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Sample records for pathways control tumour

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

    International Nuclear Information System (INIS)

    Oliveira, Soraya I de; Andrade, Luciana NS; Onuchic, Ana C; Nonogaki, Sueli; Fernandes, Patrícia D; Pinheiro, Mônica C; Rohde, Ciro BS; Chammas, Roger; Jancar, Sonia

    2010-01-01

    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. 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. 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 the cells from inside the tumour, but not the

  2. Tumour angiogenesis pathways: related clinical issues and implications for nuclear medicine imaging

    International Nuclear Information System (INIS)

    Wiele, Christophe van de; De Winter, Olivier; Dierckx, Rudi Andre; Oltenfreiter, Ruth; Slegers, Guido; Signore, Alberto

    2002-01-01

    Tumour angiogenesis is essential for growth, invasion and metastasis. Retrospective studies suggest that it is an independent prognostic factor that merits prospective validation. Furthermore, as tumour blood vessels show many differences from normal vessels and are not genetically unstable, they form a key area for therapy development. However, as anti-angiogenic therapy is primarily cytostatic and not cytotoxic, novel tailor-made specific end-points for treatment monitoring are required. In this regard, suitable molecular parameters for imaging tumour angiogenesis by means of nuclear medicine are being explored. Here we review current knowledge on the multiple pathways controlling tumour angiogenesis and try to assess which are the most clinically relevant for nuclear medicine imaging. Parameters that may influence the imaging potential of radiopharmaceuticals for angiogenesis imaging such as molecular weight and structure, their targeted location within the tumour and their usefulness in terms of specificity and constancy of the targeted molecular pathway are discussed. (orig.)

  3. Oncogenic signalling pathways in benign odontogenic cysts and tumours.

    Science.gov (United States)

    Diniz, Marina Gonçalves; Gomes, Carolina Cavalieri; de Sousa, Sílvia Ferreira; Xavier, Guilherme Machado; Gomez, Ricardo Santiago

    2017-09-01

    The first step towards the prevention of cancer is to develop an in-depth understanding of tumourigenesis and the molecular basis of malignant transformation. What drives tumour initiation? Why do most benign tumours fail to metastasize? Oncogenic mutations, previously considered to be the hallmark drivers of cancers, are reported in benign cysts and tumours, including those that have an odontogenic origin. Despite the presence of such alterations, the vast majority of odontogenic lesions are benign and never progress to the stage of malignant transformation. As these lesions are likely to develop due to developmental defects, it is possible that they harbour quiet genomes. Now the question arises - do they result from DNA replication errors? Specific candidate genes have been sequenced in odontogenic lesions, revealing recurrent BRAF mutation in the case of ameloblastoma, KRAS mutation in adenomatoid odontogenic tumours, PTCH1 mutation in odontogenic keratocysts, and CTNNB1 (Beta-catenin) mutation in calcifying odontogenic cysts. Studies on these benign and rare entities might reveal important information about the tumorigenic process and the mechanisms that hinder/halt neoplastic progression. This is because the role of relatively common oncogenic mutations seems to be context dependent. In this review, each mutation signature of the odontogenic lesion and the affected signalling pathways are discussed in the context of tooth development and tumorigenesis. Furthermore, behavioural differences between different types of odontogenic lesions are explored and discussed based on the molecular alteration described. This review also includes the employment of molecular results for guiding therapeutic approaches towards odontogenic lesions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Increasing the radiosensitivity of tumours in an hypoxic environment using inhibitors of the pentose phosphate pathway

    International Nuclear Information System (INIS)

    Sahasrabudhe, M.B.; Bhonsle, S.R.; Krishnamurti, K.; Tilak, B.D.

    1977-01-01

    Rapidly growing tumours contain few blood vessels in the tumour mass. Cells in such tumours obtain nutrients and oxygen from the periphery by diffusion, resulting in a diminishing oxygen and nutrient gradient from the periphery to centre of the tumour mass. In normal tissues, oxygen is utilized via a tricarboxylic acid (TCA) cycle; in tumour cells oxygen is utilized via a hexose monophosphate (HMP) pathway and through the TCA cycle at a 30% reduced level. Interference with the HMP pathway selectively inhibits the utilization of oxygen by tumour cells, thus increasing the availability of oxygen to hypoxic cells situated deeper in the tumour mass. This effect has been exploited for increasing the radiosensitivity of tumour cells situated in an hypoxic environment. The influence of sixteen potential antimetabolites on the HMP pathway has been studied. Of these, six compounds, namely, (1) 2-carboxy 5-hydroxymethyl thiophene, (2) the sodium salt of 2:5 dicarbethoxy 3:4 dihydroxy thiophene, (3) the dihydrazide of 2:5 dicarboxy thiophene, (4) the dihydrazide of 3:4 dimethoxy 2:5 dicarboxy thiophene, (5) trithiocyanuric acid, and (6) cyanuric trithioglycollic acid showed an inhibiting effect on the HMP pathway without any influence on the TCA cycle. Influence of administration of compounds (1), (2) and (4) prior to radiation on the growth of transplanted fibrosarcomas in mice has been studied and is reported here. These three compounds showed marked potentiation of radiosensitivity of tumours. (author)

  5. Interleukin 21 controls tumour growth and tumour immunosurveillance in colitis-associated tumorigenesis in mice.

    Science.gov (United States)

    Jauch, Dominik; Martin, Maria; Schiechl, Gabriela; Kesselring, Rebecca; Schlitt, Hans Jürgen; Geissler, Edward K; Fichtner-Feigl, Stefan

    2011-12-01

    Colitis-associated tumorigenesis is a balance between proliferation of tumour cells and tumour immunosurveillance. The role of T-helper-cell-derived cytokines in tumour growth is not fully understood. In this study the authors investigated the influence of interleukin (IL) 21 on intestinal tumorigenesis. Chronic colitis was induced in IL-21(-/-) and littermate control wild-type mice with three cycles of 1.5% dextran sulphate sodium (DSS) over 7 days followed by 7 days of drinking water. Mice received an azoxymethane injection on day 0 of DSS-colitis to induce tumorigenesis. Immunohistochemistry was performed on inflamed and tumour-bearing areas of colons. Cytokine expression of isolated colonic CD4 T cells was determined by ELISA. Cytotoxic capacity of isolated colonic CD8 T cells targeting tumour cells was evaluated by flow cytometry and quantitative cytotoxicity assay. Apoptosis of tumour cells was determined by TUNEL assay of colonic sections. Increasing expression of IL-21 was observed in chronic colitis, which showed functional importance, since IL-21 deficiency prevented chronic DSS-colitis development. Further, in the absence of IL-21, significantly fewer tumour nodules were detected, despite a similar extent of intestinal inflammation. In wild-type mice, 8.6±1.9 tumour nodules were found compared with 1.0±1.2 in IL-21-deficient mice. In tumour-bearing IL-21-deficient mice, intestinal inflammation was restored and partly dependent on interferon (IFN)-γ, whereas the inflammation in wild-type mice showed high IL-17A concentrations. In these rare tumours in IL-21-deficient mice, tumour cell proliferation (Ki-67) was decreased, while cell apoptosis was increased, compared with wild-type mice. Increased IFNγ expression in tumour-bearing IL-21-deficient mice led to increased tumour immunosurveillance mediated by cytotoxic CD8CD103 T cells targeting E-cadherin(+) colonic tumour cells and therefore limited tumour growth. These results indicate that IL-21

  6. Converting dose distributions into tumour control probability

    International Nuclear Information System (INIS)

    Nahum, A.E.

    1996-01-01

    The endpoints in radiotherapy that are truly of relevance are not dose distributions but the probability of local control, sometimes known as the Tumour Control Probability (TCP) and the Probability of Normal Tissue Complications (NTCP). A model for the estimation of TCP based on simple radiobiological considerations is described. It is shown that incorporation of inter-patient heterogeneity into the radiosensitivity parameter a through s a can result in a clinically realistic slope for the dose-response curve. The model is applied to inhomogeneous target dose distributions in order to demonstrate the relationship between dose uniformity and s a . The consequences of varying clonogenic density are also explored. Finally the model is applied to the target-volume DVHs for patients in a clinical trial of conformal pelvic radiotherapy; the effect of dose inhomogeneities on distributions of TCP are shown as well as the potential benefits of customizing the target dose according to normal-tissue DVHs. (author). 37 refs, 9 figs

  7. Converting dose distributions into tumour control probability

    Energy Technology Data Exchange (ETDEWEB)

    Nahum, A E [The Royal Marsden Hospital, London (United Kingdom). Joint Dept. of Physics

    1996-08-01

    The endpoints in radiotherapy that are truly of relevance are not dose distributions but the probability of local control, sometimes known as the Tumour Control Probability (TCP) and the Probability of Normal Tissue Complications (NTCP). A model for the estimation of TCP based on simple radiobiological considerations is described. It is shown that incorporation of inter-patient heterogeneity into the radiosensitivity parameter a through s{sub a} can result in a clinically realistic slope for the dose-response curve. The model is applied to inhomogeneous target dose distributions in order to demonstrate the relationship between dose uniformity and s{sub a}. The consequences of varying clonogenic density are also explored. Finally the model is applied to the target-volume DVHs for patients in a clinical trial of conformal pelvic radiotherapy; the effect of dose inhomogeneities on distributions of TCP are shown as well as the potential benefits of customizing the target dose according to normal-tissue DVHs. (author). 37 refs, 9 figs.

  8. From genotypes to phenotypes: classification of the tumour profiles for different variants of the cadherin adhesion pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ramis-Conde, Ignacio [Facultad de Educación de Cuenca, Avenida de los Alfares 44, 16071 Universidad de Castilla la Mancha, Cuenca (Spain); Drasdo, Dirk [Institut National de Recherche en Informatique et en Automatique (INRIA), Rocquencourt/Paris (France)

    2012-06-01

    The E-cadherin adhesive profile expressed by a tumour is a characterization of the intracellular and intercellular protein interactions that control cell–cell adhesion. Within the intracellular proteins that determine the tumour adhesive profile, Src and PI3 are two essentials to initiate the formation of the E-cadherin adhesion complex. On the other hand, Src has also the capability of disrupting the β-catenin–E-cadherin complex and down-regulating cell–cell adhesion. In this paper, using a multi-scale mathematical model, we study the role of each of these proteins in the adhesive profile and invasive properties of the tumour. To do this, we create three versions of an intracellular model that explains the interplay between the proteins E-cadherin, β-catenin, Src and PI3; and we couple them to the strength of the cell–cell adhesion forces within an individual-cell-based model. The simulation results show how the tumour profile and its aggressive potential may change depending on the intrinsic characteristics of the protein pathways, and how these pathways may influence the early stages of cancer invasion. Our major findings may be summarized as follows. (1) Intermediate levels of Src synthesis rates generate the least invasive tumour phenotype. (2) Conclusions drawn from findings obtained from the intracellular molecular dynamics (here cadherin–catenin binding complexes) to the multi-cellular invasive potential of a tumour may be misleading or erroneous. The conclusions should be validated in a multi-cellular context on timescales relevant for population growth. (3) Monoclonal populations of more cohesive cells with otherwise equal properties tend to grow slower. (4) Less cohesive cells tend to outcompete more cohesive cells. (5) Less cohesive cells have a larger probability of invasion as migration forces can more easily outbalance cohesive forces. (paper)

  9. From genotypes to phenotypes: classification of the tumour profiles for different variants of the cadherin adhesion pathway

    International Nuclear Information System (INIS)

    Ramis-Conde, Ignacio; Drasdo, Dirk

    2012-01-01

    The E-cadherin adhesive profile expressed by a tumour is a characterization of the intracellular and intercellular protein interactions that control cell–cell adhesion. Within the intracellular proteins that determine the tumour adhesive profile, Src and PI3 are two essentials to initiate the formation of the E-cadherin adhesion complex. On the other hand, Src has also the capability of disrupting the β-catenin–E-cadherin complex and down-regulating cell–cell adhesion. In this paper, using a multi-scale mathematical model, we study the role of each of these proteins in the adhesive profile and invasive properties of the tumour. To do this, we create three versions of an intracellular model that explains the interplay between the proteins E-cadherin, β-catenin, Src and PI3; and we couple them to the strength of the cell–cell adhesion forces within an individual-cell-based model. The simulation results show how the tumour profile and its aggressive potential may change depending on the intrinsic characteristics of the protein pathways, and how these pathways may influence the early stages of cancer invasion. Our major findings may be summarized as follows. (1) Intermediate levels of Src synthesis rates generate the least invasive tumour phenotype. (2) Conclusions drawn from findings obtained from the intracellular molecular dynamics (here cadherin–catenin binding complexes) to the multi-cellular invasive potential of a tumour may be misleading or erroneous. The conclusions should be validated in a multi-cellular context on timescales relevant for population growth. (3) Monoclonal populations of more cohesive cells with otherwise equal properties tend to grow slower. (4) Less cohesive cells tend to outcompete more cohesive cells. (5) Less cohesive cells have a larger probability of invasion as migration forces can more easily outbalance cohesive forces. (paper)

  10. Deregulation of the RB pathway in human testicular germ cell tumours

    DEFF Research Database (Denmark)

    Bartkova, Jirina; Lukas, Claudia; Sørensen, Claus S

    2003-01-01

    Deregulation of the RB pathway is shared by most human malignancies. Components upstream of the retinoblastoma tumour suppressor (pRB), namely the INK4 family of cyclin-dependent kinase (CDK) inhibitors, the D-type cyclins, their partner kinases CDK4/CDK6, and pRB as their critical substrate...

  11. Mutant p53 drives cancer by subverting multiple tumour suppression pathways

    Directory of Open Access Journals (Sweden)

    Sue eHaupt

    2016-01-01

    Full Text Available The tumour suppressor p53 normally acts as a brake to halt damaged cells from perpetrating their genetic errors into future generations. If p53 is disrupted by mutation, it may not only lose these corrective powers, but counter-productively acquire new capacities that drive cancer. A newly emerging manner in which mutant p53 executes its cancer promoting functions is by harnessing key proteins (including many transcription factors, which normally partner with its wild type, tumour-inhibiting counterpart. In association with the subverted activities of these protein partners, mutant p53 is empowered to act across multiple fundamental cellular pathways (regulating cell division and metabolism and corrupt them to become cancer promoting.

  12. Tumour chemotherapy strategy based on impulse control theory.

    Science.gov (United States)

    Ren, Hai-Peng; Yang, Yan; Baptista, Murilo S; Grebogi, Celso

    2017-03-06

    Chemotherapy is a widely accepted method for tumour treatment. A medical doctor usually treats patients periodically with an amount of drug according to empirical medicine guides. From the point of view of cybernetics, this procedure is an impulse control system, where the amount and frequency of drug used can be determined analytically using the impulse control theory. In this paper, the stability of a chemotherapy treatment of a tumour is analysed applying the impulse control theory. The globally stable condition for prescription of a periodic oscillatory chemotherapeutic agent is derived. The permanence of the solution of the treatment process is verified using the Lyapunov function and the comparison theorem. Finally, we provide the values for the strength and the time interval that the chemotherapeutic agent needs to be applied such that the proposed impulse chemotherapy can eliminate the tumour cells and preserve the immune cells. The results given in the paper provide an analytical formula to guide medical doctors to choose the theoretical minimum amount of drug to treat the cancer and prevent harming the patients because of over-treating.This article is part of the themed issue 'Horizons of cybernetical physics'. © 2017 The Author(s).

  13. Pathway-based analysis of a melanoma genome-wide association study: analysis of genes related to tumour-immunosuppression.

    Directory of Open Access Journals (Sweden)

    Nils Schoof

    Full Text Available Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs in 43 genes (39 genomic regions related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (p(emp=0.002, as well as the subgroups related to the generation of tolerogenic dendritic cells (p(emp=0.006 and secretion of suppressive factors (p(emp=0.0004, thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges.

  14. ERK5 pathway regulates the phosphorylation of tumour suppressor hDlg during mitosis

    Energy Technology Data Exchange (ETDEWEB)

    Inesta-Vaquera, Francisco A. [Departamento de Inmunologia y Oncologia, Centro Nacional de Biotecnologia-CSIC, Campus de Cantoblanco-UAM, 28049 Madrid (Spain); Campbell, David G.; Arthur, J. Simon C. [MRC Protein Phosphorylation Unit, Sir James Black Building, School of Life Sciences, University of Dundee, Dundee DD1 5EH (United Kingdom); Cuenda, Ana, E-mail: acuenda@cnb.csic.es [Departamento de Inmunologia y Oncologia, Centro Nacional de Biotecnologia-CSIC, Campus de Cantoblanco-UAM, 28049 Madrid (Spain)

    2010-08-13

    Research highlights: {yields} hDlg is phosphorylated during mitosis in multiple residues. {yields} Prospho-hDlg is excluded from the midbody during mitosis. {yields} hDlg is not phosphorylated by p38{gamma} or JNK1/2 during mitosis. {yields} ERK5 pathway mediates hDlg phosphorylation in mitosis. -- Abstract: Human disc-large (hDlg) is a scaffold protein critical for the maintenance of cell polarity and adhesion. hDlg is thought to be a tumour suppressor that regulates the cell cycle and proliferation. However, the mechanism and pathways involved in hDlg regulation during these processes is still unclear. Here we report that hDlg is phosphorylated during mitosis, and we establish the identity of at least three residues phosphorylated in hDlg; some are previously unreported. Phosphorylation affects hDlg localisation excluding it from the contact point between the two daughter cells. Our results reveal a previously unreported pathway for hDlg phosphorylation in mitosis and show that ERK5 pathway mediates hDlg cell cycle dependent phosphorylation. This is likely to have important implications in the correct timely mitotic entry and mitosis progression.

  15. ERK5 pathway regulates the phosphorylation of tumour suppressor hDlg during mitosis

    International Nuclear Information System (INIS)

    Inesta-Vaquera, Francisco A.; Campbell, David G.; Arthur, J. Simon C.; Cuenda, Ana

    2010-01-01

    Research highlights: → hDlg is phosphorylated during mitosis in multiple residues. → Prospho-hDlg is excluded from the midbody during mitosis. → hDlg is not phosphorylated by p38γ or JNK1/2 during mitosis. → ERK5 pathway mediates hDlg phosphorylation in mitosis. -- Abstract: Human disc-large (hDlg) is a scaffold protein critical for the maintenance of cell polarity and adhesion. hDlg is thought to be a tumour suppressor that regulates the cell cycle and proliferation. However, the mechanism and pathways involved in hDlg regulation during these processes is still unclear. Here we report that hDlg is phosphorylated during mitosis, and we establish the identity of at least three residues phosphorylated in hDlg; some are previously unreported. Phosphorylation affects hDlg localisation excluding it from the contact point between the two daughter cells. Our results reveal a previously unreported pathway for hDlg phosphorylation in mitosis and show that ERK5 pathway mediates hDlg cell cycle dependent phosphorylation. This is likely to have important implications in the correct timely mitotic entry and mitosis progression.

  16. Apoptotic intrinsic pathway proteins predict survival in canine cutaneous mast cell tumours.

    Science.gov (United States)

    Barra, C N; Macedo, B M; Cadrobbi, K G; Pulz, L H; Huete, G C; Kleeb, S R; Xavier, J G; Catão-Dias, J L; Nishiya, A T; Fukumasu, H; Strefezzi, R F

    2018-03-01

    Mast cell tumours (MCTs) are the most frequent canine round cell neoplasms and show variable biological behaviours with high metastatic and recurrence rates. The disease is treated surgically and wide margins are recommended. Adjuvant chemotherapy and radiotherapy used in this disease cause DNA damage in neoplastic cells, which is aimed to induce apoptotic cell death. Resisting cell death is a hallmark of cancer, which contributes to the development and progression of tumours. The aim of this study was to investigate the expression of the proteins involved in the apoptotic intrinsic pathway and to evaluate their potential use as prognostic markers for canine cutaneous MCTs. Immunohistochemistry for BAX, BCL2, APAF1, Caspase-9, and Caspase-3 was performed in 50 canine cases of MCTs. High BAX expression was associated with higher mortality rate and shorter survival. BCL2 and APAF1 expressions offered additional prognostic information to the histopathological grading systems. The present results indicate that variations in the expression of apoptotic proteins are related to malignancy of cutaneous MCTs in dogs. © 2017 John Wiley & Sons Ltd.

  17. Mathematical modeling of liver metastases tumour growth and control with radiotherapy

    International Nuclear Information System (INIS)

    Campbell, Adrienne; Sivakumaran, Thiru; Wong, Eugene; Davidson, Melanie; Lock, Michael

    2008-01-01

    Generating an optimized radiation treatment plan requires understanding the factors affecting tumour control. Mathematical models of tumour dynamics may help in future studies of factors predicting tumour sensitivity to radiotherapy. In this study, a time-dependent differential model, incorporating biological cancer markers, is presented to describe pre-treatment tumour growth, response to radiation, and recurrence. The model uses Gompertzian-Exponential growth to model pre-treatment tumour growth. The effect of radiotherapy is handled by a realistic cell-kill term that includes a volume-dependent change in tumour sensitivity. Post-treatment, a Gompertzian, accelerated, delayed repopulation is employed. As proof of concept, we examined the fit of the model's prediction using various liver enzyme levels as markers of metastatic liver tumour growth in a liver cancer patient. A tumour clonogen population model was formulated. Each enzyme was coupled to the same tumour population, and served as surrogates of the tumour. This dynamical model was solved numerically and compared to the measured enzyme levels. By minimizing the mean-squared error of the model enzyme predictions, we determined the following tumour model parameters: growth rate prior to treatment was 0.52% per day; the fractional radiation cell kill for the prescribed dose (60 Gy in 15 fractions) was 42% per day, and the tumour repopulation rate was 2.9% per day. These preliminary results provided the basis to test the model in a larger series of patients, to apply biological markers for improving the efficacy of radiotherapy by determining the underlying tumour dynamics.

  18. Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay

    International Nuclear Information System (INIS)

    Knight, Louise A; Kurbacher, Christian M; Glaysher, Sharon; Fernando, Augusta; Reichelt, Ralf; Dexel, Susanne; Reinhold, Uwe; Cree, Ian A

    2009-01-01

    Previous data suggest that lipophilic statins such as fluvastatin and N-bisphosphonates such as zoledronic acid, both inhibitors of the mevalonate metabolic pathway, have anti-cancer effects in vitro and in patients. We have examined the effect of fluvastatin alone and in combination with zoledronic acid in the ATP-based tumour chemosensitivity assay (ATP-TCA) for effects on breast and ovarian cancer tumour-derived cells. Both zoledronic acid and fluvastatin showed activity in the ATP-TCA against breast and ovarian cancer, though fluvastatin alone was less active, particularly against breast cancer. The combination of zoledronic acid and fluvastatin was more active than either single agent in the ATP-TCA with some synergy against breast and ovarian cancer tumour-derived cells. Sequential drug experiments showed that pre-treatment of ovarian tumour cells with fluvastatin resulted in decreased sensitivity to zoledronic acid. Addition of mevalonate pathway components with zoledronic acid with or without fluvastatin showed little effect, while mevalonate did reduced inhibition due to fluvastatin. These data suggest that the combination of zoledronic acid and fluvastatin may have activity against breast and ovarian cancer based on direct anti-cancer cell effects. A clinical trial to test this is in preparation

  19. Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer.

    Science.gov (United States)

    Murase, Ryuichi; Kawamura, Rumi; Singer, Eric; Pakdel, Arash; Sarma, Pranamee; Judkins, Jonathon; Elwakeel, Eiman; Dayal, Sonali; Martinez-Martinez, Esther; Amere, Mukkanti; Gujjar, Ramesh; Mahadevan, Anu; Desprez, Pierre-Yves; McAllister, Sean D

    2014-10-01

    The psychoactive cannabinoid Δ(9) -tetrahydrocannabinol (THC) and the non-psychoactive cannabinoid cannabidiol (CBD) can both reduce cancer progression, each through distinct anti-tumour pathways. Our goal was to discover a compound that could efficiently target both cannabinoid anti-tumour pathways. To measure breast cancer cell proliferation/viability and invasion, MTT and Boyden chamber assays were used. Modulation of reactive oxygen species (ROS) and apoptosis was measured using dichlorodihydrofluorescein and annexin/propidium iodide, respectively, in combination with cell flow cytometry. Changes in protein levels were evaluated using Western analysis. Orthotopic and i.v. mouse models of breast cancer metastasis were used to test the activity of cannabinoids in vivo. CBD reduced breast cancer metastasis in advanced stages of the disease as the direct result of down-regulating the transcriptional regulator Id1. However, this was associated with moderate increases in survival. We therefore screened for analogues that could co-target cannabinoid anti-tumour pathways (CBD- and THC-associated) and discovered the compound O-1663. This analogue inhibited Id1, produced a marked stimulation of ROS, up-regulated autophagy and induced apoptosis. Of all the compounds tested, it was the most potent at inhibiting breast cancer cell proliferation and invasion in culture and metastasis in vivo. O-1663 prolonged survival in advanced stages of breast cancer metastasis. Developing compounds that can simultaneously target multiple cannabinoid anti-tumour pathways efficiently may provide a novel approach for the treatment of patients with metastatic breast cancer. © 2014 The British Pharmacological Society.

  20. Characterisation of the p53 pathway in cell lines established from TH-MYCN transgenic mouse tumours.

    Science.gov (United States)

    Chen, Lindi; Esfandiari, Arman; Reaves, William; Vu, Annette; Hogarty, Michael D; Lunec, John; Tweddle, Deborah A

    2018-03-01

    Cell lines established from the TH-MYCN transgenic murine model of neuroblastoma are a valuable preclinical, immunocompetent, syngeneic model of neuroblastoma, for which knowledge of their p53 pathway status is important. In this study, the Trp53 status and functional response to Nutlin-3 and ionising radiation (IR) were determined in 6 adherent TH-MYCN transgenic cell lines using Sanger sequencing, western blot analysis and flow cytometry. Sensitivity to structurally diverse MDM2 inhibitors (Nutlin-3, MI-63, RG7388 and NDD0005) was determined using XTT proliferation assays. In total, 2/6 cell lines were Trp53 homozygous mutant (NHO2A and 844MYCN+/+) and 1/6 (282MYCN+/-) was Trp53 heterozygous mutant. For 1/6 cell lines (NHO2A), DNA from the corresponding primary tumour was found to be Trp53 wt. In all cases, the presence of a mutation was consistent with aberrant p53 signalling in response to Nutlin-3 and IR. In comparison to TP53 wt human neuroblastoma cells, Trp53 wt murine control and TH-MYCN cell lines were significantly less sensitive to growth inhibition mediated by MI-63 and RG7388. These murine Trp53 wt and mutant TH-MYCN cell lines are useful syngeneic, immunocompetent neuroblastoma models, the former to test p53-dependent therapies in combination with immunotherapies, such as anti-GD2, and the latter as models of chemoresistant relapsed neuroblastoma when aberrations in the p53 pathway are more common. The spontaneous development of Trp53 mutations in 3 cell lines from TH-MYCN mice may have arisen from MYCN oncogenic driven and/or ex vivo selection. The identified species-dependent selectivity of MI-63 and RG7388 should be considered when interpreting in vivo toxicity studies of MDM2 inhibitors.

  1. Investigation of the impact of dose fluctuations on tumour control

    International Nuclear Information System (INIS)

    Zavgorodni, S.F.; Royal Adelaide Hospital,; Booth, J.; Adelaide University,; Rosenfeld, A.

    2001-01-01

    Full text: The importance of spatial uniformity of the dose across the Planning Target Volume (PTV) has been investigated previously with the conclusion stated in 'uniform dose theorem' concluding that the uniform dose results in the highest Tumour Control Probability (TCP). The dose fluctuations, which appear in fractionated treatments as a result of setup errors, organ motion, treatment machine calibration and other reasons can be seen as temporal dose non-uniformity. The intuitive expectation, that the temporal dose non-uniformity would also reduce TCP, has been tested. The impact of temporal dose non-uniformity has been investigated considering intra and inter-treatment dose fluctuations. The dose was considered to be spatially uniform. The convolution technique was used and analytical expression of TCP accounting for the dose fluctuation has also been derived. Both techniques used Probability Density Function (PDF) to account for the dose fluctuations. The dose fluctuations with PDF symmetrical around its mean value (Gaussian) as well as non-symmetrical PDFs were both investigated. The symmetrical PDFs represented the fluctuations, which appear in the whole PTV as a result of day to day variation in treatment machine output. Non-symmetrical PDFs represented the dose fluctuations at the edges of PTV as a result of setup errors and organ motion. The effect of the dose fluctuations has been expressed in terms of an extra dose δ (positive or negative) which should be added to the value of temporally uniform dose in order to provide the same TCP as the one resulting from temporally non-uniform (fluctuating) dose. Intra-treatment dose fluctuations resulted in an increased TCP, though the effect is relatively small (δ<1 Gy for the treatment dose of 60 Gy). However, inter-treatment fluctuations of the dose reduced TCP for a patient population. The size of effect increases with the standard deviation of the PDF. Random ultra-treatment dose fluctuations resulted in

  2. Combined treatment of the immunoconjugate bivatuzumab mertansine and fractionated irradiation improves local tumour control in vivo

    International Nuclear Information System (INIS)

    Gurtner, Kristin; Hessel, Franziska; Eicheler, Wolfgang; Dörfler, Annegret; Zips, Daniel; Heider, Karl-Heinz; Krause, Mechthild; Baumann, Michael

    2012-01-01

    Background and purpose: To test whether BIWI 1 (bivatuzumab mertansine), an immunoconjugate of the humanized anti-CD44v6 monoclonal antibody BIWA 4 and the maytansinoid DM1, given simultaneously to fractionated irradiation improves local tumour control in vivo compared with irradiation alone. Material and methods: For growth delay, FaDu tumours were treated with 5 intravenous injections (daily) of phosphate buffered saline (PBS, control), BIWA 4 (monoclonal antibody against CD44v6) or BIWI 1 (bivatuzumab mertansine) at two different dose levels (50 μg/kg DM1 and 100 μg/kg DM1). For local tumour control, FaDu tumours received fractionated irradiation (5f/5d) with simultaneous PBS, BIWA 4 or BIWI 1 (two dose levels). Results: BIWI 1 significantly improved local tumour control after irradiation with 5 fractions already in the lower concentration. The dose modifying factor of 1.9 is substantial compared to the majority of other modifiers of radiation response. Conclusion: Because of the magnitude of the curative effect, this approach is highly promising and should be further evaluated using similar combinations with improved tumour-specificity.

  3. The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation.

    Science.gov (United States)

    Han, Zhi-Yan; Richer, Wilfrid; Fréneaux, Paul; Chauvin, Céline; Lucchesi, Carlo; Guillemot, Delphine; Grison, Camille; Lequin, Delphine; Pierron, Gaelle; Masliah-Planchon, Julien; Nicolas, André; Ranchère-Vince, Dominique; Varlet, Pascale; Puget, Stéphanie; Janoueix-Lerosey, Isabelle; Ayrault, Olivier; Surdez, Didier; Delattre, Olivier; Bourdeaut, Franck

    2016-01-28

    Rhabdoid tumours (RTs) are highly aggressive tumours of infancy, frequently localized in the central nervous system (CNS) where they are termed atypical teratoid/rhabdoid tumours (AT/RTs) and characterized by bi-allelic inactivation of the SMARCB1 tumour suppressor gene. In this study, by temporal control of tamoxifen injection in Smarcb1(flox/flox);Rosa26-Cre(ERT2) mice, we explore the phenotypes associated with Smarcb1 inactivation at different developmental stages. Injection before E6, at birth or at 2 months of age recapitulates previously described phenotypes including embryonic lethality, hepatic toxicity or development of T-cell lymphomas, respectively. Injection between E6 and E10 leads to high penetrance tumours, mainly intra-cranial, with short delays (median: 3 months). These tumours demonstrate anatomical, morphological and gene expression profiles consistent with those of human AT/RTs. Moreover, intra- and inter-species comparisons of tumours reveal that human and mouse RTs can be split into different entities that may underline the variety of RT cells of origin.

  4. PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia.

    Science.gov (United States)

    Banh, Robert S; Iorio, Caterina; Marcotte, Richard; Xu, Yang; Cojocari, Dan; Rahman, Anas Abdel; Pawling, Judy; Zhang, Wei; Sinha, Ankit; Rose, Christopher M; Isasa, Marta; Zhang, Shuang; Wu, Ronald; Virtanen, Carl; Hitomi, Toshiaki; Habu, Toshiyuki; Sidhu, Sachdev S; Koizumi, Akio; Wilkins, Sarah E; Kislinger, Thomas; Gygi, Steven P; Schofield, Christopher J; Dennis, James W; Wouters, Bradly G; Neel, Benjamin G

    2016-07-01

    Tumours exist in a hypoxic microenvironment and must limit excessive oxygen consumption. Hypoxia-inducible factor (HIF) controls mitochondrial oxygen consumption, but how/if tumours regulate non-mitochondrial oxygen consumption (NMOC) is unknown. Protein-tyrosine phosphatase-1B (PTP1B) is required for Her2/Neu-driven breast cancer (BC) in mice, although the underlying mechanism and human relevance remain unclear. We found that PTP1B-deficient HER2(+) xenografts have increased hypoxia, necrosis and impaired growth. In vitro, PTP1B deficiency sensitizes HER2(+) BC lines to hypoxia by increasing NMOC by α-KG-dependent dioxygenases (α-KGDDs). The moyamoya disease gene product RNF213, an E3 ligase, is negatively regulated by PTP1B in HER2(+) BC cells. RNF213 knockdown reverses the effects of PTP1B deficiency on α-KGDDs, NMOC and hypoxia-induced death of HER2(+) BC cells, and partially restores tumorigenicity. We conclude that PTP1B acts via RNF213 to suppress α-KGDD activity and NMOC. This PTP1B/RNF213/α-KGDD pathway is critical for survival of HER2(+) BC, and possibly other malignancies, in the hypoxic tumour microenvironment.

  5. Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target.

    Science.gov (United States)

    Apps, John R; Carreno, Gabriela; Gonzalez-Meljem, Jose Mario; Haston, Scott; Guiho, Romain; Cooper, Julie E; Manshaei, Saba; Jani, Nital; Hölsken, Annett; Pettorini, Benedetta; Beynon, Robert J; Simpson, Deborah M; Fraser, Helen C; Hong, Ying; Hallang, Shirleen; Stone, Thomas J; Virasami, Alex; Donson, Andrew M; Jones, David; Aquilina, Kristian; Spoudeas, Helen; Joshi, Abhijit R; Grundy, Richard; Storer, Lisa C D; Korbonits, Márta; Hilton, David A; Tossell, Kyoko; Thavaraj, Selvam; Ungless, Mark A; Gil, Jesus; Buslei, Rolf; Hankinson, Todd; Hargrave, Darren; Goding, Colin; Andoniadou, Cynthia L; Brogan, Paul; Jacques, Thomas S; Williams, Hywel J; Martinez-Barbera, Juan Pedro

    2018-05-01

    Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP

  6. Multiple model predictive control for optimal drug administration of mixed immunotherapy and chemotherapy of tumours.

    Science.gov (United States)

    Sharifi, N; Ozgoli, S; Ramezani, A

    2017-06-01

    Mixed immunotherapy and chemotherapy of tumours is one of the most efficient ways to improve cancer treatment strategies. However, it is important to 'design' an effective treatment programme which can optimize the ways of combining immunotherapy and chemotherapy to diminish their imminent side effects. Control engineering techniques could be used for this. The method of multiple model predictive controller (MMPC) is applied to the modified Stepanova model to induce the best combination of drugs scheduling under a better health criteria profile. The proposed MMPC is a feedback scheme that can perform global optimization for both tumour volume and immune competent cell density by performing multiple constraints. Although current studies usually assume that immunotherapy has no side effect, this paper presents a new method of mixed drug administration by employing MMPC, which implements several constraints for chemotherapy and immunotherapy by considering both drug toxicity and autoimmune. With designed controller we need maximum 57% and 28% of full dosage of drugs for chemotherapy and immunotherapy in some instances, respectively. Therefore, through the proposed controller less dosage of drugs are needed, which contribute to suitable results with a perceptible reduction in medicine side effects. It is observed that in the presence of MMPC, the amount of required drugs is minimized, while the tumour volume is reduced. The efficiency of the presented method has been illustrated through simulations, as the system from an initial condition in the malignant region of the state space (macroscopic tumour volume) transfers into the benign region (microscopic tumour volume) in which the immune system can control tumour growth. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Scribble Modulates the MAPK/Fra1 Pathway to Disrupt Luminal and Ductal Integrity and Suppress Tumour Formation in the Mammary Gland

    Science.gov (United States)

    Godde, Nathan J.; Sheridan, Julie M.; Smith, Lorey K.; Pearson, Helen B.; Britt, Kara L.; Galea, Ryan C.; Yates, Laura L.; Visvader, Jane E.; Humbert, Patrick O.

    2014-01-01

    Polarity coordinates cell movement, differentiation, proliferation and apoptosis to build and maintain complex epithelial tissues such as the mammary gland. Loss of polarity and the deregulation of these processes are critical events in malignant progression but precisely how and at which stage polarity loss impacts on mammary development and tumourigenesis is unclear. Scrib is a core polarity regulator and tumour suppressor gene however to date our understanding of Scrib function in the mammary gland has been limited to cell culture and transplantation studies of cell lines. Utilizing a conditional mouse model of Scrib loss we report for the first time that Scrib is essential for mammary duct morphogenesis, mammary progenitor cell fate and maintenance, and we demonstrate a critical and specific role for Scribble in the control of the early steps of breast cancer progression. In particular, Scrib-deficiency significantly induced Fra1 expression and basal progenitor clonogenicity, which resulted in fully penetrant ductal hyperplasia characterized by high cell turnover, MAPK hyperactivity, frank polarity loss with mixing of apical and basolateral membrane constituents and expansion of atypical luminal cells. We also show for the first time a role for Scribble in mammalian spindle orientation with the onset of mammary hyperplasia being associated with aberrant luminal cell spindle orientation and a failure to apoptose during the final stage of duct tubulogenesis. Restoring MAPK/Fra1 to baseline levels prevented Scrib-hyperplasia, whereas persistent Scrib deficiency induced alveolar hyperplasia and increased the incidence, onset and grade of mammary tumours. These findings, based on a definitive genetic mouse model provide fundamental insights into mammary duct maturation and homeostasis and reveal that Scrib loss activates a MAPK/Fra1 pathway that alters mammary progenitor activity to drive premalignancy and accelerate tumour progression. PMID:24852022

  8. Long-term quality of life and tumour control following gamma knife radiosurgery for vestibular schwannoma

    DEFF Research Database (Denmark)

    Wangerid, Theresa; Bartek, Jiri; Svensson, Mikael

    2014-01-01

    Gamma knife radiosurgery (GKRS) has for the last decades been an established treatment option for patients with small- or medium-sized vestibular schwannomas (VS), although little data is reported on long-term outcome regarding quality of life (QOL) and tumour control in this patient category...

  9. The effects of radiotherapy treatment uncertainties on the delivered dose distribution and tumour control probability

    International Nuclear Information System (INIS)

    Booth, J.T.; Zavgorodni, S.F.; Royal Adelaide Hospital, SA

    2001-01-01

    Uncertainty in the precise quantity of radiation dose delivered to tumours in external beam radiotherapy is present due to many factors, and can result in either spatially uniform (Gaussian) or spatially non-uniform dose errors. These dose errors are incorporated into the calculation of tumour control probability (TCP) and produce a distribution of possible TCP values over a population. We also study the effect of inter-patient cell sensitivity heterogeneity on the population distribution of patient TCPs. This study aims to investigate the relative importance of these three uncertainties (spatially uniform dose uncertainty, spatially non-uniform dose uncertainty, and inter-patient cell sensitivity heterogeneity) on the delivered dose and TCP distribution following a typical course of fractionated external beam radiotherapy. The dose distributions used for patient treatments are modelled in one dimension. Geometric positioning uncertainties during and before treatment are considered as shifts of a pre-calculated dose distribution. Following the simulation of a population of patients, distributions of dose across the patient population are used to calculate mean treatment dose, standard deviation in mean treatment dose, mean TCP, standard deviation in TCP, and TCP mode. These parameters are calculated with each of the three uncertainties included separately. The calculations show that the dose errors in the tumour volume are dominated by the spatially uniform component of dose uncertainty. This could be related to machine specific parameters, such as linear accelerator calibration. TCP calculation is affected dramatically by inter-patient variation in the cell sensitivity and to a lesser extent by the spatially uniform dose errors. The positioning errors with the 1.5 cm margins used cause dose uncertainty outside the tumour volume and have a small effect on mean treatment dose (in the tumour volume) and tumour control. Copyright (2001) Australasian College of

  10. Treatment fractionation for stereotactic radiotherapy of lung tumours: a modelling study of the influence of chronic and acute hypoxia on tumour control probability

    International Nuclear Information System (INIS)

    Lindblom, Emely; Antonovic, Laura; Dasu, Alexandru; Lax, Ingmar; Wersäll, Peter; Toma-Dasu, Iuliana

    2014-01-01

    Stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC) has led to promising local control and overall survival for fractionation schemes with increasingly high fractional doses. A point has however been reached where the number of fractions used might be too low to allow efficient local inter-fraction reoxygenation of the hypoxic cells residing in the tumour. It was therefore the purpose of this study to investigate the impact of hypoxia and extreme hypofractionation on the tumour control probability (TCP) from SBRT. A three-dimensional model of tumour oxygenation able to simulate oxygenation changes on the microscale was used. The TCP was determined for clinically relevant SBRT fractionation schedules of 1, 3 and 5 fractions assuming either static tumour oxygenation or that the oxygenation changes locally between fractions due to fast reoxygenation of acute hypoxia without an overall reduction in chronic hypoxia. For the schedules applying three or five fractions the doses required to achieve satisfying levels of TCP were considerably lower when local oxygenation changes were assumed compared to the case of static oxygenation; a decrease in D 50 of 17.7 Gy was observed for a five-fractions schedule applied to a 20% hypoxic tumour when fast reoxygenation was modelled. Assuming local oxygenation changes, the total doses required for a tumor control probability of 50% were of similar size for one, three and five fractions. Although attractive from a practical point of view, extreme hypofractionation using just one single fraction may result in impaired local control of hypoxic tumours, as it eliminates the possibility for any kind of reoxygenation

  11. Diverse effects of combined radiotherapy and EGFR inhibition with antibodies or TK inhibitors on local tumour control and correlation with EGFR gene expression

    International Nuclear Information System (INIS)

    Gurtner, Kristin; Deuse, Yvonne; Buetof, Rebecca; Schaal, Katja; Eicheler, Wolfgang; Oertel, Reinhard; Grenman, Reidar; Thames, Howard; Yaromina, Ala; Baumann, Michael; Krause, Mechthild

    2011-01-01

    Purpose: To compare functional effects of combined irradiation and EGFR inhibition in different HNSCC tumour models in vivo with the results of molecular evaluations, aiming to set a basis for the development of potential biomarkers for local tumour control. Material and methods: In five HNSCC tumour models, all wild-type for EGFR and KRAS, the effect of radiotherapy alone (30 fractions/6 weeks) and with simultaneous cetuximab or erlotinib treatment on local tumour control were evaluated and compared with molecular data on western blot, immunohistochemistry and fluorescence-in situ-hybridisation (FISH). Results: Erlotinib and cetuximab alone significantly prolonged tumour growth time in 4/5 tumour models. Combined irradiation and cetuximab treatment significantly improved local tumour control in 3/5 tumour models, whereas erlotinib did not alter local tumour control in any of the tumour models. The amount of the cetuximab-effect on local tumour control significantly correlated with the EGFR/CEP-7 ratios obtained by FISH. Conclusion: Both drugs prolonged growth time in most tumour models, but only application of cetuximab during irradiation significantly improved local tumour control in 3/5 tumour models. The significant correlation of this curative effect with the genetic EGFR expression measured by FISH will be further validated in preclinical and clinical studies.

  12. Utilitarian prioritization of radiation oncology patients based on maximization of population tumour control

    Science.gov (United States)

    Ebert, M. A.; Li, W.; Jennings, L.; Kearvell, R.; Bydder, S.

    2013-06-01

    An objective method for establishing patient prioritization in the context of a radiotherapy waiting list is investigated. This is based on a utilitarian objective, being the greatest probability of local tumour control in the population of patients. A numerical simulation is developed and a clinical patient case-mix is used to determine the influence of the characteristics of the patient population on resulting optimal patient scheduling. With the utilitarian objective, large gains in tumour control probability (TCP) can be achieved for individuals or cohorts by prioritizing patients for that fraction of the patient population with relatively small sacrifices in TCP for a smaller fraction of the population. For a waiting list in steady state with five patients per day commencing treatment and leaving the list (and so with five patients per day entering the list), and a mean wait time of 35 days and a maximum of 90 days, optimized wait times ranged from a mean of one day for patients with tumour types with short effective doubling times to a mean of 66.9 days for prostate cancer patients. It is found that, when seeking the optimal daily order of patients on the waiting list in a constrained simulation, the relative rather than absolute value of TCP is the determinant of the resulting optimal waiting times. An increase in the mean waiting time mostly influences (increases) the optimal waiting times of patients with fast-growing tumours. The proportional representation of groups (separated by tumour type) in the patient population has an influence on the resulting distribution of optimal waiting times for patients in those groups, though has only a minor influence on the optimal mean waiting time for each group.

  13. Utilitarian prioritization of radiation oncology patients based on maximization of population tumour control

    International Nuclear Information System (INIS)

    Ebert, M A; Li, W; Kearvell, R; Bydder, S; Jennings, L

    2013-01-01

    An objective method for establishing patient prioritization in the context of a radiotherapy waiting list is investigated. This is based on a utilitarian objective, being the greatest probability of local tumour control in the population of patients. A numerical simulation is developed and a clinical patient case-mix is used to determine the influence of the characteristics of the patient population on resulting optimal patient scheduling. With the utilitarian objective, large gains in tumour control probability (TCP) can be achieved for individuals or cohorts by prioritizing patients for that fraction of the patient population with relatively small sacrifices in TCP for a smaller fraction of the population. For a waiting list in steady state with five patients per day commencing treatment and leaving the list (and so with five patients per day entering the list), and a mean wait time of 35 days and a maximum of 90 days, optimized wait times ranged from a mean of one day for patients with tumour types with short effective doubling times to a mean of 66.9 days for prostate cancer patients. It is found that, when seeking the optimal daily order of patients on the waiting list in a constrained simulation, the relative rather than absolute value of TCP is the determinant of the resulting optimal waiting times. An increase in the mean waiting time mostly influences (increases) the optimal waiting times of patients with fast-growing tumours. The proportional representation of groups (separated by tumour type) in the patient population has an influence on the resulting distribution of optimal waiting times for patients in those groups, though has only a minor influence on the optimal mean waiting time for each group. (paper)

  14. Tumour control probability (TCP) for non-uniform activity distribution in radionuclide therapy

    International Nuclear Information System (INIS)

    Uusijaervi, Helena; Bernhardt, Peter; Forssell-Aronsson, Eva

    2008-01-01

    Non-uniform radionuclide distribution in tumours will lead to a non-uniform absorbed dose. The aim of this study was to investigate how tumour control probability (TCP) depends on the radionuclide distribution in the tumour, both macroscopically and at the subcellular level. The absorbed dose in the cell nuclei of tumours was calculated for 90 Y, 177 Lu, 103m Rh and 211 At. The radionuclides were uniformly distributed within the subcellular compartment and they were uniformly, normally or log-normally distributed among the cells in the tumour. When all cells contain the same amount of activity, the cumulated activities required for TCP = 0.99 (A-tilde TCP=0.99 ) were 1.5-2 and 2-3 times higher when the activity was distributed on the cell membrane compared to in the cell nucleus for 103m Rh and 211 At, respectively. TCP for 90 Y was not affected by different radionuclide distributions, whereas for 177 Lu, it was slightly affected when the radionuclide was in the nucleus. TCP for 103m Rh and 211 At were affected by different radionuclide distributions to a great extent when the radionuclides were in the cell nucleus and to lesser extents when the radionuclides were distributed on the cell membrane or in the cytoplasm. When the activity was distributed in the nucleus, A-tilde TCP=0.99 increased when the activity distribution became more heterogeneous for 103m Rh and 211 At, and the increase was large when the activity was normally distributed compared to log-normally distributed. When the activity was distributed on the cell membrane, A-tilde TCP=0.99 was not affected for 103m Rh and 211 At when the activity distribution became more heterogeneous. A-tilde TCP=0.99 for 90 Y and 177 Lu were not affected by different activity distributions, neither macroscopic nor subcellular

  15. Simultaneous PLK1 inhibition improves local tumour control after fractionated irradiation

    International Nuclear Information System (INIS)

    Krause, Mechthild; Kummer, Berit; Deparade, Andre; Eicheler, Wolfgang; Pfitzmann, Dorothee; Yaromina, Ala; Kunz-Schughart, Leoni A.

    2013-01-01

    Purpose: Polo-like kinase 1 (PLK1) plays an important role in mitotic progression, is frequently overexpressed and associated with a poor prognosis of cancer patients, thus providing a promising target in anticancer treatment. Aim of the current project was to evaluate the effect of the novel PLK1 inhibitor BI 6727 in combination with irradiation. Material and methods: In vitro proliferation and radiation cell survival assays as well as in vivo local tumour control assays after single treatment and combined radiation and drug application were carried out using the squamous cell carcinoma models A431 and FaDu. In addition, cell cycle phases were monitored in vitro and in vivo. Results: BI 6727 showed a dose-dependent antiproliferative effect and an increase in the mitotic fraction. BI 6727 alone reduced clonogenic cell survival, while radiosensitivity in vitro (SF2) and in vivo (single-dose TCD 50 under clamped hypoxia) was not affected. In contrast, local tumour control was significantly improved after application of BI 6727 simultaneously to fractionated irradiation (A431: TCD 50 = 60.5 Gy [95% C.I. 57; 63] after IR alone and <30 Gy after combined treatment; FaDu: 49.5 Gy [43; 56 Gy] versus 32.9 Gy [26; 40]). Conclusions: Despite the lack of direct cellular radiosensitisation, PLK1 inhibition with BI 6727 during fractionated irradiation significantly improves local tumour control when compared to irradiation alone. This result is likely explained by a considerable effect on cell cycle and an independent cytotoxic potential of BI 6727

  16. Optimising radiation outcomes, scheduling patient waiting lists for maximum population tumour control

    International Nuclear Information System (INIS)

    Ebert, M.A.; Jennings, L.; Kearvell, R.; Bydder, S.

