toxic strategy in treating other tumours has been suggested. We show that brief inactivation of c-Myc fails to sustain tumour regression in two distinct models of tumourigenesis: pancreatic islets and skin epidermis. These findings challenge the potential for cancer therapies aimed at transient oncogene inactivation, at least under those circumstances where tumour cell differentiation and alteration of epigenetic context fail to reinstate apoptosis. Together, these results suggest that treatment schedules will need to be informed by knowledge of the molecular basis and


    Directory of Open Access Journals (Sweden)

    Uma Devi


    Full Text Available OBJECTIVE: To study incidence age distribution of benign and malignant ovarian tu mours in general population. METHODS AND MATERIAL : To study 120 patients with ovarian tumours in Govt . general hospital during June 2003 and June 2005. RESULTS: Clinical and pathological evaluation of all ovarian tumours was done and incidence, age distrib ution of various benign and malignant ovarian neoplasms were tabulated and compared with other studies. CONCLUSIONS: Most common ovarian tumours are benign tumours and serous cystadenoma is the commonest benign tumour and S erous cystadeno carcinoma is the most common malignant tumour.

  18. The Notch ligand Jagged1 as a target for anti-tumour therapy

    Directory of Open Access Journals (Sweden)

    Demin eLi


    Full Text Available The Notch pathway is increasingly attracting attention as a source of therapeutic targets for cancer. Ligand-induced Notch signalling has been implicated in various aspects of cancer biology; as a consequence pan-Notch inhibitors and therapeutic antibodies targeting one or more of the Notch receptors have been investigated for cancer therapy. Alternatively, Notch ligands provide attractive options for therapy in cancer treatment due to their more restricted expression and better-defined functions, as well as their low rate of mutations in cancer. One of the Notch ligands, Jagged1 (JAG1, is overexpressed in many cancer types, and plays an important role in several aspects of tumour biology. In fact, JAG1-stimulated Notch activation is directly implicated in tumour growth through maintaining cancer stem cell populations, promoting cell survival, inhibiting apoptosis and driving cell proliferation and metastasis. In addition, JAG1 can indirectly affect cancer by influencing tumour microenvironment components such as tumour vasculature and immune cell infiltration. This article gives an overview of JAG1 and its role in tumour biology, and its potential as a therapeutic target.

  19. MRI of intracranial germ cell tumours

    Energy Technology Data Exchange (ETDEWEB)

    Sumida, M. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Uozumi, T. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Kiya, K. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Mukada, K. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Arita, K. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Kurisu, K. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Sugiyama, K. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Onda, J. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Satoh, H. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Ikawa, F. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan); Migita, K. [Dept. of Neurosurgery, Hiroshima Univ. School of Medicine, Hiroshima (Japan)


    We reviewed MRI findings in proven intracranial germ cell tumours in 22 cases, 12 of whom received Gd-DTPA. On T1-weighted images, the signal intensity of the tumour parenchyma was moderately low in 19 cases and isointense in 3; on T2-weighted images, it was high in all cases. Regions of different intensity thought to be cysts were found in 17 (77 %): 7 of 12 patients with germinoma (58 %) and in all other cases. Of the 13 patients with pineal lesions T1-weighted sagittal images showed the aqueduct to be obstructed in 5, stenotic in 7 and normal in 1. Strong contrast enhancement was observed in all 12 cases. Of the 14 patients with suprasellar lesions, 5 were found to have an intrasellar extension, and in 3 of these, the normal pituitary gland, which could be distinguished from the tumour, was displaced anteriorly. Ten patients (45 %) had multiple lesions. (orig.)

  20. Autoimmune pancreatitis mimicking Klatskin tumour on radiology. (United States)

    Hadi, Yousaf Bashir; Sohail, Abdul Malik Amir Humza; Haider, Zishan


    Autoimmune pancreatitis (AIP) is categorised into two distinct types, AIP type 1 and 2. Although there can be multisystem involvement, rarely, the cholangitis associated with AIP can present radiologically in a manner similar to that of Klatskin tumour. We present the case of a 65-year-old man who was almost misdiagnosed with a Klatskin tumour because of the similarity in radiological features of the two aforementioned clinical entities. The patient presented with a history of jaundice, pruritus and abdominal pain, and work up showed deranged liver function tests, elevated cancer antigen 19-9 levels and positive antinuclear antibodies. CT scan of the abdomen showed findings suggestive of Klatskin tumour but due to diffuse enlargement of the pancreas and surrounding low-attenuation halo found on a closer review, a diagnosis of AIP was performed. The patient was started on standard corticosteroid therapy and responded well, with complete resolution of the radiological findings.

  1. Matrix metalloproteinase inhibition delays wound healing and blocks the latent transforming growth factor-beta1-promoted myofibroblast formation and function

    DEFF Research Database (Denmark)

    Mirastschijski, Ursula; Schnabel, Reinhild; Claes, Juliane


    The ability to regulate wound contraction is critical for wound healing as well as for pathological contractures. Matrix metalloproteinases (MMPs) have been demonstrated to be obligatory for normal wound healing. This study examined the effect that the broad-spectrum MMP inhibitor BB-94 has when...... applied topically to full-thickness skin excisional wounds in rats and its ability to inhibit the promotion of myofibroblast formation and function by the latent transforming-growth factor-beta1 (TGF-beta1). BB-94 delayed wound contraction, as well as all other associated aspects of wound healing examined...... and may explain why wound contraction and other associated events of wound healing were only delayed and not completely inhibited. BB-94 was also found to inhibit the ability of latent TGF-beta1 to promote the formation and function of myofibroblasts. These results suggest that BB-94 could delay wound...

  2. From Theory to Practice: Utilizing Competency-based Milestones to Assess Professional Growth and Development in the Foundational Science Blocks of a Pre-Clerkship Medical School Curriculum. (United States)

    Pettepher, Cathleen C; Lomis, Kimberly D; Osheroff, Neil


    Physicians-in-training require skills and attitudes beyond medical knowledge in order to mature into successful clinicians. However, because assessments in pre-clerkship curricula historically have focused almost exclusively on medical knowledge, faculty contributions to early student development often have been limited. To address this challenge and enhance student progress, we re-designed our pre-clerkship curriculum to include settings in which diverse facets of student performance could be observed and fostered. Concurrently, we transitioned to an assessment strategy focused on competency-based milestones. The implementation of this strategy has allowed pre-clerkship science faculty to provide early-stage students with rich holistic feedback designed to stimulate their professional growth.

  3. Combined blocked of Ras and mTOR signaling inhibit HCC cell growth%联合靶向Ras和mTOR信号抑制HCC细胞生长

    Institute of Scientific and Technical Information of China (English)

    杨件新; 施超; 施海辉


    Objective: To investigate the value of combined blockade Ras and mTOR signaling in the therapy of HCC. Methods: Specific Ras and/or mTOR inhibitors were used to inhibit Ras and mTOR relatively. Cell proliferation was assessed by using the MTT assay. Early apoptosis was detected by Annexin-V-FITC/propidium iodide double staining assay. The ef-fects of the two drugs on HCC were also assessed in xenograft models. Results:Ras inhibitor FTS and mTOR inhibitor all in-hibited HepG2 and Huh-7 cell growth, induced cell apoptosis. Conclusion: Con-target Ras and mTOR could markedly in-hibited HCC cell growth in vitro and in vivo.%目的:探讨联合靶向Ras和mTOR信号在肝细胞癌(hepatocellular carcinoma,HCC)治疗中的价值。方法:四甲基偶氮唑盐(methylthiazolyl tetrazolium,MTT)检测不同浓度Ras抑制剂(farnesylthiosalicylic acid,FTS)和(或)mTOR抑制剂雷帕霉素对肝癌细胞增殖的影响;流式细胞仪检测细胞凋亡;进一步研究两种药物联合对Balb/c小鼠肝癌移植瘤生长的影响。结果:FTS联合雷帕霉素更能抑制HepG2细胞增殖、抑制小鼠肝癌移植瘤的生长,诱导肝癌细胞凋亡。结论:Ras和mTOR信号在HCC治疗中具有联合靶向价值。

  4. Nerve growth factor blocks the glucose-induced down-regulation of caveolin-1 expression in Schwann cells via p75 neurotrophin receptor signaling. (United States)

    Tan, Wenbin; Rouen, Shefali; Barkus, Kristin M; Dremina, Yelena S; Hui, Dongwei; Christianson, Julie A; Wright, Douglas E; Yoon, Sung Ok; Dobrowsky, Rick T


    Altered neurotrophism in diabetic peripheral neuropathy (DPN) is associated in part with substantial degenerative changes in Schwann cells (SCs) and an increased expression of the p75 neurotrophin receptor (p75NTR). Caveolin-1 (Cav-1) is highly expressed in adult SCs, and changes in its expression can regulate signaling through Erb B2, a co-receptor that mediates the effects of neuregulins in promoting SC growth and differentiation. We examined the hypothesis that hyperglycemia-induced changes in Cav-1 expression and p75NTR signaling may contribute to altered neurotrophism in DPN by modulating SC responses to neuregulins. In an animal model of type 1 diabetes, hyperglycemia induced a progressive decrease of Cav-1 in SCs of sciatic nerve that was reversed by insulin therapy. Treatment of primary neonatal SCs with 20-30 mm d-glucose, but not l-glucose, was sufficient to inhibit transcription from the Cav-1 promoter and decrease Cav-1 mRNA and protein expression. Hyperglycemia prolonged the kinetics of Erb B2 phosphorylation and significantly enhanced the mitogenic response of SCs to neuregulin1-beta1, and this effect was mimicked by the forced down-regulation of Cav-1. Intriguingly, nerve growth factor antagonized the enhanced mitogenic response of SCs to neuregulin1-beta1 and inhibited the glucose-induced down-regulation of Cav-1 transcription, mRNA, and protein expression through p75NTR-dependent activation of JNK. Our data suggest that Cav-1 down-regulation may contribute to altered neurotrophism in DPN by enhancing the response of SCs to neuregulins and that p75NTR-mediated JNK activation may provide a mechanism for the neurotrophic modulation of hyperglycemic stress.

  5. Melatonin blocks inhibitory effects of prolactin on photoperiodic induction of gain in body mass, testicular growth and feather regeneration in the migratory male redheaded bunting (Emberiza bruniceps

    Directory of Open Access Journals (Sweden)

    Rani Sangeeta


    Full Text Available Abstract Little is known about how hormones interact in the photoperiodic induction of seasonal responses in birds. In this study, two experiments determined if the treatment with melatonin altered inhibitory effects of prolactin on photoperiodic induction of seasonal responses in the Palearctic-Indian migratory male redheaded bunting Emberiza bruniceps. Each experiment employed three groups (N = 6–7 each of photosensitive birds that were held under 8 hours light: 16 hours darkness (8L:16D since early March. In the experiment 1, beginning in mid June 2001, birds were exposed to natural day lengths (NDL at 27 degree North (day length = ca.13.8 h, sunrise to sunset for 23 days. In the experiment 2, beginning in early April 2002, birds were exposed to 14L:10D for 22 days. Beginning on day 4 of NDL or day 1 of 14L:10D, they received 10 (experiment 1 or 13 (experiment 2 daily injections of both melatonin and prolactin (group 1 or prolactin alone (group 2 at a dose of 20 microgram per bird per day in 200 microliter of vehicle. Controls (group 3 received similar volume of vehicle. Thereafter, birds were left uninjected for the next 10 (experiment 1 or 9 days (experiment 2. All injections except those of melatonin were made at the zeitgeber time 10 (ZT 0 = time of sunrise, experiment 1; time of lights on, experiment 2; melatonin was injected at ZT 9.5 and thus 0.5 h before prolactin. Observations were recorded on changes in body mass, testicular growth and feather regeneration. Under NDL (experiment 1, testis growth in birds that received melatonin 0.5 h prior to prolactin (group 1 was significantly greater (P

  6. Ex-vivo HRMAS of adult brain tumours: metabolite quantification and assignment of tumour biomarkers

    Directory of Open Access Journals (Sweden)

    Wilson M


    Full Text Available Abstract Background High-resolution magic angle spinning (HRMAS NMR spectroscopy allows detailed metabolic analysis of whole biopsy samples for investigating tumour biology and tumour classification. Accurate biochemical assignment of small molecule metabolites that are "NMR visible" will improve our interpretation of HRMAS data and the translation of NMR tumour biomarkers to in-vivo studies. Results 1D and 2D 1H HRMAS NMR was used to determine that 29 small molecule metabolites, along with 8 macromolecule signals, account for the majority of the HRMAS spectrum of the main types of brain tumour (astrocytoma grade II, grade III gliomas, glioblastomas, metastases, meningiomas and also lymphomas. Differences in concentration of 20 of these metabolites were statistically significant between these brain tumour types. During the course of an extended 2D data acquisition the HRMAS technique itself affects sample analysis: glycine, glutathione and glycerophosphocholine all showed small concentration changes; analysis of the sample after HRMAS indicated structural damage that may affect subsequent histopathological analysis. Conclusions A number of small molecule metabolites have been identified as potential biomarkers of tumour type that may enable development of more selective in-vivo 1H NMR acquisition methods for diagnosis and prognosis of brain tumours.

  7. How to express tumours using membrane systems

    Institute of Scientific and Technical Information of China (English)

    Miguel A. Gutiérrez-Naranjo; Mario J. Pérez-Jiménez; Agustín Riscos-Nú(n)ez; Francisco J. Romero-Campero


    In this paper we discuss the potential usefulness of membrane systems as tools for modelling tumours. The approach is followed both from a macroscopic and a microscopic point of view. In the first case, one considers the tumour as a growing mass of cells,focusing on its external shape. In the second case, one descends to the microscopic level, studying molecular signalling pathways that are crucial to determine if a cell is cancerous or not. In each of these approaches we work with appropriate variants of membrane systems.

  8. High dose radiotherapy for pituitary tumours

    Energy Technology Data Exchange (ETDEWEB)

    Mead, K.W. (Queensland Radium Inst., Herston (Australia))


    The results of treatment of 120 pituitary tumours are presented. Based on this experience operable chromophobe adenomas are now treated with 5,000 rads in 4 weeks and inoperable ones receive an additional central dose to 7,500 rads. Pituitary Cushing's tumours are given 10,000 rads in 5 weeks using small fields and acromegalics 5,000 rads to the whole sella and 7,500 to its lower half. The absence of complications at these dose levels is attributed to the use of small fields and the precise application of treatment.

  9. Coordinated regulation of myeloid cells by tumours. (United States)

    Gabrilovich, Dmitry I; Ostrand-Rosenberg, Suzanne; Bronte, Vincenzo


    Myeloid cells are the most abundant nucleated haematopoietic cells in the human body and are a collection of distinct cell populations with many diverse functions. The three groups of terminally differentiated myeloid cells - macrophages, dendritic cells and granulocytes - are essential for the normal function of both the innate and adaptive immune systems. Mounting evidence indicates that the tumour microenvironment alters myeloid cells and can convert them into potent immunosuppressive cells. Here, we consider myeloid cells as an intricately connected, complex, single system and we focus on how tumours manipulate the myeloid system to evade the host immune response.