    2011-01-01

    Full text: Delays in the commencement of radiotherapy, possibly due to resource constraints, are known to impact on control-related outcomes. We sought an objective solution for patient prioritisation based on tumour control probability (TCP). With a utilitarian objective for maximising TCP in a population of M patients, with patient i waiting a time between diagnosis and treatment of Ti and a mean wait time of TMean, the optimisation problem is as shown. A linear-quadratic/Poissonian model for cell survival/TCP was considered including cell doubling during the wait time. Solutions to several distributions of patient population characteristics were examined together with the expected change in TCP for the population and individuals. An analytical solution to the optimisation problem was found which gives the optimal wait time for each patient as a function of the distribution of radiobiological characteristics in the population. This solution does not allow a negativity constraint on an individual's optimised waiting time so a waiting list simulation was developed to enforce that. Optimal wait time distributions were calculated for situations where patients are allocated distinct diagnostic groups (sharing radiobiological parameters) and for a (log-normal) distribution of doubling times in the population. In order to meet the utilitarian objective, the optimal solutions require patients with rapid cell doubling times to be accelerated up the waiting list at the expense of those with slowly proliferating tumours. The net population benefit however is comparable to or greater then the expected benefit from beam intensity modulation or dose escalation.

  17. Optimum parameters in a model for tumour control probability, including interpatient heterogeneity: evaluation of the log-normal distribution

    International Nuclear Information System (INIS)

    Keall, P J; Webb, S

    2007-01-01

    The heterogeneity of human tumour radiation response is well known. Researchers have used the normal distribution to describe interpatient tumour radiosensitivity. However, many natural phenomena show a log-normal distribution. Log-normal distributions are common when mean values are low, variances are large and values cannot be negative. These conditions apply to radiosensitivity. The aim of this work was to evaluate the log-normal distribution to predict clinical tumour control probability (TCP) data and to compare the results with the homogeneous (δ-function with single α-value) and normal distributions. The clinically derived TCP data for four tumour types-melanoma, breast, squamous cell carcinoma and nodes-were used to fit the TCP models. Three forms of interpatient tumour radiosensitivity were considered: the log-normal, normal and δ-function. The free parameters in the models were the radiosensitivity mean, standard deviation and clonogenic cell density. The evaluation metric was the deviance of the maximum likelihood estimation of the fit of the TCP calculated using the predicted parameters to the clinical data. We conclude that (1) the log-normal and normal distributions of interpatient tumour radiosensitivity heterogeneity more closely describe clinical TCP data than a single radiosensitivity value and (2) the log-normal distribution has some theoretical and practical advantages over the normal distribution. Further work is needed to test these models on higher quality clinical outcome datasets

  18. Gene variations in sex hormone pathways and the risk of testicular germ cell tumour: a case-parent triad study in a Norwegian-Swedish population.

    Science.gov (United States)

    Kristiansen, W; Andreassen, K E; Karlsson, R; Aschim, E L; Bremnes, R M; Dahl, O; Fosså, S D; Klepp, O; Langberg, C W; Solberg, A; Tretli, S; Adami, H-O; Wiklund, F; Grotmol, T; Haugen, T B

    2012-05-01

    Testicular germ cell tumour (TGCT) is the most common cancer in young men, and an imbalance between the estrogen and androgen levels in utero is hypothesized to influence TGCT risk. Thus, polymorphisms in genes involved in the action of sex hormones may contribute to variability in an individual's susceptibility to TGCT. We conducted a Norwegian-Swedish case-parent study. A total of 105 single-nucleotide polymorphisms (SNPs) in 20 sex hormone pathway genes were genotyped using Sequenom MassArray iPLEX Gold, in 831 complete triads and 474 dyads. To increase the statistical power, the analysis was expanded to include 712 case singletons and 3922 Swedish controls, thus including triads, dyads and the case-control samples in a single test for association. Analysis for allelic associations was performed with the UNPHASED program, using a likelihood-based association test for nuclear families with missing data, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. False discovery rate (FDR) was used to adjust for multiple testing. Five genetic variants across the ESR2 gene [encoding estrogen receptor beta (ERβ)] were statistically significantly associated with the risk of TGCT. In the case-parent analysis, the markers rs12434245 and rs10137185 were associated with a reduced risk of TGCT (OR = 0.66 and 0.72, respectively; both FDRs <5%), whereas rs2978381 and rs12435857 were associated with an increased risk of TGCT (OR = 1.21 and 1.19, respectively; both FDRs <5%). In the combined case-parent/case-control analysis, rs12435857 and rs10146204 were associated with an increased risk of TGCT (OR = 1.15 and 1.13, respectively; both FDRs <5%), whereas rs10137185 was associated with a reduced risk of TGCT (OR = 0.79, FDR <5%). In addition, we found that three genetic variants in CYP19A1 (encoding aromatase) were statistically significantly associated with the risk of TGCT in the case-parent analysis. The T alleles of the rs2414099, rs8025374 and rs3751592

  19. Childhood brain tumours and use of mobile phones: comparison of a case–control study with incidence data

    Directory of Open Access Journals (Sweden)

    Aydin Denis

    2012-05-01

    Full Text Available Abstract The first case–control study on mobile phone use and brain tumour risk among children and adolescents (CEFALO study has recently been published. In a commentary published in Environmental Health, Söderqvist and colleagues argued that CEFALO suggests an increased brain tumour risk in relation to wireless phone use. In this article, we respond and show why consistency checks of case–control study results with observed time trends of incidence rates are essential, given the well described limitations of case–control studies and the steep increase of mobile phone use among children and adolescents during the last decade. There is no plausible explanation of how a notably increased risk from use of wireless phones would correspond to the relatively stable incidence time trends for brain tumours among children and adolescents observed in the Nordic countries. Nevertheless, an increased risk restricted to heavy mobile phone use, to very early life exposure, or to rare subtypes of brain tumours may be compatible with stable incidence trends at this time and thus further monitoring of childhood brain tumour incidence rate time trends is warranted.

  20. EGFR-TK inhibition before radiotherapy reduces tumour volume but does not improve local control: Differential response of cancer stem cells and nontumourigenic cells?

    International Nuclear Information System (INIS)

    Krause, Mechthild; Prager, Jenny; Zhou Xuanjing; Yaromina, Ala; Doerfler, Annegret; Eicheler, Wolfgang; Baumann, Michael

    2007-01-01

    Background and purpose: Waiting times before radiotherapy may reduce tumour control probability due to proliferation of tumour cells. The aim of the experiment was to test whether the growth inhibiting effect of epidermal growth factor receptor (EGFR)-inhibitors after surgery or tumour transplantation results in a lower tumour mass at time of irradiation and can thereby improve local tumour control. Materials and methods: The EGFR-tyrosine kinase inhibitor BIBX1382BS was applied over 14 days starting from microscopically non-in-sano-resection of FaDu tumours or from tumour transplantation, followed by irradiation (5f/5d). Endpoint was local tumour control. In addition, vital tumour areas, pimonidazole hypoxic fraction, BrdU labelling index, and colony forming ability in vitro were tested in control tumours and after BIBX1382BS treatment (starting from transplantation). Results: The tumour volume at start of irradiation was significantly lower in the BIBX1382BS treated tumours as compared to the control groups by factors of 11 (post-surgery setting) and 2.7 (transplantation setting). However, the reduced volume did not translate into improved local control after irradiation. The TCD 50 values after surgery were 25.4 Gy [95% CI 18; 33 Gy] in the control group and 30.5 Gy [24; 37] in the BIBX1382BS group (p = 0.25). Treatment after transplantation resulted in TCD 50 values of 41.1 Gy [35; 47] in the control group and 41.1 Gy [33; 49] in the BIBX1382BS group (p = 1). While the proportion of S-phase cells decreased after BIBX1382BS treatment, no differences were observed between the pimonidazole hypoxic fractions and in vitro colony forming ability. Conclusions: EGFR-TK inhibition with BIBX1382BS over 14 days between macroscopically complete tumour resection or tumour transplantation and start of radiotherapy significantly reduced tumour volume but did not improve local tumour control. One possible explanation is that the EGFR-TK inhibitor has a higher activity in

  1. Epigenetic regulations in the IFNγ signalling pathway: IFNγ-mediated MHC class I upregulation on tumour cells is associated with DNA demethylation of antigen-presenting machinery genes

    Czech Academy of Sciences Publication Activity Database

    Vlková, Veronika; Štěpánek, Ivan; Hrušková, Veronika; Šenigl, Filip; Mayerová, Veronika; Šrámek, Martin; Šímová, Jana; Bieblová, Jana; Indrová, Marie; Hejhal, Tomáš; Dérian, N.; Klatzmann, D.; Six, A.; Reiniš, Milan

    2014-01-01

    Roč. 5, č. 16 (2014), s. 6923-35 ISSN 1949-2553 R&D Projects: GA ČR GAP301/10/2174; GA MZd NT14461 EU Projects: European Commission(XE) 18933 - CLINIGENE Grant - others:French state funds within the Investissements d’Avenir program(FR) ANR-11-IDEX-0004-02 Institutional support: RVO:68378050 Keywords : IFNγ signalling pathway * DNA demethylation * tumour Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.359, year: 2014

  2. TUMOUR VACCINE

    NARCIS (Netherlands)

    Wagner, Ernst; Kircheis, Ralf; Crommelin, D.; Van Slooten, Maaike; Storm, Gert

    1999-01-01

    The invention relates to a tumour vaccine with a tumour antigen base. In addition to a source of tumour antigens, the vaccine contains a release system for the delayed release of the active agent IFN- gamma , the active dose of IFN- gamma being 50 ng to 5 mu g. The IFN- gamma is released over a

  3. Identification of genes involved in the biology of atypical teratoid/rhabdoid tumours using Drosophila melanogaster

    Science.gov (United States)

    Jeibmann, Astrid; Eikmeier, Kristin; Linge, Anna; Kool, Marcel; Koos, Björn; Schulz, Jacqueline; Albrecht, Stefanie; Bartelheim, Kerstin; Frühwald, Michael C.; Pfister, Stefan M.; Paulus, Werner; Hasselblatt, Martin

    2014-06-01

    Atypical teratoid/rhabdoid tumours (AT/RT) are malignant brain tumours. Unlike most other human brain tumours, AT/RT are characterized by inactivation of one single gene, SMARCB1. SMARCB1 is a member of the evolutionarily conserved SWI/SNF chromatin remodelling complex, which has an important role in the control of cell differentiation and proliferation. Little is known, however, about the pathways involved in the oncogenic effects of SMARCB1 inactivation, which might also represent targets for treatment. Here we report a comprehensive genetic screen in the fruit fly that revealed several genes not yet associated with loss of snr1, the Drosophila homologue of SMARCB1. We confirm the functional role of identified genes (including merlin, kibra and expanded, known to regulate hippo signalling pathway activity) in human rhabdoid tumour cell lines and AT/RT tumour samples. These results demonstrate that fly models can be employed for the identification of clinically relevant pathways in human cancer.

  4. Saponins extracted from by-product of Asparagus officinalis L. suppress tumour cell migration and invasion through targeting Rho GTPase signalling pathway.

    Science.gov (United States)

    Wang, Jieqiong; Liu, Yali; Zhao, Jingjing; Zhang, Wen; Pang, Xiufeng

    2013-04-01

    The inedible bottom part (~30-40%) of asparagus (Asparagus officinalis L.) spears is usually discarded as waste. However, since this by-product has been reported to be rich in many bioactive phytochemicals, it might be utilisable as a supplement in foods or natural drugs for its therapeutic effects. In this study it was identifed that saponins from old stems of asparagus (SSA) exerted potential inhibitory activity on tumour growth and metastasis. SSA suppressed cell viability of breast, colon and pancreatic cancers in a concentration-dependent manner, with half-maximum inhibitory concentrations ranging from 809.42 to 1829.96 µg mL(-1). However, SSA was more functional in blocking cell migration and invasion as compared with its cytotoxic effect, with an effective inhibitory concentration of 400 µg mL(-1). A mechanistic study showed that SSA markedly increased the activities of Cdc42 and Rac1 and decreased the activity of RhoA in cancer cells. SSA inhibits tumour cell motility through modulating the Rho GTPase signalling pathway, suggesting a promising use of SSA as a supplement in healthcare foods and natural drugs for cancer prevention and treatment. © 2012 Society of Chemical Industry.

  5. National survey on internal quality control for tumour markers in clinical laboratories in China.

    Science.gov (United States)

    Wang, Wei; Zhong, Kun; Yuan, Shuai; He, Falin; Du, Yuxuan; Hu, Zhehui; Wang, Zhiguo

    2018-06-15

    This survey was initiated to obtain knowledge on the current situation of internal quality control (IQC) practice for tumour markers (TMs) in China. Additionally, we tried to acquire the most appropriate quality specifications. This survey was a current status survey. The IQC information had been collected via online questionnaires. All of 1821 clinical laboratories which participated in the 2016 TMs external quality assessment (EQA) programme had been enrolled. The imprecision evaluation criteria were the minimal, desirable, and optimal allowable imprecisions based on biological variations, and 1/3 total allowable error (TEa) and 1/4 TEa. A total of 1628 laboratories answered the questionnaires (89%). The coefficients of variation (CVs) of the IQC of participant laboratories varied greatly from 1% (5 th percentile) to 13% (95 th percentile). More than 82% (82 - 91%) of participant laboratories two types of CVs met 1/3 TEa except for CA 19-9. The percentiles of current CVs were smaller than cumulative CVs. A number of 1240 laboratories (76%) reported their principles and systems used. The electrochemiluminescence was the most used principle (45%) and had the smallest CVs. The performance of laboratories for TMs IQC has yet to be improved. On the basis of the obtained results, 1/3 TEa would be realistic and attainable quality specification for TMs IQC for clinical laboratories in China.

  6. BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer.

    Science.gov (United States)

    Shields, Sarah; Conroy, Emer; O'Grady, Tony; McGoldrick, Alo; Connor, Kate; Ward, Mark P; Useckaite, Zivile; Dempsey, Eugene; Reilly, Rebecca; Fan, Yue; Chubb, Anthony; Matallanas, David Gomez; Kay, Elaine W; O'Connor, Darran; McCann, Amanda; Gallagher, William M; Coppinger, Judith A

    2018-03-20

    Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by absence of expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of amplification of human epidermal growth factor receptor 2 (HER2). TNBC patients can exhibit poor prognosis and high recurrence stages despite early response to chemotherapy treatment. In this study, we identified a pro-survival signalling protein BCL2- associated athanogene 3 (BAG3) to be highly expressed in a subset of TNBC cell lines and tumour tissues. High mRNA expression of BAG3 in TNBC patient cohorts significantly associated with a lower recurrence free survival. The epidermal growth factor receptor (EGFR) is amplified in TNBC and EGFR signalling dynamics impinge on cancer cell survival and disease recurrence. We found a correlation between BAG3 and EGFR expression in TNBC cell lines and determined that BAG3 can regulate tumour cell proliferation, migration and invasion in EGFR expressing TNBC cells lines. We identified an interaction between BAG3 and components of the EGFR signalling networks using mass spectrometry. Furthermore, BAG3 contributed to regulation of proliferation in TNBC cell lines by reducing the activation of components of the PI3K/AKT and FAK/Src signalling subnetworks. Finally, we found that combined targeting of BAG3 and EGFR was more effective than inhibition of EGFR with Cetuximab alone in TNBC cell lines. This study demonstrates a role for BAG3 in regulation of distinct EGFR modules and highlights the potential of BAG3 as a therapeutic target in TNBC.

  7. A multinational case-control study on childhood brain tumours, anthropogenic factors, birth characteristics and prenatal exposures

    DEFF Research Database (Denmark)

    Vienneau, Danielle; Infanger, Denis; Feychting, Maria

    2016-01-01

    supplement intake) in relation to risk of brain tumour diagnosis among 7-19 year olds. The multinational case-control study in Denmark, Sweden, Norway and Switzerland (CEFALO) included interviews with 352 (participation rate=83.2%) eligible cases and 646 (71.1%) population-based controls. Interview data were...... complemented with data from birth registries and validated by assessing agreement (Cohen's Kappa). We used conditional logistic regression models matched on age, sex and geographical region (adjusted for maternal age and parental education) to explore associations between birth factors and childhood brain...... during pregnancy was indicative of a protective effect (OR 0.75, 95%-CI: 0.56-1.01). No association was seen for maternal smoking during pregnancy or working during pregnancy. We found little evidence that the considered birth factors were related to brain tumour risk among children and adolescents....

  8. Tumour-induced osteomalacia.

    Science.gov (United States)

    Minisola, Salvatore; Peacock, Munro; Fukumoto, Seijii; Cipriani, Cristiana; Pepe, Jessica; Tella, Sri Harsha; Collins, Michael T

    2017-07-13

    Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation.

  9. Electrochemotherapy of tumours

    International Nuclear Information System (INIS)

    Sersa, G.; Cemazar, M.; Rudolf, Z.; Miklavcic, D.

    2006-01-01

    Electrochemotherapy consists of chemotherapy followed by local application of electric pulses to the tumour to increase drug delivery into cells. Drug uptake can be increased by electroporation for only those drugs whose transport through the plasma membrane is impeded. Among many drugs that have been tested so far, only bleomycin and cisplatin found their way from preclinical testing to clinical trials. In vitro studies demonstrated several fold increase of their cytotoxicity after electroporation of cells. In vivo, electroporation of tumours after local or systemic administration of either of the drugs, i.e. electrochemotherapy, proved to be an effective antitumour treatment. In preclinical studies on several tumour models, electrochemotherapy either with bleomycin or cisplatin was elaborated and parameters for effective local tumour control were determined. In veterinary medicine, electrochemotherapy also proved to be effective in the treatment of primary tumours in cats, dogs and horses. In human clinical studies, electrochemotherapy was performed on the patients with progressive disease and accessible tumour nodules of different malignancies. All clinical studies demonstrated that electrochemotherapy is an effective treatment for local tumour control in cancer patients. (author)

  10. Leucine-rich diet alters the 1H-NMR based metabolomic profile without changing the Walker-256 tumour mass in rats.

    Science.gov (United States)

    Viana, Laís Rosa; Canevarolo, Rafael; Luiz, Anna Caroline Perina; Soares, Raquel Frias; Lubaczeuski, Camila; Zeri, Ana Carolina de Mattos; Gomes-Marcondes, Maria Cristina Cintra

    2016-10-03

    Cachexia is one of the most important causes of cancer-related death. Supplementation with branched-chain amino acids, particularly leucine, has been used to minimise loss of muscle tissue, although few studies have examined the effect of this type of nutritional supplementation on the metabolism of the tumour-bearing host. Therefore, the present study evaluated whether a leucine-rich diet affects metabolomic derangements in serum and tumour tissues in tumour-bearing Walker-256 rats (providing an experimental model of cachexia). After 21 days feeding Wistar female rats a leucine-rich diet, distributed in L-leucine and LW-leucine Walker-256 tumour-bearing groups, we examined the metabolomic profile of serum and tumour tissue samples and compared them with samples from tumour-bearing rats fed a normal protein diet (C - control; W - tumour-bearing groups). We utilised 1 H-NMR as a means to study the serum and tumour metabolomic profile, tumour proliferation and tumour protein synthesis pathway. Among the 58 serum metabolites examined, we found that 12 were altered in the tumour-bearing group, reflecting an increase in activity of some metabolic pathways related to energy production, which diverted many nutrients toward tumour growth. Despite displaying increased tumour cell activity (i.e., higher Ki-67 and mTOR expression), there were no differences in tumour mass associated with changes in 23 metabolites (resulting from valine, leucine and isoleucine synthesis and degradation, and from the synthesis and degradation of ketone bodies) in the leucine-tumour group. This result suggests that the majority of nutrients were used for host maintenance. A leucine rich-diet, largely used to prevent skeletal muscle loss, did not affect Walker 256 tumour growth and led to metabolomic alterations that may partially explain the positive effects of leucine for the whole tumour-bearing host.

  11. Mitochondrial quality control pathways as determinants of metabolic health

    NARCIS (Netherlands)

    Held, Ntsiki M.; Houtkooper, Riekelt H.

    2015-01-01

    Mitochondrial function is key for maintaining cellular health, while mitochondrial failure is associated with various pathologies, including inherited metabolic disorders and age-related diseases. In order to maintain mitochondrial quality, several pathways of mitochondrial quality control have

  12. Postural control and central motor pathway involvement in type 2 ...

    African Journals Online (AJOL)

    Mona Mokhtar El Bardawil

    2013-04-18

    Apr 18, 2013 ... Postural control and central motor pathway involvement in type 2 .... with a high power 90 mm circular coil, capable of generating. 2 T maximum field ..... advanced glycation end products, oxidative damage and microvascular ...

  13. Development and Evaluation of Controlled-Release Cisplatin Dry Powders for Inhalation against Lung Tumours

    OpenAIRE

    Levet, Vincent

    2017-01-01

    Lung cancer is the deadliest cancer in the world, with a global 5-year survival rate of about 15%. Despite a notable impact of the latest improvements in prevention, screening, detection and staging, the efficacy of conventional treatments is not sufficient and has reached a therapeutic plateau. These conventional treatments involve a combination of surgery, radiotherapy (RT) and chemotherapy (CT). CT is used in almost all stages: in operable and inoperable stages to limit tumour cell invasio...

  14. A multinational case-control study on childhood brain tumours, anthropogenic factors, birth characteristics and prenatal exposures: A validation of interview data.

    OpenAIRE

    Vienneau Danielle; Infanger Denis; Feychting Maria; Schüz Joachim; Schmidt Lisbeth Samsø; Poulsen Aslak Harbo; Tettamanti Giorgio; Klæboe Lars; Kuehni Claudia E; Tynes Tore; Von der Weid Nicolas; Lannering Birgitta; Röösli Martin

    2016-01-01

    Little is known about the aetiology of childhood brain tumours. We investigated anthropometric factors (birth weight length maternal age) birth characteristics (e.g. vacuum extraction preterm delivery birth order) and exposures during pregnancy (e.g. maternal: smoking working dietary supplement intake) in relation to risk of brain tumour diagnosis among 7 19 year olds. The multinational case control study in Denmark Sweden Norway and Switzerland (CEFALO) included interviews with 352 (particip...

  15. CG200745, an HDAC inhibitor, induces anti-tumour effects in cholangiocarcinoma cell lines via miRNAs targeting the Hippo pathway.

    Science.gov (United States)

    Jung, Dawoon E; Park, Soo Been; Kim, Kahee; Kim, Chanyang; Song, Si Young

    2017-09-07

    Cholangiocarcinoma is a devastating malignancy with fatal complications that exhibits low response and resistance to chemotherapy. Here, we evaluated the anticancer effects of CG200745, a novel histone deacetylase inhibitor, either alone or in combination with standard chemotherapy drugs in cholangiocarcinoma cells. CG200745 dose-dependently reduced the viability of cholangiocarcinoma cells in vitro and decreased tumour volume and weight in a xenograft model. Administering CG200745 along with other chemotherapeutic agents including gemcitabine, 5-fluorouracil (5-FU), cisplatin, oxaliplatin, or gemcitabine plus cisplatin further decreased cholangiocarcinoma cell viability, with a combination index CG200745 also enhanced the sensitivity of gemcitabine-resistant cells to gemcitabine and 5-FU, thereby decreasing cell viability and inducing apoptosis. This was accompanied by downregulation of YAP, TEAD4, TGF-β2, SMAD3, NOTCH3, HES5, Axl, and Gas6 and upregulation of the miRNAs miR-22-3p, miR-22-5p, miR-194-5p, miR-194-3p, miR-194-5p, miR-210-3p, and miR-509-3p. The Ingenuity Pathway Analysis revealed that CG200745 mainly targets the Hippo signalling pathway by inducing miR-509-3p expression. Thus, CG200745 inhibits cholangiocarcinoma growth in vitro and in vivo, and acts synergistically when administered in combination with standard chemotherapeutic agents, enabling dose reduction. CG200745 is therefore expected to improve the outcome of cholangiocarcinoma patients who exhibit resistance to conventional therapies.

  16. Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer.

    Science.gov (United States)

    Ribas, Ricardo; Pancholi, Sunil; Rani, Aradhana; Schuster, Eugene; Guest, Stephanie K; Nikitorowicz-Buniak, Joanna; Simigdala, Nikiana; Thornhill, Allan; Avogadri-Connors, Francesca; Cutler, Richard E; Lalani, Alshad S; Dowsett, Mitch; Johnston, Stephen R; Martin, Lesley-Ann

    2018-06-08

    Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER + ) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. A panel of ER + BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1 wt or ESR1 Y537S , modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER

  17. Version control of pathway models using XML patches.

    Science.gov (United States)

    Saffrey, Peter; Orton, Richard

    2009-03-17

    Computational modelling has become an important tool in understanding biological systems such as signalling pathways. With an increase in size complexity of models comes a need for techniques to manage model versions and their relationship to one another. Model version control for pathway models shares some of the features of software version control but has a number of differences that warrant a specific solution. We present a model version control method, along with a prototype implementation, based on XML patches. We show its application to the EGF/RAS/RAF pathway. Our method allows quick and convenient storage of a wide range of model variations and enables a thorough explanation of these variations. Trying to produce these results without such methods results in slow and cumbersome development that is prone to frustration and human error.

  18. A controlled vocabulary for pathway entities and events.

    Science.gov (United States)

    Jupe, Steve; Jassal, Bijay; Williams, Mark; Wu, Guanming

    2014-01-01

    Entities involved in pathways and the events they participate in require descriptive and unambiguous names that are often not available in the literature or elsewhere. Reactome is a manually curated open-source resource of human pathways. It is accessible via a website, available as downloads in standard reusable formats and via Representational State Transfer (REST)-ful and Simple Object Access Protocol (SOAP) application programming interfaces (APIs). We have devised a controlled vocabulary (CV) that creates concise, unambiguous and unique names for reactions (pathway events) and all the molecular entities they involve. The CV could be reapplied in any situation where names are used for pathway entities and events. Adoption of this CV would significantly improve naming consistency and readability, with consequent benefits for searching and data mining within and between databases. Database URL: http://www.reactome.org. © The Author(s) 2014. Published by Oxford University Press.

  19. A retrospective study of the role of intracavitary brachytherapy and prognotic factors determining local tumour control after primary radical radiotherapy in 903 non-disseminated nasopharyngeal carcinoma patients

    International Nuclear Information System (INIS)

    Teo, P.M.L.; Kwan, W.H.; Yu, P.; Lee, W.Y.; Leung, S.F.; Choi, P.

    1996-01-01

    The aims of this retrospective study were to determine the role of intracavitary brachytherapy given shortly after external beam radiotherapy in the primary radical treatment of non-metastatic nasopharyngeal (NPC) cancer patients, and the prognostic factors governing local tumour control. From 1984 to 1989, 903 patients with non-disseminated NPC who had no previous treatment were managed at the Prince of Wales Hospital, Hong Kong, where investigation and treatment methods had been standardized according to a departmental protocol. In the 903 non-disseminated NPCs, the patient's age and tumour involvement of the skull base and cranial nerves were significant independent prognostic factors governing local tumour control. In the 358 patients with Ho T 3 disease, tumour involvement of the orbits and the laryngopharynx significantly worsened local tumour control. The presence of local persistence at 4 weeks after external radiotherapy, for which therapeutic brachytherapy was given, was marginally significant as a prognostic factor in addition to the presence of cranial nerve palsy. (author)

  20. 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)

    2015-04-01

    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.)

  1. A multinational case-control study on childhood brain tumours, anthropogenic factors, birth characteristics and prenatal exposures: A validation of interview data.

    Science.gov (United States)

    Vienneau, Danielle; Infanger, Denis; Feychting, Maria; Schüz, Joachim; Schmidt, Lisbeth Samsø; Poulsen, Aslak Harbo; Tettamanti, Giorgio; Klæboe, Lars; Kuehni, Claudia E; Tynes, Tore; Von der Weid, Nicolas; Lannering, Birgitta; Röösli, Martin

    2016-02-01

    Little is known about the aetiology of childhood brain tumours. We investigated anthropometric factors (birth weight, length, maternal age), birth characteristics (e.g. vacuum extraction, preterm delivery, birth order) and exposures during pregnancy (e.g. maternal: smoking, working, dietary supplement intake) in relation to risk of brain tumour diagnosis among 7-19 year olds. The multinational case-control study in Denmark, Sweden, Norway and Switzerland (CEFALO) included interviews with 352 (participation rate=83.2%) eligible cases and 646 (71.1%) population-based controls. Interview data were complemented with data from birth registries and validated by assessing agreement (Cohen's Kappa). We used conditional logistic regression models matched on age, sex and geographical region (adjusted for maternal age and parental education) to explore associations between birth factors and childhood brain tumour risk. Agreement between interview and birth registry data ranged from moderate (Kappa=0.54; worked during pregnancy) to almost perfect (Kappa=0.98; birth weight). Neither anthropogenic factors nor birth characteristics were associated with childhood brain tumour risk. Maternal vitamin intake during pregnancy was indicative of a protective effect (OR 0.75, 95%-CI: 0.56-1.01). No association was seen for maternal smoking during pregnancy or working during pregnancy. We found little evidence that the considered birth factors were related to brain tumour risk among children and adolescents. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Known glioma risk loci are associated with glioma with a family history of brain tumours -- a case-control gene association study.

    Science.gov (United States)

    Melin, Beatrice; Dahlin, Anna M; Andersson, Ulrika; Wang, Zhaoming; Henriksson, Roger; Hallmans, Göran; Bondy, Melissa L; Johansen, Christoffer; Feychting, Maria; Ahlbom, Anders; Kitahara, Cari M; Wang, Sophia S; Ruder, Avima M; Carreón, Tania; Butler, Mary Ann; Inskip, Peter D; Purdue, Mark; Hsing, Ann W; Mechanic, Leah; Gillanders, Elizabeth; Yeager, Meredith; Linet, Martha; Chanock, Stephen J; Hartge, Patricia; Rajaraman, Preetha

    2013-05-15

    Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four case-control studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case-control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.25-0.61; Bonferroni adjusted ptrend , 1.7 × 10(-4) ). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours. Copyright © 2012 UICC.

  3. Adapting radiotherapy to hypoxic tumours

    Science.gov (United States)

    Malinen, Eirik; Søvik, Åste; Hristov, Dimitre; Bruland, Øyvind S.; Rune Olsen, Dag

    2006-10-01

    In the current work, the concepts of biologically adapted radiotherapy of hypoxic tumours in a framework encompassing functional tumour imaging, tumour control predictions, inverse treatment planning and intensity modulated radiotherapy (IMRT) were presented. Dynamic contrast enhanced magnetic resonance imaging (DCEMRI) of a spontaneous sarcoma in the nasal region of a dog was employed. The tracer concentration in the tumour was assumed related to the oxygen tension and compared to Eppendorf histograph measurements. Based on the pO2-related images derived from the MR analysis, the tumour was divided into four compartments by a segmentation procedure. DICOM structure sets for IMRT planning could be derived thereof. In order to display the possible advantages of non-uniform tumour doses, dose redistribution among the four tumour compartments was introduced. The dose redistribution was constrained by keeping the average dose to the tumour equal to a conventional target dose. The compartmental doses yielding optimum tumour control probability (TCP) were used as input in an inverse planning system, where the planning basis was the pO2-related tumour images from the MR analysis. Uniform (conventional) and non-uniform IMRT plans were scored both physically and biologically. The consequences of random and systematic errors in the compartmental images were evaluated. The normalized frequency distributions of the tracer concentration and the pO2 Eppendorf measurements were not significantly different. 28% of the tumour had, according to the MR analysis, pO2 values of less than 5 mm Hg. The optimum TCP following a non-uniform dose prescription was about four times higher than that following a uniform dose prescription. The non-uniform IMRT dose distribution resulting from the inverse planning gave a three times higher TCP than that of the uniform distribution. The TCP and the dose-based plan quality depended on IMRT parameters defined in the inverse planning procedure (fields

  4. Adapting radiotherapy to hypoxic tumours

    International Nuclear Information System (INIS)

    Malinen, Eirik; Soevik, Aste; Hristov, Dimitre; Bruland, Oeyvind S; Olsen, Dag Rune

    2006-01-01

    In the current work, the concepts of biologically adapted radiotherapy of hypoxic tumours in a framework encompassing functional tumour imaging, tumour control predictions, inverse treatment planning and intensity modulated radiotherapy (IMRT) were presented. Dynamic contrast enhanced magnetic resonance imaging (DCEMRI) of a spontaneous sarcoma in the nasal region of a dog was employed. The tracer concentration in the tumour was assumed related to the oxygen tension and compared to Eppendorf histograph measurements. Based on the pO 2 -related images derived from the MR analysis, the tumour was divided into four compartments by a segmentation procedure. DICOM structure sets for IMRT planning could be derived thereof. In order to display the possible advantages of non-uniform tumour doses, dose redistribution among the four tumour compartments was introduced. The dose redistribution was constrained by keeping the average dose to the tumour equal to a conventional target dose. The compartmental doses yielding optimum tumour control probability (TCP) were used as input in an inverse planning system, where the planning basis was the pO 2 -related tumour images from the MR analysis. Uniform (conventional) and non-uniform IMRT plans were scored both physically and biologically. The consequences of random and systematic errors in the compartmental images were evaluated. The normalized frequency distributions of the tracer concentration and the pO 2 Eppendorf measurements were not significantly different. 28% of the tumour had, according to the MR analysis, pO 2 values of less than 5 mm Hg. The optimum TCP following a non-uniform dose prescription was about four times higher than that following a uniform dose prescription. The non-uniform IMRT dose distribution resulting from the inverse planning gave a three times higher TCP than that of the uniform distribution. The TCP and the dose-based plan quality depended on IMRT parameters defined in the inverse planning procedure

  5. Cell size checkpoint control by the retinoblastoma tumor suppressor pathway.

    Science.gov (United States)

    Fang, Su-Chiung; de los Reyes, Chris; Umen, James G

    2006-10-13

    Size control is essential for all proliferating cells, and is thought to be regulated by checkpoints that couple cell size to cell cycle progression. The aberrant cell-size phenotypes caused by mutations in the retinoblastoma (RB) tumor suppressor pathway are consistent with a role in size checkpoint control, but indirect effects on size caused by altered cell cycle kinetics are difficult to rule out. The multiple fission cell cycle of the unicellular alga Chlamydomonas reinhardtii uncouples growth from division, allowing direct assessment of the relationship between size phenotypes and checkpoint function. Mutations in the C. reinhardtii RB homolog encoded by MAT3 cause supernumerous cell divisions and small cells, suggesting a role for MAT3 in size control. We identified suppressors of an mat3 null allele that had recessive mutations in DP1 or dominant mutations in E2F1, loci encoding homologs of a heterodimeric transcription factor that is targeted by RB-related proteins. Significantly, we determined that the dp1 and e2f1 phenotypes were caused by defects in size checkpoint control and were not due to a lengthened cell cycle. Despite their cell division defects, mat3, dp1, and e2f1 mutants showed almost no changes in periodic transcription of genes induced during S phase and mitosis, many of which are conserved targets of the RB pathway. Conversely, we found that regulation of cell size was unaffected when S phase and mitotic transcription were inhibited. Our data provide direct evidence that the RB pathway mediates cell size checkpoint control and suggest that such control is not directly coupled to the magnitude of periodic cell cycle transcription.

  6. Deregulated expression of p16INK4a and p53 pathway members in benign and malignant myoepithelial tumours of the salivary glands

    NARCIS (Netherlands)

    Vékony, H.; Röser, K.; Löning, T.; Raaphorst, F.M.; Leemans, C.R.; van der Waal, I.; Bloemena, E.

    2008-01-01

    Aims: Myoepithelial salivary gland tumours are uncommon and follow an unpredictable biological course. The aim was to examine their molecular background to acquire a better understanding of their clinical behaviour. Methods and results: Expression of protein (E2F1, p16INK4a, p53, cyclin D1, Ki67 and

  7. Metformin treatment modulates the tumour-induced wasting effects in muscle protein metabolism minimising the cachexia in tumour-bearing rats

    International Nuclear Information System (INIS)

    Oliveira, André G.; Gomes-Marcondes, Maria Cristina C.

    2016-01-01

    Cancer-cachexia state frequently induces both fat and protein wasting, leading to death. In this way, the knowledge of the mechanism of drugs and their side effects can be a new feature to treat and to have success, contributing to a better life quality for these patients. Metformin is an oral drug used in type 2 diabetes mellitus, showing inhibitory effect on proliferation in some neoplastic cells. For this reason, we evaluated its modulatory effect on Walker-256 tumour evolution and also on protein metabolism in gastrocnemius muscle and body composition. Wistar rats received or not tumour implant and metformin treatment and were distributed into four groups, as followed: control (C), Walker 256 tumour-bearing (W), metformin-treated (M) and tumour-bearing treated with metformin (WM). Animals were weighed three times a week, and after cachexia state has been detected, the rats were euthanised and muscle and tumour excised and analysed by biochemical and molecular assays. Tumour growth promoted some deleterious effects on chemical body composition, increasing water and decreasing fat percentage, and reducing lean body mass. In muscle tissue, tumour led to a decreased protein synthesis and an increased proteolysis, showing the higher activity of the ubiquitin-proteasome pathway. On the other hand, the metformin treatment likely minimised the tumour-induced wasting state; in this way, this treatment ameliorated chemical body composition, reduced the higher activities of proteolytic enzymes and decreased the protein waste. Metformin treatment not only decreases the tumour growth but also improves the protein metabolism in gastrocnemius muscle in tumour-bearing rats

  8. Total {sup 18}F-dopa PET tumour uptake reflects metabolic endocrine tumour activity in patients with a carcinoid tumour

    Energy Technology Data Exchange (ETDEWEB)

    Fiebrich, Helle-Brit; Walenkamp, Annemiek M.; Vries, Elisabeth G.E. de [University Medical Centre Groningen, Department of Medical Oncology, Groningen (Netherlands); Jong, Johan R. de; Koopmans, Klaas Pieter; Dierckx, Rudi A.J.O.; Brouwers, Adrienne H. [University Medical Centre Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); Kema, Ido P. [University Medical Centre Groningen, Department of Laboratory Medicine, Groningen (Netherlands); Sluiter, Wim; Links, Thera P. [University Medical Centre Groningen, Department of Endocrinology, Groningen (Netherlands)

    2011-10-15

    Positron emission tomography (PET) using 6-[{sup 18}F]fluoro-L-dihydroxyphenylalanine ({sup 18}F-dopa) has an excellent sensitivity to detect carcinoid tumour lesions. {sup 18}F-dopa tumour uptake and the levels of biochemical tumour markers are mediated by tumour endocrine metabolic activity. We evaluated whether total {sup 18}F-dopa tumour uptake on PET, defined as whole-body metabolic tumour burden (WBMTB), reflects tumour load per patient, as measured with tumour markers. Seventy-seven consecutive carcinoid patients who underwent an {sup 18}F-dopa PET scan in two previously published studies were analysed. For all tumour lesions mean standardised uptake values (SUVs) at 40% of the maximal SUV and tumour volume on {sup 18}F-dopa PET were determined and multiplied to calculate a metabolic burden per lesion. WBMTB was the sum of the metabolic burden of all individual lesions per patient. The 24-h urinary serotonin, urine and plasma 5-hydroxindoleacetic acid (5-HIAA), catecholamines (nor)epinephrine, dopamine and their metabolites, measured in urine and plasma, and serum chromogranin A served as tumour markers. All but 1 were evaluable for WBMTB; 74 patients had metastatic disease. {sup 18}F-dopa PET detected 979 lesions. SUV{sub max} on {sup 18}F-dopa PET varied up to 29-fold between individual lesions within the same patients. WBMTB correlated with urinary serotonin (r = 0.51) and urinary and plasma 5-HIAA (r = 0.78 and 0.66). WBMTB also correlated with urinary norepinephrine, epinephrine, dopamine and plasma dopamine, but not with serum chromogranin A. Tumour load per patient measured with {sup 18}F-dopa PET correlates with tumour markers of the serotonin and catecholamine pathway in urine and plasma in carcinoid patients, reflecting metabolic tumour activity. (orig.)

  9. Gastric Calcifying Fibrous Tumour

    Directory of Open Access Journals (Sweden)

    Tan Attila

    2006-01-01

    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.

  10. 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

    2009-12-01

    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.

  11. Characterization of Translationally Controlled Tumour Protein from the Sea Anemone Anemonia viridis and Transcriptome Wide Identification of Cnidarian Homologues.

    Science.gov (United States)

    Nicosia, Aldo; Bennici, Carmelo; Biondo, Girolama; Costa, Salvatore; Di Natale, Marilena; Masullo, Tiziana; Monastero, Calogera; Ragusa, Maria Antonietta; Tagliavia, Marcello; Cuttitta, Angela

    2018-01-11

    Gene family encoding translationally controlled tumour protein (TCTP) is defined as highly conserved among organisms; however, there is limited knowledge of non-bilateria. In this study, the first TCTP homologue from anthozoan was characterised in the Mediterranean Sea anemone, Anemonia viridis . The release of the genome sequence of Acropora digitifera , Exaiptasia pallida , Nematostella vectensis and Hydra vulgaris enabled a comprehensive study of the molecular evolution of TCTP family among cnidarians. A comparison among TCTP members from Cnidaria and Bilateria showed conserved intron exon organization, evolutionary conserved TCTP signatures and 3D protein structure. The pattern of mRNA expression profile was also defined in A. viridis . These analyses revealed a constitutive mRNA expression especially in tissues with active proliferation. Additionally, the transcriptional profile of A. viridis TCTP ( AvTCTP ) after challenges with different abiotic/biotic stresses showed induction by extreme temperatures, heavy metals exposure and immune stimulation. These results suggest the involvement of AvTCTP in the sea anemone defensome taking part in environmental stress and immune responses.

  12. Characterization of Translationally Controlled Tumour Protein from the Sea Anemone Anemonia viridis and Transcriptome Wide Identification of Cnidarian Homologues

    Directory of Open Access Journals (Sweden)

    Aldo Nicosia

    2018-01-01

    Full Text Available Gene family encoding translationally controlled tumour protein (TCTP is defined as highly conserved among organisms; however, there is limited knowledge of non-bilateria. In this study, the first TCTP homologue from anthozoan was characterised in the Mediterranean Sea anemone, Anemonia viridis. The release of the genome sequence of Acropora digitifera, Exaiptasia pallida, Nematostella vectensis and Hydra vulgaris enabled a comprehensive study of the molecular evolution of TCTP family among cnidarians. A comparison among TCTP members from Cnidaria and Bilateria showed conserved intron exon organization, evolutionary conserved TCTP signatures and 3D protein structure. The pattern of mRNA expression profile was also defined in A. viridis. These analyses revealed a constitutive mRNA expression especially in tissues with active proliferation. Additionally, the transcriptional profile of A. viridis TCTP (AvTCTP after challenges with different abiotic/biotic stresses showed induction by extreme temperatures, heavy metals exposure and immune stimulation. These results suggest the involvement of AvTCTP in the sea anemone defensome taking part in environmental stress and immune responses.

  13. Prophylactic antibiotic regimens in tumour surgery (PARITY) : a pilot multicentre randomised controlled trial

    NARCIS (Netherlands)

    Ghert, M.; Bhandari, M.; Deheshi, B.; Guyatt, G.; Holt, G.; O'Shea, T.; Randall, R. L.; Thabane, L.; Wunder, J.; Evaniew, N.; McKay, P.; Schneider, P.; Turcotte, R.; Madden, K.; Scott, T.; Sprague, S.; Simunovic, N.; Swinton, M.; Racano, A.; Heels-Ansdell, D.; Buckingham, L.; Rose, P.; Brigman, B.; Pullenayegum, E.; Ghert, M.; Evaniew, N.; Mckay, P.; Schneider, P.; Sobhi, G.; Chan, R.; Biljan, M.; Ferguson, P.; Wunder, J.; Griffin, A.; Mantas, I.; Wylie, A.; Han, A.; Grewal, G.; Turcotte, R.; Goulding, K.; Dandachli, F.; Matte, G.; Werier, J.; Abdelbary, H.; Paquin, K.; Cosgrove, H.; Dugal, A-M.; Jutte, P.; Ploegmakers, J. J. W.; Stevens, M.

    2015-01-01

    Objective Clinical studies of patients with bone sarcomas have been challenged by insufficient numbers at individual centres to draw valid conclusions. Our objective was to assess the feasibility of conducting a definitive multi-centre randomised controlled trial (RCT) to determine whether a

  14. CG200745, an HDAC inhibitor, induces anti-tumour effects in cholangiocarcinoma cell lines via miRNAs targeting the Hippo pathway

    OpenAIRE

    Jung, Dawoon E.; Park, Soo Been; Kim, Kahee; Kim, Chanyang; Song, Si Young

    2017-01-01

    Cholangiocarcinoma is a devastating malignancy with fatal complications that exhibits low response and resistance to chemotherapy. Here, we evaluated the anticancer effects of CG200745, a novel histone deacetylase inhibitor, either alone or in combination with standard chemotherapy drugs in cholangiocarcinoma cells. CG200745 dose-dependently reduced the viability of cholangiocarcinoma cells in vitro and decreased tumour volume and weight in a xenograft model. Administering CG200745 along with...

  15. Can exercise suppress tumour growth in advanced prostate cancer patients with sclerotic bone metastases? A randomised, controlled study protocol examining feasibility, safety and efficacy.

    Science.gov (United States)

    Hart, Nicolas H; Newton, Robert U; Spry, Nigel A; Taaffe, Dennis R; Chambers, Suzanne K; Feeney, Kynan T; Joseph, David J; Redfern, Andrew D; Ferguson, Tom; Galvão, Daniel A

    2017-05-30

    Exercise may positively alter tumour biology through numerous modulatory and regulatory mechanisms in response to a variety of modes and dosages, evidenced in preclinical models to date. Specifically, localised and systemic biochemical alterations produced during and following exercise may suppress tumour formation, growth and distribution by virtue of altered epigenetics and endocrine-paracrine activity. Given the impressive ability of targeted mechanical loading to interfere with metastasis-driven tumour formation in human osteolytic tumour cells, it is of equal interest to determine whether a similar effect is observed in sclerotic tumour cells. The study aims to (1) establish the feasibility and safety of a combined modular multimodal exercise programme with spinal isometric training in advanced prostate cancer patients with sclerotic bone metastases and (2) examine whether targeted and supervised exercise can suppress sclerotic tumour growth and activity in spinal metastases in humans. A single-blinded, two-armed, randomised, controlled and explorative phase I clinical trial combining spinal isometric training with a modular multimodal exercise programme in 40 men with advanced prostate cancer and stable sclerotic spinal metastases. Participants will be randomly assigned to (1) the exercise intervention or (2) usual medical care. The intervention arm will receive a 3-month, supervised and individually tailored modular multimodal exercise programme with spinal isometric training. Primary endpoints (feasibility and safety) and secondary endpoints (tumour morphology; biomarker activity; anthropometry; musculoskeletal health; adiposity; physical function; quality of life; anxiety; distress; fatigue; insomnia; physical activity levels) will be measured at baseline and following the intervention. Statistical analyses will include descriptive characteristics, t-tests, effect sizes and two-way (group × time) repeated-measures analysis of variance (or analysis of

  16. Tumour sleuths

    International Nuclear Information System (INIS)

    Beyers, M.; Springolo, E.; Conradie, J.D.

    1986-01-01

    Hepatocellular carcinoma is a common disease in South Africa and its identification difficult. Methods for the diagnosis of this disease includes the production of hybridoma cell lines by inoculating laboratory mice with a purified human tumour-associated antigen or the antigen-containing surface membranes or the intact cells. In the diagnosis of hepatocellular carcinoma, high concentrations of serum alpha fetoprotein (AFP) can be measured by means of radioimmunoassay techniques. The need for specific methods of diagnosis and treatment of hepatocellular carcinoma led to the investigation by the Isotope Production Centre at Pelindaba into the possibility of using radiolabelled monoclonal anti-AFP for diagnosis, and later, therapy of hepatocellular carcinoma. The monoclonal antibodies can also be labelled with 131 I. Recently the Department of Nuclear Medicine of the University of the Witwatersrand is conducting diagnostic trials on patients who have given their informed consent, to assess the specificity of 131 I radiolabelled anti-AFP monoclonal antibodies to hepatocellular carcinoma cells in humans. Although the investigation is still in its infancy, monoclonal antibodies may prove to be successful non-invasive agents for detecting tumors in early stages

  17. Role of Cerebellum in Fine Speech Control in Childhood: Persistent Dysarthria after Surgical Treatment for Posterior Fossa Tumour

    Science.gov (United States)

    Morgan, A. T.; Liegeois, F.; Liederkerke, C.; Vogel, A. P.; Hayward, R.; Harkness, W.; Chong, K.; Vargha-Khadem, F.

    2011-01-01

    Dysarthria following surgical resection of childhood posterior fossa tumour (PFT) is most commonly documented in a select group of participants with mutism in the acute recovery phase, thus limiting knowledge of post-operative prognosis for this population of children as a whole. Here we report on the speech characteristics of 13 cases seen…

  18. International Case-Control Study of Adult Brain, Head and Neck Tumours: Results of the Feasibility Study (invited paper)

    International Nuclear Information System (INIS)

    Cardis, E.; Kilkenny, M.

    1999-01-01

    The objectives of the feasibility study were to collect and analyse the information necessary to assess the feasibility of a multi-centric study of adult head and neck tumours (including brain tumours) and mobile telephones. Information was obtained on the availability and accessibility of records from companies, the prevalence of mobile telephone use over time and the expected number of tumour cases in the proposed study regions. The conclusion is that it is feasible to develop a study of the relation between mobile telephone use and brain cancer risk. The feasibility of a study of the relation between radiofrequency exposure and cancer risk is, however, unclear at present. It is unknown whether a sufficiently accurate and precise RF exposure gradient can be derived to classify adequately each subject in the proposed study. A study of the relation between mobile telephone use and risk of salivary gland tumours and acoustic neurinomas is probably feasible, but more information is required about the logistic difficulties of ascertaining these cases in the study regions. Two subcommittees have been formed to develop the exposure measurement and epidemiological aspect of the study. (author)

  19. Inhibitory effects of CP on the growth of human gastric adenocarcinoma BGC-823 tumours in nude mice.

    Science.gov (United States)

    Wang, Hai-Jun; Liu, Yu; Zhou, Bao-Jun; Zhang, Zhan-Xue; Li, Ai-Ying; An, Ran; Yue, Bin; Fan, Li-Qiao; Li, Yong

    2018-05-01

    Objective To investigate the potential antitumour effects of [2-(6-amino-purine-9-yl)-1-hydroxy-phosphine acyl ethyl] phosphonic acid (CP) against gastric adenocarcinoma. Methods Human BGC-823 xenotransplants were established in nude mice. Animals were randomly divided into control and CP groups, which were administered NaHCO 3 vehicle alone or CP dissolved in NaHCO 3 (200 µg/kg body weight) daily, respectively. Tumour volume was measured weekly for 6 weeks. Resected tumours were assayed for proliferative activity with anti-Ki-67 or anti-proliferating cell nuclear antigen (PCNA) antibodies. Cell apoptosis was examined using terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assays and with caspase-3 immunostaining. Proteins were measured by Western blotting. Results There was a significant reduction in tumour volume and a reduced percentage of Ki-67-positive or PCNA-positive cells in the CP group compared with the control group. The percentage of TUNEL-positive or caspase 3-positive cells significantly increased following CP treatment compared with the control group. Tumours from the CP group had higher levels of phosphorylated-extracellular signal-regulated kinase (p-ERK) and phosphorylated-AKT (p-AKT) compared with control tumours. Conclusion CP treatment inhibited tumour growth and induced tumour cell apoptosis in a nude mouse model of BGC-823 gastric adenocarcinoma. Activation of the AKT and ERK signalling pathways may mediate this antitumour activity.