  10. Effect on tumour control of time interval between surgery and postoperative radiotherapy: an empirical approach using Monte Carlo simulation

    Energy Technology Data Exchange (ETDEWEB)

    Al-Dweri, Feras M O [Departamento de FIsica Moderna, Universidad de Granada, E-18071 Granada (Spain); Guirado, Damian [Servicio de RadiofIsica, Hospital Universitario ' San Cecilio' , E-18012 Granada (Spain); Lallena, Antonio M [Servicio de RadiofIsica, Hospital Universitario ' San Cecilio' , E-18012 Granada (Spain); Pedraza, Vicente [Departamento de RadiologIa y Medicina FIsica, Universidad de Granada, Hospital Universitario ' San Cecilio' , E-18012 Granada (Spain)


    In this work, a procedure, based on Monte Carlo techniques, to analyse the effect on the tumour control probability of the time interval between surgery and postoperative radiotherapy is presented. The approach includes the tumour growth as well as the survival of tumour cells undergoing fractionated radiotherapy. Both processes are described in terms of the binomial distribution. We have considered two different growth models, exponential and Gompertz, the parameters of which have been fixed to reproduce the clinical outcome corresponding to a retrospective study for patients with head and neck squamous cell carcinomas. In the cases analysed, we have not found significant differences between the results obtained for both growth models. The mean doubling times found for residual clonogens after surgery are less than 40 days. The rate of decrease in local control is around 0.09% per day of delay between surgery and radiotherapy and the corresponding time factor is about 0.11 Gy per day.

  11. Experimental studies on ultralow frequency pulsed gradient magnetic field inducing apoptosis of cancer cell and inhibiting growth of cancer cell

    Institute of Scientific and Technical Information of China (English)

    曾繁清; 郑从义; 张新晨; 李宗山; 李朝阳; 王川婴; 张新松; 黄晓玲; 张沪生


    The morphology characteristics of cell apoptosis of the malignant tumour cells in magnetic field-treated mouse was observed for the first time. The apoptotic cancer cell contracted, became rounder and divorced from adjacent cells; the heterochromatin condensed and coagulated together along the inner side of the nuclear membrane; the endoplasmic reticulums(ER) expanded and fused with the cellular membrane; many apoptotic bodies which were packed by the cellular membrane appeared and were devoured by some lymphocytes and plasma. Apoptosis of cancer cells was detected by terminal deoxynucleotidyl transferase mediated in situ nick end labeling(TUNEL). It was found that the number of apoptosis cancer cells of the sample treated by the magnetic field is more than that of the control sample. The growth of malignant tumour in mice was inhibited and the ability of immune cell to dissolve cancer cells was improved by ultralow frequency(ULF) pulsed gradient magnetic field; the nuclei DNA contents decreased, indicating that magnetic field can block DNA replication and inhibit mitosis of cancer cells. It was suggested that magnetic field could inhibit the metabolism of cancer cell, lower its malignancy, and restrain its rapid and heteromorphic growth. Since ULF pulsed gradient magnetic field can induce apoptosis of cancer cells and inhibit the growth of malignant tumour, it could be used as a new method to treat cancer.

  12. Employment of synchronized cells and flow microfluorometry in investigations on the JB-1 ascites tumour chalones. (United States)

    Bichel, P; Barfod, N M; Jakobsen, A


    In most experimental ascites tumours the growth rate decreases with increasing age and cell number. This decrease is caused by a prolongation of the cell cycle and an increasing accumulation of non-cycling cells in resting (or quiescent) G1 and G2 compartments. In cell-free ascitic fluid from the JB-1 ascites tumour in the plateau phase of growth lowmolecular-weight substances have been found which reversibly and specifically arrest JB-1 cells in G1 and G2. The present paper describes an in-vitro model for testing the effect of the humoral growth inhibitors contained in the ascitic fluid. The test system is based on synchronized JB-1 cells analysed by flow-through cytofluorometry. Addition to the synchronous cells of a ultrafiltrate (less than 50000 Daltons) of the JB-1 ascitic fluid was found to induce a complete, but temporary arrest of the cells at the G1-S border.

  13. Carcinoid Klatskin tumour: A rare cause of obstructive jaundice. (United States)

    Khuroo, Suhail; Rashid, Arshad; Bali, Rajandeep Singh; Mushtaque, Majid; Khuroo, Farzana


    Carcinoid tumours of the extrahepatic biliary ducts represent an extremely rare cause of bile duct obstruction. We report a case of obstructive jaundice secondary to carcinoid tumour arising at the hilar confluence. Resection of the primary tumour was done and the patient is doing well on follow-up. This case demonstrated that surgery offers the only potential cure for biliary carcinoid and aggressive surgical therapy should be the preferred treatment in cases of potentially resectable biliary tumours.

  14. MR diffusion imaging of human intracranial tumours

    DEFF Research Database (Denmark)

    Krabbe, K; Gideon, P; Wagn, P;


    We used MRI for in vivo measurement of brain water self-diffusion in patients with intracranial tumours. The study included 28 patients (12 with high-grade and 3 with low-grade gliomas, 7 with metastases, 5 with meningiomas and 1 with a cerebral abscess). Apparent diffusion coefficients (ADC) wer...

  15. The role of methylation in urological tumours

    NARCIS (Netherlands)

    Heijden, A.G. van der


    Alterations in DNA methylation have been described in human cancer for more than thirty years now. Since the last decade DNA methylation gets more and more important in cancer research. In this review the different alterations of DNA methylation are discussed in testicular germ cell tumours, Wilms't

  16. Bone scintigraphy (B S) in testicle tumours

    Energy Technology Data Exchange (ETDEWEB)

    Braga, F.J.H.N.; Arbex, M.A.; Souza, J.F.; Haddad, J. [Sao Paulo Univ., Ribeirao Preto, SP (Brazil). Faculdade de Medicina


    Full text. Testicle tumours are not very frequent and radiotherapy has an important role in the cure of many patients. The detection of metastases is not an easy task and we do not know any study concerning B S in the search for bone metastases in such cases. We studied 28 patients (8-52 years old) with proven testicle tumours by means of 99 m Tc-M D P (750 MBq intravenously). Images were obtained 2 h after. B S was normal in 21 studies. In 7 evaluations the only abnormality we found was variable but diffuse involvement of the iliac bone on the same side as the affected testicle. Five out of these patients showed important uptake of M D P (4 seminoma and 1 epididymoma) and the 2 others showed moderate uptake of the radio pharmaceutical (2 seminoma). Metastases were confirmed by biopsy. Testicle tumour metastases are known to occur through the lymphatic drainage which goes to the iliac lymph node chain and this makes our findings very logical. The scintigraphic aspect of the affected iliac bone is characteristic and makes it possible to imagine an `iliac sign` for such cases. Early detection of metastases is very important because of radiotherapy efficacy and B S may play an important role in such cases. Testicle tumour metastases should be thought of when this scintigraphic aspect is seen. Differential diagnosis is Paget`s Disease

  17. Analysis of nanoparticle delivery to tumours (United States)

    Wilhelm, Stefan; Tavares, Anthony J.; Dai, Qin; Ohta, Seiichi; Audet, Julie; Dvorak, Harold F.; Chan, Warren C. W.


    Targeting nanoparticles to malignant tissues for improved diagnosis and therapy is a popular concept. However, after surveying the literature from the past 10 years, only 0.7% (median) of the administered nanoparticle dose is found to be delivered to a solid tumour. This has negative consequences on the translation of nanotechnology for human use with respect to manufacturing, cost, toxicity, and imaging and therapeutic efficacy. In this article, we conduct a multivariate analysis on the compiled data to reveal the contributions of nanoparticle physicochemical parameters, tumour models and cancer types on the low delivery efficiency. We explore the potential causes of the poor delivery efficiency from the perspectives of tumour biology (intercellular versus transcellular transport, enhanced permeability and retention effect, and physicochemical-dependent nanoparticle transport through the tumour stroma) as well as competing organs (mononuclear phagocytic and renal systems) and present a 30-year research strategy to overcome this fundamental limitation. Solving the nanoparticle delivery problem will accelerate the clinical translation of nanomedicine.

  18. Solitary fibrous tumour of the vagus nerve. (United States)

    Scholsem, Martin; Scholtes, Felix


    We describe the complete removal of a foramen magnum solitary fibrous tumour in a 36-year-old woman. It originated on a caudal vagus nerve rootlet, classically described as the 'cranial' accessory nerve root. This ninth case of immunohistologically confirmed cranial or spinal nerve SFT is the first of the vagus nerve.

  19. Molecular mechanisms for tumour resistance to chemotherapy. (United States)

    Pan, Shu-Ting; Li, Zhi-Ling; He, Zhi-Xu; Qiu, Jia-Xuan; Zhou, Shu-Feng


    Chemotherapy is one of the prevailing methods used to treat malignant tumours, but the outcome and prognosis of tumour patients are not optimistic. Cancer cells gradually generate resistance to almost all chemotherapeutic drugs via a variety of distinct mechanisms and pathways. Chemotherapeutic resistance, either intrinsic or acquired, is caused and sustained by reduced drug accumulation and increased drug export, alterations in drug targets and signalling transduction molecules, increased repair of drug-induced DNA damage, and evasion of apoptosis. In order to better understand the mechanisms of chemoresistance, this review highlights our current knowledge of the role of altered drug metabolism and transport and deregulation of apoptosis and autophagy in the development of tumour chemoresistance. Reduced intracellular activation of prodrugs (e.g. thiotepa and tegafur) or enhanced drug inactivation by Phase I and II enzymes contributes to the development of chemoresistance. Both primary and acquired resistance can be caused by alterations in the transport of anticancer drugs which is mediated by a variety of drug transporters such as P-glycoprotein (P-gp), multidrug resistance associated proteins, and breast cancer resistance protein. Presently there is a line of evidence indicating that deregulation of programmed cell death including apoptosis and autophagy is also an important mechanism for tumour resistance to anticancer drugs. Reversal of chemoresistance is likely via pharmacological and biological approaches. Further studies are warranted to grasp the full picture of how each type of cancer cells develop resistance to anticancer drugs and to identify novel strategies to overcome it.

  20. Gastrointestinal stromal tumour presenting as gastroduodenal intussusception.

    LENUS (Irish Health Repository)

    Wilson, Mark H


    Gastroduodenal intussusception secondary to gastrointestinal stromal tumour is a very rare cause for intestinal obstruction. The diagnosis of this condition can be challenging, as symptoms are often non-specific and intermittent. This article reports a case where the diagnosis was made preoperatively with abdominal imaging and was treated by a combination of endoscopic reduction and laparoscopic resection.

  1. Granular cell tumour of the urinary bladder

    Directory of Open Access Journals (Sweden)

    Christoph von Klot


    Full Text Available With only 16 cases reported in the literature, the mostly benign granular cell tumour of the urinary bladder is exceptionally rare. We present the case of a 68-year old patient with one of these lesions demonstrating our histological findings including several immunohistochemical stainings used to differentiate between other more common entities.

  2. Tumour and tumour-like lesions of the patella - a multicentre experience

    Energy Technology Data Exchange (ETDEWEB)

    Singh, J.; James, S.L.; Davies, A.M. [The Royal Orthopaedic Hospital, Department of Radiology, Birmingham (United Kingdom); Kroon, H.M. [Leiden University Medical Centre, Department of Radiology, C-2-S, P. O Box 9600, Leiden (Netherlands); Woertler, K. [Technische Universitaet Muenchen, Department of Radiology, Munich (Germany); Anderson, S.E. [Knochentumor- Referenzzentrum der Schweizerischen Gesellschaft fuer Pathologie, Basel (Switzerland)


    Fifty-nine cases of lesions presenting in the patella were identified after review of the databases of four European bone tumour registries. Of the 59 cases, 46% were non neoplastic, 39% were benign and 15% were malignant. The commonest benign neoplasm was giant cell tumour (GCT) (11 cases). Younger patients were more likely to have a benign neoplasm. Lesions in patients less than 40 years of age included giant cell tumour, chondroblastoma, aneurysmal bone cyst (ABC), osteomyelitis, osteoid osteoma and solitary bone cyst. In patients older than 40 years, the following were common lesions: intra-osseous gout, metastasis and intra-osseous ganglion. Expansion of the patella with thinning of cortex was seen more commonly in GCT and brown tumour in hyperparathyroidism. There was associated soft tissue extension in gout and malignant lesions. (orig.)

  3. Improved classification, diagnosis and prognosis of canine round cell tumours

    NARCIS (Netherlands)

    Cangul, Taci


    As the name suggests, canine round cell tumour (RCTs) are composed of cells with a round morphology. There is some discrepancy amongst authors as to which tumours belong to this category, but most designate lymphomas, melanomas, plasmacytomas, transmissible venereal tumours (TVTs), histiocytomas, an

  4. [Malignant germinal tumours of the mediastinum: diagnosis and treatment]. (United States)

    Lemarié, E


    Mediastinal germinal tumours are composed of tissues resembling those that follow one another during embryo development, by differentiation of the primordial and extraembryonic layers. Such practice separates the mature teratomas (benign), seminomas and non-seminomatous germinal tumours (NSGT). Platin-based chemotherapy has shattered the prognosis of such tumours.

  5. Tumour suppressor genes in sporadic epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Liu, Ying; Ganesan, Trivadi S


    of the evolution of tumour progression. A major focus of research has been to identify tumour suppressor genes implicated in sporadic ovarian cancer over the past decade. Several tumour suppressor genes have been identified by strategies such as positional cloning and differential expression display. Further...

  6. Relevance of high-dose chemotherapy in solid tumours

    NARCIS (Netherlands)

    Nieboer, P; de Vries, EGE; Mulder, NH; van der Graaf, WTA


    Drug resistance is a major problem in the treatment of solid tumours. Based on a steep dose-response relationship for especially alkylating agents on tumour cell survival, high-dose chemotherapy was considered of interest for the treatment of solid tumours. Results of phase 1 and 2 studies with high

  7. Orbital tumours and tumour-like lesions: exploring the armamentarium of multiparametric imaging. (United States)

    Purohit, Bela S; Vargas, Maria Isabel; Ailianou, Angeliki; Merlini, Laura; Poletti, Pierre-Alexandre; Platon, Alexandra; Delattre, Bénédicte M; Rager, Olivier; Burkhardt, Karim; Becker, Minerva


    Although the orbit is a small anatomical space, the wide range of structures present within it are often the site of origin of various tumours and tumour-like conditions, both in adults and children. Cross-sectional imaging is mandatory for the detection, characterization, and mapping of these lesions. This review focuses on multiparametric imaging of orbital tumours. Each tumour is reviewed in relation to its clinical presentation, compartmental location, imaging characteristics, and its histological features. We herein describe orbital tumours as lesions of the globe (retinoblastoma, uveal melanoma), optic nerve sheath complex (meningioma, optic nerve glioma), conal-intraconal compartment (hemangioma), extraconal compartment (dermoid/epidermoid, lacrimal gland tumours, lymphoma, rhabdomysarcoma), and bone and sinus compartment (fibrous dysplasia). Lesions without any typical compartmental localization and those with multi-compartment involvement (veno-lymphatic malformation, plexiform neurofibroma, idiopathic orbital pseudotumour, IgG4 related disease, metastases) are also reviewed. We discuss the role of advanced imaging techniques, such as MR diffusion-weighted imaging (DWI), diffusion tensor imaging, fluoro-2-deoxy-D-glucose positron emission tomography CT (FDG-PET CT), and positron emission tomography MRI (MRI PET) as problem-solving tools in the evaluation of those orbital masses that present with non-specific morphologic imaging findings. Main messages/Teaching points • A compartment-based approach is essential for the diagnosis of orbital tumours. • CT and MRI play a key role in the work-up of orbital tumours. • DWI, PET CT, and MRI PET are complementary tools to solve diagnostic dilemmas. • Awareness of salient imaging pearls and diagnostic pitfalls avoids interpretation errors.