  20. Adnexal Tumours Of Skin

    Directory of Open Access Journals (Sweden)

    Parate Sanjay N

    1998-01-01

    Full Text Available A total 120 cases of epidermal appendage tumours of skin were analysed and classified according to the classification provided by WHO’. Epidermal appendage tumours accounted for 12.87% of all skin tumours, of which 29.17% were benign and 70.83% were malignant. Most of the tumours (75.83% were in the head and face region. The most common tumour was basal cell epithelioma (55%.

  1. Different classes of EGFR inhibitors may have different potential to improve local tumour control after fractionated irradiation: a study on C225 in FaDu hSCC

    International Nuclear Information System (INIS)

    Krause, M.; Schuetze, C.; Petersen, C.; Pimentel, N.; Hessel, F.; Harstrick, A.; Baumann, M.

    2005-01-01

    Background and purpose: Previous experiments reported from this laboratory have shown that simultaneous application of the selective epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor BIBX1382BS during fractionated irradiation significantly prolonged growth delay of FaDu human squamous cell carcinoma but did not improve local tumour control. The present study investigates the effect of the EGFR monoclonal antibody (mAb) C225 on local tumour control of FaDu tumours after combined treatment with single dose and fractionated irradiation to address whether different classes of EGFR inhibitors have different potential to improve the outcome of radiotherapy in the same tumour model. Material and methods: In unirradiated tumours, C225 was given either once or 4 times i.p. to the nude mice. Irradiation experiments were performed with graded single doses under clamp hypoxic conditions or with 30 fractions in 6 weeks with graded total doses under ambient blood flow. C225 was given 6 h before or 6 h before and 2, 5 and 7 days after single dose irradiation. During fractionated irradiation C225 was given once per week. Experimental endpoints were tumour growth delay and local tumour control 120 after end of irradiation. Results: C225 treatment resulted in prolongation of tumour growth delay after drug treatment alone as well as after single dose and fractionated irradiation. TCD 50 values were reduced from 56.3 Gy [95% CI 50; 62 Gy] after single dose irradiation alone to 46.0 Gy [41;51] (enhancement ratio [ER]=1.22, P 50 ) was 73.0 Gy [64; 82] in control tumours and 63.1 Gy [57; 69] after simultaneous C225 treatment, corresponding to an ER of 1.2 (P=0.01). Conclusion: Treatment of FaDu hSCC with the anti-EGFR mAb C225 resulted in a significant prolongation of tumour growth delay after single dose and fractionated irradiation. In contrast to previous results on the EGFR-TK inhibitor BIBX1382BS, this prolongation of growth delay translated into a slight but

  2. Efficacy and toxicity management of CAR-T-cell immunotherapy: a matter of responsiveness control or tumour-specificity?

    Science.gov (United States)

    Alonso-Camino, Vanesa; Harwood, Seandean Lykke; Álvarez-Méndez, Ana; Alvarez-Vallina, Luis

    2016-04-15

    Chimaeric antigen receptor (CAR)-expressing T-cells have demonstrated potent clinical efficacy in patients with haematological malignancies. However, the use of CAR-T-cells targeting solid tumour-associated antigens (TAAs) has been limited by organ toxicities related to activation of T-cell effector functions through the CAR. Most existing CARs recognize TAAs, which are also found in normal tissues. CAR-T-cell-mediated destruction of normal tissues constitutes a major roadblock to CAR-T-cell therapy, and must be avoided or mitigated. There is a broad range of strategies for modulating antigen responsiveness of CAR-T-cells, with varying degrees of complexity. Some of them might ameliorate the acute and chronic toxicities associated with current CAR constructs. However, further embellishments to CAR therapy may complicate clinical implementation and possibly create new immunogenicity issues. In contrast, the development of CARs targeting truly tumour-specific antigens might circumvent on-target/off-tumour toxicities without adding additional complexity to CAR-T-cell therapies, but these antigens have been elusive and may require novel selection strategies for their discovery. © 2016 Authors; published by Portland Press Limited.

  3. Neurofibromatosis type 1: brain stem tumours

    International Nuclear Information System (INIS)

    Bilaniuk, L.T.; Molloy, P.T.; Zimmerman, R.A.; Phillips, P.C.; Vaughan, S.N.; Liu, G.T.; Sutton, L.N.; Needle, M.

    1997-01-01

    We describe the clinical and imaging findings of brain stem tumours in patients with neurofibromatosis type 1 (NF1). The NF1 patients imaged between January 1984 and January 1996 were reviewed and 25 patients were identified with a brain stem tumour. Clinical, radiographical and pathological results were obtained by review of records and images. Brain stem tumour identification occurred much later than the clinical diagnosis of NF1. Medullary enlargement was most frequent (68 %), followed by pontine (52 %) and midbrain enlargement (44 %). Patients were further subdivided into those with diffuse (12 patients) and those with focal (13 patients) tumours. Treatment for hydrocephalus was required in 67 % of the first group and only 15 % of the second group. Surgery was performed in four patients and revealed fibrillary astrocytomas, one of which progressed to an anaplastic astrocytoma. In 40 % of patients both brain stem and optic pathway tumours were present. The biological behaviour of brain stem tumours in NF1 is unknown. Diffuse tumours in the patients with NF1 appear to have a much more favourable prognosis than patients with similar tumours without neurofibromatosis type 1. (orig.). With 7 figs., 3 tabs

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

    International Nuclear Information System (INIS)

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

    2011-01-01

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

  5. Gross tumor volume (GTV) and clinical target volume (CTV) for radiation therapy of benign skull base tumours

    International Nuclear Information System (INIS)

    Maire, J.P.; Liguoro, D.; San Galli, F.

    2001-01-01

    Skull base tumours represent a out 35 to 40% of all intracranial tumours. There are now many reports in the literature confirming the fact that about 80 to 90% of such tumours are controlled with fractionated radiotherapy. Stereotactic and 3-dimensional treatment planning techniques increase local control and central nervous system tolerance. Definition of the gross tumor volume (GTV) is generally easy with currently available medical imaging systems and computers for 3-dimensional dosimetry. The definition of the clinical target volume (CTV) is more difficult to appreciate: it is defined from the CTV plus a margin, which depends on the histology and anterior therapeutic history of the tumour. It is important to take into account the visible tumour and its possible extension pathways (adjacent bone, holes at the base of skull) and/or an anatomic region (sella turcica + adjacent cavernous sinus). It is necessary to evaluate these volumes with CT Scan and MRI to appreciate tumor extension in a 3-dimensional approach, in order to reduce the risk of marginal recurrences. The aim of this paper is to discuss volume definition as a function of tumour site and tumour type to be irradiated. (authors)

  6. Tumour control probability derived from dose distribution in homogeneous and heterogeneous models: assuming similar pharmacokinetics, 125Sn–177Lu is superior to 90Y–177Lu in peptide receptor radiotherapy

    International Nuclear Information System (INIS)

    Walrand, Stephan; Hanin, François-Xavier; Pauwels, Stanislas; Jamar, François

    2012-01-01

    Clinical trials on 177 Lu– 90 Y therapy used empirical activity ratios. Radionuclides (RN) with larger beta maximal range could favourably replace 90 Y. Our aim is to provide RN dose-deposition kernels and to compare the tumour control probability (TCP) of RN combinations. Dose kernels were derived by integration of the mono-energetic beta-ray dose distributions (computed using Monte Carlo) weighted by their respective beta spectrum. Nine homogeneous spherical tumours (1–25 mm in diameter) and four spherical tumours including a lattice of cold, but alive, spheres (1, 3, 5, 7 mm in diameter) were modelled. The TCP for 93 Y, 90 Y and 125 Sn in combination with 177 Lu in variable proportions (that kept constant the renal cortex biological effective dose) were derived by 3D dose kernel convolution. For a mean tumour-absorbed dose of 180 Gy, 2 mm homogeneous tumours and tumours including 3 mm diameter cold alive spheres were both well controlled (TCP > 0.9) using a 75–25% combination of 177 Lu and 90 Y activity. However, 125 Sn– 177 Lu achieved a significantly better result by controlling 1 mm-homogeneous tumour simultaneously with tumours including 5 mm diameter cold alive spheres. Clinical trials using RN combinations should use RN proportions tuned to the patient dosimetry. 125 Sn production and its coupling to somatostatin analogue appear feasible. Assuming similar pharmacokinetics 125 Sn is the best RN for combination with 177 Lu in peptide receptor radiotherapy justifying pharmacokinetics studies in rodent of 125 Sn-labelled somatostatin analogues. (paper)

  7. Response and recovery kinetics of a solid tumour after irradiation

    International Nuclear Information System (INIS)

    Rowley, R.; Hopkins, H.A.; Ritenour, E.R.; Looney, W.B.

    1980-01-01

    The effects of local tumour radiation over the dose range 7.5-30 Gy on the growth and cell kinetics of rat hepatoma H-4-II-E have been investigated. A plot of growth delays against log surviving fraction was linear below a fraction of 0.03, but failed to extrapolate to the origin. Following a single dose of 15 Gy to the tumour, DNA-precursor incorporation, labelling and mitotic indices were depressed for 7 days. Tumour cellularity, measured as DNA/g tumour was reduced and the rate of increase of total clonogenic cells slower than after complete tumour recovery. From Day 7 to Day 9 all indices of proliferation recovered to about control levels, clonogenic cell numbers increased more rapidly and tumour cellularity was restored. Repopulation of the tumour therefore appeared to take place mainly after Day 7. Incorporation of [ 3 H]-TdR into tumour DNA reached twice the control values on Day 9. The rate of tumour growth accelerated after the initial decrease, and maximum tumour growth rate was also twice the control values on Day 13. Accelerated growth rates in irradiated tumours, above those of control tumours, occurred 10-16 days after treatment. The effectiveness of sequential therapy may therefore be improved if given during this period of accelerated tumour growth. (author)

  8. of brain tumours

    African Journals Online (AJOL)

    outline of the important clinical issues related to brain tumours and psychiatry. ... Left-sided, frontal tumours also seem to be associated with higher rates of depression, while those in the frontal lobe of the right .... Oxford: Blackwell Science,.

  9. Immunity to tumour antigens.

    Science.gov (United States)

    Li, Geng; Ali, Selman A; McArdle, Stephanie E B; Mian, Shahid; Ahmad, Murrium; Miles, Amanda; Rees, Robert C

    2005-01-01

    During the last decade, a large number of human tumour antigens have been identified. These antigens are classified as tumour-specific shared antigens, tissue-specific differentiation antigens, overexpressed antigens, tumour antigens resulting from mutations, viral antigens and fusion proteins. Antigens recognised by effectors of immune system are potential targets for antigen-specific cancer immunotherapy. However, most tumour antigens are self-proteins and are generally of low immunogenicity and the immune response elicited towards these tumour antigens is not always effective. Strategies to induce and enhance the tumour antigen-specific response are needed. This review will summarise the approaches to discovery of tumour antigens, the current status of tumour antigens, and their potential application to cancer treatment.

  10. Whole brain irradiation with hippocampal sparing and dose escalation on multiple brain metastases. Local tumour control and survival

    Energy Technology Data Exchange (ETDEWEB)

    Oehlke, Oliver; Wucherpfennig, David; Prokic, Vesna [University Medical Center Freiburg, Department of Radiation Oncology, Freiburg (Germany); Fels, Franziska [University Medical Center Freiburg, Department of Radiation Oncology, Freiburg (Germany); St. Josefs Hospital, Department of Radiation Oncology, Offenburg (Germany); Frings, Lars [University Medical Center Freiburg, Department of Radiation Oncology, Freiburg (Germany); University Hospital Freiburg, Department of Geriatrics and Gerontology, Freiburg (Germany); University Medical Center Freiburg, Department of Nuclear Medicine, Freiburg (Germany); Egger, Karl [University Medical Center Freiburg, Department of Neuroradiology, Freiburg (Germany); Weyerbrock, Astrid [University Medical Center Freiburg, Department of Neurosurgery, Freiburg (Germany); Nieder, Carsten [Nordland Hospital, Department of Oncology and Palliative Medicine, Bodoe (Norway); University of Tromsoe, Institute of Clinical Medicine, Faculty of Health Sciences, Tromsoe (Norway); Grosu, Anca-Ligia [University Medical Center Freiburg, Department of Radiation Oncology, Freiburg (Germany); German Cancer Consortium (DKTK), Freiburg (Germany); German Cancer Research Center (DKFZ), Heidelberg (Germany)

    2015-01-16

    Hippocampal-avoidance whole brain radiotherapy (HA-WBRT) for multiple brain metastases may prevent treatment-related cognitive decline, compared to standard WBRT. Additionally, simultaneous integrated boost (SIB) on individual metastases may further improve the outcome. Here, we present initial data concerning local tumour control (LTC), intracranial progression-free survival (PFS), overall survival (OS), toxicity and safety for this new irradiation technique. Twenty patients, enrolled between 2011 and 2013, were treated with HA-WBRT (30 Gy in 12 fractions, D{sub 98} {sub %} to hippocampus ≤ 9 Gy) and a SIB (51 Gy) on multiple (2-13) metastases using a volumetric modulated arc therapy (VMAT) approach based on 2-4 arcs. Metastases were evaluated bidimensionally along the two largest diameters in contrast-enhanced three-dimensional T1-weighed MRI. Median follow-up was 40 weeks. The median time to progression of boosted metastases has not been reached yet, corresponding to a LTC rate of 73 %. Median intracranial PFS was 40 weeks, corresponding to a 1-year PFS of 45.3 %. Median OS was 71.5 weeks, corresponding to a 1-year OS of 60 %. No obvious acute or late toxicities grade > 2 (NCI CTCAE v4.03) were observed. D{sub mean} to the bilateral hippocampi was 6.585 Gy ± 0.847 (α/β = 2 Gy). Two patients developed a new metastasis in the area of hippocampal avoidance. HA-WBRT (simultaneous integrated protection, SIP) with SIB to metastases is a safe and tolerable regime that shows favorable LTC for patients with multiple brain metastases, while it has the potential to minimize the side-effect of cognitive deterioration. (orig.) [German] Die Hippocampus-schonende Ganzhirnbestrahlung (HS-GHB) kann im Vergleich zur Standard-GHB die Verschlechterung der neurokognitiven Funktion verhindern. Zusaetzlich vermag ein simultan integrierter Boost (SIB) auf die Metastasen die Prognose der betroffenen Patienten weiter zu verbessern. In dieser Studie praesentieren wir erste Ergebnisse

  11. Has 3-D conformal radiotherapy (3D CRT) improved the local tumour control for stage I non-small cell lung cancer?

    International Nuclear Information System (INIS)

    Lagerwaard, Frank J.; Senan, Suresh; Meerbeeck, Jan P. van; Graveland, Wilfried J.

    2002-01-01

    Aims and background: The high local failure rates observed after radiotherapy in stage I non-small cell lung cancer (NSCLC) may be improved by the use of 3-dimensional conformal radiotherapy (3D CRT). Materials and methods: The case-records of 113 patients who were treated with curative 3D CRT between 1991 and 1999 were analysed. No elective nodal irradiation was performed, and doses of 60 Gy or more, in once-daily fractions of between 2 and 3 Gy, were prescribed. Results: The median actuarial survival of patients was 20 months, with 1-, 3- and 5-year survival of 71, 25 and 12%, respectively. Local disease progression was the cause of death in 30% of patients, and 22% patients died from distant metastases. Grade 2-3 acute radiation pneumonitis (SWOG) was observed in 6.2% of patients. The median actuarial local progression-free survival (LPFS) was 27 months, with 85 and 43% of patients free from local progression at 1 and 3 years, respectively. Endobronchial tumour extension significantly influenced LPFS, both on univariate (P=0.023) and multivariate analysis (P=0.023). The median actuarial cause-specific survival (CSS) was 19 months, and the respective 1- and 3-year rates were 72 and 30%. Multivariate analysis showed T2 classification (P=0.017) and the presence of endobronchial tumour extension (P=0.029) to be adverse prognostic factors for CSS. On multivariate analysis, T-stage significantly correlated with distant failure (P=0.005). Conclusions: Local failure rates remain substantial despite the use of 3D CRT for stage I NSCLC. Additional improvements in local control can come about with the use of radiation dose escalation and approaches to address the problem of tumour mobility

  12. Case-control study of the association between malignant brain tumours diagnosed between 2007 and 2009 and mobile and cordless phone use.

    Science.gov (United States)

    Hardell, Lennart; Carlberg, Michael; Söderqvist, Fredrik; Mild, Kjell Hansson

    2013-12-01

    Previous studies have shown a consistent association between long-term use of mobile and cordless phones and glioma and acoustic neuroma, but not for meningioma. When used these phones emit radiofrequency electromagnetic fields (RF-EMFs) and the brain is the main target organ for the handheld phone. The International Agency for Research on Cancer (IARC) classified in May, 2011 RF-EMF as a group 2B, i.e. a 'possible' human carcinogen. The aim of this study was to further explore the relationship between especially long-term (>10 years) use of wireless phones and the development of malignant brain tumours. We conducted a new case-control study of brain tumour cases of both genders aged 18-75 years and diagnosed during 2007-2009. One population-based control matched on gender and age (within 5 years) was used to each case. Here, we report on malignant cases including all available controls. Exposures on e.g. use of mobile phones and cordless phones were assessed by a self-administered questionnaire. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index using the whole control sample. Of the cases with a malignant brain tumour, 87% (n=593) participated, and 85% (n=1,368) of controls in the whole study answered the questionnaire. The odds ratio (OR) for mobile phone use of the analogue type was 1.8, 95% confidence interval (CI)=1.04‑3.3, increasing with >25 years of latency (time since first exposure) to an OR=3.3, 95% CI=1.6-6.9. Digital 2G mobile phone use rendered an OR=1.6, 95% CI=0.996-2.7, increasing with latency >15-20 years to an OR=2.1, 95% CI=1.2-3.6. The results for cordless phone use were OR=1.7, 95% CI=1.1-2.9, and, for latency of 15-20 years, the OR=2.1, 95% CI=1.2-3.8. Few participants had used a cordless phone for >20-25 years. Digital type of wireless phones (2G and 3G mobile phones, cordless phones) gave increased risk with latency >1-5 years, then a lower risk in the following

  13. Deregulation of cap-dependent mRNA translation increases tumour radiosensitivity through reduction of the hypoxic fraction

    International Nuclear Information System (INIS)

    Rouschop, Kasper M.A.; Dubois, Ludwig; Schaaf, Marco B.E.; Beucken, Twan van den; Lieuwes, Natasja; Keulers, Tom G.H.; Savelkouls, Kim G.M.; Bussink, Johan; Kogel, Albert J. van der; Koritzinsky, Marianne; Wouters, Bradly G.

    2011-01-01

    Background and purpose: Tumour hypoxia is an important limiting factor in the successful treatment of cancer. Adaptation to hypoxia includes inhibition of mTOR, causing scavenging of eukaryotic initiation factor 4E (eIF4E), the rate-limiting factor for cap-dependent translation. The aim of this study was to determine the effect of preventing mTOR-dependent translation inhibition on hypoxic cell survival and tumour sensitivity towards irradiation. Material and methods: The effect of eIF4E-overexpression on cell proliferation, hypoxia-tolerance, and radiation sensitivity was assessed using isogenic, inducible U373 and HCT116 cells. Results: We found that eIF4E-overexpression significantly enhanced proliferation of cells under normal conditions, but not during hypoxia, caused by increased cell death during hypoxia. Furthermore, eIF4E-overexpression stimulated overall rates of tumour growth, but resulted in selective loss of hypoxic cells in established tumours and increased levels of necrosis. This markedly increased overall tumour sensitivity to irradiation. Conclusions: Our results demonstrate that hypoxia induced inhibition of translational control through regulation of eIF4E is an important mediator of hypoxia tolerance and radioresistance of tumours. These data also demonstrate that deregulation of metabolic pathways such as mTOR can influence the proliferation and survival of tumour cells experiencing metabolic stress in opposite ways of nutrient replete cells.

  14. Malignant tumours of the oral cavity and oropharynx: staging

    International Nuclear Information System (INIS)

    Youssefzadeh, S.; Pamberger, P.; Baumgartner, W.; Burian, M.; Becherer, A.; Wachter, S.

    1999-01-01

    Staging of malignant tumours of the oral cavity and the oropharynx not only requires far more than a basic knowledge of anatomy and the usual pathways of spread, but also a broad understanding of the diagnostic benefits of current imaging modalities. As radiology should never try to replace histology, the main aim should be precise prediction of tumour margins and differention of tumour from edema and posttherapeutic changes. Only then will imaging studies have a significant clinical impact. (orig.) [de

  15. Advanced Sensors and Controls for Building Applications: Market Assessment and Potential R&D Pathways

    Energy Technology Data Exchange (ETDEWEB)

    Brambley, M. R. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Haves, P. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); McDonald, S. C. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Torcellini, P. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Hansen, D. [U.S. Dept. of Energy, Washington, D.C. (United States); Holmberg, D. R. [National Institute of Science and Technology, Gaithersburg, MD (United States); Roth, K. W. [TIAX, LLC, Cambridge, MA (United States)

    2005-04-01

    This document provides a market assessment of existing building sensors and controls and presents a range of technology pathways (R&D options) for pursuing advanced sensors and building control strategies.

  16. EPHB6 augments both development and drug sensitivity of triple-negative breast cancer tumours.

    Science.gov (United States)

    Toosi, Behzad M; El Zawily, Amr; Truitt, Luke; Shannon, Matthew; Allonby, Odette; Babu, Mohan; DeCoteau, John; Mousseau, Darrell; Ali, Mohsin; Freywald, Tanya; Gall, Amanda; Vizeacoumar, Frederick S; Kirzinger, Morgan W; Geyer, C Ronald; Anderson, Deborah H; Kim, TaeHyung; Welm, Alana L; Siegel, Peter; Vizeacoumar, Franco J; Kusalik, Anthony; Freywald, Andrew

    2018-04-27

    Triple-negative breast cancer (TNBC) tumours that lack expression of oestrogen, and progesterone receptors, and do not overexpress the HER2 receptor represent the most aggressive breast cancer subtype, which is characterised by the resistance to therapy in frequently relapsing tumours and a high rate of patient mortality. This is likely due to the resistance of slowly proliferating tumour-initiating cells (TICs), and understanding molecular mechanisms that control TICs behaviour is crucial for the development of effective therapeutic approaches. Here, we present our novel findings, indicating that an intrinsically catalytically inactive member of the Eph group of receptor tyrosine kinases, EPHB6, partially suppresses the epithelial-mesenchymal transition in TNBC cells, while also promoting expansion of TICs. Our work reveals that EPHB6 interacts with the GRB2 adapter protein and that its effect on enhancing cell proliferation is mediated by the activation of the RAS-ERK pathway, which allows it to elevate the expression of the TIC-related transcription factor, OCT4. Consistent with this, suppression of either ERK or OCT4 activities blocks EPHB6-induced pro-proliferative responses. In line with its ability to trigger propagation of TICs, EPHB6 accelerates tumour growth, potentiates tumour initiation and increases TIC populations in xenograft models of TNBC. Remarkably, EPHB6 also suppresses tumour drug resistance to DNA-damaging therapy, probably by forcing TICs into a more proliferative, drug-sensitive state. In agreement, patients with higher EPHB6 expression in their tumours have a better chance for recurrence-free survival. These observations describe an entirely new mechanism that governs TNBC and suggest that it may be beneficial to enhance EPHB6 action concurrent with applying a conventional DNA-damaging treatment, as it would decrease drug resistance and improve tumour elimination.

  17. Molecular evolution of multiple-level control of heme biosynthesis pathway in animal kingdom.

    Science.gov (United States)

    Tzou, Wen-Shyong; Chu, Ying; Lin, Tzung-Yi; Hu, Chin-Hwa; Pai, Tun-Wen; Liu, Hsin-Fu; Lin, Han-Jia; Cases, Ildeofonso; Rojas, Ana; Sanchez, Mayka; You, Zong-Ye; Hsu, Ming-Wei

    2014-01-01

    Adaptation of enzymes in a metabolic pathway can occur not only through changes in amino acid sequences but also through variations in transcriptional activation, mRNA splicing and mRNA translation. The heme biosynthesis pathway, a linear pathway comprised of eight consecutive enzymes in animals, provides researchers with ample information for multiple types of evolutionary analyses performed with respect to the position of each enzyme in the pathway. Through bioinformatics analysis, we found that the protein-coding sequences of all enzymes in this pathway are under strong purifying selection, from cnidarians to mammals. However, loose evolutionary constraints are observed for enzymes in which self-catalysis occurs. Through comparative genomics, we found that in animals, the first intron of the enzyme-encoding genes has been co-opted for transcriptional activation of the genes in this pathway. Organisms sense the cellular content of iron, and through iron-responsive elements in the 5' untranslated regions of mRNAs and the intron-exon boundary regions of pathway genes, translational inhibition and exon choice in enzymes may be enabled, respectively. Pathway product (heme)-mediated negative feedback control can affect the transport of pathway enzymes into the mitochondria as well as the ubiquitin-mediated stability of enzymes. Remarkably, the positions of these controls on pathway activity are not ubiquitous but are biased towards the enzymes in the upstream portion of the pathway. We revealed that multiple-level controls on the activity of the heme biosynthesis pathway depend on the linear depth of the enzymes in the pathway, indicating a new strategy for discovering the molecular constraints that shape the evolution of a metabolic pathway.

  18. The Aedes aegypti toll pathway controls dengue virus infection.

    Directory of Open Access Journals (Sweden)

    Zhiyong Xi

    2008-07-01

    Full Text Available Aedes aegypti, the mosquito vector of dengue viruses, utilizes its innate immune system to ward off a variety of pathogens, some of which can cause disease in humans. To date, the features of insects' innate immune defenses against viruses have mainly been studied in the fruit fly Drosophila melanogaster, which appears to utilize different immune pathways against different types of viruses, in addition to an RNA interference-based defense system. We have used the recently released whole-genome sequence of the Ae. aegypti mosquito, in combination with high-throughput gene expression and RNA interference (RNAi-based reverse genetic analyses, to characterize its response to dengue virus infection in different body compartments. We have further addressed the impact of the mosquito's endogenous microbial flora on virus infection. Our findings indicate a significant role for the Toll pathway in regulating resistance to dengue virus, as indicated by an infection-responsive regulation and functional assessment of several Toll pathway-associated genes. We have also shown that the mosquito's natural microbiota play a role in modulating the dengue virus infection, possibly through basal-level stimulation of the Toll immune pathway.

  19. The potential role of podoplanin in tumour invasion

    Science.gov (United States)

    Wicki, A; Christofori, G

    2006-01-01

    Podoplanin is a small mucin-like transmembrane protein, widely expressed in various specialised cell types throughout the body. Here, we revisit the mechanism of podoplanin-mediated tumour invasion. We compare molecular pathways leading to single and collective cell invasion and discuss novel distinct concepts of tumour cell invasion. PMID:17179989

  20. Oxidative stress specifically downregulates survivin to promote breast tumour formation.

    Science.gov (United States)

    Pervin, S; Tran, L; Urman, R; Braga, M; Parveen, M; Li, S A; Chaudhuri, G; Singh, R

    2013-03-05

    Breast cancer, a heterogeneous disease has been broadly classified into oestrogen receptor positive (ER+) or oestrogen receptor negative (ER-) tumour types. Each of these tumours is dependent on specific signalling pathways for their progression. While high levels of survivin, an anti-apoptotic protein, increases aggressive behaviour in ER- breast tumours, oxidative stress (OS) promotes the progression of ER+ breast tumours. Mechanisms and molecular targets by which OS promotes tumourigenesis remain poorly understood. DETA-NONOate, a nitric oxide (NO)-donor induces OS in breast cancer cell lines by early re-localisation and downregulation of cellular survivin. Using in vivo models of HMLE(HRAS) xenografts and E2-induced breast tumours in ACI rats, we demonstrate that high OS downregulates survivin during initiation of tumourigenesis. Overexpression of survivin in HMLE(HRAS) cells led to a significant delay in tumour initiation and tumour volume in nude mice. This inverse relationship between survivin and OS was also observed in ER+ human breast tumours. We also demonstrate an upregulation of NADPH oxidase-1 (NOX1) and its activating protein p67, which are novel markers of OS in E2-induced tumours in ACI rats and as well as in ER+ human breast tumours. Our data, therefore, suggest that downregulation of survivin could be an important early event by which OS initiates breast tumour formation.

  1. Monte Carlo dose calculations and radiobiological modelling: analysis of the effect of the statistical noise of the dose distribution on the probability of tumour control

    International Nuclear Information System (INIS)

    Buffa, Francesca M.

    2000-01-01

    The aim of this work is to investigate the influence of the statistical fluctuations of Monte Carlo (MC) dose distributions on the dose volume histograms (DVHs) and radiobiological models, in particular the Poisson model for tumour control probability (tcp). The MC matrix is characterized by a mean dose in each scoring voxel, d, and a statistical error on the mean dose, σ d ; whilst the quantities d and σ d depend on many statistical and physical parameters, here we consider only their dependence on the phantom voxel size and the number of histories from the radiation source. Dose distributions from high-energy photon beams have been analysed. It has been found that the DVH broadens when increasing the statistical noise of the dose distribution, and the tcp calculation systematically underestimates the real tumour control value, defined here as the value of tumour control when the statistical error of the dose distribution tends to zero. When increasing the number of energy deposition events, either by increasing the voxel dimensions or increasing the number of histories from the source, the DVH broadening decreases and tcp converges to the 'correct' value. It is shown that the underestimation of the tcp due to the noise in the dose distribution depends on the degree of heterogeneity of the radiobiological parameters over the population; in particular this error decreases with increasing the biological heterogeneity, whereas it becomes significant in the hypothesis of a radiosensitivity assay for single patients, or for subgroups of patients. It has been found, for example, that when the voxel dimension is changed from a cube with sides of 0.5 cm to a cube with sides of 0.25 cm (with a fixed number of histories of 10 8 from the source), the systematic error in the tcp calculation is about 75% in the homogeneous hypothesis, and it decreases to a minimum value of about 15% in a case of high radiobiological heterogeneity. The possibility of using the error on the

  2. MHC class II molecules and tumour immunotherapy

    International Nuclear Information System (INIS)

    Oven, I.

    2005-01-01

    Background. Tumour immunotherapy attempts to use the specificity and capability of the immune system to kill malignant cells with a minimum damage to normal tissue. Increasing knowledge of the identity of tumour antigens should help us design more effective therapeutic vaccines. Increasing evidence has demonstrated that MHC class II molecules and CD4+ T cells play important roles in generating and maintaining antitumour immune responses in animal models. These data suggest that it may be necessary to involve both CD4+ and CD8+ T cells for more effective antitumour therapy. Novel strategies have been developed for enhancing T cell responses against cancer by prolonging antigen presentation of dendritic cells to T cells, by the inclusion of MHC class II-restricted tumour antigens and by genetically modifying tumour cells to present antigen to T lymphocytes directly. Conclusions. Vaccines against cancers aim to induce tumour-specific effector T cells that can reduce tumour mass and induce development of tumour-specific T cell memory, that can control tumour relapse. (author)

  3. Imaging of sacral tumours

    International Nuclear Information System (INIS)

    Gerber, S.; Ollivier, L.; Brisse, H.; Neuenschwander, S.; Leclere, J.; Vanel, D.; Missenard, G.; Pinieux, G. de

    2008-01-01

    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.)

  4. 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)

    2008-04-15

    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.)

  5. Improving tumour response

    International Nuclear Information System (INIS)

    Bentzen, S.

    2003-01-01

    Radiation oncology is in the middle of the most exciting developments in its 100-year history. Progress in treatment planning and delivery, in medical imaging and in basic cancer and normal tissue biology is likely to change the indication for radiotherapy as well as the way it is prescribed and delivered. Technological and conceptual advances, in particular the development of the multi-leaf collimator and the concept of inverse treatment planning, have led to the introduction of intensity modulated radiation therapy (IMRT) with its capability to plan and deliver non-uniform dose distributions in the clinic. This has forced us to re-think radiation oncology: refining the indication for radiotherapy, optimizing the prescription of dose distributions and considering how, based on clinical evidence, radiation can best be combined with other treatment modalities, surgery, cytotoxic chemotherapy and biologically targeted therapies. The attraction of radiation therapy as an element of multi-modality cancer therapy is that it induces DNA damage that can be modulated in space and time. Progress in basic cancer biology, genomics and proteomics, as well as biological imaging provides novel avenues for individualization of cancer therapy and for biological optimization of radiotherapy. In improving cancer care, it is the therapeutic ratio, rather than tumour control per se, that must be optimised. Interestingly, the two main avenues for improving the effectiveness of radiotherapy currently being actively pursued in the clinic generally aim at different sides of the therapeutic ratio: 3D conformal radiotherapy and IMRT predominantly aim to reduce normal-tissue side effects - and by doing this, open the way for dose escalation that may lead to increased tumour control rates - whereas combined radio-chemotherapy aims to improve tumour response - while keeping the fingers crossed that this will not increase normal-tissue complications to the same extent. In parallel with these

  6. Phase control of light amplification with dynamically irreversible pathways of population transfer in a Λ system

    International Nuclear Information System (INIS)

    Yuan Shi; Wu Jinhui; Gao Jinyue; Pan Chunliu

    2002-01-01

    We use the relative phase of two coherent fields for the control of light amplification with dynamically irreversible pathways of population transfer in a Λ system. The population inversion and gain with dynamically irreversible pathways of population transfer are shown as the relative phase is varied. We support our results by numerical calculation and analytical explanation

  7. Resection of the primary tumour versus no resection prior to systemic therapy in patients with colon cancer and synchronous unresectable metastases (UICC stage IV): SYNCHRONOUS - a randomised controlled multicentre trial (ISRCTN30964555)

    International Nuclear Information System (INIS)

    Rahbari, Nuh N; Koch, Moritz; Büchler, Markus W; Kieser, Meinhard; Weitz, Jürgen; Lordick, Florian; Fink, Christine; Bork, Ulrich; Stange, Annika; Jäger, Dirk; Luntz, Steffen P; Englert, Stefan; Rossion, Inga

    2012-01-01

    Currently, it remains unclear, if patients with colon cancer and synchronous unresectable metastases who present without severe symptoms should undergo resection of the primary tumour prior to systemic chemotherapy. Resection of the primary tumour may be associated with significant morbidity and delays the beginning of chemotherapy. However, it may prevent local symptoms and may, moreover, prolong survival as has been demonstrated in patients with metastatic renal cell carcinoma. It is the aim of the present randomised controlled trial to evaluate the efficacy of primary tumour resection prior to systemic chemotherapy to prolong survival in patients with newly diagnosed colon cancer who are not amenable to curative therapy. The SYNCHRONOUS trial is a multicentre, randomised, controlled, superiority trial with a two-group parallel design. Colon cancer patients with synchronous unresectable metastases are eligible for inclusion. Exclusion criteria are primary tumour-related symptoms, inability to tolerate surgery and/or systemic chemotherapy and history of another primary cancer. Resection of the primary tumour as well as systemic chemotherapy is provided according to the standards of the participating institution. The primary endpoint is overall survival that is assessed with a minimum follow-up of 36 months. Furthermore, it is the objective of the trial to assess the safety of both treatment strategies as well as quality of life. The SYNCHRONOUS trial is a multicentre, randomised, controlled trial to assess the efficacy and safety of primary tumour resection before beginning of systemic chemotherapy in patients with metastatic colon cancer not amenable to curative therapy. http://www.controlled-trials.com/ISRCTN30964555

  8. Construction of a controllable β-carotene biosynthetic pathway by decentralized assembly strategy in Saccharomyces cerevisiae.

    Science.gov (United States)

    Xie, Wenping; Liu, Min; Lv, Xiaomei; Lu, Wenqiang; Gu, Jiali; Yu, Hongwei

    2014-01-01

    Saccharomyces cerevisiae is an important platform organism for the synthesis of a great number of natural products. However, the assembly of controllable and genetically stable heterogeneous biosynthetic pathways in S. cerevisiae still remains a significant challenge. Here, we present a strategy for reconstructing controllable multi-gene pathways by employing the GAL regulatory system. A set of marker recyclable integrative plasmids (pMRI) was designed for decentralized assembly of pathways. As proof-of-principle, a controllable β-carotene biosynthesis pathway (∼16 kb) was reconstructed and optimized by repeatedly using GAL10-GAL1 bidirectional promoters with high efficiency (80-100%). By controling the switch time of the pathway, production of 11 mg/g DCW of total carotenoids (72.57 mg/L) and 7.41 mg/g DCW of β-carotene was achieved in shake-flask culture. In addition, the engineered yeast strain exhibited high genetic stability after 20 generations of subculture. The results demonstrated a controllable and genetically stable biosynthetic pathway capable of increasing the yield of target products. Furthermore, the strategy presented in this study could be extended to construct other pathways in S. cerevisisae. © 2013 Wiley Periodicals, Inc.

  9. Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour

    Science.gov (United States)

    Scott, R H; Stiller, C A; Walker, L; Rahman, N

    2006-01-01

    Wilms tumour has been reported in association with over 50 different clinical conditions and several abnormal constitutional karyotypes. Conclusive evidence of an increased risk of Wilms tumour exists for only a minority of these conditions, including WT1 associated syndromes, familial Wilms tumour, and certain overgrowth conditions such as Beckwith‐Wiedemann syndrome. In many reported conditions the rare co‐occurrence of Wilms tumour is probably due to chance. However, for several conditions the available evidence cannot either confirm or exclude an increased risk, usually because of the rarity of the syndrome. In addition, emerging evidence suggests that an increased risk of Wilms tumour occurs only in a subset of individuals for some syndromes. The complex clinical and molecular heterogeneity of disorders associated with Wilms tumour, together with the apparent absence of functional links between most of the known predisposition genes, suggests that abrogation of a variety of pathways can promote Wilms tumorigenesis. PMID:16690728

  10. Insulin resistance in vascular endothelial cells promotes intestinal tumour formation

    DEFF Research Database (Denmark)

    Wang, X; Häring, M-F; Rathjen, Thomas

    2017-01-01

    in vascular endothelial cells. Strikingly, these mice had 42% more intestinal tumours than controls, no change in tumour angiogenesis, but increased expression of vascular cell adhesion molecule-1 (VCAM-1) in primary culture of tumour endothelial cells. Insulin decreased VCAM-1 expression and leukocyte...... adhesion in quiescent tumour endothelial cells with intact insulin receptors and partly prevented increases in VCAM-1 and leukocyte adhesion after treatment with tumour necrosis factor-α. Knockout of insulin receptors in endothelial cells also increased leukocyte adhesion in mesenteric venules...

  11. Wilms' tumour (nephroblastoma)

    African Journals Online (AJOL)

    Wilms' tumour or nephroblastoma is a cancer of the kidney that ... It may be noticed by parents or it may be an incidental finding ... patients. It may lead to iron deficiency anaemia. Rarely Wilms' tumour may present with acquired von Willebrand's ... the best treatment approach. ... with multimodality therapy in paediatric.

  12. SU-E-T-144: Bayesian Inference of Local Relapse Data Using a Poisson-Based Tumour Control Probability Model

    Energy Technology Data Exchange (ETDEWEB)

    La Russa, D [The Ottawa Hospital Cancer Centre, Ottawa, ON (Canada)

    2015-06-15

    Purpose: The purpose of this project is to develop a robust method of parameter estimation for a Poisson-based TCP model using Bayesian inference. Methods: Bayesian inference was performed using the PyMC3 probabilistic programming framework written in Python. A Poisson-based TCP regression model that accounts for clonogen proliferation was fit to observed rates of local relapse as a function of equivalent dose in 2 Gy fractions for a population of 623 stage-I non-small-cell lung cancer patients. The Slice Markov Chain Monte Carlo sampling algorithm was used to sample the posterior distributions, and was initiated using the maximum of the posterior distributions found by optimization. The calculation of TCP with each sample step required integration over the free parameter α, which was performed using an adaptive 24-point Gauss-Legendre quadrature. Convergence was verified via inspection of the trace plot and posterior distribution for each of the fit parameters, as well as with comparisons of the most probable parameter values with their respective maximum likelihood estimates. Results: Posterior distributions for α, the standard deviation of α (σ), the average tumour cell-doubling time (Td), and the repopulation delay time (Tk), were generated assuming α/β = 10 Gy, and a fixed clonogen density of 10{sup 7} cm−{sup 3}. Posterior predictive plots generated from samples from these posterior distributions are in excellent agreement with the observed rates of local relapse used in the Bayesian inference. The most probable values of the model parameters also agree well with maximum likelihood estimates. Conclusion: A robust method of performing Bayesian inference of TCP data using a complex TCP model has been established.

  13. Golimumab in patients with active rheumatoid arthritis who have previous experience with tumour necrosis factor inhibitors: results of a long-term extension of the randomised, double-blind, placebo-controlled GO-AFTER study through week 160

    NARCIS (Netherlands)

    Smolen, Josef S.; Kay, Jonathan; Landewé, Robert B. M.; Matteson, Eric L.; Gaylis, Norman; Wollenhaupt, Jurgen; Murphy, Frederick T.; Zhou, Yiying; Hsia, Elizabeth C.; Doyle, Mittie K.

    2012-01-01

    The aim of this study was to assess long-term golimumab therapy in patients with rheumatoid arthritis (RA) who discontinued previous tumour necrosis factor alpha (TNFα) inhibitor(s) for any reason. Results through week 24 of this multicentre, randomised, double-blind, placebo-controlled study of

  14. Tumour control in ion beam radiotherapy with different ions in the presence of hypoxia: an oxygen enhancement ratio model based on the microdosimetric kinetic model

    Science.gov (United States)

    Strigari, L.; Torriani, F.; Manganaro, L.; Inaniwa, T.; Dalmasso, F.; Cirio, R.; Attili, A.

    2018-03-01

    Few attempts have been made to include the oxygen enhancement ratio (OER) in treatment planning for ion beam therapy, and systematic studies to evaluate the impact of hypoxia in treatment with the beam of different ion species are sorely needed. The radiobiological models used to quantify the OER in such studies are mainly based on the dose-averaged LET estimates, and do not explicitly distinguish between the ion species and fractionation schemes. In this study, a new type of OER modelling, based on the microdosimetric kinetic model, taking into account the specificity of the different ions, LET spectra, tissues and fractionation schemes, has been developed. The model has been benchmarked with published in vitro data, HSG, V79 and CHO cells in aerobic and hypoxic conditions, for different ion irradiation. The model has been included in the simulation of treatments for a clinical case (brain tumour) using proton, lithium, helium, carbon and oxygen ion beams. A study of the tumour control probability (TCP) as a function of oxygen partial pressure, dose per fraction and primary ion type has been performed. The modelled OER depends on both the LET and ion type, also showing a decrease for an increased dose per fraction with a slope that depends on the LET and ion type, in good agreement with the experimental data. In the investigated clinical case, a significant increase in TCP has been found upon increasing the ion charge. Higher OER variations as a function of dose per fraction have also been found for low-LET ions (up to 15% varying from 2 to 8 Gy(RBE) for protons). This model could be exploited in the identification of treatment condition optimality in the presence of hypoxia, including fractionation and primary particle selection.

  15. MAPK pathway control of stem cell proliferation and differentiation in the embryonic pituitary provides insights into the pathogenesis of papillary craniopharyngioma.

    Science.gov (United States)

    Haston, Scott; Pozzi, Sara; Carreno, Gabriela; Manshaei, Saba; Panousopoulos, Leonidas; Gonzalez-Meljem, Jose Mario; Apps, John R; Virasami, Alex; Thavaraj, Selvam; Gutteridge, Alice; Forshew, Tim; Marais, Richard; Brandner, Sebastian; Jacques, Thomas S; Andoniadou, Cynthia L; Martinez-Barbera, Juan Pedro

    2017-06-15

    Despite the importance of the RAS-RAF-MAPK pathway in normal physiology and disease of numerous organs, its role during pituitary development and tumourigenesis remains largely unknown. Here, we show that the over-activation of the MAPK pathway, through conditional expression of the gain-of-function alleles BrafV600E and KrasG12D in the developing mouse pituitary, results in severe hyperplasia and abnormal morphogenesis of the gland by the end of gestation. Cell-lineage commitment and terminal differentiation are disrupted, leading to a significant reduction in numbers of most of the hormone-producing cells before birth, with the exception of corticotrophs. Of note, Sox2 + stem cells and clonogenic potential are drastically increased in the mutant pituitaries. Finally, we reveal that papillary craniopharyngioma (PCP), a benign human pituitary tumour harbouring BRAF p.V600E also contains Sox2 + cells with sustained proliferative capacity and disrupted pituitary differentiation. Together, our data demonstrate a crucial function of the MAPK pathway in controlling the balance between proliferation and differentiation of Sox2 + cells and suggest that persistent proliferative capacity of Sox2 + cells may underlie the pathogenesis of PCP. © 2017. Published by The Company of Biologists Ltd.

  16. 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

    2007-01-01

    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.

  17. Critical Roles of the Direct GABAergic Pallido-cortical Pathway in Controlling Absence Seizures

    Science.gov (United States)

    Li, Min; Ma, Tao; Wu, Shengdun; Ma, Jingling; Cui, Yan; Xia, Yang; Xu, Peng; Yao, Dezhong

    2015-01-01

    The basal ganglia (BG), serving as an intermediate bridge between the cerebral cortex and thalamus, are believed to play crucial roles in controlling absence seizure activities generated by the pathological corticothalamic system. Inspired by recent experiments, here we systematically investigate the contribution of a novel identified GABAergic pallido-cortical pathway, projecting from the globus pallidus externa (GPe) in the BG to the cerebral cortex, to the control of absence seizures. By computational modelling, we find that both increasing the activation of GPe neurons and enhancing the coupling strength of the inhibitory pallido-cortical pathway can suppress the bilaterally synchronous 2–4 Hz spike and wave discharges (SWDs) during absence seizures. Appropriate tuning of several GPe-related pathways may also trigger the SWD suppression, through modulating the activation level of GPe neurons. Furthermore, we show that the previously discovered bidirectional control of absence seizures due to the competition between other two BG output pathways also exists in our established model. Importantly, such bidirectional control is shaped by the coupling strength of this direct GABAergic pallido-cortical pathway. Our work suggests that the novel identified pallido-cortical pathway has a functional role in controlling absence seizures and the presented results might provide testable hypotheses for future experimental studies. PMID:26496656

  18. Allosteric mechanism controls traffic in the chaperone/usher pathway.

    Science.gov (United States)

    Di Yu, Xiao; Dubnovitsky, Anatoly; Pudney, Alex F; Macintyre, Sheila; Knight, Stefan D; Zavialov, Anton V

    2012-11-07

    Many virulence organelles of Gram-negative bacterial pathogens are assembled via the chaperone/usher pathway. The chaperone transports organelle subunits across the periplasm to the outer membrane usher, where they are released and incorporated into growing fibers. Here, we elucidate the mechanism of the usher-targeting step in assembly of the Yersinia pestis F1 capsule at the atomic level. The usher interacts almost exclusively with the chaperone in the chaperone:subunit complex. In free chaperone, a pair of conserved proline residues at the beginning of the subunit-binding loop form a "proline lock" that occludes the usher-binding surface and blocks usher binding. Binding of the subunit to the chaperone rotates the proline lock away from the usher-binding surface, allowing the chaperone-subunit complex to bind to the usher. We show that the proline lock exists in other chaperone/usher systems and represents a general allosteric mechanism for selective targeting of chaperone:subunit complexes to the usher and for release and recycling of the free chaperone. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Renin secretion and total body sodium: Pathways of integrative control

    DEFF Research Database (Denmark)

    Bie, Peter; Damkjaer, Mads

    2009-01-01

    to a spring/shock absorber set-up: Non-adaptive RAAS functions determine the new steady state position while TGF controls the rate of change. Recruitment of renin-secreting cells during sustained stimulation may be essential for chronic adaptation, although details of this afferent arteriolar cell plasticity...

  20. Malignant thyroid tumours

    International Nuclear Information System (INIS)

    Boerner, W.; Reiners, C.

    1987-01-01

    The subjects dealt with at the symposium cover all topical aspects of pathology, epidemiology, diagnosis, therapy, and aftercare of the malignant thyroid tumours. A survey of the histological classification of the thyroid tumours and a review of the latest findings concerning the radiocarcinogenesis are followed by a detailed discussion of the most significant tumours. There are also papers dealing with controversial aspects of the histological classification, the value of diagnostic methods, radicality of the therapy, or after care. For five conference papers, separate records are available in the database. (orig./ECB) With 59 figs.; 57 tabs [de

  1. Acetyltransferases and tumour suppression

    International Nuclear Information System (INIS)

    Phillips, A C; Vousden, Karen H

    2000-01-01

    The acetyltransferase p300 was first identified associated with the adenoviral transforming protein E1A, suggesting a potential role for p300 in the regulation of cell proliferation. Direct evidence demonstrating a role for p300 in human tumours was lacking until the recentl publication by Gayther et al, which strongly supports a role for p300 as a tumour suppressor. The authors identify truncating mutations associated with the loss or mutation of the second allele in both tumour samples and cell lines, suggesting that loss of p300 may play a role in the development of a subset of human cancers

  2. Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses.