  8. Prophylactic Anticonvulsants in patients with brain tumour

    Energy Technology Data Exchange (ETDEWEB)

    Forsyth, P.A. [Depts. of Oncology and Clinical Neurosciences, Univ. of Calgary, Calgary, Alberta (Canada); Tom Baker Cancer Centre, Calgary, Alberta (Canada); Weaver, S. [Depts. of Neurology and Medicine, Albany Medical College, Albany, New York (United States); Fulton, D. [Dept. of Radiation Oncology, Cross Cancer Institute and Dept. of Medicine/Neurology, Univ. of Alberta, Edmonton, Alberta (Canada)


    We conducted a clinical trial to determine if prophylactic anticonvulsants in brain tumour patients (without prior seizures) reduced seizure frequency. We stopped accrual at 100 patients on the basis of the interim analysis. One hundred newly diagnosed brain tumour patients received anticonvulsants (AC Group) or not (No AC Group) in this prospective randomized unblinded study. Sixty patients had metastatic, and 40 had primary brain tumours. Forty-six (46%) patients were randomized to the AC Group and 54 (54%) to the No AC Group. Median follow-up was 5.44 months (range 0.13 -30.1 months). Seizures occurred in 26 (26%) patients, eleven in the AC Group and 15 in the No AC Group. Seizure-free survivals were not different; at three months 87% of the AC Group and 90% of the No AC Group were seizure-free (log rank test, p=0.98). Seventy patients died (unrelated to seizures) and survival rates were equivalent in both groups (median survival = 6.8 months versus 5.6 months, respectively; log rank test, p=0.50). We then terminated accrual at 100 patients because seizure and survival rates were much lower than expected; we would need {>=}900 patients to have a suitably powered study. These data should be used by individuals contemplating a clinical trial to determine if prophylactic anticonvulsants are effective in subsets of brain tumour patients (e.g. only anaplastic astrocytomas). When taken together with the results of a similar randomized trial, prophylactic anticonvulsants are unlikely to be effective or useful in brain tumour patients who have not had a seizure. (author)

  9. RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary. (United States)

    Ryland, Georgina L; Hunter, Sally M; Doyle, Maria A; Rowley, Simone M; Christie, Michael; Allan, Prue E; Bowtell, David D L; Gorringe, Kylie L; Campbell, Ian G


    Mucinous carcinomas represent a distinct morphological subtype which can arise from several organ sites, including the ovary, and their genetic characteristics are largely under-described. Exome sequencing of 12 primary mucinous ovarian tumours identified RNF43 as the most frequently somatically mutated novel gene, secondary to KRAS and mutated at a frequency equal to that of TP53 and BRAF. Further screening of RNF43 in a larger cohort of ovarian tumours identified additional mutations, with a total frequency of 2/22 (9%) in mucinous ovarian borderline tumours and 6/29 (21%) in mucinous ovarian carcinomas. Seven mutations were predicted to truncate the protein and one missense mutation was predicted to be deleterious by in silico analysis. Six tumours had allelic imbalance at the RNF43 locus, with loss of the wild-type allele. The mutation spectrum strongly suggests that RNF43 is an important tumour suppressor gene in mucinous ovarian tumours, similar to its reported role in mucinous pancreatic precancerous cysts.

  10. Immunohistochemical detection of tumour cell proliferation and intratumoural microvessel density in canine malignant mammary tumours

    Directory of Open Access Journals (Sweden)

    Sennazli Gulbin


    Full Text Available The objective of this study was to investigate the correlation between different histological types and grades of canine malignant mammary tumours, tumour cell proliferation and their angiogenic activity using immunohistochemical markers. Mammary tissue samples from 47 bitches with mammary cancer were evaluated. The expression of cellular proliferation marker Ki-67 and endothelial marker Von Willebrand’s factor (vWF were immunohistochemically demonstrated. The tumours with the highest Ki-67 and vWF expressions were found to share similar histomorphological features. Simple solid carcinoma had the highest levels of Ki-67, vWF, and higher histological grade while complex carcinomas, osteosarcomas, and carcinosarcomas had the lowest ones. The differences between the expressions of Ki-67 and vWF in different tumour types were considered to be of great importance in determination of biological behaviour and prognosis of these tumours. This study is one of the few studies that evaluate these differences among the subtypes of malignant canine mammary tumours

  11. {sup 18}F-FDG PET and biomarkers for tumour angiogenesis in early breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Groves, Ashley M.; Shastry, Manu; Endozo, Raymondo; Ell, Peter J. [University College London, Institute of Nuclear Medicine, London (United Kingdom); Rodriguez-Justo, Manuel [University College London, Department of Histopathology, London (United Kingdom); Malhotra, Anmol; Davidson, Timothy; Kelleher, Tina; Keshtgar, Mohammed R. [Breast Unit, Royal Free Hospital, UCL, London (United Kingdom); Miles, Kenneth A. [Brighton and Sussex University Hospitals, Brighton (United Kingdom)


    Tumour angiogenesis is an independent and strong prognostic factor in early breast carcinoma. We performed this study to investigate the ability of {sup 18}F-FDG to detect angiogenesis in early breast carcinoma using PET/CT. Twenty consecutive patients with early (T1-T2) breast carcinoma were recruited prospectively for 18F-FDG PET/CT. The PET/CT data were used to calculate whole tumour maximum standardized uptake value (SUV{sub max}) and mean standardized uptake value (SUV{sub mean}). All patients underwent subsequent surgery without prior chemotherapy or radiotherapy. The excised tumour underwent immunohistochemistry for vascular endothelial growth factor (VEGF), CD105 and glucose transporter protein 1 (GLUT1). The SUV{sub max} showed the following correlation with tumour histology: CD105: r = 0.60, p = 0.005; GLUT1: r = 0.21, p = 0.373; VEGF: r = -0.16, p = 0.496. The SUV{sub mean} showed the following correlation with tumour histology: CD105: r = 0.65, p = 0.002; GLUT1: r = 0.34, p = 0.144; VEGF: r = -0.18, p = 0.443 {sup 18}F-FDG uptake is highly significantly associated with angiogenesis as measured by the immunohistochemistry with CD105 for new vessel formation. Given that tumour angiogenesis is an important prognostic indicator and a predictor of treatment response, {sup 18}F-FDG PET may have a role in the management of primary breast cancer patients even in early-stage disease. (orig.)

  12. Pulmonary tumours in the Netherlands : focus on temporal trends in histology and stage and on rare tumours

    NARCIS (Netherlands)

    de Jong, W. K.; Schaapveld, M.; Blaauwgeers, J. L. G.; Groen, H. J. M.


    Background: Recent temporal trends in histology and stage of pulmonary tumours in the Netherlands were studied. The incidence of rare pulmonary tumours was determined. Methods: All tumours originating from the trachea, bronchus and lung recorded in the Netherlands Cancer Registry were included. Base

  13. Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma

    Energy Technology Data Exchange (ETDEWEB)

    Mautner, V.F. [Department of Neurology, Klinikum Nord Hamburg, Langenhorner Chaussee 560, 22419, Hamburg (Germany); Friedrich, R.E. [Department of Maxillofacial Surgery, Universitaetsklinikum Eppendorf, Hamburg (Germany); Deimling, A. von [Department of Neuropathology, Charite, Berlin (Germany); Hagel, C. [Department of Neuropathology, Universitaetsklinikum Eppendorf, Hamburg (Germany); Korf, B. [Center for Human Genetics, Harvard Institutes of Medicine, Boston, MA (United States); Knoefel, M.T. [Department of Surgery, Universitaetsklinikum Eppendorf, Hamburg (Germany); Wenzel, R.; Fuensterer, C. [MRI-Institute Hamburg Othmarschen, Hamburg (Germany)


    Plexiform neurofibroma (PNF) is a typical feature of neurofibromatosis 1 (NF1). About 10% of patients with NF1 develop malignant peripheral nerve-sheath tumours (MPNST), usually arising from PNF, and this is the major cause of poor survival. A better prognosis can be achieved if the tumours are diagnosed at an early stage. Our objective was to establish MRI criteria for MPNST and to test their usefulness in detecting early malignant change in PNF. MRI was performed on 50 patients with NF1 and nerve-sheath tumours, of whom seven had atypical pain, tumour growth or neurological deficits indicative of malignancy; the other 43 were asymptomatic. On MRI all seven symptomatic patients had inhomogeneous lesions, due to necrosis and haemorrhage and patchy contrast enhancement. In one patient, the multiplicity of confluent tumours with inhomogeneous areas in addition to central lesions did not allow exclusion of malignancy. Only three of the 43 asymptomatic patients had comparable changes; the other 40 patients had tumours being of relatively homogeneous structure on T1- and T2-weighted images before and after contrast enhancement. All three asymptomatic patients with inhomogeneous lesions were shown to have MPNST. (orig.)

  14. Ovarian Steroid Cell Tumour: Correlation of Histopathology with Clinicopathologic Features

    Directory of Open Access Journals (Sweden)

    Ghazala Mehdi


    Full Text Available Ovarian steroid cell tumours (not otherwise specified are rare neoplasms of the ovary and are classified under lipid cell tumours. Their diagnosis can be considered as one of exclusion. Histopathologically, the tumour should carefully be evaluated for microscopic features of malignancy, but it is essential for the clinician and the pathologist to remember that in these tumours, pathologically benign histomorphology does not exclude the possibility of clinically malignant behaviour. Our case study focuses on the comparative findings in a postmenopausal female diagnosed with an ovarian steroid tumour (not otherwise specified. A careful correlation between clinical and surgical evaluation and microscopic analysis is necessary, as is a regular followup.

  15. Total Spinal Block after Thoracic Paravertebral Block. (United States)

    Beyaz, Serbülent Gökhan; Özocak, Hande; Ergönenç, Tolga; Erdem, Ali Fuat; Palabıyık, Onur


    Thoracic paravertebral block (TPVB) can be performed with or without general anaesthesia for various surgical procedures. TPVB is a popular anaesthetic technique due to its low side effect profile and high analgesic potency. We used 20 mL of 0.5% levobupivacaine for a single injection of unilateral TPVB at the T7 level with neurostimulator in a 63 year old patient with co-morbid disease who underwent cholecystectomy. Following the application patient lost consciousness, and was intubated. Haemodynamic instability was normalised with rapid volume replacement and vasopressors. Anaesthetic drugs were stopped at the end of the surgery and muscle relaxant was antagonised. Return of mucle strenght was shown with neuromuscular block monitoring. Approximately three hours after TPVB, spontaneous breathing started and consciousness returned. A total spinal block is a rare and life-threatening complication. A total spinal block is a complication of spinal anaesthesia, and it can also occur after peripheral blocks. Clinical presentation is characterised by hypotension, bradicardia, apnea, and cardiac arrest. An early diagnosis and appropriate treatment is life saving. In this case report, we want to present total spinal block after TPVB.

  16. Oral and maxillofacial tumours in children: a review. (United States)

    Sato, M; Tanaka, N; Sato, T; Amagasa, T


    This retrospective review presents our experience of oral and maxillofacial tumours in children. The subjects were 250 children under the age of 15 years (out of a total of 2747 patients with oral and maxillofacial tumours), who were treated after histopathological confirmation of their diagnoses during the 28 years 1965-92. Diagnosis, incidence, and age at presentation were the main outcome measures and the results showed that 232 patients (93%) had benign tumours and 18 (7%) were malignant. The most common benign tumour was haemangioma (n = 69) and the most common malignant tumour sarcoma (n = 14). The most common odontogenic tumour was odontoma (n = 47) and non-odontogenic tumour ossifying fibroma (n = 5). The most common site of soft tissue tumours was the tongue (n = 65) and of bony tumours the mandible (n = 62). About a third of the tumours developed in patients between the ages of 6 and 11 years. Most of the angiomas developed in patients less than 6 years old, and most of the ameloblastomas in those over 12 years of age. Children accounted for 55% of patients with lymphangoma, 41% of those with odontoma, and 22% of those with haemangioma. It is concluded that most of these lesions were probably developmental malformations rather than neoplasms, and that the definition of oral and maxillofacial tumours in children should be reconsidered.

  17. Metronomic chemotherapy following the maximum tolerated dose is an effective anti-tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells. (United States)

    Vives, Marta; Ginestà, Mireia M; Gracova, Kristina; Graupera, Mariona; Casanovas, Oriol; Capellà, Gabriel; Serrano, Teresa; Laquente, Berta; Viñals, Francesc


    In this article, the effectiveness of a multi-targeted chemo-switch (C-S) schedule that combines metronomic chemotherapy (MET) after treatment with the maximum tolerated dose (MTD) is reported. This schedule was tested with gemcitabine in two distinct human pancreatic adenocarcinoma orthotopic models and with cyclophosphamide in an orthotopic ovarian cancer model. In both models, the C-S schedule had the most favourable effect, achieving at least 80% tumour growth inhibition without increased toxicity. Moreover, in the pancreatic cancer model, although peritoneal metastases were observed in control and MTD groups, no dissemination was observed in the MET and C-S groups. C-S treatment caused a decrease in angiogenesis, and its effect on tumour growth was similar to that produced by the MTD followed by anti-angiogenic DC101 treatment. C-S treatment combined an increase in thrombospondin-1 expression with a decrease in the number of CD133+ cancer cells and triple-positive CD133+/CD44+/CD24+ cancer stem cells (CSCs). These findings confirm that the C-S schedule is a challenging clinical strategy with demonstrable inhibitory effects on tumour dissemination, angiogenesis and CSCs.

  18. Primary Malignant Neuroendocrine Tumour of Pleura: First Case Report

    Directory of Open Access Journals (Sweden)

    Anirban Das


    Full Text Available Metastatic tumours of pleura are the most common malignant tumours causing malignant pleural effusion. Lungs are the most common primary sites. Primary pleural tumours are rarely seen and diffuse malignant mesothelioma is the most common malignant tumour of pleura. Primary malignant neuroendocrine tumour of pleura is not reported in the literature. Here, we report a rare case of primary malignant neuroendocrine tumour of pleura in a fifty-two-year-old, nonsmoker female who presented with right-sided pleural effusion and ipsilateral, dull aching chest pain. Clinical presentations of inflammatory lesions like tuberculous pleuritis and benign and malignant neoplasms of pleura are indistinguishable; hence, fluid cytology, pleural biopsy, and immunohistochemistry are necessary for exact tissue diagnosis of the tumours, which is mandatory for correct treatment and prognostic assessment.

  19. Giant Mediastinal Germ Cell Tumour: An Enigma of Surgical Consideration (United States)

    Ali, Nurayub Mohd; Azizan, Nornazirah; Zakaria, Andee Dzulkarnaen; Rahman, Mohd Ramzisham Abdul


    We present a case of 16-year-old male, who was referred from private centre for dyspnoea, fatigue, and orthopnea. The chest radiograph revealed complete opacification of left chest which was confirmed by computed tomography as a large left mediastinal mass measuring 14 × 15 × 18 cm. The diagnostic needle core biopsy revealed mixed germ cell tumour with possible combination of embryonal carcinoma, yolk sac, and teratoma. After 4 cycles of neoadjuvant BEP regime, there was initial response of tumour markers but not tumour bulk. Instead of classic median sternotomy or clamshell incision, posterolateral approach with piecemeal manner was chosen. Histology confirmed mixed germ cell tumour with residual teratomatous component without yolk sac or embryonal carcinoma component. Weighing 3.5 kg, it is one of the largest mediastinal germ cell tumours ever reported. We describe this rare and gigantic intrathoracic tumour and discuss the spectrum of surgical approach and treatment of this exceptional tumour.

  20. The in vitro effect of gefitinib ('Iressa' alone and in combination with cytotoxic chemotherapy on human solid tumours

    Directory of Open Access Journals (Sweden)

    Knight Louise A


    Full Text Available Abstract Background Activation of the epidermal growth factor receptor (EGFR triggers downstream signaling pathways that regulate many cellular processes involved in tumour survival and growth. Gefitinib ('Iressa' is an orally active tyrosine kinase inhibitor (TKI targeted to the ATP-binding domain of EGFR (HER1; erbB1. Methods In this study we have used a standardised ATP-based tumour chemosensitivity assay (ATP-TCA to measure the activity of gefitinib alone or in combination with different cytotoxic drugs (cisplatin, gemcitabine, oxaliplatin and treosulfan against a variety of solid tumours (n = 86, including breast, colorectal, oesophageal and ovarian cancer, carcinoma of unknown primary site, cutaneous and uveal melanoma, non-small cell lung cancer (NSCLC and sarcoma. The IC50 and IC90 were calculated for each single agent or combination. To allow comparison between samples the IndexSUM was calculated based on the percentage tumour growth inhibition (TGI at each test drug concentration (TDC. Gefitinib was tested at concentrations ranging from 0.0625–2 microM (TDC = 0.446 microg/ml. This study represents the first use of a TKI in the assay. Results There was heterogeneity in the degree of TGI observed when tumours were tested against single agent gefitinib. 7% (6/86 of tumours exhibited considerable inhibition, but most showed a more modest response resulting in a low TGI. The median IC50 value for single agent gefitinib in all tumours tested was 3.98 microM. Interestingly, gefitinib had both positive and negative effects when used in combination with different cytotoxics. In 59% (45/76 of tumours tested, the addition of gefitinib appeared to potentiate the effect of the cytotoxic agent or combination (of these, 11% (5/45 had a >50% decrease in their IndexSUM. In 38% of tumours (29/76, the TGI was decreased when the combination of gefitinib + cytotoxic was used in comparison to the cytotoxic alone. In the remaining 3% (2/76 there was no

  1. The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor α expression in the synovium (United States)

    Wijbrandts, C A; Dijkgraaf, M G W; Kraan, M C; Vinkenoog, M; Smeets, T J; Dinant, H; Vos, K; Lems, W F; Wolbink, G J; Sijpkens, D; Dijkmans, B A C; Tak, P P


    Objective: To determine whether the heterogeneous clinical response to tumour necrosis factor (TNF)α blocking therapy in rheumatoid arthritis (RA) can be predicted by TNFα expression in the synovium before initiation of treatment. Methods: Prior to initiation of infliximab treatment, arthroscopic synovial tissue biopsies were obtained from 143 patients with active RA. At week 16, clinical response was evaluated using the 28-joint Disease Activity Score (DAS28). Immunohistochemistry was used to analyse the cell infiltrate as well as the expression of various cytokines, adhesion molecules and growth factors. Stained sections were evaluated by digital image analysis. Student t tests were used to compare responders (decrease in DAS28 ⩾1.2) with non-responders (decrease in DAS28 <1.2) and multivariable regression was used to identify the independent predictors of clinical response. Results: Synovial tissue analysis confirmed our hypothesis that the baseline level of TNFα expression is a significant predictor of response to TNFα blocking therapy. TNFα expression in the intimal lining layer and synovial sublining were significantly higher in responders than in non-responders (p = 0.047 and p = 0.008, respectively). The numbers of macrophages, macrophage subsets and T cells (all able to produce TNFα) were also significantly higher in responders than in non-responders. The expression of interleukin (IL)1β, IL6, IL18, IL10, E-selectin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was not associated with response to anti-TNFα treatment. Conclusion: The effects of TNFα blockade are in part dependent on synovial TNFα expression and infiltration by TNFα producing inflammatory cells. Clinical response cannot be predicted completely, indicating involvement of other as yet unknown mechanisms. PMID:18055470

  2. Egg yolk phospholipids enriched with 1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-palmitoyl) ethanolamine inhibit development of experimentally induced tumours. (United States)

    Karafiát, V; Veselý, P; Dvořák, M


    Dietary phospholipids (PLs) and their derivatives have proved active in suppression of various health problems and conditions including cancer. In this work we compared the effect of dietary phospholipids from hen egg yolk enriched with N-acyl ether-phosphatidyl ethanolamine (NAEPE) termed bioactive phospholipids (BAP+ preparation) with PLs lacking NAEPE (BAP- preparation) on the growth of transformed cells in vitro and on the promotion and progression of experimental tumours in vivo. For the in vivo experiments we used the chicken model in which liver, lung, and kidney tumours arose via natural selection from single cells initiated by experimentally introduced somatic mutations caused by insertional mutagenesis. Mutagenized animals were fed BAP+ or BAP- diet in various regimens. We observed that BAP+ at low concentrations killed cells of various tumour cell lines in culture but did not compromise viability of non-transformed cells. Oral administration of the BAP+ preparation efficiently reduced progression of all tumour types. However, it did not significantly reduce the number of already initiated tumours and their growth when BAP+ was discontinued. Our data suggest that NAEPE combined with hen egg PLs significantly interferes with tumour progression, possibly through the inhibition of tumour cell viability.

  3. Clinical features, outcome and prognostic factors in dogs diagnosed with non-cortisol-secreting adrenal tumours without adrenalectomy: 20 cases (1994-2009). (United States)

    Arenas, C; Pérez-Alenza, D; Melián, C


    The aims of this study were to describe the clinical features, the outcome and the prognostic factors of dogs with non-cortisol-secreting adrenal masses without adrenalectomy, and also to provide clinical data that can be useful for making decisions when managing dogs with these types of neoplasms. Medical records from 1994 to 2009 were reviewed and 20 dogs were included in the study. The results showed that mean age at diagnosis for dogs with non-cortisol-secreting adrenal masses was 12 years with no sex predisposition. Most dogs were asymptomatic. The most frequent clinical signs, when present, were lethargy, weakness and hypertension. Radiological evidence of metastases at diagnosis was not frequent. The maximal dorso-ventral thickness of the adrenal mass ranged from 10.0 to 45.0 mm. Right adrenal gland masses were more frequent than left-sided. Hypertension was found to be related to tumour growth during follow-up. The median survival time of dogs with non-cortisol-secreting tumours was 17.8 months. Body weight at diagnosis, tumour size and the presence of metastases at diagnosis were inversely related to survival. In conclusion, survival of dogs with non-cortisol-secreting adrenal tumours without adrenalectomy is relatively high and comparable with that of dogs treated with adrenalectomy. Dogs with metastasis and large adrenal tumours have a poorer prognosis. Hypertension is related to tumour growth, and might be used as an additional tool to assess the potential growing capacity of the tumour.

  4. Generalized Block Failure

    DEFF Research Database (Denmark)

    Jönsson, Jeppe


    Block tearing is considered in several codes as a pure block tension or a pure block shear failure mechanism. However in many situations the load acts eccentrically and involves the transfer of a substantial moment in combination with the shear force and perhaps a normal force. A literature study...... yield lines around the block leads to simple interaction formulas similar to other interaction formulas in the codes.......Block tearing is considered in several codes as a pure block tension or a pure block shear failure mechanism. However in many situations the load acts eccentrically and involves the transfer of a substantial moment in combination with the shear force and perhaps a normal force. A literature study...

  5. Genetic variants in toll-like receptors are not associated with rheumatoid arthritis susceptibility or anti-tumour necrosis factor treatment outcome

    DEFF Research Database (Denmark)

    Coenen, Marieke J H; Enevold, Christian; Barrera, Pilar


    Several studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication....

  6. The hypoxic tumour microenvironment and metastatic progression. (United States)

    Subarsky, Patrick; Hill, Richard P


    The microenvironment of solid tumours contains regions of poor oxygenation and high acidity. Growing evidence from clinical and experimental studies points to a fundamental role for hypoxia in metastatic progression. Prolonged hypoxia increases genomic instability, genomic heterogeneity, and may act as a selective pressure for tumour cell variants. Hypoxia can also act in an epigenetic fashion, altering the expression of genes. Hypoxia-induced changes in gene expression alter non-specific stress responses, anaerobic metabolism, angiogenesis, tissue remodeling, and cell-cell contacts. Experimental studies have demonstrated that inhibition of proteins involved in these processes can modify metastasis formation, suggesting a causal role in metastatic progression. Recent advances in high-throughput screening techniques have allowed identification of many hypoxia-induced genes that are involved in the processes associated with metastasis. Here we review the epigenetic control of gene expression by the hypoxic microenvironment and its potential contribution to metastatic progression.

  7. Malignant peripheral nerve sheath tumour of penis. (United States)

    Kaur, J; Madan, R; Singh, L; Sharma, D N; Julka, P K; Rath, G K; Roy, S


    Malignant peripheral nerve sheath tumour (MPNST) is a rare variety of soft tissue sarcoma that originates from Schwann cells or pluripotent cells of neural crest origin. They have historically been difficult tumours to diagnose and treat. Surgery is the mainstay of treatment with a goal to achieve negative margins. Despite aggressive surgery and adjuvant therapy, the prognosis of patients with MPNST remains poor. MPNST arising from penis is a very rare entity; thus, it presents a diagnostic and therapeutic challenge. We present a case of penile MPNST in a 38-year-old man in the absence of neurofibromatosis treated with surgery followed by post-operative radiotherapy to a dose of 60 Gray in 30 fractions and adjuvant chemotherapy with ifosfamide and adriamycin.

  8. SPECT/CT and tumour imaging

    Energy Technology Data Exchange (ETDEWEB)

    Abikhzer, Gad [Rambam Health Care Campus, Department of Nuclear Medicine, Haifa (Israel); Keidar, Zohar [Rambam Health Care Campus, Department of Nuclear Medicine, Haifa (Israel); Technion - Israel Institute of Technology, The Ruth and Bruce Rappaport Faculty of Medicine, Haifa (Israel)


    Scintigraphic techniques are sensitive imaging modalities in the diagnosis and follow-up of cancer patients providing the functional and metabolic activity characteristics of the tumour. Hybrid SPECT/CT improves the diagnostic accuracy of these well-established imaging techniques by precise anatomical localization and characterization of morphological findings, differentiation between foci of physiological and pathological tracer uptake, resulting in a significant impact on patient management and more definitive interpretations. The use of SPECT/CT has been studied in a variety of applications in tumour imaging which are reviewed in this article. By combining functional and anatomical information in a single imaging session, SPECT/CT has become a one-stop cancer imaging modality. (orig.)

  9. Nasopharyngeal carcinoma presented as cavernous sinus tumour. (United States)

    Moona, Mohammad Shafi; Mehdi, Itrat


    A 32 year Libyan male presented with the complaints of headache and diplopia. He was diagnosed with a cavernous sinus meningioma on the basis of MRI findings but no initial biopsy was taken. Depending on the radiologic diagnosis the patient was treated with gamma knife surgery twice, abroad. During follow up he developed left ear deafness and left cervical lymph adenopathy. An ENT evaluation with biopsy from the nasopharynx and cervical lymph node was taken. The histopathologic diagnosis of the resected tumour showed a nasopharyngeal carcinoma with cervical lymph node metastasis (poorly differentiated lympho-epithelial carcinoma). The cavernous sinus tumour which was initially treated as a meningioma was in fact metastasis from the nasopharyngeal carcinoma, making this an interesting and rare occurrence.

  10. Tumour Debulking for Esophageal Cancer - Thermal Modalities

    Directory of Open Access Journals (Sweden)

    David Fleischer


    Full Text Available Esophageal cancer usually is discovered at a late stage and curative therapy seldom is possible. The prognosis is poor and most therapy is palliative. Endoscopic therapy commonly is employed; two common treatments involve thermal modalities. The Nd:YAG laser has been employed for 10 years and is effective in relieving obstruction in approximately 90% of cases. Re-ohstruction usually occurs in two to three months and repeat treatment may be necessary. Limitations to laser use include the fact that equipment is expensive and there are technical restrictions. An alternative thermal modality is the bipolar coagulation tumour probe which employs bipolar electrocoagulation. It is less expensive and, if the tumour is circumferential, tends to be easier to use. (It should not be used if the cancer is noncircumferential. The advantages and limitations of each modality are addressed.

  11. Electrochemotherapy for rat implanted liver tumour

    Institute of Scientific and Technical Information of China (English)


    @@ The most common interventional therapies for liver cancer at present include transcatheter hepatic arterial chemoembolization (TACE),1 percutaneous ethanol injection2 and radiofrequency ablation,3 but all these therapies have some intrinsic disadvantages. Since the advent of electrochemo- therapy (EChT), it has been accepted as a safe and effective therapy for malignant tumors4,5 There are only a few experimental studies reporting the use of EChT in the treatment of liver cancer in the foreign medical literature.6-8 However, there have been some clinical studies, and even fewer reports of experimental studies on EChT for liver cancer in China. We used a rat implanted liver cancer animal model to monitor changes in tumour size, tumour necrosis, cellular apoptosis, expression of peripheral immunological markers (IL-2, sIL-2R, IL-6 and TNF-α) and survival.

  12. Peptide receptor radionuclide therapy of neuroendocrine tumours. (United States)

    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


    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.