    Science.gov (United States)

    Holm, Christian K; Rahbek, Stine H; Gad, Hans Henrik; Bak, Rasmus O; Jakobsen, Martin R; Jiang, Zhaozaho; Hansen, Anne Louise; Jensen, Simon K; Sun, Chenglong; Thomsen, Martin K; Laustsen, Anders; Nielsen, Camilla G; Severinsen, Kasper; Xiong, Yingluo; Burdette, Dara L; Hornung, Veit; Lebbink, Robert Jan; Duch, Mogens; Fitzgerald, Katherine A; Bahrami, Shervin; Mikkelsen, Jakob Giehm; Hartmann, Rune; Paludan, Søren R

    2016-02-19

    Stimulator of interferon genes (STING) is known be involved in control of DNA viruses but has an unexplored role in control of RNA viruses. During infection with DNA viruses STING is activated downstream of cGAMP synthase (cGAS) to induce type I interferon. Here we identify a STING-dependent, cGAS-independent pathway important for full interferon production and antiviral control of enveloped RNA viruses, including influenza A virus (IAV). Further, IAV interacts with STING through its conserved hemagglutinin fusion peptide (FP). Interestingly, FP antagonizes interferon production induced by membrane fusion or IAV but not by cGAMP or DNA. Similar to the enveloped RNA viruses, membrane fusion stimulates interferon production in a STING-dependent but cGAS-independent manner. Abolishment of this pathway led to reduced interferon production and impaired control of enveloped RNA viruses. Thus, enveloped RNA viruses stimulate a cGAS-independent STING pathway, which is targeted by IAV.

  3. Targeting radiation to tumours

    International Nuclear Information System (INIS)

    Wheldon, T.E.; Greater Glasgow Health Board, Glasgow

    1994-01-01

    Biologically targeted radiotherapy entails the preferential delivery of radiation to solid tumours or individual tumour cells by means of tumour-seeking delivery vehicles to which radionuclides can be conjugated. Monoclonal antibodies have attracted attention for some years as potentially selective targeting agents, but advances in tumour and molecular biology are now providing a much wider choice of molecular species. General radiobiological principles may be derived which are applicable to most forms of targeted radiotherapy. These principles provide guidelines for the appropriate choice of radionuclide in specific treatment situations and its optimal combination with other treatment modalities. In future, the availability of gene targeting agents will focus attention on the use of Auger electron emitters whose high potency and short range selectivity makes them attractive choices for specific killing of cancer cells whose genetic peculiarities are known. (author)

  4. [Gastric mesenchymal tumours (GIST)].

    Science.gov (United States)

    Spivach, Arrigo; Fezzi, Margherita; Sartori, Alberto; Belgrano, Manuel; Rimondini, Alessandra; Cuttin-Zernich, Roberto; Covab, Maria Assunta; Bonifacio, Daniela; Buri, Luigi; Pagani, Carlo; Zanconati, Fabrizio

    2008-01-01

    The incidence of gastrointestinal stromal tumours (GIST) has increased in recent years. A number of authors have attempted to define the actual nature of these tumours. Immunohistochemistry highlighting the positivity of tyrosine-kinase (CD117/c-Kit) has revealed the difference between gastrointestinal stromal tumours and other mesenchymal tumours and, therefore, the possibility of medical rather than surgical therapy. We retrospectively reviewed 19 patients affected by primary gastric GIST, who underwent surgery in recent years with subsequent follow-up. Gastroscopy and gastrointestinal tract radiography were used not only to obtain the diagnosis but also to establish the size, density, contours, ulceration, regional lymphadenopathy, mesenteric infiltration and the presence of metastases. The aim of this study was to evaluate the roles of endoscopy and radiology in this pathology and the advantages and limitations of each individual technique.

  5. Post-translational Control of Intracellular Pathogen Sensing Pathways.

    Science.gov (United States)

    Chiang, Cindy; Gack, Michaela U

    2017-01-01

    Mammalian cells recognize virus-derived nucleic acids using a defined set of intracellular sensors including the DNA sensors cyclic GMP-AMP (cGAMP) synthase (cGAS) and interferon gamma (IFNγ)-inducible protein 16 (IFI16) as well as viral RNA receptors of the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family. Following innate immune recognition, these sensors launch an immune response that is characterized by the transcriptional upregulation of many antiviral molecules, including proinflammatory cytokines, chemokines, and IFN-stimulated genes. Recent studies have demonstrated that the signal transduction initiated by these sensors is sophisticatedly regulated by post-translational modifications (PTMs) resulting in a robust yet 'tunable' cytokine response to maintain immune homeostasis. Here we summarize recent advances in our understanding of how PTMs and regulatory enzymes control the signaling activity of RLRs, cGAS, and IFI16 as well as their proximal adaptor proteins. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties.

    Science.gov (United States)

    de Medina, Philippe; Paillasse, Michael R; Segala, Gregory; Voisin, Maud; Mhamdi, Loubna; Dalenc, Florence; Lacroix-Triki, Magali; Filleron, Thomas; Pont, Frederic; Saati, Talal Al; Morisseau, Christophe; Hammock, Bruce D; Silvente-Poirot, Sandrine; Poirot, Marc

    2013-01-01

    We previously synthesized dendrogenin A and hypothesized that it could be a natural metabolite occurring in mammals. Here we explore this hypothesis and report the discovery of dendrogenin A in mammalian tissues and normal cells as an enzymatic product of the conjugation of 5,6α-epoxy-cholesterol and histamine. Dendrogenin A was not detected in cancer cell lines and was fivefold lower in human breast tumours compared with normal tissues, suggesting a deregulation of dendrogenin A metabolism during carcinogenesis. We established that dendrogenin A is a selective inhibitor of cholesterol epoxide hydrolase and it triggered tumour re-differentiation and growth control in mice and improved animal survival. The properties of dendrogenin A and its decreased level in tumours suggest a physiological function in maintaining cell integrity and differentiation. The discovery of dendrogenin A reveals a new metabolic pathway at the crossroads of cholesterol and histamine metabolism and the existence of steroidal alkaloids in mammals.

  7. Is palliative resection of the primary tumour, in the presence of advanced rectal cancer, a safe and useful technique for symptom control?

    International Nuclear Information System (INIS)

    Al-Sanea, N.; Isbister, W.H.

    2004-01-01

    Over an 8-year period 22 patients (average age 54 years) underwent rectal resectional surgery in the presence of metastatic disease. There were 13 men and nine women. The commonest complaint was rectal bleeding. All patients had chest radiographs. Pulmonary metastases were identified in four patients. Nineteen abdominal and pelvic computed tomography scans were performed and eight showed evidence of metastases. Skeletal radiographs in two patients showed evidence of bone metastasis. At operation, intraperitoneal metastases were found in 18 patients. Nine of these were not identified preoperatively. Six patients underwent abdomino-perineal resection, nine anterior resection and seven a Hartmann's procedure. Eight patients developed a significant postoperative complication and one died 42 days after surgery. The mean length of hospital stay was 18.6 days. Nine patients received preoperative radiotherapy. Four patients had palliative radiotherapy, two for bony, one for liver and one for peritoneal metastases. Patients were followed up for a mean of 1.1 years. During follow up, 11 returned to the emergency room on 24 occasions. Two patients required readmission. No patient had further rectal bleeding. The mean survival was 1.3 years. It is concluded that patients with rectal cancer and unresectable distant metastases can be successfully palliated by resection of the primary tumour with low morbidity and mortality. The early involvement of a palliative care team facilitates patient management and helps patients enjoy what remains of the rest of their lives at home, in comfort and with good symptom control. Copyright (2004) Blackwell Publishing

  8. Antigen-specific primed cytotoxic T cells eliminate tumour cells in vivo and prevent tumour development, regardless of the presence of anti-apoptotic mutations conferring drug resistance.

    Science.gov (United States)

    Jaime-Sánchez, Paula; Catalán, Elena; Uranga-Murillo, Iratxe; Aguiló, Nacho; Santiago, Llipsy; M Lanuza, Pilar; de Miguel, Diego; A Arias, Maykel; Pardo, Julián

    2018-05-09

    Cytotoxic CD8 + T (Tc) cells are the main executors of transformed and cancer cells during cancer immunotherapy. The latest clinical results evidence a high efficacy of novel immunotherapy agents that modulate Tc cell activity against bad prognosis cancers. However, it has not been determined yet whether the efficacy of these treatments can be affected by selection of tumoural cells with mutations in the cell death machinery, known to promote drug resistance and cancer recurrence. Here, using a model of prophylactic tumour vaccination based on the LCMV-gp33 antigen and the mouse EL4 T lymphoma, we analysed the molecular mechanism employed by Tc cells to eliminate cancer cells in vivo and the impact of mutations in the apoptotic machinery on tumour development. First of all, we found that Tc cells, and perf and gzmB are required to efficiently eliminate EL4.gp33 cells after LCMV immunisation during short-term assays (1-4 h), and to prevent tumour development in the long term. Furthermore, we show that antigen-pulsed chemoresistant EL4 cells overexpressing Bcl-X L or a dominant negative form of caspase-3 are specifically eliminated from the peritoneum of infected animals, as fast as parental EL4 cells. Notably, antigen-specific Tc cells control the tumour growth of the mutated cells, as efficiently as in the case of parental cells. Altogether, expression of the anti-apoptotic mutations does not confer any advantage for tumour cells neither in the short-term survival nor in long-term tumour formation. Although the mechanism involved in the elimination of the apoptosis-resistant tumour cells is not completely elucidated, neither necroptosis nor pyroptosis seem to be involved. Our results provide the first experimental proof that chemoresistant cancer cells with mutations in the main cell death pathways are efficiently eliminated by Ag-specific Tc cells in vivo during immunotherapy and, thus, provide the molecular basis to treat chemoresistant cancer cells with CD8 Tc

  9. Provision of a simplified methodology for determining estradiol and progesterone receptors in human breast tumours. Internal and external quality control

    International Nuclear Information System (INIS)

    Farinate, Z.

    1990-10-01

    A simplified assay for the detection of progesterone receptors (PR) in human breast tissue is described. Tissue storage is at -20 deg. C rather than -70 deg. C and a centrifugation speed of 20,000 rpm avoids requirement of an ultracentrifuge. Cytosol preparations obtained from homogenized oestradiol benzoate primed wistar rat uteri performed satisfactorily as positive controls with stability of two months in liquid nitrogen. The use of iodinated tracer (progesterone 11 alpha glucuronide 125 I iodotyramine) proved disappointing in the progesterone receptor assay in contrast to 125 I oestradiol which worked well in a oestrogen receptor assay, previously developed. Hydroxyl-apatite was a better separating agent than dextran coated charcoal in both assays and yielded better sensitivity, particularly when protein concentrations were low. Five breast cancer specimens assayed yielded, by Scatchard analysis, Kd values between 12 to 22x10 -9 m|h, comparable to the positive controls. However, two of these had binding site capacity of less than 5 fmol/mg cytosol as compared to the three others and the positive controls where values ranged from 47-196 fmol/mg cytosol. 28 refs, 6 figs, 14 tabs

  10. Experimental tumour treatment

    International Nuclear Information System (INIS)

    1985-08-01

    This report of 1984 is the seventh in a series and presents that year's results of continuous studies in the domain of experimental tumour radiotherapy. In the year under review, more personnel has been available for the studies, and the scientific programmes for the assessment of acute and chronic side effects of radiotherapies have been extended. New models have been developed, among them a first system based on animal experiments, for quantifying the mucositis of the oral and pharyngeal mucosa, a limiting condition in the radiotherapy of head and throat tumours. Another significant advancement is a model for quantification of chronical damage to the ureter, which still is a serious problem in the radiotherapy of gynaecological tumours. The 1984 experimental tumour studies have been mainly devoted to the repopulation and split-dose recovery in various tumours, concentrating on dose fractionation as one of the major problems studies. Particular interest has been attached to the processes involved in treatments over several weeks with a daily effective dose of 2 Gy. (orig./MG) [de

  11. Endoplasmic reticulum stress pathway required for immune homeostasis is neurally controlled by arrestin-1.

    Science.gov (United States)

    Singh, Varsha; Aballay, Alejandro

    2012-09-28

    In response to pathogen infection, the host innate immune system activates microbial killing pathways and cellular stress pathways that need to be balanced because insufficient or excessive immune responses have deleterious consequences. Recent studies demonstrate that two G protein-coupled receptors (GPCRs) in the nervous system of Caenorhabditis elegans control immune homeostasis. To investigate further how GPCR signaling controls immune homeostasis at the organismal level, we studied arrestin-1 (ARR-1), which is the only GPCR adaptor protein in C. elegans. The results indicate that ARR-1 is required for GPCR signaling in ASH, ASI, AQR, PQR, and URX neurons, which control the unfolded protein response and a p38 mitogen-activated protein kinase signaling pathway required for innate immunity. ARR-1 activity also controlled immunity through ADF chemosensory and AFD thermosensory neurons that regulate longevity. Furthermore, we found that although ARR-1 played a key role in the control of immunity by AFD thermosensory neurons, it did not control longevity through these cells. However, ARR-1 partially controlled longevity through ADF neurons.

  12. Malignant Peripheral Nerve Sheath Tumour of the Maxilla

    Directory of Open Access Journals (Sweden)

    Puja Sahai

    2014-01-01

    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.

  13. A flexible 70 MHz phase-controlled double waveguide system for hyperthermia treatment of superficial tumours with deep infiltration.

    Science.gov (United States)

    van Stam, Gerard; Kok, H Petra; Hulshof, Maarten C C M; Kolff, M Willemijn; van Tienhoven, Geertjan; Sijbrands, Jan; Bakker, Akke; Zum Vörde Sive Vörding, Paul J; Oldenborg, Sabine; de Greef, Martijn; Rasch, Coen R N; Crezee, Hans

    2017-11-01

    Superficial tumours with deep infiltration in the upper 15 cm of the trunk cannot be treated adequately with existing hyperthermia systems. The aim of this study was to develop, characterise and evaluate a new flexible two-channel hyperthermia system (AMC-2) for tumours in this region. The two-channel AMC-2 system has two horizontally revolving and height adjustable 70 MHz waveguides. Three different interchangeable antennas with sizes 20 × 34, 15 × 34 and 8.5 × 34 cm were developed and their electrical properties were determined. The performance of the AMC-2 system was tested by measurements of the electric field distribution in a saline water filled elliptical phantom, using an electric field vector probe. Clinical feasibility was demonstrated by treatment of a melanoma in the axillary region. Phantom measurements showed a good performance for all waveguides. The large reflection of the smallest antenna has to be compensated by increased forward power. Field patterns become asymmetrical when using smaller top antennas, necessitating phase corrections. The clinical application showed that tumours deeper than 4 cm can be heated adequately. A median tumour temperature of 42 °C can be reached up to 12 cm depth with adequate antenna positioning and phase-amplitude steering. This 70 MHz AMC-2 waveguide system is a useful addition to existing loco-regional hyperthermia equipment as it is capable of heating axillary tumours and other tumours deeper than 4 cm.

  14. Advanced Sensors and Controls for Building Applications: Market Assessment and Potential R&D Pathways

    Energy Technology Data Exchange (ETDEWEB)

    Brambley, Michael R.; Haves, Philip; McDonald, Sean C.; Torcellini, Paul; Hansen, David G.; Holmberg, David; Roth, Kurt

    2005-04-13

    Significant energy savings can be achieved in commercial building operation, along with increased comfort and control for occupants, through the implementation of advanced technologies. This document provides a market assessment of existing building sensors and controls and presents a range of technology pathways (R&D options) for pursuing advanced sensors and building control strategies. This paper is actually a synthesis of five other white papers: the first describes the market assessment including estimates of market potential and energy savings for sensors and control strategies currently on the market as well as a discussion of market barriers to these technologies. The other four cover technology pathways: (1) current applications and strategies for new applications, (2) sensors and controls, (3) networking, security, and protocols and standards, and (4) automated diagnostics, performance monitoring, commissioning, optimal control and tools. Each technology pathway chapter gives an overview of the technology or application. This is followed by a discussion of needs and the current status of the technology. Finally, a series of research topics is proposed.

  15. Control of the classical and the MBL pathway of complement activation

    DEFF Research Database (Denmark)

    Petersen, Steen Vang; Thiel, S; Jensen, L

    2000-01-01

    and the influence of high ionic strength on the complexes indicate that the activation and control of the MBL pathway differ from that of the classical pathway. MBL deficiency is linked to various clinical manifestations such as recurrent infections, severe diarrhoea, and recurrent miscarriage. On the other hand...... incubation at 37 degrees C in physiological buffer, the associated inhibitors as well as MASP-1, MASP-2, and MAp19 dissociated from MBL, whereas only little dissociation of the complex occurred in buffer with high ionic strength (1 M NaCl). The difference in sensitivity to various inhibitors...

  16. Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways.

    Science.gov (United States)

    Twu, Cheryl; Liu, Nancy Q; Popik, Waldemar; Bukrinsky, Michael; Sayre, James; Roberts, Jaclyn; Rania, Shammas; Bramhandam, Vishnu; Roos, Kenneth P; MacLellan, W Robb; Fiala, Milan

    2002-10-29

    We investigated 18 AIDS hearts (5 with and 13 without cardiomyopathy) by using immunocytochemistry and computerized image analysis regarding the roles of HIV-1 proteins and tumor necrosis factor ligands in HIV cardiomyopathy (HIVCM). HIVCM and cardiomyocyte apoptosis were significantly related to each other and to the expression by inflammatory cells of gp120 and tumor necrosis factor-alpha. In HIVCM heart, active caspase 9, a component of the mitochondrion-controlled apoptotic pathway, and the elements of the death receptor-mediated pathway, tumor necrosis factor-alpha and Fas ligand, were expressed strongly on macrophages and weakly on cardiomyocytes. HIVCM showed significantly greater macrophage infiltration and cardiomyocyte apoptosis rate compared with non-HIVCM. HIV-1 entered cultured neonatal rat ventricular myocytes by macropinocytosis but did not replicate. HIV-1- or gp120-induced apoptosis of rat myocytes through a mitochondrion-controlled pathway, which was inhibited by heparin, AOP-RANTES, or pertussis toxin, suggesting that cardiomyocyte apoptosis is induced by signaling through chemokine receptors. In conclusion, in patients with HIVCM, cardiomyocytes die through both mitochondrion- and death receptor-controlled apoptotic pathways.

  17. Liver safety of non-tumour necrosis factor inhibitors in rheumatic patients with past hepatitis B virus infection: an observational, controlled, long-term study.

    Science.gov (United States)

    Papalopoulos, Ioannis; Fanouriakis, Antonis; Kougkas, Nikolaos; Flouri, Irini; Sourvinos, George; Bertsias, George; Repa, Argyro; Avgoustidis, Nestor; Sidiropoulos, Prodromos

    2018-01-01

    The risk of hepatitis B virus (HBV) reactivation with non-tumour necrosis factor inhibitor (non-TNFi) biologic agents in patients with rheumatic diseases and past HBV infection has not been definively elucidated. We assessed the comparative safety of non-TNFi and TNFi biologic agents in such patients in real-life clinical settings. We carried out a retrospective cohort study from the Department of Rheumatology, University Hospital of Heraklion. Patients who received abatacept (ABA), tocilizumab (TCZ) or rituximab (RTX) during the period 2003-2016 and were HbsAg(-), anti-HBc(+), anti-HBs(±) at baseline, were monitored for HBV reactivation. Patients treated with TNFi agents during the same period were used as a control group. 101 cases of non-TNFi (39 ABA, 32 RTX and 30 TCZ) and 111 cases of TNFi treatment were identified. In non-TNFi, 76 cases (75.2%) were anti-HBc(+)/anti-HBs(+) and 25 (24.8%) were anti-HBc(+)/anti-HBs(-), as compared to 82 (73.9%) and 29 (26.1%) in TNFi-treated, respectively. After a median (IQR) observation of 24.0 (34.7) months, two cases (2.0%) of HBV reactivation were identified in the non-TNFi group; one with ABA, successfully treated with entecavir, and one fatal case with RTX and prior exposure to cyclophosphamide. No reactivation was observed in the TNFi group (p=0.226 vs. non-TNFi). Αnti-HBs titres were significantly reduced compared to baseline in the non-TNFi group [median (IQR) 203.9 (954.7) mIU/ml before treatment versus 144.9 (962.9) mIU/ml after treatment, p=0.03]. Two cases of HBV reactivation highlight the risk for this complication in patients with past HBV infection under biologic therapy.

  18. Prevention and treatment of colon cancer by peroral administration of HAMLET (human α-lactalbumin made lethal to tumour cells).

    Science.gov (United States)

    Puthia, Manoj; Storm, Petter; Nadeem, Aftab; Hsiung, Sabrina; Svanborg, Catharina

    2014-01-01

    Most colon cancers start with dysregulated Wnt/β-catenin signalling and remain a major therapeutic challenge. Examining whether HAMLET (human α-lactalbumin made lethal to tumour cells) may be used for colon cancer treatment is logical, based on the properties of the complex and its biological context. To investigate if HAMLET can be used for colon cancer treatment and prevention. Apc(Min)(/+) mice, which carry mutations relevant to hereditary and sporadic human colorectal tumours, were used as a model for human disease. HAMLET was given perorally in therapeutic and prophylactic regimens. Tumour burden and animal survival of HAMLET-treated and sham-fed mice were compared. Tissue analysis focused on Wnt/β-catenin signalling, proliferation markers and gene expression, using microarrays, immunoblotting, immunohistochemistry and ELISA. Confocal microscopy, reporter assay, immunoprecipitation, immunoblotting, ion flux assays and holographic imaging were used to determine effects on colon cancer cells. Peroral HAMLET administration reduced tumour progression and mortality in Apc(Min)(/+) mice. HAMLET accumulated specifically in tumour tissue, reduced β-catenin and related tumour markers. Gene expression analysis detected inhibition of Wnt signalling and a shift to a more differentiated phenotype. In colon cancer cells with APC mutations, HAMLET altered β-catenin integrity and localisation through an ion channel-dependent pathway, defining a new mechanism for controlling β-catenin signalling. Remarkably, supplying HAMLET to the drinking water from the time of weaning also significantly prevented tumour development. These data identify HAMLET as a new, peroral agent for colon cancer prevention and treatment, especially needed in people carrying APC mutations, where colon cancer remains a leading cause of death.

  19. Dynamics and control of the ERK signaling pathway: Sensitivity, bistability, and oscillations.

    Science.gov (United States)

    Arkun, Yaman; Yasemi, Mohammadreza

    2018-01-01

    Cell signaling is the process by which extracellular information is transmitted into the cell to perform useful biological functions. The ERK (extracellular-signal-regulated kinase) signaling controls several cellular processes such as cell growth, proliferation, differentiation and apoptosis. The ERK signaling pathway considered in this work starts with an extracellular stimulus and ends with activated (double phosphorylated) ERK which gets translocated into the nucleus. We model and analyze this complex pathway by decomposing it into three functional subsystems. The first subsystem spans the initial part of the pathway from the extracellular growth factor to the formation of the SOS complex, ShC-Grb2-SOS. The second subsystem includes the activation of Ras which is mediated by the SOS complex. This is followed by the MAPK subsystem (or the Raf-MEK-ERK pathway) which produces the double phosphorylated ERK upon being activated by Ras. Although separate models exist in the literature at the subsystems level, a comprehensive model for the complete system including the important regulatory feedback loops is missing. Our dynamic model combines the existing subsystem models and studies their steady-state and dynamic interactions under feedback. We establish conditions under which bistability and oscillations exist for this important pathway. In particular, we show how the negative and positive feedback loops affect the dynamic characteristics that determine the cellular outcome.

  20. Tumour resistance to cisplatin: a modelling approach

    International Nuclear Information System (INIS)

    Marcu, L; Bezak, E; Olver, I; Doorn, T van

    2005-01-01

    Although chemotherapy has revolutionized the treatment of haematological tumours, in many common solid tumours the success has been limited. Some of the reasons for the limitations are: the timing of drug delivery, resistance to the drug, repopulation between cycles of chemotherapy and the lack of complete understanding of the pharmacokinetics and pharmacodynamics of a specific agent. Cisplatin is among the most effective cytotoxic agents used in head and neck cancer treatments. When modelling cisplatin as a single agent, the properties of cisplatin only have to be taken into account, reducing the number of assumptions that are considered in the generalized chemotherapy models. The aim of the present paper is to model the biological effect of cisplatin and to simulate the consequence of cisplatin resistance on tumour control. The 'treated' tumour is a squamous cell carcinoma of the head and neck, previously grown by computer-based Monte Carlo techniques. The model maintained the biological constitution of a tumour through the generation of stem cells, proliferating cells and non-proliferating cells. Cell kinetic parameters (mean cell cycle time, cell loss factor, thymidine labelling index) were also consistent with the literature. A sensitivity study on the contribution of various mechanisms leading to drug resistance is undertaken. To quantify the extent of drug resistance, the cisplatin resistance factor (CRF) is defined as the ratio between the number of surviving cells of the resistant population and the number of surviving cells of the sensitive population, determined after the same treatment time. It is shown that there is a supra-linear dependence of CRF on the percentage of cisplatin-DNA adducts formed, and a sigmoid-like dependence between CRF and the percentage of cells killed in resistant tumours. Drug resistance is shown to be a cumulative process which eventually can overcome tumour regression leading to treatment failure

  1. Tumour resistance to cisplatin: a modelling approach

    Energy Technology Data Exchange (ETDEWEB)

    Marcu, L [School of Chemistry and Physics, University of Adelaide, North Terrace, SA 5000 (Australia); Bezak, E [School of Chemistry and Physics, University of Adelaide, North Terrace, SA 5000 (Australia); Olver, I [Faculty of Medicine, University of Adelaide, North Terrace, SA 5000 (Australia); Doorn, T van [School of Chemistry and Physics, University of Adelaide, North Terrace, SA 5000 (Australia)

    2005-01-07

    Although chemotherapy has revolutionized the treatment of haematological tumours, in many common solid tumours the success has been limited. Some of the reasons for the limitations are: the timing of drug delivery, resistance to the drug, repopulation between cycles of chemotherapy and the lack of complete understanding of the pharmacokinetics and pharmacodynamics of a specific agent. Cisplatin is among the most effective cytotoxic agents used in head and neck cancer treatments. When modelling cisplatin as a single agent, the properties of cisplatin only have to be taken into account, reducing the number of assumptions that are considered in the generalized chemotherapy models. The aim of the present paper is to model the biological effect of cisplatin and to simulate the consequence of cisplatin resistance on tumour control. The 'treated' tumour is a squamous cell carcinoma of the head and neck, previously grown by computer-based Monte Carlo techniques. The model maintained the biological constitution of a tumour through the generation of stem cells, proliferating cells and non-proliferating cells. Cell kinetic parameters (mean cell cycle time, cell loss factor, thymidine labelling index) were also consistent with the literature. A sensitivity study on the contribution of various mechanisms leading to drug resistance is undertaken. To quantify the extent of drug resistance, the cisplatin resistance factor (CRF) is defined as the ratio between the number of surviving cells of the resistant population and the number of surviving cells of the sensitive population, determined after the same treatment time. It is shown that there is a supra-linear dependence of CRF on the percentage of cisplatin-DNA adducts formed, and a sigmoid-like dependence between CRF and the percentage of cells killed in resistant tumours. Drug resistance is shown to be a cumulative process which eventually can overcome tumour regression leading to treatment failure.

  2. Genetically modified tumour vaccines

    Czech Academy of Sciences Publication Activity Database

    Bubeník, Jan

    2005-01-01

    Roč. 3, Suppl. 1 (2005), S7 ISSN 1214-021X. [Cells VI - Biological Days /18./. 24.10.2005-26.10.2005, České Budějovice] Institutional research plan: CEZ:AV0Z50520514 Keywords : tumour vaccines * HPV16 Subject RIV: EC - Immunology

  3. Putting tumours in context.

    Science.gov (United States)

    Bissell, M J; Radisky, D

    2001-10-01

    The interactions between cancer cells and their micro- and macroenvironment create a context that promotes tumour 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.

  4. Tumour-cell killing by X-rays and immunity quantitated in a mouse model system

    International Nuclear Information System (INIS)

    Porteous, D.D.; Porteous, K.M.; Hughes, M.J.

    1979-01-01

    As part of an investigation of the interaction of X-rays and immune cytotoxicity in tumour control, an experimental mouse model system has been used in which quantitative anti-tumour immunity was raised in prospective recipients of tumour-cell suspensions exposed to varying doses of X-rays in vitro before injection. Findings reported here indicate that, whilst X-rays kill a proportion of cells, induced immunity deals with a fixed number dependent upon the immune status of the host, and that X-rays and anti-tumour immunity do not act synergistically in tumour-cell killing. The tumour used was the ascites sarcoma BP8. (author)

  5. Reduction of postoperative chemotherapy in children with stage I intermediate-risk and anaplastic Wilms' tumour (SIOP 93-01 trial): a randomised controlled trial

    NARCIS (Netherlands)

    de Kraker, J.; Graf, N.; van Tinteren, H.; Pein, F.; Sandstedt, B.; Godzinski, J.; Tournade, M. F.

    2004-01-01

    Background Present treatment for Wilms' tumour is very successful. Now, efforts are aimed at reducing toxicity and burden of treatment by shortening schedules without loss of effectiveness. The objective of this randomised trial was to assess whether postoperative chemotherapy for patients with

  6. Life history, immunity, Peto's paradox and tumours in birds.

    Science.gov (United States)

    Møller, A P; Erritzøe, J; Soler, J J

    2017-05-01

    Cancer and tumours may evolve in response to life-history trade-offs between growth and duration of development on one hand, and between growth and maintenance of immune function on the other. Here, we tested whether (i) bird species with slow developmental rates for their body size experience low incidence of tumours because slow development allows for detection of rapid proliferation of cell lineages. We also test whether (ii) species with stronger immune response during development are more efficient at detecting tumour cells and hence suffer lower incidence of tumours. Finally, we tested Peto's paradox, that there is a positive relationship between tumour incidence and body mass. We used information on developmental rates and body mass from the literature and of tumour incidence (8468 birds) and size of the bursa of Fabricius for 7659 birds brought to a taxidermist in Denmark. We found evidence of the expected negative relationship between incidence of tumours and developmental rates and immunity after controlling for the positive association between tumour incidence and body size. These results suggest that evolution has modified the incidence of tumours in response to life history and that Peto's paradox may be explained by covariation between body mass, developmental rates and immunity. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

  7. SWITCH: a dynamic CRISPR tool for genome engineering and metabolic pathway control for cell factory construction in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Garcia Vanegas, Katherina; Lehka, Beata Joanna; Mortensen, Uffe Hasbro

    2017-01-01

    to the pathway control state where production was optimized by downregulating an essential gene TSC13, hence, reducing formation of a byproduct. Conclusions We have successfully integrated two CRISPR tools, one for genetic engineering and one for pathway control, into one system and successfully used it for cell...

  8. 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.

    Science.gov (United States)

    Liu, Yi; Zhang, Lingyun; Zhu, Xiangxiang; Wang, Yuehua; Liu, WenWei; Gong, Wei

    2015-11-01

    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. © 2015 John Wiley & Sons Ltd.

  9. The TOR Signaling Pathway in Spatial and Temporal Control of Cell Size and Growth

    Directory of Open Access Journals (Sweden)

    Suam Gonzalez

    2017-06-01

    Full Text Available Cell size is amenable by genetic and environmental factors. The highly conserved nutrient-responsive Target of Rapamycin (TOR signaling pathway regulates cellular metabolic status and growth in response to numerous inputs. Timing and duration of TOR pathway activity is pivotal for both cell mass built up as well as cell cycle progression and is controlled and fine-tuned by the abundance and quality of nutrients, hormonal signals, growth factors, stress, and oxygen. TOR kinases function within two functionally and structurally discrete multiprotein complexes, TORC1 and TORC2, that are implicated in temporal and spatial control of cell size and growth respectively; however, recent data indicate that such functional distinctions are much more complex. Here, we briefly review roles of the two complexes in cellular growth and cytoarchitecture in various experimental model systems.

  10. Paravascular pathways contribute to vasculitis and neuroinflammation after subarachnoid hemorrhage independently of glymphatic control.

    Science.gov (United States)

    Luo, C; Yao, X; Li, J; He, B; Liu, Q; Ren, H; Liang, F; Li, M; Lin, H; Peng, J; Yuan, T F; Pei, Z; Su, H

    2016-03-31

    Subarachnoid hemorrhage (SAH) is a devastating disease with high mortality. The mechanisms underlying its pathological complications have not been fully identified. Here, we investigate the potential involvement of the glymphatic system in the neuropathology of SAH. We demonstrate that blood components rapidly enter the paravascular space following SAH and penetrate into the perivascular parenchyma throughout the brain, causing disastrous events such as cerebral vasospasm, delayed cerebral ischemia, microcirculation dysfunction and widespread perivascular neuroinflammation. Clearance of the paravascular pathway with tissue-type plasminogen activator ameliorates the behavioral deficits and alleviates histological injury of SAH. Interestingly, AQP4(-/-) mice showed no improvements in neurological deficits and neuroinflammation at day 7 after SAH compared with WT control mice. In conclusion, our study proves that the paravascular pathway dynamically mediates the pathological complications following acute SAH independently of glymphatic control.

  11. Comparison of the distribution of fluorine-18 fluoromisonidazole, deoxyglucose and methionine in tumour tissue

    International Nuclear Information System (INIS)

    Kubota, Kazuo; Tada, Masao; Yamada, Susumu; Hori, Katsuyoshi; Saito, Sachiko; Sato, Kazunori; Fukuda, Hiroshi; Iwata, Ren; Ido, Tatsuo

    1999-01-01

    To evaluate the tumour imaging potential of fluorine-18 fluoromisonidazole (FMISO), we studied FMISO uptake in an experimental tumour model and examined the correlation between intratumoral distributions of FMISO, 14 C-2-deoxyglucose (2DG) and 14 C-methionine (Met). The study was performed using control rats with the AH109A tumour and rats with the same tumour under local hypoxia. Tumour uptake of FMISO was constant between 30 min and 2 h after injection, and the tumour to muscle ratio was 2 from 2 to 4 h. A tumour study with FMISO was scheduled at 2 h. Double-tracer autoradiography of the tumour demonstrated that in the areas of high FMISO uptake, there was low uptake of Met, while areas of low FMISO uptake showed high Met uptake. FMISO showed high grain density in the rim of the tumour surrounding the necrotic area. 2DG showed a more uniform distribution over the entire section of viable cells. The mean uptake of FMISO by hypoxic, radioresistant tumours was significantly higher than that by the control tumours (P<0.05), while both 2DG and Met uptake by the control tumours was higher than uptake by hypoxic tumours. When individual tumours were examined, the uptake of FMISO was inversely correlated with that of Met (r = -0.507, P<0.02), while 2DG showed almost uniform uptake with no significant correlation to FMISO. In conclusion, hypoxic and radioresistant tumours could be identified by increased FMISO uptake in our model, consistent with findings reported by others. We found a large overlap in the distribution of FMISO and 2DG within the tumour, but only a small overlap in the distribution of FMISO and Met. A combination of FMISO and other tracers in positron emission tomography or single-photon emission tomography studies might be more helpful than single-tracer studies in predicting the response of tumour tissues to radiotherapy. (orig.)

  12. Intra-arterial mitomycin C treatment of unresectable liver tumours

    International Nuclear Information System (INIS)

    Starkhammar, H.; Haakansson, L.; Morales, O.; Svedberg, J.; Linkoeping Univ.; Linkoeping Univ.

    1987-01-01

    Regional chemotherapy might be more efficient if the cytostatic drug is injected together with degradable starch microspheres (DSM), which induce temporary blockage of arterioles and trap the co-injected drug in tumour. Eighteen patients with non-resectable liver cancer were included. Mitomycin C (15 mg/m 2 ) was injected intra-arterially mixed with 900 mg of DSM every six weeks. For estimation of the effect of DSM in the liver a radiolabelled tracer was injected via the same route. Its passage through the liver to the systemic circulation was continuously measured by a detector situated over peripheral blood vessels. The effect of DSM on the tracer passage varied considerably between different patients. The study also indicated opening of new vascular pathways some minutes after the initial injection. The dose of DSM for total blockage of the arterial blood flow, indicated by angiography, also varied. In some patients 540 mg induced total occlusion. In others neither angiographic nor tracer passage were affected by the microspheres although 900 mg (or even more) were injected. Factors such as size of the vascular bed, portal and arterial blood flow and arterio-venous shunting seemed to be of great importance and should be controlled in order to optimize the use of DSM in conjunction with chemotherapy of liver tumours. (orig.)

  13. Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial.

    Science.gov (United States)

    Scott, David L; Ibrahim, Fowzia; Farewell, Vern; O'Keeffe, Aidan G; Walker, David; Kelly, Clive; Birrell, Fraser; Chakravarty, Kuntal; Maddison, Peter; Heslin, Margaret; Patel, Anita; Kingsley, Gabrielle H

    2015-03-13

    To determine whether intensive combinations of synthetic disease modifying drugs can achieve similar clinical benefits at lower costs to high cost biologics such as tumour necrosis factor inhibitors in patients with active rheumatoid arthritis resistant to initial methotrexate and other synthetic disease modifying drugs. Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months. 24 rheumatology clinics in England. Patients with rheumatoid arthritis who were eligible for treatment with tumour necrosis factor inhibitors according to current English guidance were randomised to either the tumour necrosis factor inhibitor strategy or the combined disease modifying drug strategy. Biologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for non-responders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders. reduction in disability at 12 months measured with patient recorded heath assessment questionnaire (range 0.00-3.00) with a 0.22 non-inferiority margin for combination treatment versus the biologic strategy. quality of life, joint damage, disease activity, adverse events, and costs. Intention to treat analysis used multiple imputation methods for missing data. 432 patients were screened: 107 were randomised to tumour necrosis factor inhibitors and 101 started taking; 107 were randomised to the combined drug strategy and 104 started taking the drugs. Initial assessments were similar; 16 patients were lost to follow-up (seven with the tumour necrosis factor inhibitor strategy, nine with the combined drug strategy); 42 discontinued the intervention but were followed-up (19 and 23, respectively). The primary outcome showed mean falls in scores on the health assessment questionnaire of -0.30 with the tumour necrosis factor inhibitor strategy and -0.45 with the alternative combined drug strategy. The difference between

  14. Linking metabolic QTLs with network and cis-eQTLs controlling biosynthetic pathways.

    Directory of Open Access Journals (Sweden)

    Adam M Wentzell

    2007-09-01

    Full Text Available Phenotypic variation between individuals of a species is often under quantitative genetic control. Genomic analysis of gene expression polymorphisms between individuals is rapidly gaining popularity as a way to query the underlying mechanistic causes of variation between individuals. However, there is little direct evidence of a linkage between global gene expression polymorphisms and phenotypic consequences. In this report, we have mapped quantitative trait loci (QTLs-controlling glucosinolate content in a population of 403 Arabidopsis Bay x Sha recombinant inbred lines, 211 of which were previously used to identify expression QTLs controlling the transcript levels of biosynthetic genes. In a comparative study, we have directly tested two plant biosynthetic pathways for association between polymorphisms controlling biosynthetic gene transcripts and the resulting metabolites within the Arabidopsis Bay x Sha recombinant inbred line population. In this analysis, all loci controlling expression variation also affected the accumulation of the resulting metabolites. In addition, epistasis was detected more frequently for metabolic traits compared to transcript traits, even when both traits showed similar distributions. An analysis of candidate genes for QTL-controlling networks of transcripts and metabolites suggested that the controlling factors are a mix of enzymes and regulatory factors. This analysis showed that regulatory connections can feedback from metabolism to transcripts. Surprisingly, the most likely major regulator of both transcript level for nearly the entire pathway and aliphatic glucosinolate accumulation is variation in the last enzyme in the biosynthetic pathway, AOP2. This suggests that natural variation in transcripts may significantly impact phenotypic variation, but that natural variation in metabolites or their enzymatic loci can feed back to affect the transcripts.

  15. Value of skeletal scintiscanning in cases of primary bone tumours and tumourous alterations

    International Nuclear Information System (INIS)

    Sokolowski, U.

    1982-01-01

    In the course of an investigation on the storage behaviour of primary bone tumours and tumourous bone alterations the skeletal scintigrams of a total of 26 patients were evaluated. Bone scintiscanning was done according to current practice after injection of an average amount of 10mCi sup(99m)Tc-MDP, followed by a semiquantitative evaluation. In all cases of malignant bone tumours there was fond to be increased storage of radionuclide; with benign bone alterations this was so in 70 per cent of cases. To differentiate between benign and malignant tumours respectively inflammatory bone diseases was not as a rule possible; however, the investigation yielded additional information completing the X-ray findings essentially. Thus very high storage of radioactivity was established for all osteosarcomas, whereas benign bone growths exhibited more circumscribed accumulations of activity. Skeletal scintiscanning for diagnostical purposes is particularly informative as to the early detection of bone foci evading X-ray diagnosis, more accurate delimitation of tumourous processes, and course control of tumours tending to degenerate. (orig./MG) [de

  16. File list: InP.Oth.20.AllAg.Tumour_tissues [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Oth.20.AllAg.Tumour_tissues hg19 Input control Others Tumour tissues SRX371456,...0,SRX371458,SRX371461,SRX371455,SRX371451,SRX371462 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Oth.20.AllAg.Tumour_tissues.bed ...

  17. File list: InP.Oth.10.AllAg.Tumour_tissues [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Oth.10.AllAg.Tumour_tissues hg19 Input control Others Tumour tissues SRX371456,...1,SRX371450,SRX371458,SRX371461,SRX371455,SRX371462 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Oth.10.AllAg.Tumour_tissues.bed ...

  18. File list: InP.Oth.50.AllAg.Tumour_tissues [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Oth.50.AllAg.Tumour_tissues hg19 Input control Others Tumour tissues SRX371456,...0,SRX371458,SRX371461,SRX371455,SRX371451,SRX371462 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Oth.50.AllAg.Tumour_tissues.bed ...

  19. Pathways from emotional adjustment to glycemic control in youths with diabetes in Hong Kong.

    Science.gov (United States)

    Stewart, S M; Lee, P W; Low, L C; Cheng, A; Yeung, W; Huen, K F; O'Donnell, D

    2000-09-01

    To examine factors that influence emotional adjustment, adherence to diabetic care, and glycemic control in Hong Kong youths with insulin-dependent diabetes mellitus (IDDM). Seventy youths, their mothers, and matched controls provided information on health beliefs, authoritarian parenting style, parent-child conflict, emotional adjustment, and adherence to medical regimen. Glycosylated hemoglobin levels were obtained to measure glycemic control. Predictors explained 34% of the variance in emotional adjustment and 39% of the variance in glycemic control. The data supported a pathway from emotional adjustment to self-efficacy to adherence behaviors to glycemic control. In contrast to Western culture and consistent with prediction, parenting style did not associate with negative outcomes, and even relatively low levels of parent-child conflict correlated negatively with emotional adjustment in this culture. Management of conflict and self-efficacy enhancing interactions are suggested interventions to enhance adherence to diabetic care in Hong Kong youths with IDDM.

  20. Leucine-rich diet alters the eukaryotic translation initiation factors expression in skeletal muscle of tumour-bearing rats

    Directory of Open Access Journals (Sweden)

    Mello Maria

    2007-03-01

    Full Text Available Abstract Background Cancer-cachexia induces a variety of metabolic disorders on protein turnorver, decreasing protein synthesis and increasing protein degradation. Controversly, insulin, other hormones, and branched-chain amino acids, especially leucine, stimulate protein synthesis and modulate the activity of translation initiation factors involved in protein synthesis. Since the tumour effects are more pronounced when associated with pregnancy, ehancing muscle-wasting proteolysis, in this study, the influence of a leucine-rich diet on the protein synthesis caused by cancer were investigated. Methods Pregnant rats with or without Walker 256 tumour were distributed into six groups. During 20 days of experiment, three groups were fed with a control diet: C – pregnant control, W – tumour-bearing, and P – pair-fed, which received the same amount of food as ingested by the W group; three other groups of pregnant rats were fed a leucine-rich diet: L – pregnant leucine, WL – tumour-bearing, and PL – pair-fed, which received the same amount of food as ingested by the WL group. Results The gastrocnemius muscle of WL rats showed increased incorporation of leucine in protein compared to W rats; the leucine-rich diet also prevented the decrease in plasma insulin normally seen in W. The expression of translation initiation factors increased when tumour-bearing rats fed leucine-rich diet, with increase of ~35% for eIF2α and eIF5, ~17% for eIF4E and 20% for eIF4G; the expression of protein kinase S6K1 and protein kinase C was also highly enhanced. Conclusion The results suggest that a leucine-rich diet increased the protein synthesis in skeletal muscle in tumour-bearing rats possibly through the activation of eIF factors and/or the S6kinase pathway.

  1. Leucine-rich diet alters the eukaryotic translation initiation factors expression in skeletal muscle of tumour-bearing rats

    International Nuclear Information System (INIS)

    Ventrucci, Gislaine; Mello, Maria Alice R; Gomes-Marcondes, Maria Cristina C

    2007-01-01

    Cancer-cachexia induces a variety of metabolic disorders on protein turnorver, decreasing protein synthesis and increasing protein degradation. Controversly, insulin, other hormones, and branched-chain amino acids, especially leucine, stimulate protein synthesis and modulate the activity of translation initiation factors involved in protein synthesis. Since the tumour effects are more pronounced when associated with pregnancy, ehancing muscle-wasting proteolysis, in this study, the influence of a leucine-rich diet on the protein synthesis caused by cancer were investigated. Pregnant rats with or without Walker 256 tumour were distributed into six groups. During 20 days of experiment, three groups were fed with a control diet: C – pregnant control, W – tumour-bearing, and P – pair-fed, which received the same amount of food as ingested by the W group; three other groups of pregnant rats were fed a leucine-rich diet: L – pregnant leucine, WL – tumour-bearing, and PL – pair-fed, which received the same amount of food as ingested by the WL group. The gastrocnemius muscle of WL rats showed increased incorporation of leucine in protein compared to W rats; the leucine-rich diet also prevented the decrease in plasma insulin normally seen in W. The expression of translation initiation factors increased when tumour-bearing rats fed leucine-rich diet, with increase of ~35% for eIF2α and eIF5, ~17% for eIF4E and 20% for eIF4G; the expression of protein kinase S6K1 and protein kinase C was also highly enhanced. The results suggest that a leucine-rich diet increased the protein synthesis in skeletal muscle in tumour-bearing rats possibly through the activation of eIF factors and/or the S6kinase pathway

  2. Leucine-rich diet alters the eukaryotic translation initiation factors expression in skeletal muscle of tumour-bearing rats

    Energy Technology Data Exchange (ETDEWEB)

    Ventrucci, Gislaine [Laboratório de Nutrição e Câncer, Departamento de Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, 13083-970, São Paulo (Brazil); Mello, Maria Alice R [Departamento de Fisiologia e Biofísica, Instituto Biociências, Universidade Estadual de São Paulo, UNESP, Rio Claro, 13506-900, São Paulo (Brazil); Gomes-Marcondes, Maria Cristina C [Laboratório de Nutrição e Câncer, Departamento de Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, 13083-970, São Paulo (Brazil)

    2007-03-06

    Cancer-cachexia induces a variety of metabolic disorders on protein turnorver, decreasing protein synthesis and increasing protein degradation. Controversly, insulin, other hormones, and branched-chain amino acids, especially leucine, stimulate protein synthesis and modulate the activity of translation initiation factors involved in protein synthesis. Since the tumour effects are more pronounced when associated with pregnancy, ehancing muscle-wasting proteolysis, in this study, the influence of a leucine-rich diet on the protein synthesis caused by cancer were investigated. Pregnant rats with or without Walker 256 tumour were distributed into six groups. During 20 days of experiment, three groups were fed with a control diet: C – pregnant control, W – tumour-bearing, and P – pair-fed, which received the same amount of food as ingested by the W group; three other groups of pregnant rats were fed a leucine-rich diet: L – pregnant leucine, WL – tumour-bearing, and PL – pair-fed, which received the same amount of food as ingested by the WL group. The gastrocnemius muscle of WL rats showed increased incorporation of leucine in protein compared to W rats; the leucine-rich diet also prevented the decrease in plasma insulin normally seen in W. The expression of translation initiation factors increased when tumour-bearing rats fed leucine-rich diet, with increase of ~35% for eIF2α and eIF5, ~17% for eIF4E and 20% for eIF4G; the expression of protein kinase S6K1 and protein kinase C was also highly enhanced. The results suggest that a leucine-rich diet increased the protein synthesis in skeletal muscle in tumour-bearing rats possibly through the activation of eIF factors and/or the S6kinase pathway.

  3. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib: an international, multicentre, prospective, randomised, placebo-controlled phase 3 trial (GRID)

    Science.gov (United States)

    Demetri, George D; Reichardt, Peter; Kang, Yoon-Koo; Blay, Jean-Yves; Rutkowski, Piotr; Gelderblom, Hans; Hohenberger, Peter; Leahy, Michael; von Mehren, Margaret; Joensuu, Heikki; Badalamenti, Giuseppe; Blackstein, Martin; Cesne, Axel Le; Schöffski, Patrick; Maki, Robert G; Bauer, Sebastian; Nguyen, Binh Bui; Xu, Jianming; Nishida, Toshirou; Chung, John; Kappeler, Christian; Kuss, Iris; Laurent, Dirk; Casali, Paolo

    2013-01-01

    Summary Background To date, only two agents, imatinib and sunitinib, have shown clinical benefit in patients with gastrointestinal stromal tumours (GISTs), but almost all metastatic GISTs eventually develop resistance to these agents, resulting in fatal disease progression. This phase 3 trial assessed efficacy and safety of regorafenib in patients with metastatic and/or unresectable GIST progressing after failure of at least imatinib and sunitinib. Methods Patients were randomised 2:1 to receive either regorafenib 160 mg orally daily or placebo, plus best supportive care in both arms, for the first 3 weeks of each 4-week cycle. The primary endpoint was progression-free survival (PFS). Upon disease progression, patients on placebo could cross over to regorafenib. Secondary endpoints included overall survival (OS), objective response rate, disease control rate (DCR: rate of durable stable disease lasting for ≥12 weeks plus complete or partial responses), and safety. This trial is registered at ClinicalTrials.gov (NCT01271712). Results From January to August 2011, 240 patients were screened at 57 centres in 17 countries, and 199 patients were randomised to receive regorafenib (n=133) or matching placebo (n=66). Median PFS per independent blinded central review was 4·8 months and 0·9 months, respectively (hazard ratio [HR] 0·27, 95% confidence interval [CI] 0·19–0·39; pregorafenib, resulting in no significant difference in OS between study arms (HR 0·77, 95% CI 0·42–1·41; p=0·199). A best response of partial response or stable disease was observed in 101/133 patients (75·9%) on regorafenib and 23/66 patients (34·8%) on placebo. DCR was 52·6% (70/133 patients) and 9·1% (6/66 patients), respectively. Drug-related adverse events were reported in 130 (98·5%) of 132 regorafenib patients and 45 (68·2%) of 66 placebo patients. The most common grade ≥3 regorafenib-related adverse events were hypertension (31/132, 23·5%), hand–foot skin reaction (26

  4. Haemorrhagic pituitary tumours

    International Nuclear Information System (INIS)

    Lazaro, C.M.; Philippine General Hospital, Manila; Guo, W.Y.; Sami, M.; Hindmarsch, T.; Ericson, K.; Hulting, A.L.; Wersaell, J.