  13. Metastatic carcinoid tumour with spinal cord compression. (United States)

    Scott, Si; Antwi-Yeboah, Y; Bucur, Sd


    Carcinoid tumours are rare with an incidence of 5.25/100,000. They predominantly originate in the gastrointestinal tract (50-60%) or bronchopulmonary system (25-30%). Common sites of metastasis are lymph nodes, liver, lungs and bone. Spinal metastasis are rare, but has been reported in patients with symptoms of spinal cord compression including neurological deficits. We report a rare case of carcinoid metastasis with spinal cord compression, in a 63-year-old man, presenting with a one-year history of back pain without any neurological symptoms. The patient underwent a two-level decompressive laminectomy of T10 and T11 as well as piecemeal tumour resection. Post-operatively the patient made a good recovery without complications.

  14. COX-2, VEGF and tumour angiogenesis.

    LENUS (Irish Health Repository)

    Toomey, D P


    Epidemiological evidence suggests a protective effective of regular NSAID use against developing cancer. Cyclooxygenase-2, a target of NSAIDs, is upregulated in many cancers and has been associated with increased VEGF production and angiogenesis. Angiogenesis is the formation of new vessels from existing vasculature and as an essential process for tumour development represents an important therapeutic target. Following an extensive review of the literature this article details the current knowledge on the role of COX-2 in tumorigenesis focusing on its relationship to angiogenesis and VEGF production by tumour cells. While COX-2 is clearly detrimental to prognosis and NSAIDs have a beneficial effect, the possibility of COX-2 independent effects being partly or wholly responsible for this benefit cannot be excluded.

  15. Endometrial stromal sarcoma: a rare tumour

    Directory of Open Access Journals (Sweden)

    Amrit Pal Kaur


    Full Text Available Endometrial stromal sarcomas (ESS are rare endometrial tumours arising from stroma of endometrium i.e. connective tissue of endometrium rather than glands. Usually a pre-operative diagnosis is difficult. Total abdominal hysterectomy with bilateral salpingo-oophorectomy is main line of treatment. Adjuvant hormone therapy in the form of progesterones, GnRH analogues, aromatase inhibitors are effective for prevention of recurrences as these tumours are invariably positive for oestrogen & progesterone receptors. Surgical excision, radiotherapy, hormone therapy are recommended for recurrences. We report a 52 yrs widow with undifferentiated endometrial stromal sarcoma weighing 3.75 kg with a short history of 3 months diagnosed only after histopathology. [Int J Reprod Contracept Obstet Gynecol 2014; 3(1.000: 276-278

  16. In vitro evaluation of human hybrid cell lines generated by fusion of B-lymphoblastoid cells and ex vivo tumour cells as candidate vaccines for haematological malignancies. (United States)

    Mohamed, Yehia S; Dunnion, Debbie; Teobald, Iryna; Walewska, Renata; Browning, Michael J


    Fusions of dendritic cells (DCs) and tumour cells have been shown to induce protective immunity to tumour challenge in animal models, and to represent a promising approach to cancer immunotherapy. The broader clinical application of this approach, however, is potentially constrained by the lack of replicative capacity and limited standardisation of fusion cell preparations. We show here that fusion of ex vivo tumour cells isolated from patients with a range of haematological malignancies with the human B-lymphoblastoid cell line (LCL), HMy2, followed by chemical selection of the hybridomas, generated stable, self-replicating human hybrid cell lines that grew continuously in tissue culture, and survived freeze/thawing cycles. The hybrid cell lines expressed HLA class I and class II molecules, and the major T-cell costimulatory molecules, CD80 and CD86. All but two of 14 hybrid cell lines generated expressed tumour-associated antigens that were not expressed by HMy2 cells, and were therefore derived from the parent tumour cells. The hybrid cell lines stimulated allogeneic T-cell proliferative responses and interferon-gamma release in vitro to a considerably greater degree than their respective parent tumour cells. The enhanced T-cell stimulation was inhibited by CTLA4-Ig fusion protein, and by blocking antibodies to MHC class I and class II molecules. Finally, all of five LCL/tumour hybrid cell lines tested induced tumour antigen-specific cytotoxic T-cell responses in vitro in PBL from healthy, HLA-A2+ individuals, as detected by HLA-A2-peptide pentamer staining and cellular cytotoxicity. These data show that stable hybrid cell lines, with enhanced immunostimulatory properties and potential for therapeutic vaccination, can be generated by in vitro fusion and chemical selection of B-LCL and ex vivo haematological tumour cells.

  17. Activation of tumour cell ECM degradation by thrombin-activated platelet membranes: potentially a P-selectin and GPIIb/IIIa-dependent process. (United States)

    Pang, J H; Coupland, L A; Freeman, C; Chong, B H; Parish, Christopher R


    The promotion of tumour metastasis by platelets may occur through several mechanisms including the induction of a more metastatic phenotype in tumour cells and assisted extravasation of circulating tumour cells. Whilst the mechanisms underlying platelet-assisted extravasation have been extensively studied, much less attention has been paid to the mechanisms underlying platelet promotion of an aggressive phenotype within a tumour cell population. Herein, we demonstrate in vitro that MDA-MB-231 breast carcinoma cells incubated with washed thrombin-activated platelet membranes adopt a Matrigel-degrading phenotype in a dose- and contact time-dependent manner. The same phenotypic change was observed with three other human tumour cell lines of diverse anatomical origin. Moreover, tumour cell lines that had been cultured with washed thrombin-activated platelet membranes had a greater metastatic capacity when injected into mice. This in vivo effect was reliant upon a co-incubation period of >2 h implying a mechanism involving more than platelet membrane binding that occurred within 5 min. Upon further investigation it was found that simultaneous blocking of the platelet-membrane proteins P-selectin and GPIIb/IIIa prevented interactions between platelet membranes and MDA-MB-231 cells but also significantly reduced the ability of tumour cells to degrade Matrigel. These results confirm that platelets induce a more aggressive phenotype in tumour cells but also identify the platelet proteins involved in this effect. P-selectin and GPIIb/IIIa also play a role in assisting tumour cell extravasation and, thus, are ideal targets for the therapeutic intervention of both stages of platelet-assisted metastasis.

  18. [De novo tumours of renal transplants]. (United States)

    Hétet, J F; Rigaud, J; Dorel-Le Théo, M; Láuté, F; Karam, G; Blanchet, P


    Kidney cancer occurs rarely and late in renal transplants. The lack of grafts and the increasing age of the cadaver donors are likely to result in an increasing number of such cancers. To date, the treatment of choice is the transplant removal. Nevertheless partial nephrectomy may be discussed in selected cases. Ultrasonographic screening should allow detection of low volume tumours suitable for partial nephrectomy. Alternative techniques (radiofrequency, cryoablation) are to be assessed in such patients.

  19. mprA, an Escherichia coli gene that reduces growth-phase-dependent synthesis of microcins B17 and C7 and blocks osmoinduction of proU when cloned on a high-copy-number plasmid. (United States)

    del Castillo, I; Gómez, J M; Moreno, F


    Microcins B17 and C7 are plasmid-determined, peptide antibiotics produced by Escherichia coli when cells enter the stationary phase of growth. Microcinogenic strains are immune to the action of the microcin they synthesize. A well-characterized deficient-immunity phenotype is exhibited by microcin B17-producing cells in the absence of the immunity gene mcbG (M.C. Garrido, M. Herrero, R. Kolter, and F. Moreno, EMBO J. 7:1853-1862, 1988). A 14.6-kilobase-pair EcoRI chromosomal fragment was isolated by its ability to suppress this phenotype when cloned into a multicopy vector. This fragment was mapped to 57.5 min on the E. coli genetic map. The position of the gene responsible for suppression, designated mprA, was determined by insertional mutagenesis and deletion analysis. mprA was shown to be transcribed clockwise on the E. coli chromosome, and its product was identified as a 19-kilodalton polypeptide. Suppression was shown to be achieved by decreasing microcin B17 production. Increased mprA gene dosage also caused a decrease in microcin C7 production and blocked the osmoinduction of the proU locus in high-osmolarity media. Our results suggest that the mprA gene product could play a regulatory role on expression of several E. coli genes, this control being exerted at the transcriptional level.

  20. Tumour exosome integrins determine organotropic metastasis. (United States)

    Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; Rodrigues, Goncalo; Hashimoto, Ayako; Tesic Mark, Milica; Molina, Henrik; Kohsaka, Shinji; Di Giannatale, Angela; Ceder, Sophia; Singh, Swarnima; Williams, Caitlin; Soplop, Nadine; Uryu, Kunihiro; Pharmer, Lindsay; King, Tari; Bojmar, Linda; Davies, Alexander E; Ararso, Yonathan; Zhang, Tuo; Zhang, Haiying; Hernandez, Jonathan; Weiss, Joshua M; Dumont-Cole, Vanessa D; Kramer, Kimberly; Wexler, Leonard H; Narendran, Aru; Schwartz, Gary K; Healey, John H; Sandstrom, Per; Labori, Knut Jørgen; Kure, Elin H; Grandgenett, Paul M; Hollingsworth, Michael A; de Sousa, Maria; Kaur, Sukhwinder; Jain, Maneesh; Mallya, Kavita; Batra, Surinder K; Jarnagin, William R; Brady, Mary S; Fodstad, Oystein; Muller, Volkmar; Pantel, Klaus; Minn, Andy J; Bissell, Mina J; Garcia, Benjamin A; Kang, Yibin; Rajasekhar, Vinagolu K; Ghajar, Cyrus M; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Lyden, David


    Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

  1. [Epidemiology and risk factors of testicular tumours]. (United States)

    Kozłowski, Piotr; Starosławska, Elżbieta; Szumiło, Justyna; Jankiewicz, Małgorzata; Kozłowska, Magdalena; Burdan, Franciszek


    Testicular tumours are rare neoplasms, which most commonly affects men aged 25 to 35 years. Among young adult males it is the most common cause of testicular swelling. In recent decades, the number of cases of testicular tumours has greatly increased. The most significant predisposing factors are cryptorchidism and some endocrine disorders, especially increased levels of gonadotropins and female sex hormones. Testicular trauma, inguinal hernia, extreme values of body mass index (BMI), high-calorie diet rich in dairy products as well as high social status are also regarded as risk factors. Furthermore, some chromosomal abnormalities like increased number of chromosomes 7, 8. 12, 21 and X, loss of chromosomes 4, 5, 11, 13, 18, or Y, mutation in the gene Xq27; as well as multiplied copy of the gene i(12p) are associated with tumor development. It has been proven that high testosterone levels and regular physical activity may prevent testicular tumours. Since one of the first sign the lesion is often a lump or swelling of the testis and the appearance of abnormal structure in the scrotum routine testicular self-examination seems to be important in early detection. In all suspected cases an immediate ultrasound examination of both testicles is highly recommended. It is also advised to conduct a computerized tomography (CT) and a positron emission tomography (PET) scan for staging of the tumor to select the best mode of treatment.

  2. Differences in food intake of tumour-bearing cachectic mice are associated with hypothalamic serotonin signalling


    Dwarkasing, Jvalini T; Mark V Boekschoten; Argilès, Joseph M; van Dijk, Miriam; Busquets, Silvia; Penna, Fabio; Toledo, Miriam; Laviano, Alessandro; Witkamp, R F; van Norren, Klaske


    Background Anorexia is a common symptom among cancer patients and contributes to malnutrition and strongly impinges on quality of life. Cancer-induced anorexia is thought to be caused by an inability of food intake-regulating systems in the hypothalamus to respond adequately to negative energy balance during tumour growth. Here, we show that this impaired response of food-intake control is likely to be mediated by altered serotonin signalling and by failure in post-transcriptional neuropeptid...

  3. FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients. (United States)

    Streit, S; Mestel, D S; Schmidt, M; Ullrich, A; Berking, C


    A single nucleotide polymorphism in the gene for FGFR4 (-Arg388) has been associated with progression in various types of human cancer. Although fibroblast growth factors (FGFs) belong to the most important growth factors in melanoma, expression of FGF receptor subtype 4 has not been investigated yet. In this study, the protein expression of this receptor was analysed in 137 melanoma tissues of different progression stages by immunohistochemistry. FGFR4 protein was expressed in 45% of the specimens and correlated with pTNM tumour stages (UICC, P = 0.023 and AJCC, P = 0.046), presence of microulceration (P = 0.009), tumour vascularity (P = 0.001), metastases (P = 0.025), number of primary tumours (P = 0.022), overall survival (P = 0.047) and disease-free survival (P = 0.024). Furthermore, FGFR4 Arg388 polymorphism was analysed in 185 melanoma patients by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The Arg388 allele was detected in 45% of the melanoma patients and was significantly associated with tumour thickness (by Clark's level of invasion (P = 0.004) and by Breslow in mm (P = 0.02)) and the tumour subtype nodular melanoma (P = 0.002). However, there was no correlation of the FGFR4 Arg388 allele with overall and disease-free survival. In conclusion, the Arg388 genotype and the protein expression of FGFR4 may be potential markers for progression of melanoma.

  4. Osteoprotegerin regulates cancer cell migration through SDF-1/CXCR4 axis and promotes tumour development by increasing neovascularization. (United States)

    Benslimane-Ahmim, Zahia; Pereira, Jessica; Lokajczyk, Anna; Dizier, Blandine; Galy-Fauroux, Isabelle; Fischer, Anne-Marie; Heymann, Dominique; Boisson-Vidal, Catherine


    We previously reported that OPG is involved in ischemic tissue neovascularization through the secretion of SDF-1 by pretreated-OPG endothelial colony-forming cells (ECFCs). As the vascularization is one of the key factor influencing the tumour growth and cancer cell dissemination, we investigated whether OPG was able to modulate the invasion of human MNNG-HOS osteosarcoma and DU145 prostate cancer cell lines in vitro and in vivo. Cell motility was analysed in vitro by using Boyden chambers. Human GFP-labelled MMNG-HOS cells were inoculated in immunodeficient mice and the tumour nodules formed were then injected with OPG and/or FGF-2, AMD3100 or 0.9% NaCl (control group). Tumour growth was manually followed and angiogenesis was assessed by immunohistochemistry. In vitro, SDF-1 released by OPG-pretreated ECFCs markedly attracted both MNNG-HOS and DU145 cells and induced spontaneous migration of cancer cells. In vivo, tumour volumes were significantly increased in OPG-treated group compared to the control group and OPG potentiated the effect of FGF-2. Concomitantly, OPG alone or combined with FGF-2 increased the number of new vasculature compared to the control group. Interestingly AMD3100, an inhibitor of SDF-1, prevented the in vivo effects of OPG induced by SDF-1 This study provides experimental evidence that OPG promotes tumour development trough SDF-1/CXCR4 axis.