    1994-01-01

    In a group of 69 patients with pituitary tumours, 12 were found to have evidence of intratumoral haemorrhage on MRI, characterized by high signal intensity on short TR/TE sequences. This was verified in all but 1 patient. The majority of the bleedings occurred in macroadenomas. Five (42%) were prolactinomas and 4 (33%) were non-functioning adenomas. There were 2 GH- and 1 ACTH-secreting tumours. All 5 patients with prolactinomas were on bromocriptine medication. Two of the patients had a clinical picture of pituitary apoplexy. The haemorrhage was not large enough to prompt surgery in any of the patients. However, surgical verification of the diagnosis was obtained in 5 cases, while 6 patients were examined with follow-up MRI. (orig.)

  5. Tumours following retinoblastoma radiotherapy

    International Nuclear Information System (INIS)

    Mollot, J.-P.

    1978-01-01

    Radioinduced tumours in young patients irradiated in childhood for retinoblastoma take on a particularly deadly aspect. The onset of this true clinical entity characterized by a long post-irradiation latency period induced by a dose above 6000 rads is a real tragedy. The vast majority of patients then enter into a long martyrdom ending in death. The only cure is surgical, but seldom possible. Treatment is limited to palliative radiotherapy, effective for a while, and chemiotherapy as a last resort but often difficult to prescribe. Prevention alone is the answer. The quality and reliability of the radiotherapeutic treatment depend not only on the personal talent of the radiotherapist but above all on the standard of the equipment. A strong reduction in the doses employed as well as recent technological progress improving the material, its precision and reproducibility appear already to have lowered the frequency curve of these fatal radioinduced tumours [fr

  6. 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: borgesalexandra@clix.pt

    2008-06-15

    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.

  7. Skull base tumours

    International Nuclear Information System (INIS)

    Borges, Alexandra

    2008-01-01

    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. Malignant salivary gland tumours

    International Nuclear Information System (INIS)

    Thompson, S.H.

    1982-01-01

    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

  9. Malignant salivary gland tumours

    Energy Technology Data Exchange (ETDEWEB)

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

    1982-08-01

    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.

  10. Imaging brain tumour microstructure.

    Science.gov (United States)

    Nilsson, Markus; Englund, Elisabet; Szczepankiewicz, Filip; van Westen, Danielle; Sundgren, Pia C

    2018-05-08

    Imaging is an indispensable tool for brain tumour diagnosis, surgical planning, and follow-up. Definite diagnosis, however, often demands histopathological analysis of microscopic features of tissue samples, which have to be obtained by invasive means. A non-invasive alternative may be to probe corresponding microscopic tissue characteristics by MRI, or so called 'microstructure imaging'. The promise of microstructure imaging is one of 'virtual biopsy' with the goal to offset the need for invasive procedures in favour of imaging that can guide pre-surgical planning and can be repeated longitudinally to monitor and predict treatment response. The exploration of such methods is motivated by the striking link between parameters from MRI and tumour histology, for example the correlation between the apparent diffusion coefficient and cellularity. Recent microstructure imaging techniques probe even more subtle and specific features, providing parameters associated to cell shape, size, permeability, and volume distributions. However, the range of scenarios in which these techniques provide reliable imaging biomarkers that can be used to test medical hypotheses or support clinical decisions is yet unknown. Accurate microstructure imaging may moreover require acquisitions that go beyond conventional data acquisition strategies. This review covers a wide range of candidate microstructure imaging methods based on diffusion MRI and relaxometry, and explores advantages, challenges, and potential pitfalls in brain tumour microstructure imaging. Copyright © 2018. Published by Elsevier Inc.

  11. [Adrenal tumours in childhood].

    Science.gov (United States)

    Martos-Moreno, G A; Pozo-Román, J; Argente, J

    2013-09-01

    This special article aims to summarise the current knowledge regarding the two groups of tumours with their origin in the adrenal gland: 1) adrenocortical tumours, derived from the cortex of the adrenal gland and 2) phaeochromocytomas and paragangliomas, neuroendocrine tumours derived from nodes of neural crest derived cells symmetrically distributed at both sides of the entire spine (paragangliomas [PG]). These PGs can be functioning tumors that secrete catecholamines, which confers their typical dark colour after staining with chromium salts (chromaffin tumors). Among these, the term phaeochromocytoma (PC) is restricted to those PGs derived from the chromaffin cells in the adrenal medulla (intra-adrenal PGs), whereas the term PG is used for those sympathetic or parasympathetic ones in an extra-adrenal location. We analyse the state of the art of their pathogenic and genetic bases, as well as their clinical signs and symptoms, the tests currently available for performing their diagnosis (biochemical, hormonal, imaging and molecular studies) and management (surgery, pre- and post-surgical medical treatment), considering the current and developing strategies in chemo- and radiotherapy. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  12. Standard effective doses for proliferative tumours

    International Nuclear Information System (INIS)

    Jones, L.C.; Hoban, P.

    1999-01-01

    This study was undertaken to investigate the treatment schedules used clinically for highly proliferative tumours, particularly with reference to the effects of fraction size, fraction number and treatment duration. The linear quadratic model (with time component) is used here to compare non-standard treatment regimens (e.g. accelerated and hyperfractionated schedules), currently the focus of randomized trials, with each other and some common 'standard regimens'. To ensure easy interpretation of results, two parameters known as proliferative standard effective dose one (PSED 1 ) and proliferative standard effective dose two (PSED 2 ) have been calculated for each regimen. Graphs of PSED 1 and PSED 2 versus potential doubling time (T p ) have been generated for a range of fractionation regimens which are currently under trial in various randomized studies. From these graphs it can be seen that the highly accelerated schedules (such as CHART) only show advantages for tumours with very short potential doubling times. Calculations for most of the schedules considered showed at least equivalent tumour control expected for the trial schedule compared with the control arm used and these values agree quite well with clinical results. These calculations are in good agreement with clinical results available at present. The greater the PSED 1 or PSED 2 for the schedule considered the greater the tumour control, which can be expected. However, as has been seen with clinical trials, this higher cell kill also results in higher acute effects which have proved too great for some accelerated schedules to continue. (author)

  13. Work-family conflict, locus of control, and women's well-being: tests of alternative pathways.

    Science.gov (United States)

    Noor, Noraini M

    2002-10-01

    The author tested for the 3 possible pathways (i.e., direct, moderator, and mediator effects) in which locus of control can influence the relationship between work-family conflict and well-being. The author predicted that work-family conflict would be negatively correlated with well-being. In a sample of 310 Malaysian employed women with families, work-family conflict was a significant predictor of both job satisfaction and distress--negatively related to job satisfaction and positively related to symptoms of distress. More important, the results provided support for the effects of all 3 pathways of control on the relationship between work-family conflict and well-being, depending on the outcome measure: For job satisfaction, locus of control had direct effects, acted as a partial mediator, and played a significant moderating role. In contrast, only the direct effect of locus of control predicted distress. The author discusses those findings with reference to the literature on work-family conflict, locus of control, and the issue of stress-distress specificity.

  14. Physical Property Control on the Cellular Uptake Pathway and Spatial Distribution of Nanoparticles in Cells.

    Science.gov (United States)

    Ahn, Sungsook; Seo, Eunseok; Kim, Ki Hean; Lee, Sang Joon

    2015-06-01

    Nanoparticles have been developed in broad biomedical research in terms of effective cellular interactions to treat and visualize diseased cells. Considering the charge and polar functional groups of proteins that are embedded in cellular membranes, charged nanoparticles have been strategically developed to enhance electrostatic cellular interactions. In this study, we show that cellular uptake efficiency, pathway, and spatial distribution of gold nanoparticles in a cell are significantly modulated based on the surface condition of gold nanoparticles and human cancer cells that were tuned by controlling the pH of the medium and by introducing an electron beam. Cellular uptake efficiency is increased when electrostatic attraction is induced between the cells and the gold nanoparticles. Cell surface modification changes the cellular uptake pathways of the gold nanoparticles and concentrates the gold nanoparticles at the membrane region. Surface modification of the gold nanoparticles also contributes to deep penetration and homogeneous spatial distributions in a cell.

  15. Multiple signalling pathways redundantly control glucose transporter GLUT4 gene transcription in skeletal muscle

    DEFF Research Database (Denmark)

    Murgia, Marta; Elbenhardt Jensen, Thomas; Cusinato, Marzia

    2009-01-01

    on pharmacological evidence. Here, we have used a more specific genetic approach to establish the relative role of the three pathways in fast and slow muscles. Plasmids coding for protein inhibitors of CaMKII or calcineurin were co-transfected in vivo with a GLUT4 enhancer-reporter construct either in normal mice...... or in mice expressing a dominant negative AMPK mutant. GLUT4 reporter activity was not inhibited in the slow soleus muscle by blocking either CaMKII or calcineurin alone, but was inhibited by blocking both pathways. GLUT4 reporter activity was likewise unchanged in the soleus of dnAMPK mice......, but was significantly reduce by incapacitation of either CaMKII or calcineurin in these mice. On the other hand, in the fast tibialis anterior muscle, calcineurin appears to exert a prominent role in the control of GLUT4 reporter activity, independent of CaMKII and AMPK. The results point to a muscle type...

  16. Control of neuropeptide expression by parallel activity-dependent pathways in caenorhabditis elegans

    DEFF Research Database (Denmark)

    Rojo Romanos, Teresa; Petersen, Jakob Gramstrup; Pocock, Roger

    2017-01-01

    Monitoring of neuronal activity within circuits facilitates integrated responses and rapid changes in behavior. We have identified a system in Caenorhabditis elegans where neuropeptide expression is dependent on the ability of the BAG neurons to sense carbon dioxide. In C. Elegans, CO 2 sensing...... is predominantly coordinated by the BAG-expressed receptor-type guanylate cyclase GCY-9. GCY-9 binding to CO 2 causes accumulation of cyclic GMP and opening of the cGMP-gated TAX-2/TAX-4 cation channels; provoking an integrated downstream cascade that enables C. Elegans to avoid high CO 2. Here we show that c...... that expression of flp-19::GFP is controlled in parallel to GCY-9 by the activity-dependent transcription factor CREB (CRH-1) and the cAMP-dependent protein kinase (KIN-2) signaling pathway. We therefore show that two parallel pathways regulate neuropeptide gene expression in the BAG sensory neurons: the ability...

  17. Vaginal haemangioendothelioma: an unusual tumour.

    LENUS (Irish Health Repository)

    Mohan, H

    2012-02-01

    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.

  18. Neutron therapy for malignant tumours of the salivary glands

    International Nuclear Information System (INIS)

    Duncan, W.; Orr, J.A.; Arnott, S.J.; Jack, W.J.L.

    1987-01-01

    A group of 28 patients with malignant tumours of the salivary glands have been treated by d(15)+Be neutron irradiation. Nineteen patients had inoperable cancers. Three had gross recurrent cancer and three had measurable residual cancer after surgery. Three patients were treated post-operatively for microscopic residual disease. Seven different histological types of tumour were included. Six out of 8 patients with adenoid cystic carcinomas have lasting local tumour control. 54% of the gross tumours were locally controlled. All three of those classified as microscopic residual disease have no evidence of local recurrence. 11/14 cancers given 16.0 Gy or more in 20 fractions in 4 weeks were controlled compared with only 1/8 given a lower dose. 12/19 cancers less than 10.0 cm maximum diameter were controlled. The radiation-related morbidity was similar to that observed after photon therapy. (Auth.)

  19. Pathways from maternal effortful control to child self-regulation: The role of maternal emotional support.

    Science.gov (United States)

    Zeytinoglu, Selin; Calkins, Susan D; Swingler, Margaret M; Leerkes, Esther M

    2017-03-01

    This study examined the direct and indirect pathways from maternal effortful control to 2 aspects of children's self-regulation-executive functioning and behavioral regulation-via maternal emotional support. Two hundred seventy-eight children and their primary caregivers (96% mothers) participated in laboratory visits when children were 4 and 5 years, and teachers reported on children's behavior at kindergarten. At the 4-year assessment, maternal effortful control was measured using the Adult Temperament Questionnaire (Evans & Rothbart, 2007) and maternal emotional support was observed during a semistructured mother-child problem-solving task. At the 5-year assessment, children's executive functioning was measured using laboratory tasks designed to assess updating/working memory, inhibitory control, and cognitive flexibility, whereas behavioral regulation was assessed via teacher-report questionnaires on children's attention control, discipline and persistence, and work habits. Results from structural equation modeling indicated that, after controlling for child gender and minority status, and maternal education, maternal effortful control was indirectly associated with both child executive functioning and behavioral regulation through maternal emotional support. Maternal effortful control had a direct association with children's teacher-reported behavioral regulation but not observed executive functioning. These findings suggest that maternal effortful control may be a key contributing factor to the development of children's self-regulatory competencies through its impact on maternal emotional support. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  20. 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.

    1985-09-01

    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.

  1. Radiological diagnosis of liver tumours

    International Nuclear Information System (INIS)

    Lundstedt, C.

    1987-01-01

    Sixty patients treated with an intra-arterial cytostatic drug for metastases from colo-rectal carcinoma were evaluated with angiography to determine prognostic parameters. The extent of tumour in the liver and an unchanged or diminished tumour volume following treatment, as demonstrated with angiography, were associated with significant prolongation of survival. Patients who developed occlusion of the hepatic artery or of branches of the portal vein, also survived longer. 189 patients examined with angiography, 161 with computed tomography (CT), 95 with computed tomographic arteriography (CTA) and 71 with ultrasound (US) were subjected to liver evaluation at laparotomy consisting of inspection and palpation. The result of this surgical liver evaluation was for the purpose of the study regarded as completely accurate and was used to assess the accuracy of the different radiological methods. The location of tumour in the liver lobes or segments was analysed, with a separate evaluation of the right and left liver lobes. The rate of detection of individual tumour nodules was also determined. Angiography detected 55% of liver areas affected by tumour and 47% of individual tumour nodules. CT detected 83% of liver lobes or segments containing tumour, and 70% of the tumour nodules. US detected 69% of the portions of liver holding tumour, and also 69% of the tumour nodules. CTA detected 85% of tumours areas and 74% of separate tumour nodules. Some lesions detected with CT were not seen with CTA and vice versa. More false-positive results were recorded with CTA than with CT using intravenous contrast enhancement. (orig.)

  2. Advanced Instrumentation, Information, and Control Systems Technologies Pathway: FY 2016 External Review

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, Kenneth David [Idaho National Lab. (INL), Idaho Falls, ID (United States); Hallbert, Bruce Perry [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2016-11-01

    This report describes an External Review conducted by the LWRS Program Advanced Instrumentation, Information, and Control (II&C) Systems Technologies Pathway to solicit feedback on the topics and results of the ongoing II&C research program. This review was held in conjunction with the Nuclear Energy Institute (NEI) Digital I&C Working Group meeting that was held at Idaho National Laboratory (INL) on August 9-10, 2016. Given the opportunity to visit INL and see the pathway research projects, NEI agreed that the Working Group would serve as the External Review panel for the purpose of obtaining expert input on the value and timing of the research projects. This consisted of demonstrations in the Human Systems Simulation Laboratory followed by presentations on the II&C research program in general as well as the five technology development areas. Following the meeting, the presentations were sent to each of the attendees so they could review them in more detail and refer to them in completing the feedback form. Follow-up activities were conducted with the attendees following the meeting to obtain the completed feedback forms. A total of 13 forms were returned. The feedback forms were reviewed by the pathway to compile the data and comments received, which are documented in the report. In all, the feedback provided by the External Review participants is taken to be a strong endorsement of the types of projects being conducted by the pathway, the value they hold for the nuclear plants, and the general timing of need. The feedback aligns well with the priorities, levels of efforts allocated for the research projects, and project schedules. The feedback also represents realistic observations on the practicality of some aspects of implementing these technologies. In some cases, the participants provided thoughtful challenges to certain assumptions in the formulation of the technologies or in deployment plans. These deserve further review and revision of plans if warranted

  3. Advanced Instrumentation, Information, and Control Systems Technologies Pathway: FY 2016 External Review

    International Nuclear Information System (INIS)

    Thomas, Kenneth David; Hallbert, Bruce Perry

    2016-01-01

    This report describes an External Review conducted by the LWRS Program Advanced Instrumentation, Information, and Control (II&C) Systems Technologies Pathway to solicit feedback on the topics and results of the ongoing II&C research program. This review was held in conjunction with the Nuclear Energy Institute (NEI) Digital I&C Working Group meeting that was held at Idaho National Laboratory (INL) on August 9-10, 2016. Given the opportunity to visit INL and see the pathway research projects, NEI agreed that the Working Group would serve as the External Review panel for the purpose of obtaining expert input on the value and timing of the research projects. This consisted of demonstrations in the Human Systems Simulation Laboratory followed by presentations on the II&C research program in general as well as the five technology development areas. Following the meeting, the presentations were sent to each of the attendees so they could review them in more detail and refer to them in completing the feedback form. Follow-up activities were conducted with the attendees following the meeting to obtain the completed feedback forms. A total of 13 forms were returned. The feedback forms were reviewed by the pathway to compile the data and comments received, which are documented in the report. In all, the feedback provided by the External Review participants is taken to be a strong endorsement of the types of projects being conducted by the pathway, the value they hold for the nuclear plants, and the general timing of need. The feedback aligns well with the priorities, levels of efforts allocated for the research projects, and project schedules. The feedback also represents realistic observations on the practicality of some aspects of implementing these technologies. In some cases, the participants provided thoughtful challenges to certain assumptions in the formulation of the technologies or in deployment plans. These deserve further review and revision of plans if warranted

  4. Conserved genetic pathways controlling the development of the diffuse endocrine system in vertebrates and Drosophila.

    Science.gov (United States)

    Hartenstein, Volker; Takashima, Shigeo; Adams, Katrina L

    2010-05-01

    The midgut epithelium is formed by absorptive enterocytes, secretory cells and endocrine cells. Each of these lineages is derived from the pluripotent progenitors that constitute the embryonic endoderm; the mature midgut retains pools of self-renewing stem cells that continue to produce all lineages. Recent findings in vertebrates and Drosophila shed light on the genetic mechanism that specifies the fate of the different lineages. A pivotal role is played by the Notch signaling pathway that, in a manner that appears to be very similar to the way in which Notch signaling selects neural progenitors within the neurectoderm, distinguishes the fate of secretory/endocrine cells and enterocytes. Proneural genes encoding bHLH transcription factors are expressed and required in prospective endocrine cells; activation of the Notch pathways restricts the number of these cells and promotes enterocyte development. In this review we compare the development of the intestinal endocrine cells in vertebrates and insects and summarize recent findings dealing with genetic pathways controlling this cell type. Copyright 2009. Published by Elsevier Inc.

  5. Direct and indirect spino-cerebellar pathways: shared ideas but different functions in motor control

    Directory of Open Access Journals (Sweden)

    Juan eJiang

    2015-07-01

    Full Text Available The impressive precision of mammalian limb movements relies on internal feedback pathways that convey information about ongoing motor output to cerebellar circuits. The spino-cerebellar tracts (SCT in the cervical, thoracic and lumbar spinal cord have long been considered canonical neural substrates for the conveyance of internal feedback signals. Here we consider the distinct features of an indirect spino-cerebellar route, via the brainstem lateral reticular nucleus (LRN, and the implications of this pre-cerebellar ‘detour’ for the execution and evolution of limb motor control. Both direct and indirect spino-cerebellar pathways signal spinal interneuronal activity to the cerebellum during movements, but evidence suggests that direct SCT neurons are mainly modulated by rhythmic activity, whereas the LRN also receives information from systems active during postural adjustment, reaching and grasping. Thus, while direct and indirect spino-cerebellar circuits can both be regarded as internal copy pathways, it seems likely that the direct system is principally dedicated to rhythmic motor acts like locomotion, while the indirect system also provides a means of pre-cerebellar integration relevant to the execution and coordination of de

  6. Metabolic control analysis of biochemical pathways based on a thermokinetic description of reaction rates

    DEFF Research Database (Denmark)

    Nielsen, Jens Bredal

    1997-01-01

    Metabolic control analysis is a powerful technique for the evaluation of flux control within biochemical pathways. Its foundation is the elasticity coefficients and the flux control coefficients (FCCs). On the basis of a thermokinetic description of reaction rates it is here shown...... that the elasticity coefficients can be calculated directly from the pool levels of metabolites at steady state. The only requirement is that one thermodynamic parameter be known, namely the reaction affinity at the intercept of the tangent in the inflection point of the curve of reaction rate against reaction...... of the thermokinetic description of reaction rates to include the influence of effecters. Here the reaction rate is written as a linear function of the logarithm of the metabolite concentrations. With this type of rate function it is shown that the approach of Delgado and Liao [Biochem. J. (1992) 282, 919-927] can...

  7. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway

    Science.gov (United States)

    Pavlov, Valentin A.; Parrish, William R.; Rosas-Ballina, Mauricio; Ochani, Mahendar; Puerta, Margot; Ochani, Kanta; Chavan, Sangeeta; Al-Abed, Yousef; Tracey, Kevin J.

    2015-01-01

    The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the “cholinergic anti-inflammatory pathway,” defined as neural signals transmitted via the vagus nerve that inhibit cytokine release through a mechanism that requires the alpha7 subunit-containing nicotinic acetylcholine receptor (α7nAChR). Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks, but despite considerable importance, little is known about the molecular basis for central regulation of the vagus nerve-based cholinergic anti-inflammatory pathway. Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF production during endotoxemia. Peripheral administration of the acetylcholinesterase inhibitor galantamine significantly reduced serum TNF levels through vagus nerve signaling, and protected against lethality during murine endotoxemia. Administration of a centrally-acting muscarinic receptor antagonist abolished the suppression of TNF by galantamine, indicating that suppressing acetylcholinesterase activity, coupled with central muscarinic receptors, controls peripheral cytokine responses. Administration of galantamine to α7nAChR knockout mice failed to suppress TNF levels, indicating that the α7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of galantamine. These findings show that inhibition of brain acetylcholinesterase suppresses systemic inflammation through a central muscarinic receptor-mediated and vagal- and α7nAChR-dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor can be utilized to suppress abnormal inflammation to therapeutic advantage. PMID:18639629

  8. Neurohypophysis granular cell tumours. Upon neurohypophysis rare tumours

    International Nuclear Information System (INIS)

    Barrande, G.; Kujas, M.; Gancel, A.; Turpin, G.; Bruckert, E.; Kuhn, J.M.; Luton, J.P.

    1995-01-01

    Granular cell tumours of neurohypophysis are rare. These tumours are more often encountered as incidental autopsy findings seen in up to 17 % of unselected adult autopsy cases. There are few reports of para-sellar granular cell tumours large enough to cause symptoms. We present three cases of neurohypophysis granular cell tumour and a review of the literature. In one patient, the asymptomatic granular cell tumour was incidentally discovered at surgical removal of a corticotrophic micro-adenoma. The remaining 2 patients had a symptomatic tumour which caused neurological symptoms such as visual disturbance and headaches and endocrine disorders such as hypopituitarism or hyper-prolactinaemia. In these 2 cases, computerized tomography showed a well-circumscribed, contrast-enhanced, intra-sellar and supra-sellar mass. Magnetic resonance imaging demonstrated an isointense gadolinium-enhanced mass in T1-weighted-images. Trans-sphenoidal partial resection was performed and histology was interpreted as a granular cell tumour. The immunohistochemical study was positive for glial fibrillary acidic protein (GEAP) and neuron specific enolase (NSE) in 1 of the 2 tumours and positive for S100 protein and vimentin in both tumours but negative for CD68. The histogenesis of neurohypophysis granular cell tumours is still controversial but ultrastructural and immunohistochemical studies support the theory that may arise from pituicytes, the glial cells of neurohypophysis. Management of these benign, slow growing, tumours is based mainly on neurosurgical resection. Data from the literature do not support a beneficial effect of post operative radiation therapy on postoperative recurrences. (authors). 23 refs., 4 figs., 1 tab

  9. Chondroblastoma and chondromyxoid fibroma : disentangling the neoplastic chondrogenesis of two rare cartilaginous tumours

    NARCIS (Netherlands)

    Romeo, Salvatore

    2010-01-01

    The scope of this study was to disentangle neoplastic chondrogenesis in two rare cartilaginous tumours: chondroblastoma and chondromyxoid fibroma. It was addressed: 1 The spectrum of phenotypic differentiation in chondroblastoma and chondromyxoid fibroma, 2 The signalling pathways driving

  10. Management of parapharyngeal space tumours

    International Nuclear Information System (INIS)

    Ahmad, F.; Waqar-Uddin; Khan, M.S.; Khawar, A.; Bangush, W.; Aslam, J.

    2006-01-01

    Objective: To determine the role of clinical features, fine needle aspiration cytology (FNAC) and computed tomography (CT) scan in diagnosing Para pharyngeal space (PPS) tumours and treatment options. Design: A descriptive study. Place and Duration of Study: From July 2000 to July 2002 at Pakistan Institute of Medical Sciences, Islamabad. Patients and Methods: Patients diagnosed as having PPS tumours were studied. The medical record of patients was reviewed for their age, gender, clinical features, investigations (FNAC and CT scan) and treatment. The mean age, percentage of different clinical features and the sensitivity and specificity of FNAC was determined. Results: The mean age of patients presenting with PPS tumours was 33.6 years. The most common clinical features were neck mass (93%) and bulge in lateral pharyngeal wall (80%). The CT scan showed exact location and extent of tumour in 11 out of 15 cases. The sensitivity and specificity of FNAC was 70% and 85% respectively. The most common tumours were neurogenic tumours and salivary gland tumours. Surgery was performed in all except 2 patients with lymphoma in whom radiation and chemotherapy was recommended. Conclusion: This study indicates that PPS tumours are usually benign neurosurgeon and salivary gland tumours presenting with neck mass and bulge in or oropharynx. FNAC and CT scan are important in diagnostic work up and treatment planning. Surgery has the best results in most cases. (author)

  11. Biology and treatment of renal tumours in childhood

    DEFF Research Database (Denmark)

    Brok, Jesper; Treger, Taryn D; Gooskens, Saskia L

    2016-01-01

    potential targeted therapies for high-risk subgroups. Our understanding of Wilms' tumourigenesis is evolving and several signalling pathways, microRNA processing and epigenetics are now known to play pivotal roles. Most rhabdoid tumours display somatic and/or germline mutations in the SMARCB1 gene, whereas...

  12. Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth

    NARCIS (Netherlands)

    Lamers, Fieke; Schild, Linda; den Hartog, Ilona J. M.; Ebus, Marli E.; Westerhout, Ellen M.; Ora, Ingrid; Koster, Jan; Versteeg, Rogier; Caron, Huib N.; Molenaar, Jan J.

    2012-01-01

    Genomic aberrations of key regulators of the apoptotic pathway have hardly been identified in neuroblastoma. We detected high BCL2 mRNA and protein levels in the majority of neuroblastoma tumours by Affymetrix expression profiling and Tissue Micro Array analysis. This BCL2 mRNA expression is

  13. Askin Tumour: Case Report

    International Nuclear Information System (INIS)

    Gomez, Carolina; Ramirez, Sandra Milena; Quesada, Diana Constanza; Unigarro Luz Adriana

    2011-01-01

    In this article we report a case of a 19 year-old woman with a final diagnosis of an extra skeletal Primitive Neuroectodermal Tumor/Ewing sarcoma of the chest, also known as Askin tumour. The histologic features and the immunohistochemical profile were consistent with this aggressive malignancy of the chest wall that affects young people. Because the low incidence of this entity, as well as the clear radiological findings, we considered it interesting to describe this documented case and undertake a review of the literature.

  14. Best strategies to implement clinical pathways in an emergency department setting: study protocol for a cluster randomized controlled trial.

    Science.gov (United States)

    Jabbour, Mona; Curran, Janet; Scott, Shannon D; Guttman, Astrid; Rotter, Thomas; Ducharme, Francine M; Lougheed, M Diane; McNaughton-Filion, M Louise; Newton, Amanda; Shafir, Mark; Paprica, Alison; Klassen, Terry; Taljaard, Monica; Grimshaw, Jeremy; Johnson, David W

    2013-05-22

    The clinical pathway is a tool that operationalizes best evidence recommendations and clinical practice guidelines in an accessible format for 'point of care' management by multidisciplinary health teams in hospital settings. While high-quality, expert-developed clinical pathways have many potential benefits, their impact has been limited by variable implementation strategies and suboptimal research designs. Best strategies for implementing pathways into hospital settings remain unknown. This study will seek to develop and comprehensively evaluate best strategies for effective local implementation of externally developed expert clinical pathways. We will develop a theory-based and knowledge user-informed intervention strategy to implement two pediatric clinical pathways: asthma and gastroenteritis. Using a balanced incomplete block design, we will randomize 16 community emergency departments to receive the intervention for one clinical pathway and serve as control for the alternate clinical pathway, thus conducting two cluster randomized controlled trials to evaluate this implementation intervention. A minimization procedure will be used to randomize sites. Intervention sites will receive a tailored strategy to support full clinical pathway implementation. We will evaluate implementation strategy effectiveness through measurement of relevant process and clinical outcomes. The primary process outcome will be the presence of an appropriately completed clinical pathway on the chart for relevant patients. Primary clinical outcomes for each clinical pathway include the following: Asthma--the proportion of asthmatic patients treated appropriately with corticosteroids in the emergency department and at discharge; and Gastroenteritis--the proportion of relevant patients appropriately treated with oral rehydration therapy. Data sources include chart audits, administrative databases, environmental scans, and qualitative interviews. We will also conduct an overall process

  15. Biological evaluation of 99mTC cis-Pt iminoacetic acid complexes as tumour imaging agents

    International Nuclear Information System (INIS)

    Awaluddin, A.; Jacobs, J.J.; Bourne, D.W.; Maddalena, D.J.; Wilson, J.G.; Boyd, D.W.

    1987-01-01

    The biodistributions of three new 99m Tc labelled cis-platinum bifunctional tumour imaging agents were examined in mice bearing a certain type of sarcoma between 15 minutes and 24 hours post injection. The three complexes were excreted primarily via the renal pathway into the urine but at quite different rates. All complexes had some affinity for the tumour, but complexes III had the greatest, with tumour to blood and tumour to muscle rates at 24 hours in excess of 10:1 and 18:1. Biodistribution results were calculated using Tiscon Program. Suggesting that the three complexes may be useful as tumour imaging agents. (M.E.L.) [es

  16. Control of cell proliferation, endoreduplication, cell size, and cell death by the retinoblastoma-related pathway in maize endosperm

    KAUST Repository

    Sabelli, Paolo A.; Liu, Yan; Dante, Ricardo Augusto; Lizarraga, Lucina E.; Nguyen, Hong N.; Brown, Sara W.; Klingler, John; Yu, Jingjuan; LaBrant, Evan; Layton, Tracy M.; Feldman, Max; Larkins, Brian A.

    2013-01-01

    , and programmed cell death. Although manipulation of these processes could maximize grain yield, how they are regulated and integrated is poorly understood. We show that the Retinoblastoma-related (RBR) pathway controls key aspects of endosperm development

  17. Applicability of the Critical pathway analysis usually used for nuclear installations, to the control marine environment pollution by heavy metals

    International Nuclear Information System (INIS)

    Franca, E.P.; Pfeiffer, W.C.; Fiszman, M.; Lacerda, L.D. de

    1984-01-01

    The methodology of the controlling radionuclide releases from nuclear facilities by the critical pathway criteria, is given. The use of this methodology for the environmental impact studies for an industry that causes pollution is discussed. (M.A.) [pt

  18. Radiation-induced apoptosis and cell cycle checkpoints in human colorectal tumour cell lines

    International Nuclear Information System (INIS)

    Playle, L.C.

    2001-03-01

    The p53 tumour suppressor gene is mutated in 75% of colorectal carcinomas and is critical for DNA damage-induced G1 cell cycle arrest. Data presented in this thesis demonstrate that after treatment with Ionizing Radiation (IR), colorectal tumour cell lines with mutant p53 are unable to arrest at G1 and undergo cell cycle arrest at G2. The staurosporine derivative, UCN-01, was shown to abrogate the IR-induced G2 checkpoint in colorectal tumour cell lines. Furthermore, in some cell lines, abrogation of the G2 checkpoint was associated with radiosensitisation. Data presented in this study demonstrate that 2 out of 5 cell lines with mutant p53 were sensitised to IR by UCN-01. In order to determine whether radiosensitisation correlated with lack of functional p53, transfected derivatives of an adenoma-derived cell line were studied, in which endogenous wild type p53 was disrupted by expression of a dominant negative p53 mutant protein (and with a vector control). In both these cell lines UCN-01 abrogated the G2 arrest however this was not associated with radiosensitisation, indicating that radiosensitisation is a cell type-specific phenomenon. Although 2 colorectal carcinoma cell lines, with mutant p53, were sensitised to IR by UCN-01, the mechanisms of p53-independent IR-induced apoptosis in the colon are essentially unknown. The mitogen-activated protein kinase (MAPK) pathways (that is the JNK, p38 and ERK pathways) have been implicated in apoptosis in a range of cell systems and in IR-induced apoptosis in some cell types. Data presented in this study show that, although the MAPKs can be activated by the known activator anisomycin, there is no evidence of a role for MAPKs in IR-induced apoptosis in colorectal tumour cell lines, regardless of p53 status. In summary, some colorectal tumour cell lines with mutant p53 can be sensitised to IR-induced cell death by G2 checkpoint abrogation and this may be an important treatment strategy, however mechanisms of IR-induced p53

  19. Gastric neuroendocrine tumours.

    Science.gov (United States)

    Crosby, David A; Donohoe, Claire L; Fitzgerald, Louise; Muldoon, Cian; Hayes, Brian; O'Toole, Dermot; Reynolds, John V

    2012-01-01

    Gastric neuroendocrine tumours (NETs) are increasingly recognised, and management decisions may be difficult due to an incomplete understanding of aetiology, natural history and optimum therapy. This article presents a current understanding based on recent advances in epidemiology, classification, molecular profiling, and treatment. Relevant medical literature was identified from searches of PubMed and references cited in appropriate articles identified. Selection of articles was based on peer review, journal and relevance. Gastric NETs may be divided into three clinical prognostic groups: type I is associated with autoimmune atrophic gastritis and hypergastrinaemia, type II is associated with Zollinger-Ellison syndrome, and type III lesions are gastrin-independent, have the greatest metastatic potential and poorest prognosis. There has been an increased frequency of gastric NETs reported. Management approaches have evolved in parallel with advances in endoscopic staging and surgery, as well as improved understanding of the biology and natural history of NETs. Gastric NETs present a spectrum of activity from indolent tumours to metastatic malignancy. Treatment decisions for patients must be individualised and are best managed by a multidisciplinary team approach. The current evidence base is limited to small series and efforts to treat patients within clinical networks of expertise are warranted. Copyright © 2012 S. Karger AG, Basel.

  20. Radiotherapy in ocular tumours

    International Nuclear Information System (INIS)

    Pinto, J.M.

    1982-01-01

    Ocular tumours at the Tata Memorial Hospital, Bombay, form about 0.14% of all the proved cancer cases. In case of unilateral retinoblastoma with the other eye being not non-seeing for any reason, enucleation is advised, as the diagnosis may sometimes be in doubt. If after enucleation, optic nerve and/or peribulbar tissues are found to be involved, post-operative irradiation is given to the whole orbit. In bilateral retinoblastoma the more affected eye is enucleated and an attempt is made to preserve vision in the other eye. A tumour dose of 3500 to 4000 rad in about 4 weeks is given with a cobalt beam using a direct anterior field. A cataract that may develop has to be taken care of. Lateral and/or medial fields are used with deep X-rays. In certain cases, an implant of cobalt-60 or gold-198 grain is done. For carcinoma of conjuctiva, small lesions or early lesions are excised and a beta radiation dose of 2000 rad weekly for about 4 to 5 weeks is given; larger lesions require enucleation or exenteration followed by irradiation with super-voltage radiation. Post-irradiation sarcomas may develop many years later. Irradiation is repeated for recurrences. (M.G.B.)

  1. A novel Drosophila Girdin-like protein is involved in Akt pathway control of cell size

    Energy Technology Data Exchange (ETDEWEB)

    Puseenam, Aekkachai [Department of Applied Biology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Insect Biomedical Research Center, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Yoshioka, Yasuhide [Department of Applied Biology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Venture Laboratory, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Nagai, Rika [Department of Applied Biology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Insect Biomedical Research Center, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Hashimoto, Reina [Department of Applied Biology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Venture Laboratory, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Suyari, Osamu [Insect Biomedical Research Center, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Itoh, Masanobu [Department of Applied Biology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Insect Biomedical Research Center, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Enomoto, Atsushi [Department of Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi 466-8550 (Japan); Takahashi, Masahide [Insect Biomedical Research Center, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Department of Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi 466-8550 (Japan); Yamaguchi, Masamitsu, E-mail: myamaguc@kit.ac.jp [Department of Applied Biology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Insect Biomedical Research Center, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan)

    2009-11-15

    The Akt signaling pathway is well known to regulate cell proliferation and growth. Girdin, a novel substrate of Akt, plays a crucial role in organization of the actin cytoskeleton and cell motility under the control of Akt. We here identified a novel Girdin-like protein in Drosophila (dGirdin), which has two isoforms, dGirdin PA and dGirdin PB. dGirdin shows high homology with human Girdin in the N-terminal and coiled-coil domains, while diverging at the C-terminal domain. On establishment of transgenic fly lines, featuring knockdown or overexpression of dGirdin in vivo, overexpression in the wing disc cells induced ectopic apoptosis, implying a role in directing apoptosis. Knockdown of dGirdin in the Drosophila wing imaginal disc cells resulted in reduction of cell size. Furthermore, this was enhanced by half reduction of the Akt gene dose, suggesting that Akt positively regulates dGirdin. In the wing disc, cells in which dGirdin was knocked down exhibited disruption of actin filaments. From these in vivo analyses, we conclude that dGirdin is required for actin organization and regulation of appropriate cell size under control of the Akt signaling pathway.

  2. A novel Drosophila Girdin-like protein is involved in Akt pathway control of cell size

    International Nuclear Information System (INIS)

    Puseenam, Aekkachai; Yoshioka, Yasuhide; Nagai, Rika; Hashimoto, Reina; Suyari, Osamu; Itoh, Masanobu; Enomoto, Atsushi; Takahashi, Masahide; Yamaguchi, Masamitsu

    2009-01-01

    The Akt signaling pathway is well known to regulate cell proliferation and growth. Girdin, a novel substrate of Akt, plays a crucial role in organization of the actin cytoskeleton and cell motility under the control of Akt. We here identified a novel Girdin-like protein in Drosophila (dGirdin), which has two isoforms, dGirdin PA and dGirdin PB. dGirdin shows high homology with human Girdin in the N-terminal and coiled-coil domains, while diverging at the C-terminal domain. On establishment of transgenic fly lines, featuring knockdown or overexpression of dGirdin in vivo, overexpression in the wing disc cells induced ectopic apoptosis, implying a role in directing apoptosis. Knockdown of dGirdin in the Drosophila wing imaginal disc cells resulted in reduction of cell size. Furthermore, this was enhanced by half reduction of the Akt gene dose, suggesting that Akt positively regulates dGirdin. In the wing disc, cells in which dGirdin was knocked down exhibited disruption of actin filaments. From these in vivo analyses, we conclude that dGirdin is required for actin organization and regulation of appropriate cell size under control of the Akt signaling pathway.

  3. Distinct protease pathways control cell shape and apoptosis in v-src-transformed quail neuroretina cells

    International Nuclear Information System (INIS)

    Neel, Benjamin D.; Aouacheria, Abdel; Nouvion, Anne-Laure; Ronot, Xavier; Gillet, Germain

    2005-01-01

    Intracellular proteases play key roles in cell differentiation, proliferation and apoptosis. In nerve cells, little is known about their relative contribution to the pathways which control cell physiology, including cell death. Neoplastic transformation of avian neuroretina cells by p60 v-src tyrosine kinase results in dramatic morphological changes and deregulation of apoptosis. To identify the proteases involved in the cellular response to p60 v-src , we evaluated the effect of specific inhibitors of caspases, calpains and the proteasome on cell shape changes and apoptosis induced by p60 v-src inactivation in quail neuroretina cells transformed by tsNY68, a thermosensitive strain of Rous sarcoma virus. We found that the ubiquitin-proteasome pathway is recruited early after p60 v-src inactivation and is critical for morphological changes, whereas caspases are essential for cell death. This study provides evidence that distinct intracellular proteases are involved in the control of the morphology and fate of v-src-transformed cells

  4. Modeling effective transmission pathways and control of the world's most successful parasite.

    Science.gov (United States)

    Turner, Matthew; Lenhart, Suzanne; Rosenthal, Benjamin; Zhao, Xiaopeng

    2013-06-01

    Toxoplasma gondii(T. gondii) is a single-celled, intracellular protozoan responsible for the disease toxoplasmosis. The parasite is prevalent worldwide, and it infects all warm-blooded vertebrates. Consumption of meats in which this parasite has encysted confers risk of infection to people and other animals, as does ingestion of water or foods contaminated with environmentally resistant oocysts excreted by cats. Vertical transmission (from mother to offspring) is also possible, leading to disease risk and contributing additional means of ensuring perpetuation of transmission. In this work, we adopt a differential equation model to investigate the effective transmission pathways of T. gondii, as well as potential control mechanisms. Detailed analyses are carried out to examine the significance of transmission routes, virulence, vertical transmission, parasite-induced changes in host behavior, and controls based on vaccination and harvesting. Modeling and analysis efforts may shed insights into understanding the complex life cycle of T. gondii. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Occurrence studies of intracranial tumours

    Energy Technology Data Exchange (ETDEWEB)

    Larjavaara, S.

    2011-07-01

    approximately two-thirds (64%; 95% CI, 50 - 78). The underreporting was more pronounced among the elderly and in those with no histological confirmation of the meningioma diagnosis. An increasing trend of VS incidence was observed, but with considerable differences between countries. The overall annual increase of VS incidence was 2.8% per year (95% CI, 2.3 - 3.2) in 1987 - 2007, when all the four countries and both sexes were combined. However, no statistically significant increase was seen in the rates of VS incidence in Finnish men or Swedish women, and the incidence even showed some decrease in Finnish women (-0.4%, 95% CI, -1.8 to +1.1) during the study period. The overall increase in rates stabilized in the late 1990s, with relatively constant incidence rates and even some decline after 2000. Gliomas were distributed unevenly in the brain, with substantial variation between the cerebral lobes showing an excess of gliomas in the frontal and temporal lobes (over four-fold relative to occipital lobe, even after accounting for tissue volume). In the detailed spatial 3D-analysis, statistically significant heterogeneity was found with most gliomas in the anterior subcortical part of the brain. There was no excess of gliomas in the parts of the brain nearest to the typical location where mobile phones are held. Gliomas among never-regular mobile phone users and contralateral users (phone held on the opposite side of the head than the side of tumour) were closer to the source of electromagnetic field (EMF) than among regular and ipsilateral (exposure at the same side as the tumour location) users. In the case-specular analysis, the distance from the glioma cases to the mobile phone was shorter than for the speculars (hypothetical controls assigned for each glioma case). However, no such association was found in analyses by amount of phone use. In both models, glioma cases were closer to the source of exposure in long-term users (over ten years of use), but the differences

  6. Carcinoid Tumour of the Ovary

    African Journals Online (AJOL)

    Abstract. A case of bilateral carcinoid tumour of the ovary, with benign cystic teratoma in one ovary, in a 38 year old woman is presented. She had total abdominal hysterectomy, bilateral salpingoophorectomy, infracolic omentectomy and appendectomy. There was no macroscopic tumour in the vermiform appendix and the ...

  7. [Neonatal tumours and congenital malformations].

    Science.gov (United States)

    Berbel Tornero, O; Ortega García, J A; Ferrís i Tortajada, J; García Castell, J; Donat i Colomer, J; Soldin, O P; Fuster Soler, J L

    2008-06-01

    The association between pediatric cancer and congenital abnormalities is well known but, there is no exclusive data on the neonatal period and the underlying etiopathogenic mechanisms are unknown. First, to analyze the frequency of neonatal tumours associated with congenital abnormalities; and second, to comment on the likely etiopathogenic hypotheses of a relationship between neonatal tumours and congenital abnormalities. Historical series of neonatal tumours from La Fe University Children's Hospital in Valencia (Spain), from January 1990 to December 1999. Histological varieties of neonatal tumours and associated congenital abnormalities were described. A systematic review of the last 25 years was carried out using Medline, Cancerlit, Index Citation Science and Embase. The search profile used was the combination of "neonatal/congenital-tumors/cancer/neoplasms" and "congenital malformations/birth defects". 72 neonatal tumours were identified (2.8% of all pediatric cancers diagnosed in our hospital) and in 15 cases (20.8%) there was some associated malformation, disease or syndrome. The association between congenital abnormalities and neonatal tumours were: a) angiomas in three patients: two patients with congenital heart disease with a choanal stenosis, laryngomalacia; b) neuroblastomas in two patients: horseshoe kidney with vertebral anomalies and other with congenital heart disease; c) teratomas in two patients: one with cleft palate with vertebral anomalies and other with metatarsal varus; d) one tumour of the central nervous system with Bochdaleck hernia; e) heart tumours in four patients with tuberous sclerosis; f) acute leukaemia in one patient with Down syndrome and congenital heart disease; g) kidney tumour in one case with triventricular hydrocephaly, and h) adrenocortical tumour: hemihypertrophy. The publications included the tumours diagnosed in different pediatric periods and without unified criteria to classify the congenital abnormalities. Little data

  8. Novel somatic and germline mutations in intracranial germ cell tumours.

    Science.gov (United States)

    Wang, Linghua; Yamaguchi, Shigeru; Burstein, Matthew D; Terashima, Keita; Chang, Kyle; Ng, Ho-Keung; Nakamura, Hideo; He, Zongxiao; Doddapaneni, Harshavardhan; Lewis, Lora; Wang, Mark; Suzuki, Tomonari; Nishikawa, Ryo; Natsume, Atsushi; Terasaka, Shunsuke; Dauser, Robert; Whitehead, William; Adekunle, Adesina; Sun, Jiayi; Qiao, Yi; Marth, Gábor; Muzny, Donna M; Gibbs, Richard A; Leal, Suzanne M; Wheeler, David A; Lau, Ching C

    2014-07-10

    Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries, with peak incidence near the time of puberty. About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3-4:1 overall, but is even higher for tumours located in the pineal region. Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

  9. Chapter 10 the primary cilium coordinates signaling pathways in cell cycle control and migration during development and tissue repair

    DEFF Research Database (Denmark)

    Christensen, Søren T; Pedersen, Stine F; Satir, Peter

    2008-01-01

    Cell cycle control and migration are critical processes during development and maintenance of tissue functions. Recently, primary cilia were shown to take part in coordination of the signaling pathways that control these cellular processes in human health and disease. In this review, we present...... an overview of the function of primary cilia and the centrosome in the signaling pathways that regulate cell cycle control and migration with focus on ciliary signaling via platelet-derived growth factor receptor alpha (PDGFRalpha). We also consider how the primary cilium and the centrosome interact...... with the extracellular matrix, coordinate Wnt signaling, and modulate cytoskeletal changes that impinge on both cell cycle control and cell migration....

  10. Cancer and tumour markers

    International Nuclear Information System (INIS)

    Osifo, B.

    1999-02-01

    Cancer has been a major cause of death world wide and in Nigeria there are six commonest forms of manifestation of cancer known. Of these prostrate cancer is the highest with 16% occurrence of all known cancers according to a study by the Histopathology Department of the UCH. Many factors, amongst them dietary, environmental, lifestyle, age and sedentary work are possible causes. With the global rise in incidents, the IAEA initiated the Tumour Marker Project as a means of screening cancers in 15 African countries including Nigeria. In Nigeria, 4 groups of the commonest cancers have been chosen for screening. These are prostrate cancer, primary liver cancer, cancer of the GI tract and trophoblastic cancer

  11. The ExPeCT (Examining Exercise, Prostate Cancer and Circulating Tumour Cells) trial: study protocol for a randomised controlled trial.

    LENUS (Irish Health Repository)

    Sheill, Gráinne

    2017-10-04

    Prostate cancer (PrCa) is the second most common cancer in Ireland. Many men present with locally advanced or metastatic cancer for whom curative surgery is inappropriate. Advanced cancer patients are encouraged to remain physically active and therefore there is a need to investigate how patients with metastatic disease tolerate physical activity programmes. Physical activity reduces levels of systemic inflammatory mediators and so an aerobic exercise intervention may represent an accessible and cost-effective means of ameliorating the pro-inflammatory effects of obesity and subsequently decrease poor cancer-specific outcomes in this patient population. This study will assess the feasibility and safety of introducing a structured aerobic exercise intervention to an advanced cancer population. This study will also examine if the evasion of immune editing by circulating tumour cells (CTCs) is an exercise-modifiable mechanism in obese men with prostate cancer.

  12. R-spondin1 Controls Muscle Cell Fusion through Dual Regulation of Antagonistic Wnt Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Floriane Lacour

    2017-03-01

    Full Text Available Wnt-mediated signals are involved in many important steps in mammalian regeneration. In multiple cell types, the R-spondin (Rspo family of secreted proteins potently activates the canonical Wnt/β-catenin pathway. Here, we identify Rspo1 as a mediator of skeletal muscle tissue repair. First, we show that deletion of Rspo1 results in global alteration of muscle regeneration kinetics following acute injury. We find that muscle progenitor cells lacking Rspo1 show delayed differentiation due to reduced activation of Wnt/β-catenin target genes. Furthermore, muscle cells lacking Rspo1 have a fusion phenotype leading to larger myotubes containing supernumerary nuclei both in vitro and in vivo. The increase in muscle fusion was dependent on downregulation of Wnt/β-catenin and upregulation of non-canonical Wnt7a/Fzd7/Rac1 signaling. We conclude that reciprocal control of antagonistic Wnt signaling pathways by Rspo1 in muscle stem cell progeny is a key step ensuring normal tissue architecture restoration following acute damage.