  5. Prophylactic, therapeutic and anti-metastatic effects of BMDC and DC lines in mice carrying HPV 16-associated tumours. (United States)

    Mendoza, L; Bubeník, J; Símová, J; Jandlová, T; Vonka, V; Mikysková, R


    Oncogenic, moderately immunogenic MK16/1/IIIABC (MK16) cells were previously established by co-transfection of HPV 16 E6/E7 and activated H-ras oncogene DNA into C57BL/6 kidney cells. Subcutaneous transplantation of the MK16 cells produced progressively growing neoplasms which metastasized spontaneously to lungs. In this communication we report that prophylactic administration of bone marrow-derived dendritic cells (BMDC) as well as dendritic cell (DC) lines DC2.4 and JAWS II at the site of subsequent MK16 tumour transplants inhibited tumour growth and reduced the number of lung metastases. Similarly, in therapeutic experiments, administration of BMDC and DC lines at the site of the growing MK16 tumours or at the site of MK16 tumour residua after surgery inhibited tumour growth. Both BMDC-based vaccines and vaccines based on DC lines had also an antimetastatic effect. These results indicate that the DC line-based vaccines, which represent a standard, well-characterized and more homogeneous material, technically easier to prepare than the fresh BMDC-based vaccines, can be utilized for therapy of surgical minimal residual disease in HPV 16-associated neoplasms and are prospective for relevant clinical trials.

  6. Evaluating the agreement between tumour volumetry and the estimated volumes of tumour lesions using an algorithm

    Energy Technology Data Exchange (ETDEWEB)

    Laubender, Ruediger P. [German Cancer Consortium (DKTK), Heidelberg (Germany); University Hospital Munich - Campus Grosshadern, Institute of Medical Informatics, Biometry, and Epidemiology (IBE), Munich (Germany); German Cancer Research Center (DKFZ), Heidelberg (Germany); Lynghjem, Julia; D' Anastasi, Melvin; Graser, Anno [University Hospital Munich - Campus Grosshadern, Institute for Clinical Radiology, Munich (Germany); Heinemann, Volker; Modest, Dominik P. [University Hospital Munich - Campus Grosshadern, Department of Medical Oncology, Munich (Germany); Mansmann, Ulrich R. [University Hospital Munich - Campus Grosshadern, Institute of Medical Informatics, Biometry, and Epidemiology (IBE), Munich (Germany); Sartorius, Ute; Schlichting, Michael [Merck KGaA, Darmstadt (Germany)


    To evaluate the agreement between tumour volume derived from semiautomated volumetry (SaV) and tumor volume defined by spherical volume using longest lesion diameter (LD) according to Response Evaluation Criteria In Solid Tumors (RECIST) or ellipsoid volume using LD and longest orthogonal diameter (LOD) according to World Health Organization (WHO) criteria. Twenty patients with metastatic colorectal cancer from the CIOX trial were included. A total of 151 target lesions were defined by baseline computed tomography and followed until disease progression. All assessments were performed by a single reader. A variance component model was used to compare the three volume versions. There was a significant difference between the SaV and RECIST-based tumour volumes. The same model showed no significant difference between the SaV and WHO-based volumes. Scatter plots showed that the RECIST-based volumes overestimate lesion volume. The agreement between the SaV and WHO-based relative changes in tumour volume, evaluated by intraclass correlation, showed nearly perfect agreement. Estimating the volume of metastatic lesions using both the LD and LOD (WHO) is more accurate than those based on LD only (RECIST), which overestimates lesion volume. The good agreement between the SaV and WHO-based relative changes in tumour volume enables a reasonable approximation of three-dimensional tumour burden. (orig.)

  7. Development and characterization of 5-FU bearing ferritin appended solid lipid nanoparticles for tumour targeting. (United States)

    Jain, Sanjay K; Chaurasiya, Akash; Gupta, Yashwant; Jain, Anekant; Dagur, Pradeep; Joshi, Beenu; Katoch, Vishwa M


    Ferritin coupled solid lipid nanoparticles were investigated for tumour targeting. Solid lipid nanoparticles were prepared using HSPC, cholesterol, DSPE and triolien. The SLNs without ferritin which has similar lipid composition were used for comparison. SLNs preparations were characterized for shape, size and percentage entrapment. The average size of SLNs was found to be in the range 110-152 nm and maximum drug entrapment was found to be 34.6-39.1%. In vitro drug release from the formulations is obeying fickian release kinetics. Cellular uptake and IC50 values of the formulation were determined in vitro in MDA-MB-468 breast cancer cells. In vitro cell binding of Fr-SLN exhibits 7.7-folds higher binding to MDA-MB-468 breast cancer cells in comparison to plain SLNs. Ex-vivo cytotoxicity assay on targeted nanoparticles gave IC50 of 1.28 microM and non-targeted nanoparticles gave IC50 of 3.56 microM. In therapeutic experiments, 5-FU, SLNs and Fr-SLNs were administered at the dose of 10 mg 5-FU/kg body weight to MDA-MB-468 tumour bearing Balb/c mice. Administration of Fr-SLNs formulation results in effective reduction in tumour growth as compared with free 5-FU and plain SLNs. The result demonstrates that this delivery system possessed an enhanced anti-tumour activity. The results warrant further evaluation of this delivery system.

  8. Twin-screw extruded lipid implants containing TRP2 peptide for tumour therapy. (United States)

    Even, Marie-Paule; Bobbala, Sharan; Gibson, Blake; Hook, Sarah; Winter, Gerhard; Engert, Julia


    Much effort has been put in the development of specific anti-tumour immunotherapies over the last few years, and several studies report on the use of liposomal carriers for tumour-associated antigens. In this work, the use of lipid implants, prepared using two different extruders, was investigated for sustained delivery in tumour therapy. The implants consisted of cholesterol, soybean lecithin, Dynasan 114, trehalose, ovalbumin (OVA) or a TRP2 peptide, and Quil-A. Implants were first produced on a Haake Minilab extruder, and then a scale-down to minimal quantities of material on a small scale ZE mini extruder was performed. All formulations were characterised in terms of extrudability, implant properties and in vitro release behaviour of the model antigen ovalbumin. The type of extruder used to produce the implants had a major influence on implant properties and the release behaviour, demonstrating that extrusion parameters and lipid formulations have to be individually adapted to each extrusion device. Subsequently, lipid implants containing TRP-2 peptide were extruded on the ZE mini extruder and investigated in vitro and in vivo. The in vivo study showed that mice having received TRP2 loaded implants had delayed tumour growth for 3days compared to groups having received no TRP2.

  9. Preoperative radiotherapy and extracellular matrix remodeling in rectal mucosa and tumour matrix metalloproteinases and plasminogen components

    Energy Technology Data Exchange (ETDEWEB)

    Angenete, Eva; Oeresland, Tom; Falk, Peter; Breimer, Michael; Ivarsson, Marie-Louise (Dept. of Surgery, Inst. of Clinical Sciences, Sahlgrenska Academy at Univ. of Goeteborg, Goeteborg (Sweden)); Hultborn, Ragnar (Dept. of Oncology, Institute of Clinical Sciences, Sahlgrenska Univ. Hospital/Sahlgrenska, Goeteborg (Sweden))


    Background. Preoperative radiotherapy reduces recurrence but increases postoperative morbidity. The aim of this study was to explore the effect of radiotherapy in rectal mucosa and rectal tumour extracellular matrix (ECM) by studying enzymes and growth factors involved in ECM remodeling. Materials and methods. Twenty patients with short-term preoperative radiotherapy and 12 control patients without radiotherapy were studied. Biopsies from rectal mucosa and tumour were collected prior to radiotherapy and at surgery. Tissue MMP-1, -2, -9, TIMP-1, uPA, PAI-1, TGF-beta1 and calprotectin were determined by ELISA. Biopsies from irradiated and non-irradiated peritoneal areas were also analysed. Results. Radiotherapy increased the tissue levels of MMP-2 and PAI-1 in both the rectal mucosa and tumours while calprotectin and uPA showed an increase only in the mucosa after irradiation. The increase of calprotectin was due to an influx of inflammatory cells as revealed by immunohistochemistry. Prior to irradiation, the tumour tissues had increased levels of MMP-1, -2, -9, total TGF-beta1, uPA, PAI-1 and calprotectin compared to mucosa, while TIMP-1 and the active TGF-beta1 fraction showed no statistical difference. Conclusions. This study indicates a radiation-induced effect on selected ECM remodeling proteases. This reaction may be responsible for early and late morbidity. Interference of this response might reduce these consequences.

  10. Intramedullary tumours in patients with neurofibromatosis type 2: MRI features associated with a favourable prognosis

    Energy Technology Data Exchange (ETDEWEB)

    Rennie, A.T.M. [Department of Neuroradiology, West Wing, John Radcliffe Hospital, Headington, Oxford (United Kingdom)], E-mail:; Side, L. [Department of Clinical Genetics, Churchill Hospital, Headington, Oxford (United Kingdom); Kerr, R.S.C. [Department of Neurosurgery, West Wing, John Radcliffe Hospital, Headington, Oxford (United Kingdom); Anslow, P.; Pretorius, P. [Department of Neuroradiology, West Wing, John Radcliffe Hospital, Headington, Oxford (United Kingdom)


    Aim: To assess the magnetic resonance imaging (MRI) features and natural history of intramedullary tumours in patients with neurofibromatosis type 2 (NF2). Materials and methods: Eleven NF2 patients with intramedullary spinal cord tumours were identified from the database of the multidisciplinary NF2 clinic. All the imaging studies of these patients were individually reviewed by two neuroradiologists to evaluate the size, number, location, imaging characteristics, and interval growth of the intramedullary tumours. Results: Two of the 11 patients had lesions that required surgery. Both these lesions were in the cervical region, and extended over three and five segments respectively. Nine patients with a mean imaging follow-up period of 77 months had lesions that remained stable, apart from the development of small peritumoral cysts in three. The lesions were well circumscribed, often multiple, usually less than 1 cm in diameter, and were most frequently found in the cervical cord. Conclusion: The majority of intramedullary tumours in NF2 patients are very slow growing and share certain MRI features that differ from those of progressive or symptomatic lesions.

  11. Distinct behaviour of sorafenib in experimental cachexia-inducing tumours: the role of STAT3.

    Directory of Open Access Journals (Sweden)

    Míriam Toledo

    Full Text Available The presence of a tumour is very often associated with wasting in the host, affecting both skeletal muscle and adipose tissue. In the present study we used sorafenib, a multi-kinase inhibitor with anti-tumour activity, in order to investigate the effects of chemotherapy on wasting. Three different experimental mouse tumour models were included: C26 colon carcinoma, B16 melanoma and Lewis lung carcinoma (LLC. The results obtained clearly show that sorafenib was effective in reducing tumour growth in LLC and B16 models, while it had no effect on C26. Interestingly, sorafenib treatment reduced the signs of muscle wasting and improved the physical activity in the LLC model and also in the C26, despite the absence of antineoplastic action in the latter. Our results discard a role for IL-6 in the action of sorafenib since the drug did not affect the levels of this cytokine. Conversely, sorafenib seems to act by influencing both STAT3 and ERK activity at muscle level, leading to reduced accumulation of Pax7 and atrogin-1. Sorafenib may interfere with muscle wasting by decreasing the activation of these signal transduction pathways.

  12. Development and characterization of a microfluidic model of the tumour microenvironment (United States)

    Ayuso, Jose M.; Virumbrales-Muñoz, María; Lacueva, Alodia; Lanuza, Pilar M.; Checa-Chavarria, Elisa; Botella, Pablo; Fernández, Eduardo; Doblare, Manuel; Allison, Simon J.; Phillips, Roger M.; Pardo, Julián; Fernandez, Luis J.; Ochoa, Ignacio


    The physical microenvironment of tumours is characterized by heterotypic cell interactions and physiological gradients of nutrients, waste products and oxygen. This tumour microenvironment has a major impact on the biology of cancer cells and their response to chemotherapeutic agents. Despite this, most in vitro cancer research still relies primarily on cells grown in 2D and in isolation in nutrient- and oxygen-rich conditions. Here, a microfluidic device is presented that is easy to use and enables modelling and study of the tumour microenvironment in real-time. The versatility of this microfluidic platform allows for different aspects of the microenvironment to be monitored and dissected. This is exemplified here by real-time profiling of oxygen and glucose concentrations inside the device as well as effects on cell proliferation and growth, ROS generation and apoptosis. Heterotypic cell interactions were also studied. The device provides a live ‘window’ into the microenvironment and could be used to study cancer cells for which it is difficult to generate tumour spheroids. Another major application of the device is the study of effects of the microenvironment on cellular drug responses. Some data is presented for this indicating the device’s potential to enable more physiological in vitro drug screening. PMID:27796335


    Institute of Scientific and Technical Information of China (English)

    黄廷祝; 黎稳


    The block H-matrices are studied by the concept of G-functions, several concepts of block matrices are introduced. Equivalent characters of block H-matrices are obtained. Spectrum localizations claracterized by Gfunctions for block matrices are got.

  14. Block TERM factorization of block matrices

    Institute of Scientific and Technical Information of China (English)

    SHE Yiyuan; HAO Pengwei


    Reversible integer mapping (or integer transform) is a useful way to realize Iossless coding, and this technique has been used for multi-component image compression in the new international image compression standard JPEG 2000. For any nonsingular linear transform of finite dimension, its integer transform can be implemented by factorizing the transform matrix into 3 triangular elementary reversible matrices (TERMs) or a series of single-row elementary reversible matrices (SERMs). To speed up and parallelize integer transforms, we study block TERM and SERM factorizations in this paper. First, to guarantee flexible scaling manners, the classical determinant (det) is generalized to a matrix function, DET, which is shown to have many important properties analogous to those of det. Then based on DET, a generic block TERM factorization,BLUS, is presented for any nonsingular block matrix. Our conclusions can cover the early optimal point factorizations and provide an efficient way to implement integer transforms for large matrices.

  15. Discrimination of paediatric brain tumours using apparent diffusion coefficient histograms

    Energy Technology Data Exchange (ETDEWEB)

    Bull, Jonathan G.; Clark, Christopher A. [UCL Institute of Child Health, Imaging and Biophysics Unit, London (United Kingdom); Saunders, Dawn E. [Great Ormond Street Hospital for Children NHS Trust, Department of Radiology, London (United Kingdom)


    To determine if histograms of apparent diffusion coefficients (ADC) can be used to differentiate paediatric brain tumours. Imaging of histologically confirmed tumours with pre-operative ADC maps were reviewed (54 cases, 32 male, mean age 6.1 years; range 0.1-15.8 years) comprising 6 groups. Whole tumour ADC histograms were calculated; normalised for volume. Stepwise logistic regression analysis was used to differentiate tumour types using histogram metrics, initially for all groups and then for specific subsets. All 6 groups (5 dysembryoplastic neuroectodermal tumours, 22 primitive neuroectodermal tumours (PNET), 5 ependymomas, 7 choroid plexus papillomas, 4 atypical teratoid rhabdoid tumours (ATRT) and 9 juvenile pilocytic astrocytomas (JPA)) were compared. 74% (40/54) were correctly classified using logistic regression of ADC histogram parameters. In the analysis of posterior fossa tumours, 80% of ependymomas, 100% of astrocytomas and 94% of PNET-medulloblastoma were classified correctly. All PNETs were discriminated from ATRTs (22 PNET and 4 supratentorial ATRTs) (100%). ADC histograms are useful in differentiating paediatric brain tumours, in particular, the common posterior fossa tumours of childhood. PNETs were differentiated from supratentorial ATRTs, in all cases, which has important implications in terms of clinical management. (orig.)

  16. A spatio-temporal simulation model of the response of solid tumours to radiotherapy in vivo: parametric validation concerning oxygen enhancement ratio and cell cycle duration (United States)

    Antipas, Vassilis P.; Stamatakos, Georgios S.; Uzunoglu, Nikolaos K.; Dionysiou, Dimitra D.; Dale, Roger G.


    Advanced bio-simulation methods are expected to substantially improve radiotherapy treatment planning. To this end a novel spatio-temporal patient-specific simulation model of the in vivo response of malignant tumours to radiotherapy schemes has been recently developed by our group. This paper discusses recent improvements to the model: an optimized algorithm leading to conformal shrinkage of the tumour as a response to radiotherapy, the introduction of the oxygen enhancement ratio (OER), a realistic initial cell phase distribution and finally an advanced imaging-based algorithm simulating the neovascularization field. A parametric study of the influence of the cell cycle duration Tc, OER, OERbgr for the beta LQ parameter on tumour growth, shrinkage and response to irradiation under two different fractionation schemes has been made. The model has been applied to two glioblastoma multiforme (GBM) cases, one with wild type (wt) and another one with mutated (mt) p53 gene. Furthermore, the model has been applied to a hypothetical GBM tumour with agr and bgr values corresponding to those of generic radiosensitive tumours. According to the model predictions, a whole tumour with shorter Tc tends to repopulate faster, as is to be expected. Furthermore, a higher OER value for the dormant cells leads to a more radioresistant whole tumour. A small variation of the OERbgr value does not seem to play a major role in the tumour response. Accelerated fractionation proved to be superior to the standard scheme for the whole range of the OER values considered. Finally, the tumour with mt p53 was shown to be more radioresistant compared to the tumour with wt p53. Although all simulation predictions agree at least qualitatively with the clinical experience and literature, a long-term clinical adaptation and quantitative validation procedure is in progress.

  17. Epstein-Barr virus-associated smooth muscle tumour presenting as a parasagittal brain tumour. (United States)

    Ibebuike, K E; Pather, S; Emereole, O; Ndolo, P; Kajee, A; Gopal, R; Naidoo, S


    Dural-based brain tumours, apart from meningiomas, are rare. Epstein-Barr virus (EBV)-associated smooth muscle tumor (SMT) is a documented but rare disease that occurs in immunocompromized patients. These tumours may be located at unusual sites including the brain. We present a 37-year-old patient, positive for the human immunodeficiency virus (HIV), who was admitted after generalized tonic-clonic seizures. MRI and CT scan revealed a dural-based brain tumour, intraoperatively thought to be a meningioma, but with an eventual histological diagnosis of EBV-SMT. Clinically the patient was well postoperatively with a Glasgow coma scale score of 15/15 and no focal neurologic deficit. This case confirms the association between EBV and SMT in patients with HIV/acquired immunodeficiency syndrome (AIDS). It also highlights the need to include EBV-SMT in the differential diagnosis of intracranial mass lesions in patients with HIV/AIDS.

  18. Lesson Thirteen Trifascicular Block

    Institute of Scientific and Technical Information of China (English)

    鲁端; 王劲


    @@ A complete trifascicular block would result in complete AV block. The idio ventricular rhythm has a slower rate and a wide QRS complex because the pacemaker is located at the peripheral part of the conduction system distal to the sites of the block1. Such a rhythm may be difficult to differentiate from bifascicular or bundle branch block combined with complete block at a higher level such as the AV node or His bundle2. Besides a slower ventricular rate, a change in the morphology of the QRS complex from a previous known bifascicular pattern would be strongly suggestive of a trifascicular origin of the complete AV block3. A His bundle recording is required for a definitive diagnosis, however.

  19. Transport of calcium ions by Ehrlich ascites-tumour cells. (United States)

    Landry, Y; Lehninger, A L


    Ehrlich ascites-tumour cells accumulate Ca2+ when incubated aerobically with succinate, phosphate and rotenone, as revealed by isotopic and atomic-absorption measurements. Ca2+ does not stimulate oxygen consumption by carefully prepared Ehrlich cells, but des so when the cells are placed in a hypo-osmotic medium. Neither glutamate nor malate support Ca2+ uptake in 'intact' Ehrlich cells, nor does the endogenous NAD-linked respiration. Ca2+ uptake is completely dependent on mitochondrial energy-coupling mechansims. It was an unexpected finding that maximal Ca2+ uptake supported by succinate requires rotenone, which blocks oxidation of enogenous NAD-linked substrates. Phosphate functions as co-anion for entry of Ca2+. Ca2+ uptake is also supported by extra-cellular ATP; no other nucleoside 5'-di- or tri-phosphate was active. The accumulation of Ca2+ apparently takes place in the mitochondria, since oligomycin and atractyloside inhibit ATP-supported Ca2+ uptake. Glycolysis does not support Ca2+ uptake. Neither free mitochondria released from disrupted cells nor permeability-damaged cells capable of absorbing Trypan Blue were responsible for any large fraction of the total observed energy-coupled Ca2+ uptake. The observations reported also indicate that electron flow through energy-conserving site 1 promotes Ca2+ release from Ehrlich cells and that extra-cellular ATP increase permeability of the cell membrane, allowing both ATP and Ca2+ to enter the cells more readily.

  20. Fumonisin B1, a mycotoxin contaminant of cereal grains, and inducer of apoptosis via the tumour necrosis factor pathway and caspase activation. (United States)

    Ciacci-Zanella, J R; Jones, C


    Fumonisins are mycotoxins produced by Fusarium moniliforme, a prevalent fungus which infects corn or other cereal grains. Fumonisin B1 (FB1) is the most common mycotoxin produced by F. moniliforme, suggesting that it has toxicological significance. The structure of FB1 resembles sphingoid bases and it inhibits ceramide synthase. As sphingoid bases regulate cell growth, differentiation, transformation and apoptosis, it is reasonable to hypothesize that FB1 can also regulate these activities. Previous studies concluded that FB1 induced apoptosis or cell-cycle arrest in CV-1 cells (African green monkey kidney fibroblasts). In this study, we have identified genes that inhibit FB1-induced apoptosis in CV-1 cells and in two primary human cell types (lung fibroblasts and neonatal kidney cells). A baculovirus gene. inhibitor of apoptosis (IAP), protected CV-1 and the human cells from apoptosis. IAP blocks apoptosis which is induced by the tumour necrosis factor (TNF) pathway. Inhibition of interleukin converting enzymes (ICE proteases or caspases) by the baculovirus gene p35 also inhibited FB1-induced apoptosis. FB1 treatment led to cleavage of Rb (retinoblastoma protein) at its C-terminus in CV-1 or human lung cells. As the C-terminus of Rb is cleaved by ICE proteases during apoptosis, this supports an active role for ICE proteases in FB1-induced apoptosis. The tumour suppressor gene p53 was not required for FB1-induced apoptosis because p53-/- primary mouse embryo fibroblasts underwent apoptosis following FB1 treatment. Furthermore, Bcl-2 was not an effective inhibitor of FB1-induced apoptosis in CV-1 or IMR-90 cells. In summary, these results demonstrate that the TNF pathway and caspases plays an important role in FB1-induced apoptosis.

  1. Thoracic malignant peripheral nerve sheath tumour mimicking a pleural tumour: a rare pedunculated appearance

    Energy Technology Data Exchange (ETDEWEB)

    Komori, Masahiro [Department of Radiology, National Kyushu Cancer Centre, 3-1-1 Notame, Minami-ku, Fukuoka 811-1395 (Japan); Department of Radiology, Munakata Medical Association Hospital, 1201-1 Taguma, Munakata 811-3431 (Japan); Yabuuchi, Hidetake; Kuroiwa, Toshiro [Department of Radiology, National Kyushu Cancer Centre, 3-1-1 Notame, Minami-ku, Fukuoka 811-1395 (Japan); Nagatoshi, Yoshihisa [Department of Paediatrics, National Kyushu Cancer Centre, Fukuoka (Japan); Ichinose, Yukito [Department of Thoracic Surgery, National Kyushu Cancer Centre, Fukuoka (Japan); Hachitanda, Yoichi [Department of Pathology, National Kyushu Cancer Centre, Fukuoka (Japan)


    A malignant peripheral nerve sheath tumour (MPNST) generally occurs in adults and often in patients with neurofibromatosis-1 (NF-1). We present a rare case of a huge thoracic MPNST arising from the intercostal nerve in a 12-year-old girl without NF-1. In addition to the unusual occurrence in a child without NF-1, MRI demonstrated a unique pedunculated appearance mimicking a pleural tumour. In this report, we present the CT and MRI findings of our case, together with the histopathological findings, and review previous reports. (orig.)

  2. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. (United States)

    Kir, Serkan; White, James P; Kleiner, Sandra; Kazak, Lawrence; Cohen, Paul; Baracos, Vickie E; Spiegelman, Bruce M


    Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat. How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival.

  3. Malignant Peripheral Nerve Sheath Tumour of the Maxilla

    Directory of Open Access Journals (Sweden)

    Puja Sahai


    Full Text Available A 38-year-old man was diagnosed with malignant peripheral nerve sheath tumour of the maxilla. He was treated with total maxillectomy. Histopathological examination of the resected specimen revealed a close resection margin. The tumour was of high grade with an MIB-1 labelling index of almost 60%. At six weeks following the surgery, he developed local tumour relapse. The patient succumbed to the disease at five months from the time of diagnosis. The present report underlines the locally aggressive nature of malignant peripheral nerve sheath tumour of the maxilla which necessitates an early therapeutic intervention. A complete resection with clear margins is the most important prognostic factor for malignant peripheral nerve sheath tumour in the head and neck region. Adjuvant radiotherapy may be considered to improve the local control. Future research may demarcate the role of targeted therapy for patients with malignant peripheral nerve sheath tumour.

  4. Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis

    DEFF Research Database (Denmark)

    Madsen, Chris D; Pedersen, Jesper Thorhauge; Venning, Freja A;


    Cancer-associated fibroblasts (CAFs) interact with tumour cells and promote growth and metastasis. Here, we show that CAF activation is reversible: chronic hypoxia deactivates CAFs, resulting in the loss of contractile force, reduced remodelling of the surrounding extracellular matrix and......, which can be prevented by simultaneous depletion of HIF-1α. Treatment with the PHD inhibitor DMOG in an orthotopic breast cancer model significantly decreases spontaneous metastases to the lungs and liver, associated with decreased tumour stiffness and fibroblast activation. PHD2 depletion in CAFs co...

  5. Stroma and extracellular matrix proteins in canine tumours



    In this thesis, studies on temporal and spatial changes in stromal cells and extracellular matrix (ECM) molecules in canine gastrointestinal (GIT) tumours and canine transmissible venereal (CTVT) tumours are described. The mechanisms involved in the phenotypic transformation of fibroblasts to myofibroblasts, and ECM changes were investigated. We found that the myofibroblast is the most common stromal cell in canine GIT epithelial tumours and most likely originated from pre-existing fibroblast...

  6. The challenges of detecting circulating tumour cells in sarcoma


    Tellez-Gabriel, M.; Brown, H K; Young, R.; Heymann, M. F.; Heymann, D


    International audience; Sarcomas are a heterogenous group of malignant neoplasms of mesenchymal origin, many of which have a propensity to develop distant metastases. Cancer cells that have escaped from the primary tumour are able to invade into surrounding tissues, to intravasate into the bloodstream to become Circulating Tumour Cells (CTCs), and are responsible for the generation of distant metastases. Due to the rarity of these tumours and the absence of specific markers expressed by sarco...

  7. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting

    Directory of Open Access Journals (Sweden)

    Sander A. A. Kooijmans


    Full Text Available Background: Extracellular vesicles (EVs are attractive candidate drug delivery systems due to their ability to functionally transport biological cargo to recipient cells. However, the apparent lack of target cell specificity of exogenously administered EVs limits their therapeutic applicability. In this study, we propose a novel method to equip EVs with targeting properties, in order to improve their interaction with tumour cells. Methods: EV producing cells were transfected with vectors encoding for anti-epidermal growth factor receptor (EGFR nanobodies, which served as targeting ligands for tumour cells, fused to glycosylphosphatidylinositol (GPI anchor signal peptides derived from decay-accelerating factor (DAF. EVs were isolated using ultrafiltration/size-exclusion liquid chromatography and characterized using western blotting, Nanoparticle Tracking Analysis, and electron microscopy. EV–tumour cell interactions were analyzed under static conditions using flow cytometry and under flow conditions using a live-cell fluorescence microscopy-coupled perfusion system. Results: V analysis showed that GPI-linked nanobodies were successfully displayed on EV surfaces and were highly enriched in EVs compared with parent cells. Display of GPI-linked nanobodies on EVs did not alter general EV characteristics (i.e. morphology, size distribution and protein marker expression, but greatly improved EV binding to tumour cells dependent on EGFR density under static conditions. Moreover, nanobody-displaying EVs showed a significantly improved cell association to EGFR-expressing tumour cells under flow conditions. Conclusions: We show that nanobodies can be anchored on the surface of EVs via GPI, which alters their cell targeting behaviour. Furthermore, this study highlights GPI-anchoring as a new tool in the EV toolbox, which may be applied for EV display of a variety of proteins, such as antibodies, reporter proteins and signaling molecules.

  8. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting (United States)

    Kooijmans, Sander A. A.; Aleza, Clara Gómez; Roffler, Steve R.; van Solinge, Wouter W.; Vader, Pieter; Schiffelers, Raymond M.