  13. Discrimination and anger control as pathways linking socioeconomic disadvantage to allostatic load in midlife.

    Science.gov (United States)

    Zilioli, Samuele; Imami, Ledina; Ong, Anthony D; Lumley, Mark A; Gruenewald, Tara

    2017-12-01

    Recent evidence suggests that experiences of discrimination contribute to socioeconomic status health disparities. The current study examined if the experience and regulation of anger-an expected emotional response to discrimination-serves as an explanatory factor for the previously documented links between socioeconomic disadvantage (SED), discrimination, and allostatic load. Data were drawn from the second wave of the Midlife in the United States (MIDUS) study and included 909 adults who participated in the biomarkers subproject. Results revealed that perceived discrimination was associated with higher levels of allostatic load. Furthermore, we found evidence that perceived discrimination and anger control sequentially explained the relationship between SED and allostatic load, such that greater discrimination was associated with lower levels of anger control, which, in turn accounted for the effects of discrimination on allostatic load. These results remained significant after controlling for negative affect, positive affect, other forms of anger expression, as well as demographic covariates. Our findings suggest that low anger control may be an important psychological pathway through which experiences of discrimination influence health. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. VIP secreting tumours in infancy

    International Nuclear Information System (INIS)

    Davies, R.P.; Slavotinek, J.P.; Dorney, S.F.A.

    1990-01-01

    Vasoactive intestinal polypeptide (VIP) secreting neural crest tumours are an uncommon but important treatable cause of intractable childhood diarrhoea. The radiological appearances of two cases are presented with a review of radiological findings in childhood VIP secreting neural crest tumours. Twenty eight cases of childhood VIP secreting neural crest tumours were reviewed. Nineteen (68%) were ganglioneuroblastomas and nine (32%) were ganglioneuromas. The majority of tumours (66%) were in a paravertebral location in the abdomen indicating that a search for such a tumour should be initiated at this site. Eighteen of the twenty eight cases reviewed discussed relevant radiological investigations. Calcification was detected in 50% of abdominal radiographs. Gut dilatation was often a prominent feature. A mass was detected in 5 of 5 cases where ultrasound findings were reported, and seven of seven cases with CT findings reported. Prior to the availability of CT and ultrasound the most useful investigation was IVU which demonstrated evidence of a mass in 5 of 9 cases. The presence of paravertebral calcification and gut dilatation on the plain radiograph of a child with intractable diarrhoea suggests the presence of a VIP secreting neural crest tumour. If an abdominal tumour is not found in the appropriate clinical setting and VIP levels are elevated, a widespread search of the paravertebral region is indicated. (orig.)

  15. Narrative skills of children treated for brain tumours: The impact of tumour and treatment related variables on microstructure and macrostructure.

    Science.gov (United States)

    Docking, Kimberley; Munro, Natalie; Marshall, Tara; Togher, Leanne

    2016-01-01

    The narrative skills of children with brain tumours were examined. Influence of tumour location, radiotherapy, time post-treatment and presence of hydrocephalus was also investigated, as well as associations between narrative and language abilities. Seventeen children (aged 5;6-14;11) treated for brain tumour and their matched controls completed a narrative assessment and comprehensive language testing. Audio recorded narratives were analysed for microstructure and macrostructure elements. Between-group comparisons were conducted. Narrative elements were explored in association with tumour and treatment-related variables. Correlation analysis examined relationships between narrative scores and language test performance. While significant differences were not found between two groups of children across narrative elements, sub-group comparisons revealed marginal differences in macrostructure related to tumour location and hydrocephalus. Children treated with methods other than radiotherapy showed a significant increase in number of mazes in their narratives compared to children who received radiotherapy. Strong positive correlations also existed between narrative elements and language performance. Preliminary findings highlight the importance of investigating narrative abilities as part of a comprehensive language assessment. Macrostructure should be routinely examined where children are diagnosed with either posterior fossa tumour or hydrocephalus or have undergone surgery and/or chemotherapy for brain tumour.

  16. Cryopreservation in fish: current status and pathways to quality assurance and quality control in repository development.

    Science.gov (United States)

    Torres, Leticia; Hu, E; Tiersch, Terrence R

    2016-01-07

    Cryopreservation in aquatic species in general has been constrained to research activities for more than 60 years. Although the need for application and commercialisation pathways has become clear, the lack of comprehensive quality assurance and quality control programs has impeded the progress of the field, delaying the establishment of germplasm repositories and commercial-scale applications. In this review we focus on the opportunities for standardisation in the practices involved in the four main stages of the cryopreservation process: (1) source, housing and conditioning of fish; (2) sample collection and preparation; (3) freezing and cryogenic storage of samples; and (4) egg collection and use of thawed sperm samples. In addition, we introduce some key factors that would assist the transition to commercial-scale, high-throughput application.

  17. Intertissue Control of the Nucleolus via a Myokine-Dependent Longevity Pathway

    Directory of Open Access Journals (Sweden)

    Fabio Demontis

    2014-06-01

    Full Text Available Recent evidence indicates that skeletal muscle influences systemic aging, but little is known about the signaling pathways and muscle-released cytokines (myokines responsible for this intertissue communication. Here, we show that muscle-specific overexpression of the transcription factor Mnt decreases age-related climbing defects and extends lifespan in Drosophila. Mnt overexpression in muscle autonomously decreases the expression of nucleolar components and systemically decreases rRNA levels and the size of the nucleolus in adipocytes. This nonautonomous control of the nucleolus, a regulator of ribosome biogenesis and lifespan, relies on Myoglianin, a myokine induced by Mnt and orthologous to human GDF11 and Myostatin. Myoglianin overexpression in muscle extends lifespan and decreases nucleolar size in adipocytes by activating p38 mitogen-activated protein kinase (MAPK, whereas Myoglianin RNAi in muscle has converse effects. Altogether, these findings highlight a key role for myokine signaling in the integration of signaling events in muscle and distant tissues during aging.

  18. Rac1 controls epithelial tube length through the apical secretion and polarity pathways

    Directory of Open Access Journals (Sweden)

    Kévin Sollier

    2016-01-01

    Full Text Available The morphometric parameters of epithelial tubes are critical to the physiology and homeostasis of most organs. In addition, many human diseases are associated with tube-size defects. Here, we show that Rac1 limits epithelial tube elongation in the developing fly trachea by promoting Rab5-dependent endocytosis of the apical determinant Crumbs. Rac1 is also involved in a positive feedback loop with the septate junction protein Coracle. Thereby, Rac1 precludes paracellular diffusion and contributes to the septate junction-dependent secretion of the chitin-modifying enzymes Vermiform and Serpentine, which restrict epithelial tube length independently of Crumbs. Thus, Rac1 is a critical component of two important pathways controlling epithelial tube morphogenesis.

  19. Genomic aberrations in spitzoid tumours and their implications for diagnosis, prognosis and therapy

    Science.gov (United States)

    Wiesner, Thomas; Kutzner, Heinz; Cerroni, Lorenzo; Mihm, Martin J.; Busam, Klaus J.; Murali, Rajmohan

    2016-01-01

    Summary Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas conventional naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion, may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or reduce and alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic

  20. The development of tumours under a ketogenic diet in association with the novel tumour marker TKTL1: A case series in general practice.

    Science.gov (United States)

    Jansen, Natalie; Walach, Harald

    2016-01-01

    Since the initial observations by Warburg in 1924, it has become clear in recent years that tumour cells require a high level of glucose to proliferate. Therefore, a ketogenic diet that provides the body with energy mainly through fat and proteins, but contains a reduced amount of carbohydrates, has become a dietary option for supporting tumour treatment and has exhibited promising results. In the present study, the first case series of such a treatment in general practice is presented, in which 78 patients with tumours were treated within a time window of 10 months. The patients were monitored regarding their levels of transketolase-like-1 (TKTL1), a novel tumour marker associated with aerobic glycolysis of tumour cells, and the patients' degree of adherence to a ketogenic diet. Tumour progression was documented according to oncologists' reports. Tumour status was correlated with TKTL1 expression (Kruskal-Wallis test, Pketogenic diet, with one patient experiencing a stagnation in tumour progression and others an improvement in their condition. The adoption of a ketogenic diet was also observed to affect the levels of TKTL1 in those patients. In conclusion, the results from the present case series in general practice suggest that it may be beneficial to advise tumour patients to adopt a ketogenic diet, and that those who adhere to it may have positive results from this type of diet. Thus, the use of a ketogenic diet as a complementary treatment to tumour therapy must be further studied in rigorously controlled trials.

  1. Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment.

    Science.gov (United States)

    Mellon, S H; Wolkowitz, O M; Schonemann, M D; Epel, E S; Rosser, R; Burke, H B; Mahan, L; Reus, V I; Stamatiou, D; Liew, C-C; Cole, S W

    2016-05-24

    Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.

  2. 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.

    1984-03-01

    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.

  3. Quantum optimal control pathways of ozone isomerization dynamics subject to competing dissociation: A two-state one-dimensional model

    International Nuclear Information System (INIS)

    Kurosaki, Yuzuru; Ho, Tak-San; Rabitz, Herschel

    2014-01-01

    We construct a two-state one-dimensional reaction-path model for ozone open → cyclic isomerization dynamics. The model is based on the intrinsic reaction coordinate connecting the cyclic and open isomers with the O 2 + O asymptote on the ground-state 1 A ′ potential energy surface obtained with the high-level ab initio method. Using this two-state model time-dependent wave packet optimal control simulations are carried out. Two possible pathways are identified along with their respective band-limited optimal control fields; for pathway 1 the wave packet initially associated with the open isomer is first pumped into a shallow well on the excited electronic state potential curve and then driven back to the ground electronic state to form the cyclic isomer, whereas for pathway 2 the corresponding wave packet is excited directly to the primary well of the excited state potential curve. The simulations reveal that the optimal field for pathway 1 produces a final yield of nearly 100% with substantially smaller intensity than that obtained in a previous study [Y. Kurosaki, M. Artamonov, T.-S. Ho, and H. Rabitz, J. Chem. Phys. 131, 044306 (2009)] using a single-state one-dimensional model. Pathway 2, due to its strong coupling to the dissociation channel, is less effective than pathway 1. The simulations also show that nonlinear field effects due to molecular polarizability and hyperpolarizability are small for pathway 1 but could become significant for pathway 2 because much higher field intensity is involved in the latter. The results suggest that a practical control may be feasible with the aid of a few lowly excited electronic states for ozone isomerization

  4. Radiation-induced bone tumours in the guinea-pig

    International Nuclear Information System (INIS)

    Knowles, J.F.

    1981-01-01

    A remarkably high proportion of guinea-pigs given localized irradiations of 20 Gy x-rays developed bone tumours, 46% of all irradiated with 20 Gy and 86% of those that survived at least a year. Untreated controls were not included in the present experiment, but the authors refer to an earlier experiment using guinea-pigs from the same colony where no bone tumour occurred in 69 unirradiated animals followed for their natural life span i.e. up to 87 months. It is concluded that the author's strain of guinea-pig (details given in a previous paper, Int. J. Radiol. Biol., 40, 265) is particularly prone to radiation-induced bone tumours. Their possible value for investigating processes associated with radiation induction of bone tumours is further enhanced by their relatively large size and long life span (up to 7 years). (U.K.)

  5. Incidence of brain tumours in rats exposed to an aerosol of 239PuO2

    International Nuclear Information System (INIS)

    Sanders, C.L.; Dagle, G.E.; Mahaffey, J.A.

    1992-01-01

    Incidence of brain tumours was investigated in 3390 female and male Wistar rats exposed to an aerosol of 239 PuO 2 , or as sham-exposed controls. Lung doses ranged from 0.05 to 22 Gy. In females, six brain tumours were found in 1058 control rats (incidence, 0.6%) and 24 brain tumours in 2134 rats exposed to Pu (incidence, 1.1%); the survival-adjusted level of significance was p = 0.29 for comparing control with exposed females. In males, two brain tumours were found in 60 control rats (incidence, 3.3%) and seven brain tumours in 138 rats exposed to Pu (incidence, 5.1%); the survival-adjusted level of significance was p = 0.33. Brain tumour incidence was about five times greater in male than in female rats (p = 0.0001), a highly significant sex difference in brain tumour incidence. Tumour types were distributed similarly among control and Pu-exposed groups of both sexes; most were astrocytomas. Mean lifespans for rats with brain tumours were not significantly different between control and Pu-exposed rats. (author)

  6. Comparison of Acuros (AXB) and Anisotropic Analytical Algorithm (AAA) for dose calculation in treatment of oesophageal cancer: effects on modelling tumour control probability

    International Nuclear Information System (INIS)

    Padmanaban, Sriram; Warren, Samantha; Walsh, Anthony; Partridge, Mike; Hawkins, Maria A

    2014-01-01

    To investigate systematic changes in dose arising when treatment plans optimised using the Anisotropic Analytical Algorithm (AAA) are recalculated using Acuros XB (AXB) in patients treated with definitive chemoradiotherapy (dCRT) for locally advanced oesophageal cancers. We have compared treatment plans created using AAA with those recalculated using AXB. Although the Anisotropic Analytical Algorithm (AAA) is currently more widely used in clinical routine, Acuros XB (AXB) has been shown to more accurately calculate the dose distribution, particularly in heterogeneous regions. Studies to predict clinical outcome should be based on modelling the dose delivered to the patient as accurately as possible. CT datasets from ten patients were selected for this retrospective study. VMAT (Volumetric modulated arc therapy) plans with 2 arcs, collimator rotation ± 5-10° and dose prescription 50 Gy / 25 fractions were created using Varian Eclipse (v10.0). The initial dose calculation was performed with AAA, and AXB plans were created by re-calculating the dose distribution using the same number of monitor units (MU) and multileaf collimator (MLC) files as the original plan. The difference in calculated dose to organs at risk (OAR) was compared using dose-volume histogram (DVH) statistics and p values were calculated using the Wilcoxon signed rank test. The potential clinical effect of dosimetric differences in the gross tumour volume (GTV) was evaluated using three different TCP models from the literature. PTV Median dose was apparently 0.9 Gy lower (range: 0.5 Gy - 1.3 Gy; p < 0.05) for VMAT AAA plans re-calculated with AXB and GTV mean dose was reduced by on average 1.0 Gy (0.3 Gy −1.5 Gy; p < 0.05). An apparent difference in TCP of between 1.2% and 3.1% was found depending on the choice of TCP model. OAR mean dose was lower in the AXB recalculated plan than the AAA plan (on average, dose reduction: lung 1.7%, heart 2.4%). Similar trends were seen for CRT plans

  7. Comparison of Acuros (AXB) and Anisotropic Analytical Algorithm (AAA) for dose calculation in treatment of oesophageal cancer: effects on modelling tumour control probability.

    Science.gov (United States)

    Padmanaban, Sriram; Warren, Samantha; Walsh, Anthony; Partridge, Mike; Hawkins, Maria A

    2014-12-23

    To investigate systematic changes in dose arising when treatment plans optimised using the Anisotropic Analytical Algorithm (AAA) are recalculated using Acuros XB (AXB) in patients treated with definitive chemoradiotherapy (dCRT) for locally advanced oesophageal cancers. We have compared treatment plans created using AAA with those recalculated using AXB. Although the Anisotropic Analytical Algorithm (AAA) is currently more widely used in clinical routine, Acuros XB (AXB) has been shown to more accurately calculate the dose distribution, particularly in heterogeneous regions. Studies to predict clinical outcome should be based on modelling the dose delivered to the patient as accurately as possible. CT datasets from ten patients were selected for this retrospective study. VMAT (Volumetric modulated arc therapy) plans with 2 arcs, collimator rotation ± 5-10° and dose prescription 50 Gy / 25 fractions were created using Varian Eclipse (v10.0). The initial dose calculation was performed with AAA, and AXB plans were created by re-calculating the dose distribution using the same number of monitor units (MU) and multileaf collimator (MLC) files as the original plan. The difference in calculated dose to organs at risk (OAR) was compared using dose-volume histogram (DVH) statistics and p values were calculated using the Wilcoxon signed rank test. The potential clinical effect of dosimetric differences in the gross tumour volume (GTV) was evaluated using three different TCP models from the literature. PTV Median dose was apparently 0.9 Gy lower (range: 0.5 Gy - 1.3 Gy; p AAA plans re-calculated with AXB and GTV mean dose was reduced by on average 1.0 Gy (0.3 Gy -1.5 Gy; p AAA plan (on average, dose reduction: lung 1.7%, heart 2.4%). Similar trends were seen for CRT plans. Differences in dose distribution are observed with VMAT and CRT plans recalculated with AXB particularly within soft tissue at the tumour/lung interface, where AXB has been shown to more

  8. The Janus face of death receptor signalling during tumour immunoediting.

    Directory of Open Access Journals (Sweden)

    Eimear O' Reilly

    2016-10-01

    Full Text Available Cancer immune-surveillance is essential for the inhibition of carcinogenesis. Malignantly transformed cells can be recognised by both the innate and adaptive immune systems through different mechanisms. Immune effector cells induce extrinsic cell death in the identified tumour cells by expressing death ligand cytokines of the tumour necrosis factor ligand family. However, some tumour cells can escape immune elimination and progress. Acquisition of resistance to the death-ligand induced apoptotic pathway can be obtained through cleavage of effector-cell expressed death-ligands into a poorly active form, mutations or silencing of the death receptors or overexpression of decoy receptors and pro-survival proteins. Although the immune system is highly effective in the elimination of malignantly transformed cells, abnormal/ dysfunctional death-ligand signalling curbs its cytotoxicity. Moreover, death receptors can also transmit pro-survival and pro-migratory signals. Consequently, dysfunctional death receptor-mediated apoptosis/necroptosis signalling does not only give a passive resistance against cell death, but actively drives tumour cell motility, invasion and contributes to consequent metastasis. This dual contribution of the death ligand-death receptor signalling in both the early, elimination phase and then in the late, escape phase of the tumour immunoediting process is discussed in this review. Death receptor agonists still hold potential for cancer therapy since they can execute the tumour-eliminating immune-effector function even in the absence of activation of the immune system against the tumour. The opportunities and challenges of developing death receptor agonists into effective cancer therapeutics are also discussed.

  9. Cystic tumours of the pancreas

    Energy Technology Data Exchange (ETDEWEB)

    Itai, Y. [Dept. of Radiology, Inst. of Clinical Medicine, Tsukuba Univ. (Japan); Ohtomo, K. [Univ. of Tokyo Hospital, Tokyo (Japan)

    1996-12-01

    In this pictorial essay we present the typical appearances of cystic pancreatic tumours, the wide spectrum of their features, and differential features among cystic pancreatic masses with an emphasis on CT. Pseudocysts are the most common cystic lesion in the pancreas and can be induced by pancreatitis, trauma or surgery. Pseudocysts appear as a round cystic mass with a definite wall. However, they can mimic cystic tumours associated with internal septation and/or necrotic mass of various shapes. Conversely, cystic tumours can appear as a simple cyst lacking any thickening of wall, septation or mural nodule. Pancreatic carcinoma not infrequently induces secondary cysts upstream of the obstructed pancreatic duct. The cysts are pseudocysts or retention cysts in nature. When cysts are formed in the pancreatic parenchyma or adjacent to pancreatic carcinoma they may mimic cystic tumour. (orig./VHE)

  10. Cystic tumours of the pancreas

    International Nuclear Information System (INIS)

    Itai, Y.; Ohtomo, K.

    1996-01-01

    In this pictorial essay we present the typical appearances of cystic pancreatic tumours, the wide spectrum of their features, and differential features among cystic pancreatic masses with an emphasis on CT. Pseudocysts are the most common cystic lesion in the pancreas and can be induced by pancreatitis, trauma or surgery. Pseudocysts appear as a round cystic mass with a definite wall. However, they can mimic cystic tumours associated with internal septation and/or necrotic mass of various shapes. Conversely, cystic tumours can appear as a simple cyst lacking any thickening of wall, septation or mural nodule. Pancreatic carcinoma not infrequently induces secondary cysts upstream of the obstructed pancreatic duct. The cysts are pseudocysts or retention cysts in nature. When cysts are formed in the pancreatic parenchyma or adjacent to pancreatic carcinoma they may mimic cystic tumour. (orig./VHE)

  11. Imaging oxygenation of human tumours

    International Nuclear Information System (INIS)

    Padhani, Anwar R.; Krohn, Kenneth A.; Lewis, Jason S.; Alber, Markus

    2007-01-01

    Tumour hypoxia represents a significant challenge to the curability of human tumours leading to treatment resistance and enhanced tumour progression. Tumour hypoxia can be detected by non-invasive and invasive techniques but the inter-relationships between these remains largely undefined. 18 F-MISO and Cu-ATSM-PET, and BOLD-MRI are the lead contenders for human application based on their non-invasive nature, ease of use and robustness, measurement of hypoxia status, validity, ability to demonstrate heterogeneity and general availability, these techniques are the primary focus of this review. We discuss where developments are required for hypoxia imaging to become clinically useful and explore potential new uses for hypoxia imaging techniques including biological conformal radiotherapy. (orig.)

  12. Emotional and personality changes following brain tumour resection.

    Science.gov (United States)

    Jenkins, Lisanne M; Drummond, Katharine J; Andrewes, David G

    2016-07-01

    Psychological distress has a high prevalence in brain tumour patients, and understanding the emotional and personality changes that may follow neurosurgery is important for clinical management of these patients. We aimed to characterise these emotional and personality changes using subjective, observer-rated and clinical measures. We examined subjective changes in emotional experience and observer-rated changes to personality disturbances following neurosurgery for brain tumours (n=44), compared to a control group that had undergone spinal surgery (n=26). Participants completed the Hospital Anxiety and Depression Scale and a Subjective Emotional Change Questionnaire. Observers who knew the patients well also completed the Iowa Rating Scale of Personality Change. Compared to controls, patients with tumours reported significantly more changes to their subjective experience of emotions following neurosurgery, particularly anger, disgust and sadness. For the observer-ratings, tumour patients were described as having significant changes in the personality disturbances of irritability, impulsivity, moodiness, inflexibility, and being easily overwhelmed. Anxiety and depression were not significantly different between groups. Neurosurgical resection of a brain tumour is a major life event that changes patients' subjective experiences of different emotions, and leads to observer-rated changes in personality. In this study, these changes were not accompanied by increases in anxiety or depression. We conclude with a discussion of biological and psychosocial mechanisms that can impact emotional functioning and personality in patients with brain tumours. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Tumour markers in urology

    International Nuclear Information System (INIS)

    Schmid, L.; Fornara, P.; Fabricius, P.G.

    1988-01-01

    The same applies essentially also for the bladder carcinomas: There is no reliable marker for these cancers which would be useful for clinical purposes. TPA has proven to be too non-specific in malignoma-detection and therefore hardly facilitates clinical decision-making in individual cases. The CEA is not sensitive enough to be recommendable for routine application. However, in advanced stages a CEA examination may be useful if applied within the scope of therapeutic efforts made to evaluate efficacy. In cases of carcinomas of the prostate the sour prostate-specific phosphatase (SPP) and, more recently, especially the prostate-specific antigen (PSA) have proven in follow-up and therapy monitoring, whereby the PSA is superior to the SPP. Nevertheless, both these markers should be employed in therapy monitoring because differences in behaviour will be observed when the desired treatment effect is only achieved in one of the two markers producing tumour cell clonuses. Both markers, but especially the PSA, are quite reliably in agreement with the result of the introduced chemo-/hormone therapy, whereby an increase may be a sure indicator of relapse several months previous to clinical symptoms, imaging procedures, so-called routine laboratory results and subjective complaints. However, none of the 2 markers is appropriate for the purposes of screening or early diagnosis of carcinomas of the prostate. (orig.) [de

  14. Controls on shallow landslide initiation: Diverse hydrologic pathways, 3D failure geometries, and unsaturated soil suctions

    Science.gov (United States)

    Reid, Mark; Iverson, Richard; Brien, Dianne; Iverson, Neal; LaHusen, Richard; Logan, Matthew

    2017-04-01

    Shallow landslides and ensuing debris flows are a common hazard worldwide, yet forecasting their initiation at a specific site is challenging. These challenges arise, in part, from diverse near-surface hydrologic pathways under different wetting conditions, 3D failure geometries, and the effects of suction in partially saturated soils. Simplistic hydrologic models typically used for regional hazard assessment disregard these complexities. As an alterative to field studies where the effects of these governing factors can be difficult to isolate, we used the USGS debris-flow flume to conduct controlled, field-scale landslide initiation experiments. Using overhead sprinklers or groundwater injectors on the flume bed, we triggered failures using three different wetting conditions: groundwater inflow from below, prolonged moderate-intensity precipitation, and bursts of high-intensity precipitation. Failures occurred in 6 m3 (0.65-m thick and 2-m wide) prisms of loamy sand on a 31° slope; these field-scale failures enabled realistic incorporation of nonlinear scale-dependent effects such as soil suction. During the experiments, we monitored soil deformation, variably saturated pore pressures, and moisture changes using ˜50 sensors sampling at 20 Hz. From ancillary laboratory tests, we determined shear strength, saturated hydraulic conductivities, and unsaturated moisture retention characteristics. The three different wetting conditions noted above led to different hydrologic pathways and influenced instrumental responses and failure timing. During groundwater injection, pore-water pressures increased from the bed of the flume upwards into the sediment, whereas prolonged moderate infiltration wet the sediment from the ground surface downward. In both cases, pore pressures acting on the impending failure surface slowly rose until abrupt failure. In contrast, a burst of intense sprinkling caused rapid failure without precursory development of widespread positive pore

  15. Renal angiomyoadenomatous tumour: Imaging features

    Science.gov (United States)

    Sahni, V. Anik; Hirsch, Michelle S.; Silverman, Stuart G.

    2012-01-01

    Renal angiomyoadenomatous tumour is a rare, recently described neoplasm with a distinctive histological appearance. Although reported in the pathology literature, to our knowledge, no prior reports have described its imaging appearance. We describe the computed tomography and magnetic resonance imaging features of an incidentally detected renal angiomyoadenomatous tumour that appeared as a well-marginated, solid T2-hypointense enhancing mass, in a 50-year-old woman. It is indistinguishable from a variety of benign and malignant renal neoplasms. PMID:23093565

  16. Paediatric laryngeal granular cell tumour

    Directory of Open Access Journals (Sweden)

    Dauda Ayuba

    2009-01-01

    Full Text Available Granular cell tumour (GCT affecting the larynx is not common, especially in children. Most cases are apt to be confused with respiratory papilloma and may even be mistaken for a malignant neoplasia. We present a case of laryngeal GCT in a 12-year-old child to emphasize that the tumour should be regarded in the differential of growths affecting the larynx in children.

  17. Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPARβ/δ-Dependent Vasodilator Pathway.

    Science.gov (United States)

    Kirkby, Nicholas S; Sampaio, Walkyria; Etelvino, Gisele; Alves, Daniele T; Anders, Katie L; Temponi, Rafael; Shala, Fisnik; Nair, Anitha S; Ahmetaj-Shala, Blerina; Jiao, Jing; Herschman, Harvey R; Xiaomeng, Wang; Wahli, Walter; Santos, Robson A; Mitchell, Jane A

    2018-02-01

    Cyclooxygenase-2 (COX-2) is an inducible enzyme expressed in inflammation and cancer targeted by nonsteroidal anti-inflammatory drugs. COX-2 is also expressed constitutively in discreet locations where its inhibition drives gastrointestinal and cardiovascular/renal side effects. Constitutive COX-2 expression in the kidney regulates renal function and blood flow; however, the global relevance of the kidney versus other tissues to COX-2-dependent blood flow regulation is not known. Here, we used a microsphere deposition technique and pharmacological COX-2 inhibition to map the contribution of COX-2 to regional blood flow in mice and compared this to COX-2 expression patterns using luciferase reporter mice. Across all tissues studied, COX-2 inhibition altered blood flow predominantly in the kidney, with some effects also seen in the spleen, adipose, and testes. Of these sites, only the kidney displayed appreciable local COX-2 expression. As the main site where COX-2 regulates blood flow, we next analyzed the pathways involved in kidney vascular responses using a novel technique of video imaging small arteries in living tissue slices. We found that the protective effect of COX-2 on renal vascular function was associated with prostacyclin signaling through PPARβ/δ (peroxisome proliferator-activated receptor-β/δ). These data demonstrate the kidney as the principle site in the body where local COX-2 controls blood flow and identifies a previously unreported PPARβ/δ-mediated renal vasodilator pathway as the mechanism. These findings have direct relevance to the renal and cardiovascular side effects of drugs that inhibit COX-2, as well as the potential of the COX-2/prostacyclin/PPARβ/δ axis as a therapeutic target in renal disease. © 2018 The Authors.

  18. Defining a novel leptin–melanocortin–kisspeptin pathway involved in the metabolic control of puberty

    Directory of Open Access Journals (Sweden)

    Maria Manfredi-Lozano

    2016-10-01

    Full Text Available Objective: Puberty is a key developmental phenomenon highly sensitive to metabolic modulation. Worrying trends of changes in the timing of puberty have been reported in humans. These might be linked to the escalating prevalence of childhood obesity and could have deleterious impacts on later (cardio-metabolic health, but their underlying mechanisms remain unsolved. The neuropeptide α-MSH, made by POMC neurons, plays a key role in energy homeostasis by mediating the actions of leptin and likely participates in the control of reproduction. However, its role in the metabolic regulation of puberty and interplay with kisspeptin, an essential puberty-regulating neuropeptide encoded by Kiss1, remain largely unknown. We aim here to unveil the potential contribution of central α-MSH signaling in the metabolic control of puberty by addressing its role in mediating the pubertal effects of leptin and its potential interaction with kisspeptin. Methods: Using wild type and genetically modified rodent models, we implemented pharmacological studies, expression analyses, electrophysiological recordings, and virogenetic approaches involving DREADD technology to selectively inhibit Kiss1 neurons, in order to interrogate the physiological role of a putative leptin→α-MSH→kisspeptin pathway in the metabolic control of puberty. Results: Stimulation of central α-MSH signaling robustly activated the reproductive axis in pubertal rats, whereas chronic inhibition of melanocortin receptors MC3/4R, delayed puberty, and prevented the permissive effect of leptin on puberty onset. Central blockade of MC3/4R or genetic elimination of kisspeptin receptors from POMC neurons did not affect kisspeptin effects. Conversely, congenital ablation of kisspeptin receptors or inducible, DREADD-mediated inhibition of arcuate nucleus (ARC Kiss1 neurons resulted in markedly attenuated gonadotropic responses to MC3/4R activation. Furthermore, close appositions were observed between

  19. Interleukin-1β and tumour necrosis factor-α levels in conjunctiva of diabetic patients with symptomatic moderate dry eye: case–control study

    Science.gov (United States)

    Zhang, Chen; Xi, Lei; Zhao, Shaozhen; Wei, Ruihua; Huang, Yue; Yang, Ruibo; Su, Long; Liu, Xun

    2016-01-01

    Objectives To compare expression of interleukin (IL)-1β and tumour necrosis factor (TNF)-α in the conjunctiva of diabetic and non-diabetic patients with symptomatic moderate dry eye. Setting and participants Nineteen diabetic patients with dry eye, 15 non-diabetic patients with dry eye and 14 diabetic patients without dry eye were recruited. The relative expression of IL-1β and TNF-α in conjunctival impression cytology (CIC) specimens was evaluated using immunofluorescent staining and in conjunctival biopsy specimens using immunohistochemical staining. Results The diabetic dry eye group showed significantly higher grades of metaplasia than the non-diabetic dry eye and diabetic without dry eye groups (both pdry eye group was significantly increased compared with the non-diabetic dry eye and diabetic without dry eye groups (p=0.002, pdry eye, while levels of IL-1β and TNF-α in apical conjunctival epithelium were similar in the CIC specimens. These findings suggest that the inflammatory response is not limited to the surface of conjunctival epithelial cells, and is more serious in the basal layer of the epithelium, which may play an important role in the pathogenesis of dry eye in diabetic patients. PMID:27489152

  20. Synthetic Control of Kinetic Reaction Pathway and Cationic Ordering in High-Ni Layered Oxide Cathodes

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Dawei [Sustainable Energy Technologies Department, Brookhaven National Laboratory, Upton NY 11973 USA; Collaborative Innovation Center of Chemistry for Energy Materials, State Key Laboratory Physical Chemistry Solid Surfaces, Department of Chemistry, Xiamen University, Xiamen Fujian 361005 China; Kou, Ronghui [X-Ray Science Division, Advanced Photon Source, Argonne National Laboratory, Argonne IL 60439 USA; Ren, Yang [X-Ray Science Division, Advanced Photon Source, Argonne National Laboratory, Argonne IL 60439 USA; Sun, Cheng-Jun [X-Ray Science Division, Advanced Photon Source, Argonne National Laboratory, Argonne IL 60439 USA; Zhao, Hu [Sustainable Energy Technologies Department, Brookhaven National Laboratory, Upton NY 11973 USA; Zhang, Ming-Jian [Sustainable Energy Technologies Department, Brookhaven National Laboratory, Upton NY 11973 USA; School of Advanced Materials, Peking University Shenzhen Graduate School, Shenzhen Guangdong 518055 P. R. China; Li, Yan [Chemical Sciences and Engineering Division, Argonne National Laboratory, Argonne IL 60439 USA; Huq, Ashifia [Chemical and Engineering Materials Division, Oak Ridge National Laboratory, Oak Ridge TN 37831 USA; Ko, J. Y. Peter [The Cornell High Energy Synchrotron Source, Cornell University, Ithaca NY 14853 USA; Pan, Feng [School of Advanced Materials, Peking University Shenzhen Graduate School, Shenzhen Guangdong 518055 P. R. China; Sun, Yang-Kook [Department of Energy Engineering, Hanyang University, Seoul 133-791 South Korea; Yang, Yong [Collaborative Innovation Center of Chemistry for Energy Materials, State Key Laboratory Physical Chemistry Solid Surfaces, Department of Chemistry, Xiamen University, Xiamen Fujian 361005 China; Amine, Khalil [Chemical Sciences and Engineering Division, Argonne National Laboratory, Argonne IL 60439 USA; Bai, Jianming [National Synchrotron Light Source II, Brookhaven National Laboratory, Upton NY 11973 USA; Chen, Zonghai [Chemical Sciences and Engineering Division, Argonne National Laboratory, Argonne IL 60439 USA; Wang, Feng [Sustainable Energy Technologies Department, Brookhaven National Laboratory, Upton NY 11973 USA

    2017-08-25

    Nickel-rich layered transition metal oxides, LiNi1-x(MnCo)(x)O-2 (1-x >= 0.5), are appealing candidates for cathodes in next-generation lithium-ion batteries (LIBs) for electric vehicles and other large-scale applications, due to their high capacity and low cost. However, synthetic control of the structural ordering in such a complex quaternary system has been a great challenge, especially in the presence of high Ni content. Herein, synthesis reactions for preparing layered LiNi0.7Mn0.15Co0.15O2 (NMC71515) by solid-state methods are investigated through a combination of time-resolved in situ high-energy X-ray diffraction and absorption spectroscopy measurements. The real-time observation reveals a strong temperature dependence of the kinetics of cationic ordering in NMC71515 as a result of thermal-driven oxidation of transition metals and lithium/oxygen loss that concomitantly occur during heat treatment. Through synthetic control of the kinetic reaction pathway, a layered NMC71515 with low cationic disordering and a high reversible capacity is prepared in air. The findings may help to pave the way for designing high-Ni layered oxide cathodes for LIBs.

  1. Multiple independent regulatory pathways control UBI4 expression after heat shock in Saccharomyces cerevisiae.

    Science.gov (United States)

    Simon, J R; Treger, J M; McEntee, K

    1999-02-01

    Transcription of the polyubiquitin gene UBI4 of Saccharomyces cerevisiae is strongly induced by a variety of environmental stresses, such as heat shock, nutrient depletion and exposure to DNA-damaging agents. This transcriptional response of UBI4 is likely to be the primary mechanism for increasing the pool of ubiquitin for degradation of stress-damaged proteins. Deletion and promoter fusion studies of the 5' regulatory sequences indicated that two different elements, heat shock elements (HSEs) and stress response element (STREs), contributed independently to heat shock regulation of the UBI4 gene. In the absence of HSEs, STRE sequences localized to the intervals -264 to -238 and -215 to -183 were needed for stress control of transcription after heat shock. Site-directed mutagenesis of the STRE (AG4) at -252 to -248 abolished heat shock induction of UBI4 transcription. Northern analysis demonstrated that cells containing either a temperature-sensitive HSF or non-functional Msn2p/Msn4p transcription factors induced high levels of UBI4 transcripts after heat shock. In cells deficient in both heat stress pathways, heat-induced UBI4 transcript levels were considerably lower but not abolished, suggesting a role for another factor(s) in stress control of its expression.

  2. Selective control of multiple ferroelectric switching pathways using a trailing flexoelectric field

    Science.gov (United States)

    Park, Sung Min; Wang, Bo; Das, Saikat; Chae, Seung Chul; Chung, Jin-Seok; Yoon, Jong-Gul; Chen, Long-Qing; Yang, Sang Mo; Noh, Tae Won

    2018-05-01

    Flexoelectricity is an electromechanical coupling between electrical polarization and a strain gradient1 that enables mechanical manipulation of polarization without applying an electrical bias2,3. Recently, flexoelectricity was directly demonstrated by mechanically switching the out-of-plane polarization of a uniaxial system with a scanning probe microscope tip3,4. However, the successful application of flexoelectricity in low-symmetry multiaxial ferroelectrics and therefore active manipulation of multiple domains via flexoelectricity have not yet been achieved. Here, we demonstrate that the symmetry-breaking flexoelectricity offers a powerful route for the selective control of multiple domain switching pathways in multiaxial ferroelectric materials. Specifically, we use a trailing flexoelectric field that is created by the motion of a mechanically loaded scanning probe microscope tip. By controlling the SPM scan direction, we can deterministically select either stable 71° ferroelastic switching or 180° ferroelectric switching in a multiferroic magnetoelectric BiFeO3 thin film. Phase-field simulations reveal that the amplified in-plane trailing flexoelectric field is essential for this domain engineering. Moreover, we show that mechanically switched domains have a good retention property. This work opens a new avenue for the deterministic selection of nanoscale ferroelectric domains in low-symmetry materials for non-volatile magnetoelectric devices and multilevel data storage.

  3. Surgical approach to pineal tumours.

    Science.gov (United States)

    Pluchino, F; Broggi, G; Fornari, M; Franzini, A; Solero, C L; Allegranza, A

    1989-01-01

    During a period of 10 years (1977-1986) 40 cases of tumour of the pineal region have been treated at the Istituto Neurologico "C. Besta"-of Milan. Out of these 40 cases, 27 (67.5%) were in the paediatric (10-15 years) or juvenile (15-20 years) age at the time of operation. Since 1983 a specific diagnostic and therapeutic protocol has been adopted and thereafter direct surgical removal of the tumour was performed only when the neuroradiological investigations were highly suggestive of a benign extrinsic lesion. Sixteen cases in this series underwent direct surgical removal; in the remaining 24 cases stereotactic biopsy of the tumour was performed in the first instance. On the basis of the histological diagnosis obtained by this procedure surgical excision of the tumour (9 cases) or radiotherapy (15 cases) was then performed. 25 cases underwent surgical removal of the lesion. In all the cases the infratentorial supracerebellar approach as introduced by Krause and then modified by Stein was adopted. On analysis of the data of this series it was observed that in 25% of the cases completely benign resectable tumours were found; in 25% of the cases astrocytoma (grade I-II) which could be treated at least by partial removal were present; in 30% of the cases radiosensitive lesions were encountered. In the remaining 20% of the cases highly malignant tumours were found which should be treated only by radiotherapy and/or chemotherapy.

  4. MRI characteristics of midbrain tumours

    International Nuclear Information System (INIS)

    Sun, B.; Wang, C.C.; Wang, J.

    1999-01-01

    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.)

  5. An interplay between 2 signaling pathways: Melatonin-cAMP and IP3–Ca2+ signaling pathways control intraerythrocytic development of the malaria parasite Plasmodium falciparum

    International Nuclear Information System (INIS)

    Furuyama, Wakako; Enomoto, Masahiro; Mossaad, Ehab; Kawai, Satoru; Mikoshiba, Katsuhiko; Kawazu, Shin-ichiro

    2014-01-01

    Highlights: • A melatonin receptor antagonist blocked Ca 2+ oscillation in P. falciparum and inhibited parasite growth. • P. falciparum development is controlled by Ca 2+ - and cAMP-signaling pathways. • The cAMP-signaling pathway at ring form and late trophozoite stages governs parasite growth of P. falciparum. - Abstract: Plasmodium falciparum spends most of its asexual life cycle within human erythrocytes, where proliferation and maturation occur. Development into the mature forms of P. falciparum causes severe symptoms due to its distinctive sequestration capability. However, the physiological roles and the molecular mechanisms of signaling pathways that govern development are poorly understood. Our previous study showed that P. falciparum exhibits stage-specific spontaneous Calcium (Ca 2+ ) oscillations in ring and early trophozoites, and the latter was essential for parasite development. In this study, we show that luzindole (LZ), a selective melatonin receptor antagonist, inhibits parasite growth. Analyses of development and morphology of LZ-treated P. falciparum revealed that LZ severely disrupted intraerythrocytic maturation, resulting in parasite death. When LZ was added at ring stage, the parasite could not undergo further development, whereas LZ added at the trophozoite stage inhibited development from early into late schizonts. Live-cell Ca 2+ imaging showed that LZ treatment completely abolished Ca 2+ oscillation in the ring forms while having little effect on early trophozoites. Further, the melatonin-induced cAMP increase observed at ring and late trophozoite stage was attenuated by LZ treatment. These suggest that a complex interplay between IP 3 –Ca 2+ and cAMP signaling pathways is involved in intraerythrocytic development of P. falciparum

  6. Gene expression of circulating tumour cells and its correlation with tumour stage in breast cancer patients

    Directory of Open Access Journals (Sweden)

    Bölke E

    2009-09-01

    Full Text Available Abstract Background Breast cancer (BC represents one of the leading causes of cancer related deaths worldwide. New tools for diagnostic staging and therapeutic monitoring are needed to improve individualized therapies and improve clinical outcome. The analyses of circulating tumour cells may provide important prognostic information in the clinical setting. Materials and methods Circulating tumour cells (CTC of 63 BC patients were isolated from peripheral blood (PB through immunomagnetic separation. Subsequently, RT-PCR or mPCR for the genes ga733.2, muc-1, c-erbB2, mgb-1, spdef and c-erbB2 were performed. Subsequently, expression data were correlated with the tumour stages. Fourteen healthy individuals served as controls. Results Significant correlations with tumour stages were found in single gene analyses of ga733.2, muc-1 and in multi-gene analyses of ga733.2/muc-1/mgb1/spdef. Furthermore, a significant correlation of Ca 15-3 and all studied genes was also observed. Conclusion Herein, we demonstrated a positive correlation of a gene signature consisting of ga733.2, muc-1, mgb1 and spdef and advanced stages of BC. Moreover, all studied genes and gene patterns revealed a significant correlation with Ca 15-3 positive cases.

  7. The influence of the oestrous cycle on the radiation response of solid tumours

    Science.gov (United States)

    Swann, Patricia R.

    degree of transient perfusion in the tumours was assessed. This used a fluorescent double-staining technique by intravenous injection of the fluorescent dyes Hoechst 33342 and diheptyloxacarbocyanine with a 20 minute interval between dye administrations. These dyes stain functional blood vessels and can be viewed under the fluorescent microscope. Regions of vasculature stained with both dyes indicate constant perfusion throughout the experiment, whereas only one dye indicates mismatch or transient perfusion. Tumour vasculature that experiences intermittent perfusion will result in areas of acute hypoxia that can impact on the radiation response of the tumour. The results shows that in oestrus, KHT and RIF-1 tumours showed the lowest proportion of transient perfusion, where as this oestrous stage produced the most mismatch perfusion in the SCCvii tumour. The metastatic spread of KHT tumour cells was influenced by the oestrous cycle. Fractionated irradiation of a primary tumour during metoestrus and dioestrus showed less tumour control by radiation when compared to tumours irradiated in oestrus. The intravenous injection of KHT tumour cells in oestrus and dioestrus also produced a less metastatic burden to the lungs than cells injected in pro-oestrus and metoestrus. The results of this project suggest that there are oestrous stage dependent effects that could alter the radiation response of tumours.

  8. The Askin tumour. Neuroactodermic tumour of the thoracic wall

    International Nuclear Information System (INIS)

    Velazquez, P.; Nicolas, A. I.; Vivas, I.; Damaso Aquerreta, J.; Martinez-Cuesta, A.

    1999-01-01

    The Askin tumours is an extremely rare and malignant process in the thoracic pulmonary region during infancy and youth. The differential diagnosis has to be considered with other thoracic wall tumours that are more common in pediatrics like the undifferentiated neuroblastoma, the embionic rabdomiosarcoma, the Ewing sarcoma and the linfoma. A retrospective examination was carried out on 473 thoracic wall tumours from 1994 to 1997 at our centre, resulting in 4 patients with an anatomopathologically tested Askin tumour (ages from 13-21). All the cases were studied using simple radiography and CT. In two cases MRI was also used. The most common clinical manifestation was a palpable painful mass in the thoracic wall. In the simple radiograph the main finding was a large mass of extrapleural soft material, with costal destruction ( n=3) and a pleural effusion (n=2). In the CT study the mass was heterogeneous, with internal calcifications in one case. CT and MRI showed invasion in the mediastinum (n=1), medular channel (n=1) and phrenic and sulphrenic extension (n=1). The Askin tumour should be included in the differential diagnosis of thoracic wall masses in infant-youth ages. There are no specific morphological characteristics. Both CT and MRI are useful for the diagnosis, staging and follow up. (Author) 11 refs

  9. An experimental study of tumour size and radiosensitivity

    International Nuclear Information System (INIS)

    Hill, S.A.; Denekamp, J.

    1989-01-01

    When designing experimental studies of tumours, it is considered important to control all variables that might alter the radiosensitivity and hence influence the variability of the data. One such variable is tumour size. We have studied the regrowth delay of a mammary carcinoma treated at 2-10 mm mean diameter (a 125-fold change of volume) with X-rays alone or X-rays plus misonidazole (MISO). The data were analysed to give dose-response curves, using four endpoints. Regrowth to a fixed size (4.5 mm larger than treatment size), or by a fixed increment (4 times the original volume) was expressed either as absolute delay, or as specific growth delay to allow for the changes in volume doubling time as the tumour grows. The method of analysis made no difference to the measured sensitizer enhancement ratio (SER) for MISO. The SER was dose-dependent, being higher doses, but was not different in tumours of 2 or 10 mm diameter. However, when comparing response to X-rays alone, the method of analysis made a very big difference to the conclusions. Regrowth to R + 4.5 mm showed no change in radiosensitivity with tumour size, but regrowth to 4 times the original volume (the most logical endpoint) indicated that large tumours were more sensitive than small. We conclude that regrowth delay may be an inappropriate method for comparing absolute sensitivities of tumours of different sizes. However, for studying the effectiveness of a radiomodifier the constraints of tumour size at irradiation seem to be less severe than previously believed. (author). 8 refs.; 8 figs

  10. Synchronized moving aperture radiation therapy (SMART): average tumour trajectory for lung patients

    International Nuclear Information System (INIS)

    Neicu, Toni; Shirato, Hiroki; Seppenwoolde, Yvette; Jiang, Steve B

    2003-01-01

    Synchronized moving aperture radiation therapy (SMART) is a new technique for treating mobile tumours under development at Massachusetts General Hospital (MGH). The basic idea of SMART is to synchronize the moving radiation beam aperture formed by a dynamic multileaf collimator (DMLC) with the tumour motion induced by respiration. SMART is based on the concept of the average tumour trajectory (ATT) exhibited by a tumour during respiration. During the treatment simulation stage, tumour motion is measured and the ATT is derived. Then, the original IMRT MLC leaf sequence is modified using the ATT to compensate for tumour motion. During treatment, the tumour motion is monitored. The treatment starts when leaf motion and tumour motion are synchronized at a specific breathing phase. The treatment will halt when the tumour drifts away from the ATT and will resume when the synchronization between tumour motion and radiation beam is re-established. In this paper, we present a method to derive the ATT from measured tumour trajectory data. We also investigate the validity of the ATT concept for lung tumours during normal breathing. The lung tumour trajectory data were acquired during actual radiotherapy sessions using a real-time tumour-tracking system. SMART treatment is simulated by assuming that the radiation beam follows the derived ATT and the tumour follows the measured trajectory. In simulation, the treatment starts at exhale phase. The duty cycle of SMART delivery was calculated for various treatment times and gating thresholds, as well as for various exhale phases where the treatment begins. The simulation results show that in the case of free breathing, for 4 out of 11 lung datasets with tumour motion greater than 1 cm from peak to peak, the error in tumour tracking can be controlled to within a couple of millimetres while maintaining a reasonable delivery efficiency. That is to say, without any breath coaching/control, the ATT is a valid concept for some lung

  11. Childhood Adrenocortical Tumours: a Review

    Directory of Open Access Journals (Sweden)

    Marques-Pereira Rosana

    2006-05-01

    Full Text Available Abstract Childhood adrenocortical tumour (ACT is not a common disease, but in southern Brazil the prevalence is 15 times higher than in other parts of the world. One hundred and thirty-seven patients have been identified and followed by our group over the past four decades. Affected children are predominantly girls, with a female-to-male ratio of 3.5:1 in patients below 4 years of age. Virilization alone (51.6% or mixed with Cushing's syndrome (42.0% was the predominant clinical picture observed in these patients. Tumours are unilateral, affecting both glands equally. TP53 R337H germline mutations underlie most childhood ACTs in southern Brazil. Epidemiological data from our casuistic studies revealed that this mutation has ~10% penetrance for ACT. Surgery is the definitive treatment, and a complete resection should always be attempted. Although adjuvant chemotherapy has shown some encouraging results, its influence on overall outcome is small. The survival rate is directly correlated to tumour size; patients with small, completely excised tumours have survival rates close to 90%, whereas in those patients with inoperable tumours and/or metastatic disease it is less than 10%. In the group of patients with large, excisable tumours, half of them have an intermediate outcome. Recent molecular biology techniques and genomic approaches may help us to better understand the pathogenesis of ACT, the risk of developing a tumour when TP53 R337H is present, and to predict its outcome. An ongoing pilot study consisting of close monitoring of healthy carriers of the TP53 R337H mutation - siblings and first-degree relatives of known affected cases - aims at the early detection of ACTs and an improvement of the cure rate.

  12. Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging

    NARCIS (Netherlands)

    Sapir, Amir; Tsur, Assaf; Koorman, Thijs; Ching, Kaitlin; Mishra, Prashant; Bardenheier, Annabelle; Podolsky, Lisa; Bening-Abu-Shach, Ulrike; Boxem, Mike; Chou, Tsui-Fen; Broday, Limor; Sternberg, Paul W

    2014-01-01

    Many metabolic pathways are critically regulated during development and aging but little is known about the molecular mechanisms underlying this regulation. One key metabolic cascade in eukaryotes is the mevalonate pathway. It catalyzes the synthesis of sterol and nonsterol isoprenoids, such as

  13. Increasing patient involvement in the diabetic foot pathway: a pilot randomized controlled trial.

    Science.gov (United States)

    McBride, E; Hacking, B; O'Carroll, R; Young, M; Jahr, J; Borthwick, C; Callander, A; Berrada, Z

    2016-11-01

    This pilot study aimed to explore whether the use of an intervention to increase shared decision-making (Decision Navigation) increased decision self-efficacy and foot-treatment adherence in patients with a diabetic foot ulcer. Fifty-six patients with a diabetic foot ulcer were randomized to receive Decision Navigation (N = 30) or usual care (N = 26). Primary outcomes included decision self-efficacy, adherence to foot treatment as reported by the participant and adherence to foot treatment as reported by the clinician. Secondary outcomes included foot ulcer healing rate, health-related quality of life, decision conflict and decision regret. Despite participants rating Decision Navigation as very helpful, mixed analyses of variance revealed no differences in decision self-efficacy or adherence between those receiving Decision Navigation and those receiving usual care. There were no differences between groups with regards to the secondary outcomes, with the exception of decision conflict which increased over time (12 weeks) for those receiving Decision Navigation. An intervention that facilitated patient involvement in treatment decisions did not have any impact on decisional confidence or adherence to foot treatment. This does not provide support for the suggestion that personalized care can improve health-related outcomes at this progressed stage of the patient's disease trajectory. We suggest that the diabetic foot population may benefit from interventions aimed at increasing motivation to engage with care pathways, centred on challenging personal controllability beliefs. © 2016 Diabetes UK.

  14. Atypical PKC-iota Controls Stem Cell Expansion via Regulation of the Notch Pathway

    Directory of Open Access Journals (Sweden)

    In Kyoung Mah

    2015-11-01

    Full Text Available The number of stem/progenitor cells available can profoundly impact tissue homeostasis and the response to injury or disease. Here, we propose that an atypical PKC, Prkci, is a key player in regulating the switch from an expansion to a differentiation/maintenance phase via regulation of Notch, thus linking the polarity pathway with the control of stem cell self-renewal. Prkci is known to influence symmetric cell division in invertebrates; however a definitive role in mammals has not yet emerged. Using a genetic approach, we find that loss of Prkci results in a marked increase in the number of various stem/progenitor cells. The mechanism used likely involves inactivation and symmetric localization of NUMB, leading to the activation of NOTCH1 and its downstream effectors. Inhibition of atypical PKCs may be useful for boosting the production of pluripotent stem cells, multipotent stem cells, or possibly even primordial germ cells by promoting the stem cell/progenitor fate.

  15. The diversity of the pollen tube pathway in plants: towards an increasing control by the sporophyte

    Directory of Open Access Journals (Sweden)

    Jorge eLora

    2016-02-01

    Full Text Available Plants, unlike animals, alternate multicellular diploid and haploid generations in their life cycle. While this is widespread all along the plant kingdom, the size and autonomy of the diploid sporophyte and the haploid gametophyte generations vary along evolution. Vascular plants show an evolutionary trend towards a reduction of the gametophyte, reflected both in size and lifespan, together with an increasing dependence from the sporophyte. This has resulted in an overlooking of the importance of the gametophytic phase in the evolution of higher plants. This reliance on the sporophyte is most notorious along the pollen tube journey, where the male gametophytes have to travel a long way inside the sporophyte to reach the female gametophyte. Along evolution, there is a change in the scenery of the pollen tube pathway that favors pollen competition and selection. This trend, towards apparently making complicated what could be simple, appears to be related to an increasing control of the sporophyte over the gametophyte with implications for understanding plant evolution.

  16. A reverse signaling pathway downstream of Sema4A controls cell migration via Scrib.

    Science.gov (United States)

    Sun, Tianliang; Yang, Lida; Kaur, Harmandeep; Pestel, Jenny; Looso, Mario; Nolte, Hendrik; Krasel, Cornelius; Heil, Daniel; Krishnan, Ramesh K; Santoni, Marie-Josée; Borg, Jean-Paul; Bünemann, Moritz; Offermanns, Stefan; Swiercz, Jakub M; Worzfeld, Thomas

    2017-01-02

    Semaphorins comprise a large family of ligands that regulate key cellular functions through their receptors, plexins. In this study, we show that the transmembrane semaphorin 4A (Sema4A) can also function as a receptor, rather than a ligand, and transduce signals triggered by the binding of Plexin-B1 through reverse signaling. Functionally, reverse Sema4A signaling regulates the migration of various cancer cells as well as dendritic cells. By combining mass spectrometry analysis with small interfering RNA screening, we identify the polarity protein Scrib as a downstream effector of Sema4A. We further show that binding of Plexin-B1 to Sema4A promotes the interaction of Sema4A with Scrib, thereby removing Scrib from its complex with the Rac/Cdc42 exchange factor βPIX and decreasing the activity of the small guanosine triphosphatase Rac1 and Cdc42. Our data unravel a role for Plexin-B1 as a ligand and Sema4A as a receptor and characterize a reverse signaling pathway downstream of Sema4A, which controls cell migration. © 2017 Sun et al.

  17. The translational repressor Crc controls the Pseudomonas putida benzoate and alkane catabolic pathways using a multi-tier regulation strategy.

    Science.gov (United States)

    Hernández-Arranz, Sofía; Moreno, Renata; Rojo, Fernando

    2013-01-01

    Metabolically versatile bacteria usually perceive aromatic compounds and hydrocarbons as non-preferred carbon sources, and their assimilation is inhibited if more preferable substrates are available. This is achieved via catabolite repression. In Pseudomonas putida, the expression of the genes allowing the assimilation of benzoate and n-alkanes is strongly inhibited by catabolite repression, a process controlled by the translational repressor Crc. Crc binds to and inhibits the translation of benR and alkS mRNAs, which encode the transcriptional activators that induce the expression of the benzoate and alkane degradation genes respectively. However, sequences similar to those recognized by Crc in benR and alkS mRNAs exist as well in the translation initiation regions of the mRNA of several structural genes of the benzoate and alkane pathways, which suggests that Crc may also regulate their translation. The present results show that some of these sites are functional, and that Crc inhibits the induction of both pathways by limiting not only the translation of their transcriptional activators, but also that of genes coding for the first enzyme in each pathway. Crc may also inhibit the translation of a gene involved in benzoate uptake. This multi-tier approach probably ensures the rapid regulation of pathway genes, minimizing the assimilation of non-preferred substrates when better options are available. A survey of possible Crc sites in the mRNAs of genes associated with other catabolic pathways suggested that targeting substrate uptake, pathway induction and/or pathway enzymes may be a common strategy to control the assimilation of non-preferred compounds. © 2012 Society for Applied Microbiology and Blackwell Publishing Ltd.

  18. Implications of alternative assumptions regarding future air pollution control in scenarios similar to the Representative Concentration Pathways

    NARCIS (Netherlands)

    Chuwah, C.; van Noije, T.; van Vuuren, D.P.; Hazeleger, W.; Strunk, A.; Deetman, S.; Beltran, A.M.; van Vliet, J.

    2013-01-01

    The uncertain, future development of emissions of short-lived trace gases and aerosols forms a key factor for future air quality and climate forcing. The Representative Concentration Pathways (RCPs) only explore part of this range as they all assume that worldwide ambitious air pollution control

  19. A Novel Rac1-GSPT1 Signaling Pathway Controls Astrogliosis Following Central Nervous System Injury*

    Science.gov (United States)

    Ishii, Taiji; Shigyo, Michiko; Kohta, Masaaki; Kondoh, Takeshi; Kuboyama, Tomoharu; Uebi, Tatsuya; Hamada, Takeshi; Gutmann, David H.; Aiba, Atsu; Kohmura, Eiji; Tohda, Chihiro; Saito, Naoaki

    2017-01-01

    Astrogliosis (i.e. glial scar), which is comprised primarily of proliferated astrocytes at the lesion site and migrated astrocytes from neighboring regions, is one of the key reactions in determining outcomes after CNS injury. In an effort to identify potential molecules/pathways that regulate astrogliosis, we sought to determine whether Rac/Rac-mediated signaling in astrocytes represents a novel candidate for therapeutic intervention following CNS injury. For these studies, we generated mice with Rac1 deletion under the control of the GFAP (glial fibrillary acidic protein) promoter (GFAP-Cre;Rac1flox/flox). GFAP-Cre;Rac1flox/flox (Rac1-KO) mice exhibited better recovery after spinal cord injury and exhibited reduced astrogliosis at the lesion site relative to control. Reduced astrogliosis was also observed in Rac1-KO mice following microbeam irradiation-induced injury. Moreover, knockdown (KD) or KO of Rac1 in astrocytes (LN229 cells, primary astrocytes, or primary astrocytes from Rac1-KO mice) led to delayed cell cycle progression and reduced cell migration. Rac1-KD or Rac1-KO astrocytes additionally had decreased levels of GSPT1 (G1 to S phase transition 1) expression and reduced responses of IL-1β and GSPT1 to LPS treatment, indicating that IL-1β and GSPT1 are downstream molecules of Rac1 associated with inflammatory condition. Furthermore, GSPT1-KD astrocytes had cell cycle delay, with no effect on cell migration. The cell cycle delay induced by Rac1-KD was rescued by overexpression of GSPT1. Based on these results, we propose that Rac1-GSPT1 represents a novel signaling axis in astrocytes that accelerates proliferation in response to inflammation, which is one important factor in the development of astrogliosis/glial scar following CNS injury. PMID:27941025

  20. Targeted radiotherapy with 177 Lu-DOTA-TATE in athymic mice with induced pancreatic malignant tumours

    International Nuclear Information System (INIS)

    Murphy, M. A de; Pedraza L, M.; Rodriguez C, J.; Ferro F, G.; Murphy S, E.

    2006-01-01

    Malignant pancreas tumours induced in athymic mice are a good model for targeted radiotherapy. The objective of this research was to estimate pancreatic tumour absorbed radiation doses and to evaluate 177 Lu-DOTA-TATE as a therapeutic radiopharmaceutical that could be used in humans. AR42J murine pancreas cancer cells, which over-express somatostatin receptors, were injected in athymic mice and 20 days later the mean tumour size was 3.08 square cm (n=3). A mean of 86.3 MBq 177 Lu-DOTA-TATE, was injected in a tail vein and 19 days after therapy the size of the tumours was 0.81 square cm. There was a partial relapse and after 16 days, when sacrificed, the mean tumour size was 8.28 cubic cm. An epithelial and sarcoma mixed tumour in the kidney of one treated mouse was found. The tumour of the control mouse was 8.61 cubic cm when sacrificed 14 days after tumour induction. Radiotherapy estimates to the tumours was 35.9-39.7 Gy and the tumours might have been completely reduced with a second therapy dose. These preliminary studies justify further therapeutic and dosimetry estimations to ensure that Lu- 177 -DOTA-TATE will act as expected in man, considering kidney radiation. (Author)

  1. Endogenous biotin expression in renal and testicular tumours and literature review.

    Science.gov (United States)

    Fahmy, Nader; Woo, Mark; Alameldin, Mona; Lee, Joe King; MacDonald, Kyle; Goneau, Lee W; Cadieux, Peter; Burton, Jeremy; Pautler, Stephen

    2014-07-01

    The aim of this study was to examine endogenous biotin levels in tumour specimens collected from patients with renal and testicular tumours and compare them to the surrounding non-neoplastic surgical margin. Frozen samples were obtained from the Ontario Tumour Bank. Renal and testicular tumour tissue were included in this study. Normal tissue from the negative surgical margins of each tumour served as a control. Biotin detection in tissue specimens was determined using immunohistochemistry (IHC). Specimens collected from 56 patients (36 men and 20 women) were included in this study. Histopathology of the 52 renal tumours included 31 (60%) conventional type RCC, 5 (10%) chromophobe RCC, 5 (10%) papillary RCC, 1 (2%) oncocytoma and 10 (19%) upper tract urothelial carcinoma (UC). The 4 testicular tumours included 1 seminomatous (25%) germ cell tumour and 3 (75%) non seminomatous germ cell tumours. No biotin signal was perceived in all tested tumour samples. Endogenous biotin expression was detected in the matching non-neoplastic surgical margin of tested renal tissues. This lack of staining may prove to be a valuable tool in future studies.

  2. Metastatic behaviour of primary human tumours in a zebrafish xenotransplantation model

    International Nuclear Information System (INIS)

    Marques, Ines J; Bagowski, Christoph P; Weiss, Frank Ulrich; Vlecken, Danielle H; Nitsche, Claudia; Bakkers, Jeroen; Lagendijk, Anne K; Partecke, Lars Ivo; Heidecke, Claus-Dieter; Lerch, Markus M

    2009-01-01

    Aberrant regulation of cell migration drives progression of many diseases, including cancer cell invasion and metastasis formation. Analysis of tumour invasion and metastasis in living organisms to date is cumbersome and involves difficult and time consuming investigative techniques. For primary human tumours we establish here a simple, fast, sensitive and cost-effective in vivo model to analyse tumour invasion and metastatic behaviour. We fluorescently labelled small explants from gastrointestinal human tumours and investigated their metastatic behaviour after transplantation into zebrafish embryos and larvae. The transparency of the zebrafish embryos allows to follow invasion, migration and micrometastasis formation in real-time. High resolution imaging was achieved through laser scanning confocal microscopy of live zebrafish. In the transparent zebrafish embryos invasion, circulation of tumour cells in blood vessels, migration and micrometastasis formation can be followed in real-time. Xenografts of primary human tumours showed invasiveness and micrometastasis formation within 24 hours after transplantation, which was absent when non-tumour tissue was implanted. Furthermore, primary human tumour cells, when organotopically implanted in the zebrafish liver, demonstrated invasiveness and metastatic behaviour, whereas primary control cells remained in the liver. Pancreatic tumour cells showed no metastatic behaviour when injected into cloche mutant embryos, which lack a functional vasculature. Our results show that the zebrafish is a useful in vivo animal model for rapid analysis of invasion and metastatic behaviour of primary human tumour specimen

  3. Dopaminergic and Opioid Pathways Associated with Impulse Control Disorders in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Aleksander H. Erga

    2018-02-01

    Full Text Available IntroductionImpulse control disorders (ICDs are frequent non-motor symptoms in Parkinson’s disease (PD, with potential negative effects on the quality of life and social functioning. ICDs are closely associated with dopaminergic therapy, and genetic polymorphisms in several neurotransmitter pathways may increase the risk of addictive behaviors in PD. However, clinical differentiation between patients at risk and patients without risk of ICDs is still troublesome. The aim of this study was to investigate if genetic polymorphisms across several neurotransmitter pathways were associated with ICD status in patients with PD.MethodsWhole-exome sequencing data were available for 119 eligible PD patients from the Norwegian ParkWest study. All participants underwent comprehensive neurological, neuropsychiatric, and neuropsychological assessments. ICDs were assessed using the self-report short form version of the Questionnaire for Impulsive-Compulsive Disorders in PD. Single-nucleotide polymorphisms (SNPs from 17 genes were subjected to regression with elastic net penalization to identify candidate variants associated with ICDs. The area under the curve of receiver-operating characteristic curves was used to evaluate the level of ICD prediction.ResultsAmong the 119 patients with PD included in the analysis, 29% met the criteria for ICD and 63% were using dopamine agonists (DAs. Eleven SNPs were associated with ICDs, and the four SNPs with the most robust performance significantly increased ICD predictability (AUC = 0.81, 95% CI 0.73–0.90 compared to clinical data alone (DA use and age; AUC = 0.65, 95% CI 0.59–0.78. The strongest predictive factors were rs5326 in DRD1, which was associated with increased odds of ICDs, and rs702764 in OPRK1, which was associated with decreased odds of ICDs.ConclusionUsing an advanced statistical approach, we identified SNPs in nine genes, including a novel polymorphism in DRD1, with potential application for

  4. Imaging in unilateral Wilms tumour

    International Nuclear Information System (INIS)

    Brisse, Herve J.; Smets, Anne M.; Kaste, Sue C.; Owens, Catherine M.

    2008-01-01

    Wilms tumour is one of the most common malignancies in children, with an excellent prognosis after therapy. There is a very diverse approach to treatment according to geographical location. This variation in therapeutic attitude toward Wilms tumour, particularly between the United States and Europe, has consequences for the choice of imaging modality at diagnosis. In Europe, the International Society of Paediatric Oncology (SIOP) treatment protocol is based on chemotherapy followed by surgery. Imaging (US, CT and MRI), clinical history and examination will help predict whether the findings are consistent with Wilms tumour. Furthermore, in the UK preoperative image-guided biopsy is advised to help identify the small group of patients who, despite typical imaging features of Wilms tumour, have other types of neoplasia that require alternative management. In the United States, the National Wilms Tumor Study (NWTS) advises surgery prior to chemo- and radiotherapy. Hence imaging must provide detailed anatomical information for surgical planning. This article discusses the role of imaging at diagnosis and the relative strengths and weaknesses of the available radiological techniques. We also focus on imaging the lung for metastatic disease and the consequences (to the patient's ultimate outcome) of CT-diagnosed small pulmonary nodules and discuss the radiological diagnosis and consequences of tumour rupture present at diagnosis. (orig.)

  5. A non-Mendelian MAPK-generated hereditary unit controlled by a second MAPK pathway in Podospora anserina.

    Science.gov (United States)

    Lalucque, Hervé; Malagnac, Fabienne; Brun, Sylvain; Kicka, Sébastien; Silar, Philippe

    2012-06-01

    The Podospora anserina PaMpk1 MAP kinase (MAPK) signaling pathway can generate a cytoplasmic and infectious element resembling prions. When present in the cells, this C element causes the crippled growth (CG) cell degeneration. CG results from the inappropriate autocatalytic activation of the PaMpk1 MAPK pathway during growth, whereas this cascade normally signals stationary phase. Little is known about the control of such prion-like hereditary units involved in regulatory inheritance. Here, we show that another MAPK pathway, PaMpk2, is crucial at every stage of the fungus life cycle, in particular those controlled by PaMpk1 during stationary phase, which includes the generation of C. Inactivation of the third P. anserina MAPK pathway, PaMpk3, has no effect on the development of the fungus. Mutants of MAPK, MAPK kinase, and MAPK kinase kinase of the PaMpk2 pathway are unable to present CG. This inability likely relies upon an incorrect activation of PaMpk1, although this MAPK is normally phosphorylated in the mutants. In PaMpk2 null mutants, hyphae are abnormal and PaMpk1 is mislocalized. Correspondingly, stationary phase differentiations controlled by PaMpk1 are defective in the mutants of the PaMpk2 cascade. Constitutive activation of the PaMpk2 pathway mimics in many ways its inactivation, including an effect on PaMpk1 localization. Analysis of double and triple mutants inactivated for two or all three MAPK genes undercover new growth and differentiation phenotypes, suggesting overlapping roles. Our data underscore the complex regulation of a prion-like element in a model organism.

  6. Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers.

    Science.gov (United States)

    Cleary, Allison S; Leonard, Travis L; Gestl, Shelley A; Gunther, Edward J

    2014-04-03

    Cancer genome sequencing studies indicate that a single breast cancer typically harbours multiple genetically distinct subclones. As carcinogenesis involves a breakdown in the cell-cell cooperation that normally maintains epithelial tissue architecture, individual subclones within a malignant microenvironment are commonly depicted as self-interested competitors. Alternatively, breast cancer subclones might interact cooperatively to gain a selective growth advantage in some cases. Although interclonal cooperation has been shown to drive tumorigenesis in fruitfly models, definitive evidence for functional cooperation between epithelial tumour cell subclones in mammals is lacking. Here we use mouse models of breast cancer to show that interclonal cooperation can be essential for tumour maintenance. Aberrant expression of the secreted signalling molecule Wnt1 generates mixed-lineage mammary tumours composed of basal and luminal tumour cell subtypes, which purportedly derive from a bipotent malignant progenitor cell residing atop a tumour cell hierarchy. Using somatic Hras mutations as clonal markers, we show that some Wnt tumours indeed conform to a hierarchical configuration, but that others unexpectedly harbour genetically distinct basal Hras mutant and luminal Hras wild-type subclones. Both subclones are required for efficient tumour propagation, which strictly depends on luminally produced Wnt1. When biclonal tumours were challenged with Wnt withdrawal to simulate targeted therapy, analysis of tumour regression and relapse revealed that basal subclones recruit heterologous Wnt-producing cells to restore tumour growth. Alternatively, in the absence of a substitute Wnt source, the original subclones often evolve to rescue Wnt pathway activation and drive relapse, either by restoring cooperation or by switching to a defector strategy. Uncovering similar modes of interclonal cooperation in human cancers may inform efforts aimed at eradicating tumour cell communities.

  7. The prognostic significance of parapharyngeal tumour involvement in nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    Teo, P.Y.; Lee, W.; Yu, P.

    1996-01-01

    From 1984 to 1989, 903 treatment-naive non-disseminated nasopharyngeal carcinomas (NPCs) were given primary radical radiotherapy. All patients had computed tomographic and endoscopic evaluation of the primary tumour. Potentially significant parameters were analysed by both univariate and multivariate methods for independent significance. In the whole group of patients, the male sex, skull base and cranial nerve(s) involvement, advanced Ho N-level, presence of fixed or partially fixed nodes and nodes contralateral to the side of the bulk of the nasopharyngeal primary, significantly determined survival and distant metastasis rates, whereas skull base and cranial nerve involvement, advanced age and male sex significantly worsened local control. However in the Ho T2No subgroup, parapharyngeal tumour involvement was the most significant prognosticator that determined distant metastasis and survival rates in the absence of the overriding prognosticators of skull base infiltration, cranial nerve(s) palsy, and cervical nodal metastasis. The local tumour control of the Ho T2No was adversely affected by the presence of oropharyngeal tumour extension. The administration of booster radiotherapy (20 Gy) after conventional radiotherapy (60-62.5 Gy) in tumours with parapharyngeal involvement has led to an improvement in local control, short of statistical significance

  8. Pathways and Controls of N2O Production in Nitritation-Anammox Biomass

    DEFF Research Database (Denmark)

    Ma, Chun; Jensen, Marlene Mark; Smets, Barth F.

    2017-01-01

    to investigate pathways and controls of N2O production by biomass taken from a full-scale nitritation-anammox reactor. The experiments showed that heterotrophic denitrification was a negligible source of N2O under oxic conditions (≥0.2 mg O2 L-1). Both hydroxylamine oxidation and nitrifier denitrification...... of N2O production from hydroxylamine oxidation at low O2 was unexpected and suggests that more than one enzymatic pathway may be involved in this process. N2O production by hydroxylamine oxidation was further stimulated by NH4+, whereas nitrifier denitrification at low O2 levels was stimulated by NO2...

  9. Tocopherol in irradiation of temporary hypoxic tumours

    International Nuclear Information System (INIS)

    Kaagerud, A.; Lund, N.; Peterson, H.I.

    1981-01-01

    The influence of tocopherol on the effect of local irradiation under induced ischaemia by temporary tourniquet of two rat tumours transplanted intramuscularly into one hindleg was evaluated. An impaired retardation of growth rate occurred in tumours irradiated under ischaemia. This effect was eliminated by pretreatment of animals with tocopherol. In separate experiments the method of inducing ischaemia was investigated by MDO-electrode measurements of tumour tissue oxygen pressure. A significant tumour hypoxia was found under tourniquet of the tumour-bearing leg of the animals. Pretreatment with tocopherol did not influence the tumour pO 2 . (Auth.)

  10. Pitfalls in colour photography of choroidal tumours

    Science.gov (United States)

    Schalenbourg, A; Zografos, L

    2013-01-01

    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

  11. Pitfalls in colour photography of choroidal tumours.

    Science.gov (United States)

    Schalenbourg, A; Zografos, L

    2013-02-01

    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.

  12. Dual role of delay effects in a tumour-immune system.

    Science.gov (United States)

    Yu, Min; Dong, Yueping; Takeuchi, Yasuhiro

    2017-08-01

    In this paper, a previous tumour-immune interaction model is simplified by neglecting a relatively weak direct immune activation by the tumour cells, which can still keep the essential dynamics properties of the original model. As the immune activation process is not instantaneous, we now incorporate one delay for the activation of the effector cells (ECs) by helper T cells (HTCs) into the model. Furthermore, we investigate the stability and instability regions of the tumour-presence equilibrium state of the delay-induced system with respect to two parameters, the activation rate of ECs by HTCs and the HTCs stimulation rate by the presence of identified tumour antigens. We show the dual role of this delay that can induce stability switches exhibiting destabilization as well as stabilization of the tumour-presence equilibrium. Besides, our results reveal that an appropriate immune activation time delay plays a significant role in control of tumour growth.

  13. Control of Saccharomyces cerevisiae catalase T gene (CTT1) expression by nutrient supply via the RAS-cyclic AMP pathway.

    Science.gov (United States)

    Bissinger, P H; Wieser, R; Hamilton, B; Ruis, H

    1989-03-01

    In Saccharomyces cerevisiae, lack of nutrients triggers a pleiotropic response characterized by accumulation of storage carbohydrates, early G1 arrest, and sporulation of a/alpha diploids. This response is thought to be mediated by RAS proteins, adenylate cyclase, and cyclic AMP (cAMP)-dependent protein kinases. This study shows that expression of the S. cerevisiae gene coding for a cytoplasmic catalase T (CTT1) is controlled by this pathway: it is regulated by the availability of nutrients. Lack of a nitrogen, sulfur, or phosphorus source causes a high-level expression of the gene. Studies with strains with mutations in the RAS-cAMP pathway and supplementation of a rca1 mutant with cAMP show that CTT1 expression is under negative control by a cAMP-dependent protein kinase and that nutrient control of CTT1 gene expression is mediated by this pathway. Strains containing a CTT1-Escherichia coli lacZ fusion gene have been used to isolate mutants with mutations in the pathway. Mutants characterized in this investigation fall into five complementation groups. Both cdc25 and ras2 alleles were identified among these mutants.

  14. A cluster randomized controlled trial of a clinical pathway for hospital treatment of heart failure: study design and population

    Directory of Open Access Journals (Sweden)

    Gardini Andrea

    2007-11-01

    Full Text Available Abstract Background The hospital treatment of heart failure frequently does not follow published guidelines, potentially contributing to the high morbidity, mortality and economic cost of this disorder. Consequently the development of clinical pathways has the potential to reduce the current variability in care, enhance guideline adherence, and improve outcomes for patients. Despite enthusiasm and diffusion, the widespread acceptance of clinical pathways remain questionable because very little prospective controlled data demonstrated their effectiveness. The Experimental Prospective Study on the Effectiveness and Efficiency of the Implementation of Clinical Pathways was designed in order to conduct a rigorous evaluation of clinical pathways in hospital treatment of acute heart failure. The primary objective of the trial was to evaluate the effectiveness of the implementation of clinical pathways for hospital treatment of heart failure in Italian hospitals. Methods/design Two-arm, cluster-randomized trial. 14 community hospitals were randomized either to arm 1 (clinical pathway: appropriate use of practice guidelines and supplies of drugs and ancillary services, new organization and procedures, patient education, etc. or to arm 2 (no intervention, usual care. 424 patients sample (212 in each group, 80% of power at the 5% significance level (two-sided. The primary outcome measure is in-hospital mortality. We will also analyze the impact of the clinical pathways comparing the length and the appropriateness of the stay, the rate of unscheduled readmissions, the customers' satisfaction and the costs treating the patients with the pathways and with the current practice along all the observation period. The quality of the care will be assessed by monitoring the use of diagnostic and therapeutic procedures during hospital stay and by measuring key quality indicators at discharge. Discussion This paper examines the design of the evaluation of a complex

  15. In silico design and performance of peptide microarrays for breast cancer tumour-auto-antibody testing

    Directory of Open Access Journals (Sweden)

    Andreas Weinhäusel

    2012-06-01

    Full Text Available The simplicity and potential of minimally invasive testing using sera from patients makes auto-antibody based biomarkers a very promising tool for use in cancer diagnostics. Protein microarrays have been used for the identification of such auto-antibody signatures. Because high throughput protein expression and purification is laborious, synthetic peptides might be a good alternative for microarray generation and multiplexed analyses. In this study, we designed 1185 antigenic peptides, deduced from proteins expressed by 642 cDNA expression clones found to be sero-reactive in both breast tumour patients and controls. The sero-reactive proteins and the corresponding peptides were used for the production of protein and peptide microarrays. Serum samples from females with benign and malignant breast tumours and healthy control sera (n=16 per group were then analysed. Correct classification of the serum samples on peptide microarrays were 78% for discrimination of ‘malignant versus healthy controls’, 72% for ‘benign versus malignant’ and 94% for ‘benign versus controls’. On protein arrays, correct classification for these contrasts was 69%, 59% and 59%, respectively. The over-representation analysis of the classifiers derived from class prediction showed enrichment of genes associated with ribosomes, spliceosomes, endocytosis and the pentose phosphate pathway. Sequence analyses of the peptides with the highest sero-reactivity demonstrated enrichment of the zinc-finger domain. Peptides’ sero-reactivities were found negatively correlated with hydrophobicity and positively correlated with positive charge, high inter-residue protein contact energies and a secondary structure propensity bias. This study hints at the possibility of using in silico designed antigenic peptide microarrays as an alternative to protein microarrays for the improvement of tumour auto-antibody based diagnostics.

  16. The alternative complement pathway control protein H binds to immune complexes and serves their detection

    International Nuclear Information System (INIS)

    Nydegger, U.E.; Corvetta, A.; Spaeth, P.J.; Spycher, M.

    1983-01-01

    During solubilization of immune complexes C3b becomes fixed to the immunoglobulin part and serves as a receptor for the alternative complement pathway control protein H. The H-C3b immune complex interaction can be made detectable using 4% polyethyleneglycol to separate free from bound 125 I-H. Tetanus toxoid (Te)/anti-Te complexes kept soluble with fresh serum and containing 125 IU of specific antibody bound 18% of 125 I-H; when fresh serum was chelated with 10 mM EDTA, 125 I-H binding was only 5%. On sucrose density gradients, the H-binding material sedimented in the range of 12 to 30 S. In 36 serum samples from rheumatoid arthritis (RA) patients and in 12 serum samples from patients with systemic lupus erythematosus (SLE), 125 I-H binding was significantly elevated to 9.5 +/- 4.7% (mean +/- 1 SD) and 13.3 +/- 5.6%, respectively, while 125 I-H binding by 36 normal human sera was 4 +/- 2%. RA samples (17/36, 47%) and SLE samples (9/12, 75%) had H-binding values increased by more than 2 SD above the normal mean. The serum samples were also assessed for conglutinin- and C1q-binding activities; a significant correlation between H and C1q binding was observed (P less than 0.001); there was no correlation between H and conglutinin binding. Although binding to immune complexes through its interaction with C3b, H clearly detects a population of complexes other than conglutinin, thus expanding the possibilities of further characterizing pathological complexes

  17. Orexins control intestinal glucose transport by distinct neuronal, endocrine, and direct epithelial pathways.

    Science.gov (United States)

    Ducroc, Robert; Voisin, Thierry; El Firar, Aadil; Laburthe, Marc

    2007-10-01

    Orexins are neuropeptides involved in energy homeostasis. We investigated the effect of orexin A (OxA) and orexin B (OxB) on intestinal glucose transport in the rat. Injection of orexins led to a decrease in the blood glucose level in oral glucose tolerance tests (OGTTs). Effects of orexins on glucose entry were analyzed in Ussing chambers using the Na(+)-dependent increase in short-circuit current (Isc) to quantify jejunal glucose transport. The rapid and marked increase in Isc induced by luminal glucose was inhibited by 10 nmol/l OxA or OxB (53 and 59%, respectively). Response curves to OxA and OxB were not significantly different with half-maximal inhibitory concentrations at 0.9 and 0.4 nmol/l, respectively. On the one hand, OxA-induced inhibition of Isc was reduced by the neuronal blocker tetrodotoxin (TTX) and by a cholecystokinin (CCK) 2R antagonist, indicating involvement of neuronal and endocrine CCK-releasing cells. The OX(1)R antagonist SB334867 had no effect on OxA-induced inhibition, which is likely to occur via a neuronal and/or endocrine OX(2)R. On the other hand, SB334867 induced a significant right shift of the concentration-effect curve for OxB. This OxB-preferring OX(1)R pathway was not sensitive to TTX or to CCKR antagonists, suggesting that OxB may act directly on enterocytic OX(1)R. These distinct effects of OxA and OxB are consistent with the expression of OX(1)R and OX(2)R mRNA in the epithelial and nonepithelial tissues, respectively. Our data delineate a new function for orexins as inhibitors of intestinal glucose absorption and provide a new basis for orexin-induced short-term control of energy homeostasis.

  18. Nuclear hBD-1 accumulation in malignant salivary gland tumours

    International Nuclear Information System (INIS)

    Wenghoefer, M; Merkelbach-Bruse, S; Fischer, HP; Novak, N; Winter, J; Pantelis, A; Dommisch, H; Götz, W; Reich, R; Bergé, S; Martini, M; Allam, JP; Jepsen, S

    2008-01-01

    Whereas the antimicrobial peptides hBD-2 and -3 are related to inflammation, the constitutively expressed hBD-1 might function as 8p tumour suppressor gene and thus play a key role in control of transcription and induction of apoptosis in malignant epithelial tumours. Therefore this study was conducted to characterise proteins involved in cell cycle control and host defence in different benign and malignant salivary gland tumours in comparison with healthy salivary gland tissue. 21 paraffin-embedded tissue samples of benign (n = 7), and malignant (n = 7) salivary gland tumours as well as healthy (n = 7) salivary glands were examined immunohistochemically for the expression of p53, bcl-2, and hBD-1, -2, -3. HBD-1 was distributed in the cytoplasm of healthy salivary glands and benign salivary gland tumours but seems to migrate into the nucleus of malignant salivary gland tumours. Pleomorphic adenomas showed cytoplasmic as well as weak nuclear hBD-1 staining. HBD-1, 2 and 3 are traceable in healthy salivary gland tissue as well as in benign and malignant salivary gland tumours. As hBD-1 is shifted from the cytoplasm to the nucleus in malignant salivary gland tumours, we hypothesize that it might play a role in the oncogenesis of these tumours. In pleomorphic adenomas hBD-1 might be connected to their biologic behaviour of recurrence and malignant transformation

  19. A critical role of platelet TGF-β release in podoplanin-mediated tumour invasion and metastasis.

    Science.gov (United States)

    Takemoto, Ai; Okitaka, Mina; Takagi, Satoshi; Takami, Miho; Sato, Shigeo; Nishio, Makoto; Okumura, Sakae; Fujita, Naoya

    2017-02-08

    The tumour microenvironment is critical for various characteristics of tumour malignancies. Platelets, as part of the tumour microenvironment, are associated with metastasis formation via increasing the rate of tumour embolus formation in microvasculature. However, the mechanisms underlying the ability of tumour cells to acquire invasiveness and extravasate into target organs at the site of embolization remain unclear. In this study, we reported that platelet aggregation-inducing factor podoplanin expressed on tumour cell surfaces were found to not only promote the formation of tumour-platelet aggregates via interaction with platelets, but also induced the epithelial-mesenchymal transition (EMT) of tumour cells by enhancing transforming growth factor-β (TGF-β) release from platelets. In vitro and in vivo analyses revealed that podoplanin-mediated EMT resulted in increased invasiveness and extravasation of tumour cells. Treatment of mice with a TGF-β-neutralizing antibody statistically suppressed podoplanin-mediated distant metastasis in vivo, suggesting that podoplanin promoted haematogenous metastasis in part by releasing TGF-β from platelets that was essential for EMT of tumour cells. Therefore, our findings suggested that blocking the TGF-β signalling pathway might be a promising strategy for suppressing podoplanin-mediated haematogenous metastasis in vivo.

  20. Identification of Alternative Vapor Intrusion Pathways Using Controlled Pressure Testing, Soil Gas Monitoring, and Screening Model Calculations.

    Science.gov (United States)

    Guo, Yuanming; Holton, Chase; Luo, Hong; Dahlen, Paul; Gorder, Kyle; Dettenmaier, Erik; Johnson, Paul C

    2015-11-17

    Vapor intrusion (VI) pathway assessment and data interpretation have been guided by an historical conceptual model in which vapors originating from contaminated soil or groundwater diffuse upward through soil and are swept into a building by soil gas flow induced by building underpressurization. Recent studies reveal that alternative VI pathways involving neighborhood sewers, land drains, and other major underground piping can also be significant VI contributors, even to buildings beyond the delineated footprint of soil and groundwater contamination. This work illustrates how controlled-pressure-method testing (CPM), soil gas sampling, and screening-level emissions calculations can be used to identify significant alternative VI pathways that might go undetected by conventional sampling under natural conditions at some sites. The combined utility of these tools is shown through data collected at a long-term study house, where a significant alternative VI pathway was discovered and altered so that it could be manipulated to be on or off. Data collected during periods of natural and CPM conditions show that the alternative pathway was significant, but its presence was not identifiable under natural conditions; it was identified under CPM conditions when measured emission rates were 2 orders of magnitude greater than screening-model estimates and subfoundation vertical soil gas profiles changed and were no longer consistent with the conventional VI conceptual model.

  1. The pain, depression, disability pathway in those with low back pain: a moderation analysis of health locus of control.

    Science.gov (United States)

    Campbell, Paul; Hope, Kate; Dunn, Kate M

    2017-01-01

    Low back pain (LBP) is common, impacts on the individual and society, and is a major health concern. Psychological consequences of LBP, such as depression, are significant barriers to recovery, but mechanisms for the development of depression are less well understood. One potential mechanism is the individual's health locus of control (HLoC), that is, perception of the level of control an individual has over their health. The objective of this study is to investigate the moderation effect of HLoC on the pain-depression-disability pathway in those with LBP. The design is a nested cross-sectional analysis of two existing cohorts of patients (n=637) who had previously consulted their primary care physician about LBP. Measures were taken of HLoC, pain intensity and interference, depression, disability, and bothersomeness. Structural Equation Modeling analysis was applied to two path models that examined the pain to depression to disability pathway moderated by the HLoC constructs of Internality and Externality, respectively. Critical ratio (CR) difference tests were applied to the coefficients using pairwise comparisons. The results show that both models had an acceptable model fit and pathways were significant. CR tests indicated a significant moderation effect, with stronger pathway coefficients for depression for those who report low Internality (β 0.48), compared to those with high Internality (β 0.28). No moderation effects were found within the Externality model. HLoC Internality significantly moderates the pain-depression pathway in those with LBP, meaning that those who have a low perception of control report greater levels of depression. HLoC may signify depression among people with LBP, and could potentially be a target for intervention.

  2. Detection of apoptotic cells in tumour paraffin sections

    International Nuclear Information System (INIS)

    Pizem, J.; Coer, A.

    2003-01-01

    Apoptosis is a distinct form of cell death characterised by specific morphological features and regulated by complex molecular mechanisms. Its deregulation is fundamental for tumour growth and progression and, moreover, anticancer therapies suppress tumour growth mainly by induction of apoptosis. Since the extent of apoptosis in a tumour may have prognostic as well as therapeutic implications, much effort has been invested in developing specific methods that can be routinely used to detect apoptotic cells in archival formalin- fixed paraffin-embedded tissue. Complex molecular pathways are involved in the regulation of apoptosis. Pro-apoptotic signals trigger activation of caspases that specifically cleave target proteins. Cleavage of proteins (caspase substrates) is responsible for morphological changes of apoptotic cells and DNA fragmentation. In the last decade, detection of apoptotic cells in formalin-fixed tumour tissue sections has been based mainly on morphology and characteristic DNA fragmentation. Recently, specific antibodies to activated caspases and cleaved target proteins (including cytokeratin 18, actin and PARP) have been produced that enable accurate detection of apoptosis in paraffin sections. (author)

  3. A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours.

    Science.gov (United States)

    Mercado-Lubo, Regino; Zhang, Yuanwei; Zhao, Liang; Rossi, Kyle; Wu, Xiang; Zou, Yekui; Castillo, Antonio; Leonard, Jack; Bortell, Rita; Greiner, Dale L; Shultz, Leonard D; Han, Gang; McCormick, Beth A

    2016-07-25

    Salmonella enterica serotype Typhimurium is a food-borne pathogen that also selectively grows in tumours and functionally decreases P-glycoprotein (P-gp), a multidrug resistance transporter. Here we report that the Salmonella type III secretion effector, SipA, is responsible for P-gp modulation through a pathway involving caspase-3. Mimicking the ability of Salmonella to reverse multidrug resistance, we constructed a gold nanoparticle system packaged with a SipA corona, and found this bacterial mimic not only accumulates in tumours but also reduces P-gp at a SipA dose significantly lower than free SipA. Moreover, the Salmonella nanoparticle mimic suppresses tumour growth with a concomitant reduction in P-gp when used with an existing chemotherapeutic drug (that is, doxorubicin). On the basis of our finding that the SipA Salmonella effector is fundamental for functionally decreasing P-gp, we engineered a nanoparticle mimic that both overcomes multidrug resistance in cancer cells and increases tumour sensitivity to conventional chemotherapeutics.

  4. Spatio-temporal cell dynamics in tumour spheroid irradiation

    International Nuclear Information System (INIS)

    Kempf, H.; Bleicher, M.; Meyer-Hermann, M.; Kempf, H.; Bleicher, M.; Kempf, H.; Meyer-Hermann, M.

    2010-01-01

    Multicellular tumour spheroids are realistic in vitro systems in radiation research that integrate cell-cell interaction and cell cycle control by factors in the medium. The dynamic reaction inside a tumour spheroid triggered by radiation is not well understood. Of special interest is the amount of cell cycle synchronization which could be triggered by irradiation, since this would allow follow-up irradiations to exploit the increased sensitivity of certain cell cycle phases. In order to investigate these questions we need to support irradiation experiments with mathematical models. In this article a new model is introduced combining the dynamics of tumour growth and irradiation treatments. The tumour spheroid growth is modelled using an agent-based Delaunay/Voronoi hybrid model in which the cells are represented by weighted dynamic vertices. Cell properties like full cell cycle dynamics are included. In order to be able to distinguish between different cell reactions in response to irradiation quality we introduce a probabilistic model for damage dynamics. The overall cell survival from this model is in agreement with predictions from the linear-quadratic model. Our model can describe the growth of avascular tumour spheroids in agreement to experimental results. Using the probabilistic model for irradiation damage dynamics the classic 'four Rs' of radiotherapy can be studied in silico. We found a pronounced reactivation of the tumour spheroid in response to irradiation. A majority of the surviving cells is synchronized in their cell cycle progression after irradiation. The cell synchronization could be actively triggered and should be exploited in an advanced fractionation scheme. Thus it has been demonstrated that our model could be used to understand the dynamics of tumour growth after irradiation and to propose optimized fractionation schemes in cooperation with experimental investigations. (authors)

  5. Optical angular constancy is maintained as a navigational control strategy when pursuing robots moving along complex pathways.

    Science.gov (United States)

    Wang, Wei; McBeath, Michael K; Sugar, Thomas G

    2015-03-24

    The optical navigational control strategy used to intercept moving targets was explored using a real-world object that travels along complex, evasive pathways. Fielders ran across a gymnasium attempting to catch a moving robot that varied in speed and direction, while ongoing position was measured using an infrared motion-capture system. Fielder running paths were compared with the predictions of three lateral control models, each based on maintaining a particular optical angle relative to the robotic target: (a) constant alignment angle (CAA), (b) constant eccentricity angle (CEA), and (c) linear optical trajectory (LOT). Findings reveal that running pathways were most consistent with maintenance of LOT and least consistent with CEA. This supports that fielders use the same optical control strategy of maintaining angular constancy using a LOT when navigating toward targets moving along complex pathways as when intercepting simple ballistic trajectories. In those cases in which a target dramatically deviates from its optical path, fielders appear to simply reset LOT parameters using a new constant angle value. Maintenance of such optical angular constancy has now been shown to work well with ballistic, complex, and evasive moving targets, confirming the LOT strategy as a robust, general-purpose optical control mechanism for navigating to intercept catchable targets, both airborne and ground based. © 2015 ARVO.

  6. Expression of p16(INK4A) gene in human pituitary tumours.

    Science.gov (United States)

    Machiavelli, Gloria; Cotignola, Javier; Danilowicz, Karina; Carbonara, Carolina; Paes de Lima, Andrea; Basso, Armando; Bruno, Oscar Domingo; Szijan, Irene

    2008-01-01

    Pituitary adenomas comprise 10-15% of primary intracranial tumours but the mechanisms leading to tumour development are yet to be clearly established. The retinoblastoma pathway, which regulates the progression through the cell cycle, is often deregulated in different types of tumours. We studied the cyclin-dependent kinase inhibitor p16(INK4A) gene expression at mRNA level in human pituitary adenomas. Forty-six tumour specimens of different subtypes, 21 clinically non-functioning, 12 growth hormone-secreting, 6 prolactin-secreting, 6 adrenocorticotropin-secreting, and 1 thyrotropin-secreting tumours were studied. All clinically non-functioning and most of the hormone-secreting tumours were macroadenomas (38/46). The RT-PCR assay and electrophoresis of the PCR-products showed that p16(INK4A) mRNA was undetectable in: 62% of non-functioning, 8% of growth hormone-secreting, 17% of prolactin-secreting and 17% of adrenocorticotropin-secreting adenomas. Forty percent of all macroadenomas and 25% of microadenomas had negative p16(INK4A) mRNA, the latter results suggest that the absence of p16(INK4A) product might be an early event in tumours with no expression of this suppressor gene. Within the non-functioning adenomas 63% were "null cell" and 37% were positive for some hormone, both subgroups showed similar percentage of cases with absence of p16(INK4A) mRNA. Our results show that clinically non-functioning macroadenomas have impaired p16(INK4A) expression in a clearly higher proportion than any other pituitary tumour subtype investigated. Other regulatory pathways may be implicated in the development of tumours with positive p16(INK4A) expression.

  7. Tumour markers in gynaecological practice

    International Nuclear Information System (INIS)

    Adewole, I.F.

    1999-02-01

    Gynaecological cancers are fairly common in developing countries and represent about 26 % f all cancers. Application of cervical cytology screening nationally has made cervical cancer one of the most preventable malignant diseases thus eliminating the challenges of advanced cancer management. Tumour markers has played a most crucial role in this respect

  8. Pancreatic cancer circulating tumour cells express a cell motility gene signature that predicts survival after surgery

    International Nuclear Information System (INIS)

    Sergeant, Gregory; Eijsden, Rudy van; Roskams, Tania; Van Duppen, Victor; Topal, Baki

    2012-01-01

    Most cancer deaths are caused by metastases, resulting from circulating tumor cells (CTC) that detach from the primary cancer and survive in distant organs. The aim of the present study was to develop a CTC gene signature and to assess its prognostic relevance after surgery for pancreatic ductal adenocarcinoma (PDAC). Negative depletion fluorescence activated cell sorting (FACS) was developed and validated with spiking experiments using cancer cell lines in whole human blood samples. This FACS-based method was used to enrich for CTC from the blood of 10 patients who underwent surgery for PDAC. Total RNA was isolated from 4 subgroup samples, i.e. CTC, haematological cells (G), original tumour (T), and non-tumoural pancreatic control tissue (P). After RNA quality control, samples of 6 patients were eligible for further analysis. Whole genome microarray analysis was performed after double linear amplification of RNA. ‘Ingenuity Pathway Analysis’ software and AmiGO were used for functional data analyses. A CTC gene signature was developed and validated with the nCounter system on expression data of 78 primary PDAC using Cox regression analysis for disease-free (DFS) and overall survival (OS). Using stringent statistical analysis, we retained 8,152 genes to compare expression profiles of CTC vs. other subgroups, and found 1,059 genes to be differentially expressed. The pathway with the highest expression ratio in CTC was p38 mitogen-activated protein kinase (p38 MAPK) signaling, known to be involved in cancer cell migration. In the p38 MAPK pathway, TGF-β1, cPLA2, and MAX were significantly upregulated. In addition, 9 other genes associated with both p38 MAPK signaling and cell motility were overexpressed in CTC. High co-expression of TGF-β1 and our cell motility panel (≥ 4 out of 9 genes for DFS and ≥ 6 out of 9 genes for OS) in primary PDAC was identified as an independent predictor of DFS (p=0.041, HR (95% CI) = 1.885 (1.025 – 3.559)) and OS (p=0.047, HR

  9. Nuclear hBD-1 accumulation in malignant salivary gland tumours.

    NARCIS (Netherlands)

    Wenghoefer, M.H.; Pantelis, A.; Dommisch, H.; Gotz, W.; Reich, R.; Berge, S.J.; Martini, M.; Allam, J.P.; Jepsen, S.; Merkelbach-Bruse, S.; Fischer, H.P.; Novak, N.; Winter, J.

    2008-01-01

    BACKGROUND: Whereas the antimicrobial peptides hBD-2 and -3 are related to inflammation, the constitutively expressed hBD-1 might function as 8p tumour suppressor gene and thus play a key role in control of transcription and induction of apoptosis in malignant epithelial tumours. Therefore this

  10. Presentation of a salivary tumour si mil primitive lung with metastases of carcinoid tumour of the colon

    International Nuclear Information System (INIS)

    Cataldi, S.; Ximenez; Carzoglio, J.

    2010-01-01

    ductal myoepithelial structure and chondroid and myxoid matrix. Generally they behave as low-grade malignant neoplasms with a long interval between diagnosis and the development of local recurrence or distant metastasis. The standard treatment It is surgical resection. Controls should be kept long term given the possibility of behavior biologically aggressive. Conclusions: Both carcinoid tumours of the colon and lung primary simile salivary tumours are uncommon. It is essential the correct histologic diagnosis of this unusual lung histology to implement treatment right. To our knowledge this is the first report of these two uncommon histologies in the same patient. A purpose of the communication of the case of our patient we review the literature

  11. Mohs micrographic surgery of rare cutaneous tumours

    NARCIS (Netherlands)

    Flohil, S.C.; Lee, C.B. van; Beisenherz, J.; Mureau, M.A.M.; Overbeek, L.I.H.; Nijsten, T.; Bos, R.R.

    2017-01-01

    BACKGROUND: Recurrence rates after Mohs micrographic surgery (MMS) for rare cutaneous tumours are poorly defined. OBJECTIVE: To investigate the recurrence rate after MMS for rare cutaneous tumours at a university centre. METHODS & MATERIALS: Retrospective review of all rare cutaneous tumours treated

  12. Multiple Signaling Pathways Coordinately Regulate Forgetting of Olfactory Adaptation through Control of Sensory Responses in Caenorhabditis elegans.