    Background Extracellular vesicles (EVs) are attractive candidate drug delivery systems due to their ability to functionally transport biological cargo to recipient cells. However, the apparent lack of target cell specificity of exogenously administered EVs limits their therapeutic applicability. In this study, we propose a novel method to equip EVs with targeting properties, in order to improve their interaction with tumour cells. Methods EV producing cells were transfected with vectors encoding for anti-epidermal growth factor receptor (EGFR) nanobodies, which served as targeting ligands for tumour cells, fused to glycosylphosphatidylinositol (GPI) anchor signal peptides derived from decay-accelerating factor (DAF). EVs were isolated using ultrafiltration/size-exclusion liquid chromatography and characterized using western blotting, Nanoparticle Tracking Analysis, and electron microscopy. EV–tumour cell interactions were analyzed under static conditions using flow cytometry and under flow conditions using a live-cell fluorescence microscopy-coupled perfusion system. Results EV analysis showed that GPI-linked nanobodies were successfully displayed on EV surfaces and were highly enriched in EVs compared with parent cells. Display of GPI-linked nanobodies on EVs did not alter general EV characteristics (i.e. morphology, size distribution and protein marker expression), but greatly improved EV binding to tumour cells dependent on EGFR density under static conditions. Moreover, nanobody-displaying EVs showed a significantly improved cell association to EGFR-expressing tumour cells under flow conditions. Conclusions We show that nanobodies can be anchored on the surface of EVs via GPI, which alters their cell targeting behaviour. Furthermore, this study highlights GPI-anchoring as a new tool in the EV toolbox, which may be applied for EV display of a variety of proteins, such as antibodies, reporter proteins and signaling molecules. PMID:26979463

  9. Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity. (United States)

    Luo, Chong T; Liao, Will; Dadi, Saida; Toure, Ahmed; Li, Ming O


    Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance; yet, excessive Treg cell activities suppress anti-tumour immune responses. Compared to the resting Treg (rTreg) cell phenotype in secondary lymphoid organs, Treg cells in non-lymphoid tissues exhibit an activated Treg (aTreg) cell phenotype. However, the function of aTreg cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg cell suppression of lymphoproliferative diseases, has an unexpected function in inhibiting aTreg-cell-mediated immune tolerance in mice. We find that aTreg cells turned over at a slower rate than rTreg cells, but were not locally maintained in tissues. aTreg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. Treg-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg cell homing to non-lymphoid organs, causing CD8(+) T-cell-mediated autoimmune diseases. Compared to Treg cells from healthy tissues, tumour-infiltrating Treg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated Treg cells, activate effector CD8(+) T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTreg cells that have a crucial function in suppressing CD8(+) T-cell responses; and the Foxo signalling pathway in Treg cells can be titrated to break tumour immune tolerance preferentially.

  10. Blocked Urethral Valves (United States)

    ... Blocked Urethral Valves Health Issues Listen Español Text Size Email Print Share Blocked Urethral Valves Page Content Article Body Urine leaves the bladder through a tube called the urethra, which in boys passes through the penis. Rarely, small membranes form across the urethra in ...

  11. Types of Heart Block (United States)

    ... P wave as it normally would. If an electrical signal is blocked before it reaches the ventricles, they won't contract and pump blood to the lungs and the rest of the body. Second-degree heart block is divided into two ...

  12. Related Drupal Nodes Block

    NARCIS (Netherlands)

    Van der Vegt, Wim


    Related Drupal Nodes Block This module exposes a block that uses Latent Semantic Analysis (Lsa) internally to suggest three nodes that are relevant to the node a user is viewing. This module performs three tasks. 1) It periodically indexes a Drupal site and generates a Lsa Term Document Matrix. Inde

  13. Tumour Heterogeneity: The Key Advantages of Single-Cell Analysis (United States)

    Tellez-Gabriel, Marta; Ory, Benjamin; Lamoureux, Francois; Heymann, Marie-Francoise; Heymann, Dominique


    Tumour heterogeneity refers to the fact that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity), and it is caused by genetic and non-genetic factors. The heterogeneity of cancer cells introduces significant challenges in using molecular prognostic markers as well as for classifying patients that might benefit from specific therapies. Thus, research efforts for characterizing heterogeneity would be useful for a better understanding of the causes and progression of disease. It has been suggested that the study of heterogeneity within Circulating Tumour Cells (CTCs) could also reflect the full spectrum of mutations of the disease more accurately than a single biopsy of a primary or metastatic tumour. In previous years, many high throughput methodologies have raised for the study of heterogeneity at different levels (i.e., RNA, DNA, protein and epigenetic events). The aim of the current review is to stress clinical implications of tumour heterogeneity, as well as current available methodologies for their study, paying specific attention to those able to assess heterogeneity at the single cell level. PMID:27999407

  14. Isolation and identification of marine fish tumour (odontoma) associated bacteria

    Institute of Scientific and Technical Information of China (English)

    Ramalingam Vijayakumar; Kuzhanthaivel Raja; Vijayapoopathi Singaravel; Ayyaru Gopalakrishnan


    Objective: To identify fish tumour associated bacteria. Methods: The marine fish Sphyraena jello with odontoma was collected from in Tamil Nadu (Southeast India), and tumour associated bacteria were isolated. Then the isolated bacteria were identified based on molecular characters. Results: A total of 4 different bacterial species were isolated from tumour tissue. The bacterial species were Bacillus sp., Pontibacter sp., Burkholderia sp. and Macrococcus sp., and the sequences were submitted in DNA Data Bank of Japan with accession numbers of AB859240, AB859241, AB859242 and AB859243 respectively. Conclusions: Four different bacterial species were isolated from Sphyraena jello, but the role of bacteria within tumour needs to be further investigated.

  15. Salivary gland tumours in a Mexican sample. A retrospective study. (United States)

    Ledesma-Montes, C; Garces-Ortiz, M


    Salivary gland tumours are an important part of the Oral and Maxillofacial Pathology, unfortunately, only few studies on these tumours have been done in Latin-American population. The aim of this study was to compare demographic data on salivary gland tumours in a Mexican sample with those previously published from Latin American and non-Latin American countries. All cases of salivary gland tumours or lesions diagnosed in our service were reviewed. Of the reviewed cases,67 were confirmed as salivary gland tumours. Out of these 64.2% were benign neoplasms, 35.8% were malignant and a slight female predominance (56.7%) was found. The most common location was palate followed by lips and floor of the mouth. Mean age for benign tumours was 40.6 years with female predominance (60.5%). Mean age for malignant tumours was 41 years and female predominance was found again. Palate followed by retromolar area were the usual locations. Pleomorphic adenoma (58.2%), mucoepidermoid carcinoma (17.9%) and adenoid cystic carcinoma (11.9%) were the more frequent neoplasms. All retromolar cases were malignant and all submandibular gland tumours were benign. We found a high proportion of salivary gland neoplasms in children. Our results showed that differences of the studied tumours among our sample and previously reported series exist. These differences can be related to race and geographical location.

  16. Molecular-based tumour subtypes of canine mammary carcinomas assessed by immunohistochemistry

    Directory of Open Access Journals (Sweden)

    Sarli Giuseppe


    Full Text Available Abstract Background Human breast cancer is classified by gene expression profile into subtypes consisting of two hormone (oestrogen and/or progesterone receptor-positive types (luminal-like A and luminal-like B and three hormone receptor-negative types [human epidermal growth factor receptor 2-expressing, basal-like, and unclassified ("normal-like"]. Immunohistochemical surrogate panels are also proposed to potentially identify the molecular-based groups. The present study aimed to apply an immunohistochemical panel (anti-ER, -PR, -ERB-B2, -CK 5/6 and -CK14 in a series of canine malignant mammary tumours to verify the molecular-based classification, its correlation with invasion and grade, and its use as a prognostic aid in veterinary practice. Results Thirty-five tumours with luminal pattern (ER+ and PR+ were subgrouped into 13 A type and 22 B type, if ERB-B2 positive or negative. Most luminal-like A and basal-like tumours were grade 1 carcinomas, while the percentage of luminal B tumours was higher in grades 2 and 3 (Pearson Chi-square P = 0.009. No difference in the percentage of molecular subtypes was found between simple and complex/mixed carcinomas (Pearson Chi-square P = 0.47. No significant results were obtained by survival analysis, even if basal-like tumours had a more favourable prognosis than luminal-like lesions. Conclusion The panel of antibodies identified only three tumour groups (luminal-like A and B, and basal-like in the dog. Even though canine mammary tumours may be a model of human breast cancer, the existence of the same carcinoma molecular subtypes in women awaits confirmation. Canine mammary carcinomas show high molecular heterogeneity, which would benefit from a classification based on molecular differences. Stage and grade showed independent associations with survival in the multivariate regression, while molecular subtype grouping and histological type did not show associations. This suggests that caution should be

  17. Modelling the interplay between hypoxia and proliferation in radiotherapy tumour response (United States)

    Jeong, J.; Shoghi, K. I.; Deasy, J. O.


    A tumour control probability computational model for fractionated radiotherapy was developed, with the goal of incorporating the fundamental interplay between hypoxia and proliferation, including reoxygenation over a course of radiotherapy. The fundamental idea is that the local delivery of oxygen and glucose limits the amount of proliferation and metabolically-supported cell survival a tumour sub-volume can support. The model has three compartments: a proliferating compartment of cells receiving oxygen and glucose; an intermediate, metabolically-active compartment receiving glucose; and a highly hypoxic compartment of starving cells. Following the post-mitotic cell death of proliferating cells, intermediate cells move into the proliferative compartment and hypoxic cells move into the intermediate compartment. A key advantage of the proposed model is that the initial compartmental cell distribution is uniquely determined from the assumed local growth fraction (GF) and volume doubling time (TD) values. Varying initial cell state distributions, based on the local (voxel) GF and TD, were simulated. Tumour response was simulated for head and neck squamous cell carcinoma using relevant parameter values based on published sources. The tumour dose required to achieve a 50% local control rate (TCD50) was found for various GFs and TD’s, and the effect of fraction size on TCD50 was also evaluated. Due to the advantage of reoxygenation over a course of radiotherapy, conventional fraction sizes (2-2.4 Gy fx-1) were predicted to result in smaller TCD50's than larger fraction sizes (4-5 Gy fx-1) for a 10 cc tumour with GFs of around 0.15. The time to eliminate hypoxic cells (the reoxygenation time) was estimated for a given GF and decreased as GF increased. The extra dose required to overcome accelerated stem cell accumulation in longer treatment schedules was estimated to be 0.68 Gy/day (in EQD26.6), similar to published values derived from clinical data. The model predicts

  18. The feasibility of a brain tumour website

    DEFF Research Database (Denmark)

    Piil, K; Jakobsen, J; Juhler, M


    PURPOSE: Patients with a high-grade glioma (HGG) and their caregivers have imminent and changing informational and supportive care needs. The purpose of this study was to investigate the feasibility and safety of a Danish brain tumour website (BTW) in patients with HGG and their caregivers. We...... and 2) a sample of patients with HGG (n = 9) and their caregivers (n = 8) interviewed three months after being introduced to the BTW. RESULTS: The BTW was accessed from 131 different Danish towns and cities, and from ten different countries. The website had 637 unique users. The interviews identified...

  19. The Block Neighborhood

    CERN Document Server

    Arrighi, Pablo


    We define the block neighborhood of a reversible CA, which is related both to its decomposition into a product of block permutations and to quantum computing. We give a purely combinatorial characterization of the block neighborhood, which helps in two ways. First, it makes the computation of the block neighborhood of a given CA relatively easy. Second, it allows us to derive upper bounds on the block neighborhood: for a single CA as function of the classical and inverse neighborhoods, and for the composition of several CAs. One consequence of that is a characterization of a class of "elementary" CAs that cannot be written as the composition of two simpler parts whose neighborhoods and inverse neighborhoods would be reduced by one half.

  20. Midkine promoter-driven suicide gene expression and -mediated adenovirus replication produced cytotoxic effects to immortalised and tumour cells. (United States)

    Yu, L; Hamada, K; Namba, M; Kadomatsu, K; Muramatsu, T; Matsubara, S; Tagawa, M


    We examined possible application of a regulatory region of midkine (MK) gene, which is frequently upregulated in a number of human tumours but not in normal cells, to cancer gene therapy. We examined transcriptional activity of the MK genomic fragments in paired cell lines, immortalized cells and their parental normal fibroblasts, and found that the MK fragments activated a fused reporter or a suicide gene preferentially in the immortalized cells. Recombinant adenoviruses (Ad), in which the MK fragment was inserted upstream to the E1A gene (AdMK), replicated preferentially in the immortalized cells and were cytotoxie to them. Human hepatocellular carcinoma cells were significantly susceptible to AdMK compared with human normal fibroblasts in vitro and the replication of AdMK was less than that of wild-type Ad in the infected fibroblasts. Hepatocellular carcinoma cells infected with AdMK did not form tumours in immunocompromised mice and intratumoural injection of AdMK into the hepatocellular carcinoma developed in mice retarded the subsequent tumour growth. Expression of E1A and necrosis of tumours were detected in AdMK-injected but not control Ad-injected cases. The MK promoter-driven suicide gene therapy and -mediated replicative Ad can thereby produce cytotoxic effects to immortalized and tumour cells with minimal damage to normal cells.

  1. Validation of tissue microarray for molecular profiling of canine and feline mammary tumours. (United States)

    Muscatello, L V; Sarli, G; Beha, G; Asproni, P; Millanta, F; Poli, A; De Tolla, L J; Benazzi, C; Brunetti, B


    Tissue microarray (TMA) is a high-throughput method adopted for simultaneous molecular profiling of tissue samples from large patient cohorts. The aim of this study was to validate the TMA method for the molecular classification of canine and feline mammary tumours. Twelve samples, five feline and five canine mammary tumours and two canine haemangiosarcomas, were collected. TMA construction was based on Kononen's method of extracting a cylindrical core of paraffin wax-embedded 'donor' tissue and inserting it into a 'recipient' wax block. Seven consecutive sections from each tissue array block were subjected to immunohistochemistry (IHC) using primary antibodies specific for oestrogen receptor (OR), progesterone receptor (PR), c-erbB-2, cytokeratin (CK) 5/6, CK14, CK19 and p63. The same panel of antibodies was applied to the full sections from all cases. Comparison between full sections and TMA scores revealed different results depending on the antibodies. Labelling for OR, PR, CK19 and p63 showed total concordance, c-erbB2 (score +2, +3) was concordant in nine out of ten cases, CK5/6 and CK14 in eight out of ten cases. The TMA platform preserves the molecular profile of canine and feline mammary tumour markers, representing a useful tool for rapid and cost-effective analysis for the first phenotypic screening using OR, PR and c-erbB2 antibodies. Basal cytokeratin, used for triple negative identification, shows a multifocal 'niche' expression pattern, for which IHC of the full section or multiple core array is recommended.

  2. MRI of intracranial germ-cell tumours

    Energy Technology Data Exchange (ETDEWEB)

    Liang, L.; Korogi, Y.; Sugahara, T.; Ikushima, I.; Shigematsu, Y.; Okuda, T.; Takahashi, M. [Department of Radiology, Kumamoto University School of Medicine (Japan); Kochi, M.; Ushio, Y. [Department of Neurosurgery, Kumamoto University School of Medicine (Japan)


    Abstract. Our aim was to review the MRI appearances of primary intracranial germ-cell tumours (GCT). We reviewed the MRI studies of 32 patients: 19 with germinomas, five with teratomas, one with an embryonal carcinoma, five with mixed and two with malignant nongerminomatous GCT. Eleven were in the pineal region, 12 suprasellar, five in the both sites, two in the basal ganglia and two in the corpus callosum. Contrast-enhanced images were available for 27 patients. The solid parts of GCT were nearly isointense with grey matter on both T1- and T2-weighted images. In seven patients with nongerminomatous GCT high-signal components were found on T1-weighted images, representing haemorrhage, high-protein fluid or fat. Cystic components were detected in 17 of 27 patients; eight germinomas and all nine nongerminomatous GCT had cysts. The solid components of germinomas enhanced homogeneously in eight cases and heterogeneously in 10, while all nongerminomatous GCT showed heterogeneous enhancement. MRI features tumours can facilitate correct diagnosis of GCT, including histological subtypes. (orig.)