    Science.gov (United States)

    Kitazono, Tomohiro; Hara-Kuge, Sayuri; Matsuda, Osamu; Inoue, Akitoshi; Fujiwara, Manabi; Ishihara, Takeshi

    2017-10-18

    Forgetting memories is important for animals to properly respond to continuously changing environments. To elucidate the mechanisms of forgetting, we used one of the behavioral plasticities of Caenorhabditis elegans hermaphrodite, olfactory adaptation to an attractive odorant, diacetyl, as a simple model of learning. In C. elegans, the TIR-1/JNK-1 pathway accelerates forgetting of olfactory adaptation by facilitating neural secretion from AWC sensory neurons. In this study, to identify the downstream effectors of the TIR-1/JNK-1 pathway, we conducted a genetic screen for suppressors of the gain-of-function mutant of tir-1 ( ok1052 ), which shows excessive forgetting. Our screening showed that three proteins-a membrane protein, MACO-1; a receptor tyrosine kinase, SCD-2; and its putative ligand, HEN-1-regulated forgetting downstream of the TIR-1/JNK-1 pathway. We further demonstrated that MACO-1 and SCD-2/HEN-1 functioned in parallel genetic pathways, and only MACO-1 regulated forgetting of olfactory adaptation to isoamyl alcohol, which is an attractive odorant sensed by different types of sensory neurons. In olfactory adaptation, odor-evoked Ca 2+ responses in olfactory neurons are attenuated by conditioning and recovered thereafter. A Ca 2+ imaging study revealed that this attenuation is sustained longer in maco-1 and scd-2 mutant animals than in wild-type animals like the TIR-1/JNK-1 pathway mutants. Furthermore, temporal silencing by histamine-gated chloride channels revealed that the neuronal activity of AWC neurons after conditioning is important for proper forgetting. We propose that distinct signaling pathways, each of which has a specific function, may coordinately and temporally regulate forgetting by controlling sensory responses. SIGNIFICANCE STATEMENT Active forgetting is an important process to understand the whole mechanisms of memories. Recent papers have reported that the noncell autonomous regulations are required for proper forgetting in

  13. Sensitivity analysis of intracellular signaling pathway kinetics predicts targets for stem cell fate control.

    Directory of Open Access Journals (Sweden)

    Alborz Mahdavi

    2007-07-01

    Full Text Available Directing stem cell fate requires knowledge of how signaling networks integrate temporally and spatially segregated stimuli. We developed and validated a computational model of signal transducer and activator of transcription-3 (Stat3 pathway kinetics, a signaling network involved in embryonic stem cell (ESC self-renewal. Our analysis identified novel pathway responses; for example, overexpression of the receptor glycoprotein-130 results in reduced pathway activation and increased ESC differentiation. We used a systematic in silico screen to identify novel targets and protein interactions involved in Stat3 activation. Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation is regulated by balancing the activation state of a distributed set of parameters including nuclear export of Stat3, nuclear phosphatase activity, inhibition by suppressor of cytokine signaling, and receptor trafficking. This knowledge was used to devise a temporally modulated ligand delivery strategy that maximizes signaling activation and leads to enhanced ESC self-renewal.

  14. Identification of Achaete-scute complex-like 1 (ASCL1) target genes and evaluation of DKK1 and TPH1 expression in pancreatic endocrine tumours

    International Nuclear Information System (INIS)

    Johansson, Térèse A; Westin, Gunnar; Skogseid, Britt

    2009-01-01

    ASCL1 role in pancreatic endocrine tumourigenesis has not been established. Recently it was suggested that ASCL1 negatively controls expression of the Wnt signalling antagonist DKK1. Notch signalling regulates expression of TPH1, the rate limiting enzyme in the biosyntesis of serotonin. Understanding the development and proliferation of pancreatic endocrine tumours (PETs) is essential for the development of new therapies. ASCL1 target genes in the pancreatic endocrine tumour cell line BON1 were identified by RNA interference and microarray expression analysis. Protein expressions of selected target genes in PETs were evaluated by immunohistochemistry. 158 annotated ASCL1 target genes were identified in BON1 cells, among them DKK1 and TPH1 that were negatively regulated by ASCL1. An inverse relation of ASCL1 to DKK1 protein expression was observed for 15 out of 22 tumours (68%). Nine tumours displayed low ASCL1/high DKK1 and six tumours high ASCL1/low DKK1 expression. Remaining PETs showed high ASCL1/high DKK1 (n = 4) or low ASCL1/low DKK1 (n = 3) expression. Nine of twelve analysed PETs (75%) showed TPH1 expression with no relation to ASCL1. A number of genes with potential importance for PET tumourigenesis have been identified. ASCL1 negatively regulated the Wnt signalling antagonist DKK1, and TPH1 expression in BON1 cells. In concordance with these findings DKK1 showed an inverse relation to ASCL1 expression in a subset of PETs, which may affect growth control by the Wnt signalling pathway

  15. Therapeutic effects of date fruits (Phoenix dactylifera) in the prevention of diseases via modulation of anti-inflammatory, anti-oxidant and anti-tumour activity.

    Science.gov (United States)

    Rahmani, Arshad H; Aly, Salah M; Ali, Habeeb; Babiker, Ali Y; Srikar, Sauda; Khan, Amjad A

    2014-01-01

    The current mode of treatment of various diseases based on synthetic drugs is expensive, alters genetic and metabolic pathways and also shows adverse side effects. Thus, safe and effective approach is needed to prevent the diseases development and progression. In this vista, Natural products are good remedy in the treatment/management of diseases and they are affordable and effective without any adverse effects. Dates are main fruit in the Arabian Peninsula and are considered to be one of the most significant commercial crops and also have been documented in Holy Quran and modern scientific literatures. Earlier studies have shown that constituents of dates act as potent antioxidant, anti-tumour as well as anti-inflammatory, provide a suitable alternative therapy in various diseases cure. In this review, dates fruits has medicinal value are summarized in terms of therapeutic implications in the diseases control through anti-oxidant, anti-inflammatory, anti-tumour and ant-diabetic effect.

  16. Wilms tumour: prognostic factors, staging, therapy and late effects

    International Nuclear Information System (INIS)

    Kaste, Sue C.; Dome, Jeffrey S.; Babyn, Paul S.; Graf, Norbert M.; Grundy, Paul; Godzinski, Jan; Levitt, Gill A.; Jenkinson, Helen

    2008-01-01

    Wilms tumour is the most common malignant renal tumour in children. Dramatic improvements in survival have occurred as the result of advances in anaesthetic and surgical management, irradiation and chemotherapy. Current therapies are based on trials and studies primarily conducted by large multi-institutional cooperatives including the Societe Internationale d'Oncologie Pediatrique (SIOP) and the Children's Oncology Group (COG). The primary goals are to treat patients according to well-defined risk groups in order to achieve the highest cure rates, to decrease the frequency and intensity of acute and late toxicity and to minimize the cost of therapy. The SIOP trials and studies largely focus on the issue of preoperative therapy, whereas the COG trials and studies start with primary surgery. This paper reviews prognostic factors and staging systems for Wilms tumour and its current treatment with surgery and chemotherapy. Surgery remains a crucial part of treatment for nephroblastoma, providing local primary tumour control and adequate staging and possibly controlling the metastatic spread and central vascular extension of the disease. Partial nephrectomy, when technically feasible, seems reasonable not only in those with bilateral disease but also in those with unilateral disease where the patient has urological disorders or syndromes predisposing to malignancy. Partial nephrectomy, however, is frequently not sufficient for an anaplastic variant of tumour. The late effects for Wilms tumour and its treatment are also reviewed. The treatment of Wilms tumour has been a success story, and currently in excess of 80% of children diagnosed with Wilms tumour can look forward to long-term survival, with less than 20% experiencing serious morbidity at 20 years from diagnosis. The late complications are a consequence of the type and intensity of treatment required, which in turn reflects the nature and extent of the original tumour. Continual international trial development

  17. Wilms tumour: prognostic factors, staging, therapy and late effects

    Energy Technology Data Exchange (ETDEWEB)

    Kaste, Sue C. [St. Jude Children' s Research Hospital, Department of Radiological Sciences, Memphis, TN (United States); Dome, Jeffrey S. [St. Jude Children' s Research Hospital, Department of Oncology, Memphis, TN (United States); Babyn, Paul S. [Hospital for Sick Children, Department of Radiology, Toronto (Canada); Graf, Norbert M. [University Hospital of the Saarland, Clinic for Pediatric Oncology and Hematology, Homburg (Germany); Grundy, Paul [University of Alberta, Division of Pediatric Hematology, Oncology and Palliative Care, and Northern Alberta Children' s Cancer Program, Edmonton (Canada); Godzinski, Jan [Mother and Child Institute, Department of Oncological Surgery for Children and Adolescents, Warsaw (Poland); Levitt, Gill A. [Great Ormond Street Hospital for Sick Children NHS Trust, Paediatric Oncology, London (United Kingdom); Jenkinson, Helen [Birmingham Children' s Hospital NHS Trust, Oncology Department, Birmingham (United Kingdom)

    2008-01-15

    Wilms tumour is the most common malignant renal tumour in children. Dramatic improvements in survival have occurred as the result of advances in anaesthetic and surgical management, irradiation and chemotherapy. Current therapies are based on trials and studies primarily conducted by large multi-institutional cooperatives including the Societe Internationale d'Oncologie Pediatrique (SIOP) and the Children's Oncology Group (COG). The primary goals are to treat patients according to well-defined risk groups in order to achieve the highest cure rates, to decrease the frequency and intensity of acute and late toxicity and to minimize the cost of therapy. The SIOP trials and studies largely focus on the issue of preoperative therapy, whereas the COG trials and studies start with primary surgery. This paper reviews prognostic factors and staging systems for Wilms tumour and its current treatment with surgery and chemotherapy. Surgery remains a crucial part of treatment for nephroblastoma, providing local primary tumour control and adequate staging and possibly controlling the metastatic spread and central vascular extension of the disease. Partial nephrectomy, when technically feasible, seems reasonable not only in those with bilateral disease but also in those with unilateral disease where the patient has urological disorders or syndromes predisposing to malignancy. Partial nephrectomy, however, is frequently not sufficient for an anaplastic variant of tumour. The late effects for Wilms tumour and its treatment are also reviewed. The treatment of Wilms tumour has been a success story, and currently in excess of 80% of children diagnosed with Wilms tumour can look forward to long-term survival, with less than 20% experiencing serious morbidity at 20 years from diagnosis. The late complications are a consequence of the type and intensity of treatment required, which in turn reflects the nature and extent of the original tumour. Continual international trial

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

    LENUS (Irish Health Repository)

    Tan, B

    2012-02-03

    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

  19. Quantitative MR imaging and spectroscopy of brain tumours: a step forward?

    Energy Technology Data Exchange (ETDEWEB)

    Wagnerova, Dita; Herynek, Vit; Dezortova, Monika; Jiru, Filip; Skoch, Antonin; Hajek, Milan [Institute for Clinical and Experimental Medicine, Department of Diagnostic and Interventional Radiology, Prague (Czech Republic); Malucelli, Alberto; Bartos, Robert; Sames, Martin [JE Purkyne University and Masaryk Hospital, Department of Neurosurgery, Usti nad Labem (Czech Republic); Vymazal, Josef [Na Homolce Hospital, Department of Radiology, Prague (Czech Republic); Urgosik, Dusan [Na Homolce Hospital, Stereotactic and Radiation Neurosurgery, Prague (Czech Republic); Syrucek, Martin [Na Homolce Hospital, Department of Pathology, Prague (Czech Republic)

    2012-11-15

    A prospective quantitative MR study of brain tumours was performed to show the potential of combining different MR techniques to distinguish various disease processes in routine clinical practice. Twenty-three patients with various intracranial tumours before treatment (diagnosis confirmed by a biopsy) and 59 healthy subjects were examined on a 3-T system by conventional MR imaging, 1H spectroscopic imaging, diffusion tensor imaging and T2 relaxometry. Metabolic concentrations and their ratios, T2 relaxation times and mean diffusivities were calculated and correlated on a pixel-by-pixel basis and compared to control data. Different tumour types and different localisations revealed specific patterns of correlations between metabolic concentrations and mean diffusivity or T2 relaxation times. The patterns distinguish given tissue states in the examined area: healthy tissue, tissue infiltrated by tumour, active tumour, oedema infiltrated by tumour, oedema, etc. This method is able to describe the complexity of a highly heterogeneous tissue in the tumour and its vicinity, and determines crucial parameters for tissue differentiation. A combination of different MR parameters on a pixel-by-pixel basis in individual patients enables better identification of the tumour type, direction of proliferation and assessment of the tumour extension. (orig.)

  20. Updating the Wnt pathways

    Science.gov (United States)

    Yu, Jia; Virshup, David M.

    2014-01-01

    In the three decades since the discovery of the Wnt1 proto-oncogene in virus-induced mouse mammary tumours, our understanding of the signalling pathways that are regulated by the Wnt proteins has progressively expanded. Wnts are involved in an complex signalling network that governs multiple biological processes and cross-talk with multiple additional signalling cascades, including the Notch, FGF (fibroblast growth factor), SHH (Sonic hedgehog), EGF (epidermal growth factor) and Hippo pathways. The Wnt signalling pathway also illustrates the link between abnormal regulation of the developmental processes and disease manifestation. Here we provide an overview of Wnt-regulated signalling cascades and highlight recent advances. We focus on new findings regarding the dedicated Wnt production and secretion pathway with potential therapeutic targets that might be beneficial for patients with Wnt-related diseases. PMID:25208913

  1. Components of a Fanconi-like pathway control Pso2-independent DNA interstrand crosslink repair in yeast.

    Directory of Open Access Journals (Sweden)

    Thomas A Ward

    Full Text Available Fanconi anemia (FA is a devastating genetic disease, associated with genomic instability and defects in DNA interstrand cross-link (ICL repair. The FA repair pathway is not thought to be conserved in budding yeast, and although the yeast Mph1 helicase is a putative homolog of human FANCM, yeast cells disrupted for MPH1 are not sensitive to ICLs. Here, we reveal a key role for Mph1 in ICL repair when the Pso2 exonuclease is inactivated. We find that the yeast FANCM ortholog Mph1 physically and functionally interacts with Mgm101, a protein previously implicated in mitochondrial DNA repair, and the MutSα mismatch repair factor (Msh2-Msh6. Co-disruption of MPH1, MGM101, MSH6, or MSH2 with PSO2 produces a lesion-specific increase in ICL sensitivity, the elevation of ICL-induced chromosomal rearrangements, and persistence of ICL-associated DNA double-strand breaks. We find that Mph1-Mgm101-MutSα directs the ICL-induced recruitment of Exo1 to chromatin, and we propose that Exo1 is an alternative 5'-3' exonuclease utilised for ICL repair in the absence of Pso2. Moreover, ICL-induced Rad51 chromatin loading is delayed when both Pso2 and components of the Mph1-Mgm101-MutSα and Exo1 pathway are inactivated, demonstrating that the homologous recombination stages of ICL repair are inhibited. Finally, the FANCJ- and FANCP-related factors Chl1 and Slx4, respectively, are also components of the genetic pathway controlled by Mph1-Mgm101-MutSα. Together this suggests that a prototypical FA-related ICL repair pathway operates in budding yeast, which acts redundantly with the pathway controlled by Pso2, and is required for the targeting of Exo1 to chromatin to execute ICL repair.

  2. SWITCH: a dynamic CRISPR tool for genome engineering and metabolic pathway control for cell factory construction in Saccharomyces cerevisiae.

    Science.gov (United States)

    Vanegas, Katherina García; Lehka, Beata Joanna; Mortensen, Uffe Hasbro

    2017-02-08

    The yeast Saccharomyces cerevisiae is increasingly used as a cell factory. However, cell factory construction time is a major obstacle towards using yeast for bio-production. Hence, tools to speed up cell factory construction are desirable. In this study, we have developed a new Cas9/dCas9 based system, SWITCH, which allows Saccharomyces cerevisiae strains to iteratively alternate between a genetic engineering state and a pathway control state. Since Cas9 induced recombination events are crucial for SWITCH efficiency, we first developed a technique TAPE, which we have successfully used to address protospacer efficiency. As proof of concept of the use of SWITCH in cell factory construction, we have exploited the genetic engineering state of a SWITCH strain to insert the five genes necessary for naringenin production. Next, the naringenin cell factory was switched to the pathway control state where production was optimized by downregulating an essential gene TSC13, hence, reducing formation of a byproduct. We have successfully integrated two CRISPR tools, one for genetic engineering and one for pathway control, into one system and successfully used it for cell factory construction.

  3. Induction of human airway hyperresponsiveness by tumour necrosis factor-alpha.

    Science.gov (United States)

    Anticevich, S Z; Hughes, J M; Black, J L; Armour, C L

    1995-09-15

    Tumour necrosis factor-alpha (TNF alpha) is implicated in the pathogenesis of asthma; however, little is known of its direct effect on smooth muscle reactivity. We investigated the effect of TNF alpha on the responsiveness of human bronchial tissue to electrical field stimulation in vitro. Incubation of non-sensitized tissue with 1 nM, 3 nM and 10 nM TNF alpha significantly increased responsiveness to electrical field stimulation (113 +/- 8, 110 +/- 4 and 112 +/- 2% respectively) compared to control (99 +/- 2%) (P 0.05) nor were responses to exogenous acetylcholine (93 +/- 4% versus 73 +/- 7%, n = 3, P = 0.38). These results show that TNF alpha causes an increase in responsiveness of human bronchial tissue and that this occurs prejunctionally on the parasympathetic nerve pathway. This is the first report of a cytokine increasing human airway tissue responsiveness.

  4. Fast neutron therapy in advanced malignant tumour treatment

    International Nuclear Information System (INIS)

    Avinc, A.

    1998-01-01

    In this report the fast neutron therapy applications were examined by thoroughly consideration of the fast neutron sources and the interactions of the fast neutron by the medium. The efficacy of fast neutron radiotherapy with that of patients with locally advanced tumours were compared. Radiological data indicate that fast neutrons could bring benefit in the treatment of some tumour types especially salivary glands, paranasal sinuses, soft tissue sarcomas, prostatic adenocarcinomas, palliative treatment of melanoma and rectum. There is a significant improvement in local/regional control for the neutron group, but no improvement in the survival. The neutron therapy is suggested through which this benefit could be achieved

  5. 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)

    2009-11-15

    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.)

  6. P32INCREASED PERCENTAGE RESECTION OF TUMOUR VOLUME USING NEURONAVIGATIONAL 3D INTRAOPERATIVE ULTRASOUND: A SINGLE UNIT EXPERIENCE

    OpenAIRE

    Vaqas, B.; O'Neill, K.; Awad, M.

    2014-01-01

    INTRODUCTION: The use of intraoperative 3D navigational ultrasound (Sonowand) offers a relatively inexpensive method of obtaining imaging of intrinsic brain tumours during resection which takes in account brain shift during surgery and also allows better visualisation of the tumour margin to help control resection. We designed a study to measure the volume of tumour resection in 25 consecutive Sonowand cases compared to 25 matched non-ultrasound guided controls. METHOD: A retrospective consec...

  7. Conventional megavoltage radiotherapy in the management of malignant epithelial tumours of the parotid gland

    International Nuclear Information System (INIS)

    Piedbois, P.; Bataini, J.P.; Colin, P.; Jaulerry, C.; Brunin, F.; Pontvert, D.; Durand, J.C.

    1989-01-01

    This is an evaluation of definitive conventional megavoltage radiotherapy in a consecutive series of 35 patients presenting malignant epithelial tumours of the parotid gland. In this series, the 5-year actuarial locoregional control rate was 41% with a 5-year crude survival rate of 36%. The results are analyzed according to tumour presentation and tumour doses. Six of 15 patients with tumours larger than 6 cm have had a lasting locoregional control. During the same period 43 other patients received radiotherapy as a post-operative modality. Results obtained in this group confirm the previously published data. While recent studies tend to demonstrate the specific efficacy of high LET radiation in the management of locally advanced salivary gland tumours, radical conventional radiotherapy can still be employed with a curative intent when neutron facilities are not available. (author). 34 refs.; 1 fig.; 5 tabs

  8. Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells

    Directory of Open Access Journals (Sweden)

    Nardou Katya

    2008-06-01

    Full Text Available Abstract Background Histone deacetylase inhibitors (HDACi are a new class of promising anti-tumour agent inhibiting cell proliferation and survival in tumour cells with very low toxicity toward normal cells. Neuroblastoma (NB is the second most common solid tumour in children still associated with poor outcome in higher stages and, thus NB strongly requires novel treatment modalities. Results We show here that the HDACi Sodium Butyrate (NaB, suberoylanilide hydroxamic acid (SAHA and Trichostatin A (TSA strongly reduce NB cells viability. The anti-tumour activity of these HDACi involved the induction of cell cycle arrest in the G2/M phase, followed by the activation of the intrinsic apoptotic pathway, via the activation of the caspases cascade. Moreover, HDACi mediated the activation of the pro-apoptotic proteins Bid and BimEL and the inactivation of the anti-apoptotic proteins XIAP, Bcl-xL, RIP and survivin, that further enhanced the apoptotic signal. Interestingly, the activity of these apoptosis regulators was modulated by several different mechanisms, either by caspases dependent proteolytic cleavage or by degradation via the proteasome pathway. In addition, HDACi strongly impaired the hypoxia-induced secretion of VEGF by NB cells. Conclusion HDACi are therefore interesting new anti-tumour agents for targeting highly malignant tumours such as NB, as these agents display a strong toxicity toward aggressive NB cells and they may possibly reduce angiogenesis by decreasing VEGF production by NB cells.

  9. Plasticity in One Hemisphere, Control From Two: Adaptation in Descending Motor Pathways After Unilateral Corticospinal Injury in Neonatal Rats

    Directory of Open Access Journals (Sweden)

    Tong-Chun Wen

    2018-04-01

    Full Text Available After injury to the corticospinal tract (CST in early development there is large-scale adaptation of descending motor pathways. Some studies suggest the uninjured hemisphere controls the impaired forelimb, while others suggest that the injured hemisphere does; these pathways have never been compared directly. We tested the contribution of each motor cortex to the recovery forelimb function after neonatal injury of the CST. We cut the left pyramid (pyramidotomy of postnatal day 7 rats, which caused a measurable impairment of the right forelimb. We used pharmacological inactivation of each motor cortex to test its contribution to a skilled reach and supination task. Rats with neonatal pyramidotomy were further impaired by inactivation of motor cortex in both the injured and the uninjured hemispheres, while the forelimb of uninjured rats was impaired only from the contralateral motor cortex. Thus, inactivation demonstrated motor control from each motor cortex. In contrast, physiological and anatomical interrogation of these pathways support adaptations only in the uninjured hemisphere. Intracortical microstimulation of motor cortex in the uninjured hemisphere of rats with neonatal pyramidotomy produced responses from both forelimbs, while stimulation of the injured hemisphere did not elicit responses from either forelimb. Both anterograde and retrograde tracers were used to label corticofugal pathways. There was no increased plasticity from the injured hemisphere, either from cortex to the red nucleus or the red nucleus to the spinal cord. In contrast, there were very strong CST connections to both halves of the spinal cord from the uninjured motor cortex. Retrograde tracing produced maps of each forelimb within the uninjured hemisphere, and these were partly segregated. This suggests that the uninjured hemisphere may encode separate control of the unimpaired and the impaired forelimbs of rats with neonatal pyramidotomy.

  10. Plasticity in One Hemisphere, Control From Two: Adaptation in Descending Motor Pathways After Unilateral Corticospinal Injury in Neonatal Rats.

    Science.gov (United States)

    Wen, Tong-Chun; Lall, Sophia; Pagnotta, Corey; Markward, James; Gupta, Disha; Ratnadurai-Giridharan, Shivakeshavan; Bucci, Jacqueline; Greenwald, Lucy; Klugman, Madelyne; Hill, N Jeremy; Carmel, Jason B

    2018-01-01

    After injury to the corticospinal tract (CST) in early development there is large-scale adaptation of descending motor pathways. Some studies suggest the uninjured hemisphere controls the impaired forelimb, while others suggest that the injured hemisphere does; these pathways have never been compared directly. We tested the contribution of each motor cortex to the recovery forelimb function after neonatal injury of the CST. We cut the left pyramid (pyramidotomy) of postnatal day 7 rats, which caused a measurable impairment of the right forelimb. We used pharmacological inactivation of each motor cortex to test its contribution to a skilled reach and supination task. Rats with neonatal pyramidotomy were further impaired by inactivation of motor cortex in both the injured and the uninjured hemispheres, while the forelimb of uninjured rats was impaired only from the contralateral motor cortex. Thus, inactivation demonstrated motor control from each motor cortex. In contrast, physiological and anatomical interrogation of these pathways support adaptations only in the uninjured hemisphere. Intracortical microstimulation of motor cortex in the uninjured hemisphere of rats with neonatal pyramidotomy produced responses from both forelimbs, while stimulation of the injured hemisphere did not elicit responses from either forelimb. Both anterograde and retrograde tracers were used to label corticofugal pathways. There was no increased plasticity from the injured hemisphere, either from cortex to the red nucleus or the red nucleus to the spinal cord. In contrast, there were very strong CST connections to both halves of the spinal cord from the uninjured motor cortex. Retrograde tracing produced maps of each forelimb within the uninjured hemisphere, and these were partly segregated. This suggests that the uninjured hemisphere may encode separate control of the unimpaired and the impaired forelimbs of rats with neonatal pyramidotomy.

  11. MRI of primary meningeal tumours in children

    International Nuclear Information System (INIS)

    Yoon, H.K.; Na, D.G.; Byun, H.S.; Han, B.K.; Kim, S.S.; Kim, I.O.; Shin, H.J.

    1999-01-01

    Childhood meningeal tumours are uncommon and mostly meningiomas. We reviewed the histological and radiological findings in meningeal tumours in six children aged 12 years or less (four benign meningiomas, one malignant meningioma and one haemangiopericytoma). Compared to the adult counterpart, childhood meningiomas showed atypical features: cysts, haemorrhage, aggressiveness and unusual location. MRI features varied according to the site of the tumour, histology, haemorrhage, and presence of intra- or peritumoral cysts. Diagnosis of the extra-axial tumour was relatively easy in two patients with meningiomas, one malignant meningioma and one haemangiopericytoma. MRI findings strongly suggested an intra-axial tumour in two patients with benign meningiomas, because of severe adjacent edema. Awareness of the variable findings of childhood meningiomas and similar tumours may help in differentiation from brain tumours. (orig.)

  12. Primary bone tumours of the hand

    International Nuclear Information System (INIS)

    Kozlowski, K.; Azouz, E.M.; Campbell, J.; Marton, D.; Morris, L.; Padovani, J.; Sprague, P.; Beluffi, G.; Berzero, G.F.; Cherubino, P.; Adelaide Children's Hospital; Hospital for Children, Perth; Montreal Children's Hospital, Quebec; Saint Justine Hospital, Montreal, Quebec; Children's Hospital, Denver, CO; Hopital des Enfants, 13 - Marseille; Pavia Univ.; Pavia Univ.

    1988-01-01

    Twenty-one primary bone tumours of the hand in children from 8 paediatric hospitals are reported. Osteochondromas and enchondromas were not included. Our material consisted of 16 patients with common tumours (3 Ewing's sarcoma, 5 aneurysmal bone cyst, 6 osteoid osteoma and 2 epithelioma) and 5 patients with uncommon tumours (osteoma, simple bone cyst, haemangiopericytoma, capillary angiomatous tumour and benign ossifying fibroma or osteoblastoma). The X-ray diagnosis of the common tumours should have high concordance with histology, whereas that of uncommon tumours in much more difficult and uncertain. The characteristic features of Ewing's sarcoma are stressed as all our children with this tumour had a delayed diagnosis and a fatal outcome. Differential diagnosis with other short tubular bone lesions of the hand - specifically osteomyelitis - is discussed and the posibilities of microscopic diagnosis are stressed. (orig.)

  13. Radiodiagnosis of tumours of gastrointestinal tract

    International Nuclear Information System (INIS)

    Sokolov, Yu.N.; Antonovich, V.B.

    1981-01-01

    Systematic description of X-ray picture of tumours of gastrointestinal tract organs is given. The possibilities of contemporary methods of X-ray examination in their revealing are shown. Clinical and X-ray trend of tumour diagnosis is underlined. The basic and accessory symptoms are analyzed from which X-ray semiotics of tumours is turned out. The expressiveness of X-ray symptoms is shown in relation to morphological forms and localization of the tumours. Much attention is given to radiodiagnosis of early tumours of stomach. Differential diagnosis of tumours with non-tumoural diseases is given. X-ray semiotics of lesions of gastrointestinal tract organs in malignant diseases of blood system is presented [ru

  14. Teratoid Wilms tumour with chemotherapy resistance

    Directory of Open Access Journals (Sweden)

    Renuka Gahine

    2015-01-01

    Full Text Available We present a case of Teratoid Wilms tumour (a rare histologic variant in a 4 year old male who presented with an abdominal lump. Wilms Tumour with paracaval lymphadenopathy and tumour thrombi in right renal vein and inferior vena cava was made radiologically. FNAC report was suggestive of Wilms tumour and patient was subjected to 6 cycles of chemotherapy with not much reduction in size. Post nephrectomy histological diagnosis of Teratoid Wilms tumour was established. Resistance to chemotherapy and radiotherapy is thought to be due to presence of well differentiated histologic appearance. Teratoid Wilms tumour is usually not an aggressive neoplasm and prognosis is comparatively neoplasm and prognosis is comparatively good if the tumour is excised completely thus surgery being the best treatment.

  15. CNS embryonal tumours: WHO 2016 and beyond.

    Science.gov (United States)

    Pickles, J C; Hawkins, C; Pietsch, T; Jacques, T S

    2018-02-01

    Embryonal tumours of the central nervous system (CNS) present a significant clinical challenge. Many of these neoplasms affect young children, have a very high mortality and therapeutic strategies are often aggressive with poor long-term outcomes. There is a great need to accurately diagnose embryonal tumours, predict their outcome and adapt therapy to the individual patient's risk. For the first time in 2016, the WHO classification took into account molecular characteristics for the diagnosis of CNS tumours. This integration of histological features with genetic information has significantly changed the diagnostic work-up and reporting of tumours of the CNS. However, this remains challenging in embryonal tumours due to their previously unaccounted tumour heterogeneity. We describe the recent revisions made to the 4th edition of the WHO classification of CNS tumours and review the main changes, while highlighting some of the more common diagnostic testing strategies. © 2017 British Neuropathological Society.

  16. Intra-Tumour Signalling Entropy Determines Clinical Outcome in Breast and Lung Cancer

    Science.gov (United States)

    Banerji, Christopher R. S.; Severini, Simone; Caldas, Carlos; Teschendorff, Andrew E.

    2015-01-01

    The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample’s genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers. PMID:25793737

  17. Unravelling the biology of human papillomavirus (HPV) related tumours to enhance their radiosensitivity

    International Nuclear Information System (INIS)

    Vozenin, M.C.; Lord, H.K.; Deutsch, E.; Vozenin, M.C.; Hartl, D.

    2010-01-01

    HPV infection is associated with most squamous cell carcinomas (SCC) of the uterine cervix and many head and neck SCC. While recent understanding of the mechanisms of HPV-induced carcinogenesis has lead to the development of prophylactic vaccines, the principal modality of treatment is radiotherapy and despite concurrent chemotherapy, outcomes remain suboptimal. Improving the radiotherapeutic index thus remains an important challenge as well as defining predictive assays for treatment outcome of HPV-related tumours. Therefore elucidating the influence of the HPV virus on tumour radiosensitivity is of major interest due to the prevalence of HPV-related tumours worldwide and due to evidence that head and neck HPV-tumours have markedly different clinical outcomes compared to non-HPV-related tumours. This difference may allow for different treatment strategies to be developed. The present review aims to summarize the current understanding of radiosensitivity and HPV-related tumour biology in order to subsequently develop new approaches to enhance the therapeutic index. This review also emphasizes the relevance of E6 and E7 onco-proteins to tumour cell response to radiotherapy suggesting that specific targeted approaches such as concomitant modulation of additional pathways using targeted therapies should offer new therapeutic avenues. (authors)

  18. Intra-tumour signalling entropy determines clinical outcome in breast and lung cancer.

    Directory of Open Access Journals (Sweden)

    Christopher R S Banerji

    2015-03-01

    Full Text Available The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample's genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers.

  19. Notch3 signalling promotes tumour growth in colorectal cancer.

    Science.gov (United States)

    Serafin, Valentina; Persano, Luca; Moserle, Lidia; Esposito, Giovanni; Ghisi, Margherita; Curtarello, Matteo; Bonanno, Laura; Masiero, Massimo; Ribatti, Domenico; Stürzl, Michael; Naschberger, Elisabeth; Croner, Roland S; Jubb, Adrian M; Harris, Adrian L; Koeppen, Hartmut; Amadori, Alberto; Indraccolo, Stefano

    2011-08-01

    Increased Notch1 activity has been observed in intestinal tumours, partially accomplished by β-catenin-mediated up-regulation of the Notch ligand Jagged-1. Whether further mechanisms of Notch activation exist and other Notch receptors might be involved is unclear. Microarray data indicated that Notch3 transcript levels are significantly up-regulated in primary and metastatic CRC samples compared to normal mucosa. Moreover, Notch3 protein was expressed at strong/moderate levels by 19.7% of 158 CRC samples analysed, and at weak levels by 51.2% of the samples. Intrigued by these findings, we sought to investigate whether Notch3 modulates oncogenic features of CRC cells. By exploiting xenografts of CRC cells with different tumourigenic properties in mice, we found that the aggressive phenotype was associated with altered expression of components of the Notch pathway, including Notch3, Delta-like 4 (DLL4), and Jagged-1 ligands. Stimulation with immobilized recombinant DLL4 or transduction with DLL4-expressing vectors dramatically increased Notch3 expression in CRC cells, associated with accelerated tumour growth. Forced expression of an active form of Notch3 mirrored the effects of DLL4 stimulation and increased tumour formation. Conversely, attenuation of Notch3 levels by shRNA resulted in perturbation of the cell cycle followed by reduction in cell proliferation, clonogenic capacity, and inhibition of tumour growth. Altogether, these findings indicate that Notch3 can modulate the tumourigenic properties of CRC cells and contributes to sustained Notch activity in DLL4-expressing tumours. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  20. Radiation response of tumours

    International Nuclear Information System (INIS)

    Twentyman, P.R.

    1988-01-01

    In this chapter knowledge regarding cellular radiation response and the factors which modify it is related to the volume changes and probability of control of irradiated solid tumors. After a discussion of the different cell populations present within solid tumors the cell population kinetics of the neoplastic cells are considered in more detail. The influence of factors related to the three-dimensional geometry of the tumor, particularly hypoxia, are considered, and also the role of the tumor vasculature in radiation response. Repair of sublethal damage (SLD) and potentially lethal damage (PLD) is dealt with and finally the relationship between the various end-points of tumor radioresponsiveness is discussed

  1. Mobile phone use and risk of brain tumours

    International Nuclear Information System (INIS)

    Lahkola, A.

    2010-05-01

    Mobile phone use has increased rapidly worldwide since the 1990's. As mobile telephones are used close to the head, the exposure to the radiofrequency radiation emitted by mobile phones has been suggested as a possible risk factor for brain tumours. The effect of mobile phone use on risk of brain tumours, particularly gliomas and meningiomas as well as acoustic neuromas, was evaluated using both a case-control approach and a meta-analysis. In addition, one of the most important sources of error in a case-control study, selection bias due to differential participation, was assessed in a subset of the case-control data. The risk of glioma and meningioma in relation to mobile phone use was investigated in population-based case-control studies conducted in five North European countries. All these countries used a common protocol and were included in a multinational study on mobile phone use and brain tumours, the INTERPHONE study, coordinated by the International Agency for Research on Cancer (IARC). Cases (1,521 gliomas and 1,209 meningiomas) were identified mostly from hospitals and controls (3,299) from national population registers or general practitioners' patient lists. Detailed history of mobile phone use was obtained in personal interviews. Mobile phone use was assessed using several exposure indicators, such as regular use (phone use at least once a week for at least six months), duration of use as well as cumulative number of hours and calls. To comprehensively evaluate the effect of mobile phone use on risk of brain tumours, the existing evidence from the epidemiological studies published on the issue was combined using meta-analysis. In the analysis, a pooled estimate was calculated for all brain tumours combined, and also separately for the three most common tumour types, glioma, meningioma and acoustic neuroma using inverse variance-weighted method. Pooled estimate was also obtained for different telephone types (NMT and GSM) and by the location of the

  2. Tumour targeting with systemically administered bacteria.

    LENUS (Irish Health Repository)

    Morrissey, David

    2012-01-31

    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.

  3. Multiple roles of glyoxalase 1-mediated suppression of methylglyoxal glycation in cancer biology-Involvement in tumour suppression, tumour growth, multidrug resistance and target for chemotherapy.

    Science.gov (United States)

    Rabbani, Naila; Xue, Mingzhan; Weickert, Martin O; Thornalley, Paul J

    2018-04-01

    Glyoxalase 1 (Glo1) is part of the glyoxalase system in the cytoplasm of all human cells. It catalyses the glutathione-dependent removal of the endogenous reactive dicarbonyl metabolite, methylglyoxal (MG). MG is formed mainly as a side product of anaerobic glycolysis. It modifies protein and DNA to form mainly hydroimidazolone MG-H1 and imidazopurinone MGdG adducts, respectively. Abnormal accumulation of MG, dicarbonyl stress, increases adduct levels which may induce apoptosis and replication catastrophe. In the non-malignant state, Glo1 is a tumour suppressor protein and small molecule inducers of Glo1 expression may find use in cancer prevention. Increased Glo1 expression is permissive for growth of tumours with high glycolytic activity and is thereby a biomarker of tumour growth. High Glo1 expression is a cause of multi-drug resistance. It is produced by over-activation of the Nrf2 pathway and GLO1 amplification. Glo1 inhibitors are antitumour agents, inducing apoptosis and necrosis, and anoikis. Tumour stem cells and tumours with high flux of MG formation and Glo1 expression are sensitive to Glo1 inhibitor therapy. It is likely that MG-induced cell death contributes to the mechanism of action of current antitumour agents. Common refractory tumours have high prevalence of Glo1 overexpression for which Glo1 inhibitors may improve therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Putative transcriptomic biomarkers in the inflammatory cytokine pathway differentiate major depressive disorder patients from control subjects and bipolar disorder patients.

    Directory of Open Access Journals (Sweden)

    Timothy R Powell

    Full Text Available Mood disorders consist of two etiologically related, but distinctly treated illnesses, major depressive disorder (MDD and bipolar disorder (BPD. These disorders share similarities in their clinical presentation, and thus show high rates of misdiagnosis. Recent research has revealed significant transcriptional differences within the inflammatory cytokine pathway between MDD patients and controls, and between BPD patients and controls, suggesting this pathway may possess important biomarker properties. This exploratory study attempts to identify disorder-specific transcriptional biomarkers within the inflammatory cytokine pathway, which can distinguish between control subjects, MDD patients and BPD patients. This is achieved using RNA extracted from subject blood and applying synthesized complementary DNA to quantitative PCR arrays containing primers for 87 inflammation-related genes. Initially, we use ANOVA to test for transcriptional differences in a 'discovery cohort' (total n = 90 and then we use t-tests to assess the reliability of any identified transcriptional differences in a 'validation cohort' (total n = 35. The two most robust and reliable biomarkers identified across both the discovery and validation cohort were Chemokine (C-C motif ligand 24 (CCL24 which was consistently transcribed higher amongst MDD patients relative to controls and BPD patients, and C-C chemokine receptor type 6 (CCR6 which was consistently more lowly transcribed amongst MDD patients relative to controls. Results detailed here provide preliminary evidence that transcriptional measures within inflammation-related genes might be useful in aiding clinical diagnostic decision-making processes. Future research should aim to replicate findings detailed in this exploratory study in a larger medication-free sample and examine whether identified biomarkers could be used prospectively to aid clinical diagnosis.

  5. Redundancy control in pathway databases (ReCiPa): an application for improving gene-set enrichment analysis in Omics studies and "Big data" biology.

    Science.gov (United States)

    Vivar, Juan C; Pemu, Priscilla; McPherson, Ruth; Ghosh, Sujoy

    2013-08-01

    Abstract Unparalleled technological advances have fueled an explosive growth in the scope and scale of biological data and have propelled life sciences into the realm of "Big Data" that cannot be managed or analyzed by conventional approaches. Big Data in the life sciences are driven primarily via a diverse collection of 'omics'-based technologies, including genomics, proteomics, metabolomics, transcriptomics, metagenomics, and lipidomics. Gene-set enrichment analysis is a powerful approach for interrogating large 'omics' datasets, leading to the identification of biological mechanisms associated with observed outcomes. While several factors influence the results from such analysis, the impact from the contents of pathway databases is often under-appreciated. Pathway databases often contain variously named pathways that overlap with one another to varying degrees. Ignoring such redundancies during pathway analysis can lead to the designation of several pathways as being significant due to high content-similarity, rather than truly independent biological mechanisms. Statistically, such dependencies also result in correlated p values and overdispersion, leading to biased results. We investigated the level of redundancies in multiple pathway databases and observed large discrepancies in the nature and extent of pathway overlap. This prompted us to develop the application, ReCiPa (Redundancy Control in Pathway Databases), to control redundancies in pathway databases based on user-defined thresholds. Analysis of genomic and genetic datasets, using ReCiPa-generated overlap-controlled versions of KEGG and Reactome pathways, led to a reduction in redundancy among the top-scoring gene-sets and allowed for the inclusion of additional gene-sets representing possibly novel biological mechanisms. Using obesity as an example, bioinformatic analysis further demonstrated that gene-sets identified from overlap-controlled pathway databases show stronger evidence of prior association

  6. Incoherent feedforward control governs adaptation of activated ras in a eukaryotic chemotaxis pathway.

    Science.gov (United States)

    Takeda, Kosuke; Shao, Danying; Adler, Micha; Charest, Pascale G; Loomis, William F; Levine, Herbert; Groisman, Alex; Rappel, Wouter-Jan; Firtel, Richard A

    2012-01-03

    Adaptation in signaling systems, during which the output returns to a fixed baseline after a change in the input, often involves negative feedback loops and plays a crucial role in eukaryotic chemotaxis. We determined the dynamical response to a uniform change in chemoattractant concentration of a eukaryotic chemotaxis pathway immediately downstream from G protein-coupled receptors. The response of an activated Ras showed near-perfect adaptation, leading us to attempt to fit the results using mathematical models for the two possible simple network topologies that can provide perfect adaptation. Only the incoherent feedforward network accurately described the experimental results. This analysis revealed that adaptation in this Ras pathway is achieved through the proportional activation of upstream components and not through negative feedback loops. Furthermore, these results are consistent with a local excitation, global inhibition mechanism for gradient sensing, possibly with a Ras guanosine triphosphatase-activating protein acting as a global inhibitor.

  7. [Awake craniotomy for brain tumours].

    Science.gov (United States)

    Milos, Peter; Metcalf, Kerstin; Vigren, Patrick; Lindehammar, Hans; Nilsson, Malin; Boström, Sverre

    2016-10-11

    Awake craniotomy for brain tumours  Awake neurosurgery is a useful method in lesions near eloquent brain areas, particularly low-grade gliomas.The aim is to maximise tumour resection and preserve neurological function. We performed 40 primary awake surgeries and 8 residual surgeries. Patients were operated awake throughout the procedure or with a laryngeal mask and general anaesthesia during the opening stage and then awake during intracerebral surgery. Language and motor function were mapped with direct cortical stimulation, motor evoked potential and standardised neurological testing. Radiologically, complete resection was achieved in 18 out of 40 patients in the primary surgeries. Full neurological recovery at three months was observed in 29 patients. Of the 11 patients with persisting neurological deficits at three months, symptoms were present preoperatively in 9 patients. We conclude that awake surgery, combined with intraoperative neurophysiological methods, is a safe method to improve treatment for low-grade gliomas.

  8. Do aberrant crypt foci have predictive value for the occurrence of colorectal tumours? Potential of gene expression profiling in tumours

    NARCIS (Netherlands)

    Wijnands, M.V.W.; Erk, van M.J.; Doornbos, R.P.; Krul, C.A.M.; Woutersen, R.A.

    2004-01-01

    The effects of different dietary compounds on the formation of aberrant crypt foci (ACF) and colorectal tumours and on the expression of a selection of genes were studied in rats. Azoxymethane-treated male F344 rats were fed either a control diet or a diet containing 10% wheat bran (WB), 0.2%

  9. Visual-Cerebellar Pathways and Their Roles in the Control of Avian Flight

    Directory of Open Access Journals (Sweden)

    Douglas R. Wylie

    2018-04-01

    Full Text Available In this paper, we review the connections and physiology of visual pathways to the cerebellum in birds and consider their role in flight. We emphasize that there are two visual pathways to the cerebellum. One is to the vestibulocerebellum (folia IXcd and X that originates from two retinal-recipient nuclei that process optic flow: the nucleus of the basal optic root (nBOR and the pretectal nucleus lentiformis mesencephali (LM. The second is to the oculomotor cerebellum (folia VI-VIII, which receives optic flow information, mainly from LM, but also local visual motion information from the optic tectum, and other visual information from the ventral lateral geniculate nucleus (Glv. The tectum, LM and Glv are all intimately connected with the pontine nuclei, which also project to the oculomotor cerebellum. We believe this rich integration of visual information in the cerebellum is important for analyzing motion parallax that occurs during flight. Finally, we extend upon a suggestion by Ibbotson (2017 that the hypertrophy that is observed in LM in hummingbirds might be due to an increase in the processing demands associated with the pathway to the oculomotor cerebellum as they fly through a cluttered environment while feeding.

  10. Reconstructive options in pelvic tumours

    Directory of Open Access Journals (Sweden)

    Mayilvahanan N

    2005-01-01

    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

  11. Single-Amino Acid Modifications Reveal Additional Controls on the Proton Pathway of [FeFe]-Hydrogenase

    Energy Technology Data Exchange (ETDEWEB)

    Cornish, Adam J.; Ginovska, Bojana; Thelen, Adam; da Silva, Julio C. S.; Soares, Thereza A.; Raugei, Simone; Dupuis, Michel; Shaw, Wendy J.; Hegg, Eric L.

    2016-06-07

    The proton pathway of [FeFe]-hydrogenase is essential for enzymatic H2 production and oxidation and is composed of four residues and a modeled water molecule. Recently, a computational analysis of this pathway revealed that the solvent-exposed residue of the pathway (Glu282) could form hydrogen bonds to two residues outside of the pathway (Arg286 and Ser320), implicating that these residues could function in regulating proton transfer. Substituting Arg286 with leucine eliminates hydrogen bonding with Glu282 and results in a 2.5-fold enhancement in H2 production activity, suggesting that Arg286 serves an important role in controlling the rate of proton delivery. In contrast, substitution of Ser320 with alanine reduces the rate approximately 5-fold, implying that it either acts as a member of the pathway or influences Glu282 to enable proton transfer. Interestingly, QM/MM and molecular dynamics calculations indicate that Ser320 does not play an electronic or structural role. QM calculations also estimate that including Ser320 in the pathway does not significantly change the barrier to proton movement, providing further support for its role as a member of the proton pathway. While further studies are needed to quantify the role of Ser320, collectively, these data provide evidence that the enzyme scaffold plays a significant role in modulating the activity of the enzyme, demonstrating that the rate of intraprotein proton transfer can be accelerated, particularly in a non-biological context. This work was supported by the DOE Great Lakes Bioenergy Research Center (DOE BER Office of Science, DE-FC02-07ER64494). In addition, support from the DOE Office of Science Early Career Research Program through the Office of Basic Energy Sciences (WJS, BGP, SR) is gratefully acknowledged. Computational resources were provided at W. R. Wiley Environmental Molecular Science Laboratory (EMSL), a national scientific user facility sponsored by the Department of Energy’s Office of

  12. Low tumour cell content in a lung tumour bank: implications for molecular characterisation.

    Science.gov (United States)

    Goh, Felicia; Duhig, Edwina E; Clarke, Belinda E; McCaul, Elizabeth; Passmore, Linda; Courtney, Deborah; Windsor, Morgan; Naidoo, Rishendren; Franz, Louise; Parsonson, Kylie; Yang, Ian A; Bowman, Rayleen V; Fong, Kwun M

    2017-10-01

    Lung cancer encompasses multiple malignant epithelial tumour types, each with specific targetable, potentially actionable mutations, such that precision management mandates accurate tumour typing. Molecular characterisation studies require high tumour cell content and low necrosis content, yet lung cancers are frequently a heterogeneous mixture of tumour and stromal cells. We hypothesised that there may be systematic differences in tumour cell content according to histological subtype, and that this may have implications for tumour banks as a resource for comprehensive molecular characterisation studies in lung cancer. To investigate this, we estimated tumour cell and necrosis content of 4267 samples resected from 752 primary lung tumour specimens contributed to a lung tissue bank. We found that banked lung cancer samples had low tumour cell content (33%) generally, although it was higher in carcinoids (77.5%) than other lung cancer subtypes. Tumour cells comprise a variable and often small component of banked resected tumour samples, and are accompanied by stromal reaction, inflammation, fibrosis, and normal structures. This has implications for the adequacy of unselected tumour bank samples for diagnostic and molecular investigations, and further research is needed to determine whether tumour cell content has a significant impact on analytical results in studies using tissue from tumour bank resources. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  13. Allograft in bone tumour surgery

    International Nuclear Information System (INIS)

    Sengupta, S.

    1999-01-01

    In the last twenty years, there has been a vast improvement in the prognosis of primary malignant tumours of bone. This is due to many factors including early detection, staging and classification of tumours as a result of better staining and imaging techniques, better surgical technology, e.g. endoprosthesis and most importantly adjuvant treatment with cytotoxic drugs. As a result of long term survival, amputation of limb has more or less been replaced by limb salvage surgery. This procedure consists of two parts. Primary objective is of course complete removal of the tumour by adequate soft tissue cover and secondarily by reconstruction of the locomotor system, If possible with retention of the function of the limb. These procedures include endo-prosthetic replacement or arthroplasty and arthrodesis using autologus grafts, allograft or combination. With the development of bone banks and assured safety of preserved bones, reconstructive limb salvage surgery using massive allograft is gradually replacing prosthetic implants. The advantages include replacement of articular surfaces, incorporation of the graft to the host bone, attachment of bone tissue and increased probably permanent survival. Allograft can be used for intercalary replacement, osteo-articular arthroplasty arthrodesis or filling large cavities. Inherent complication of massive allograft are disease transmission, infection, delayed and non-union, pathological fractures, mechanical failure and joint destruction. Several limb salvage procedures using allografts have been carried out in our institution with one failure due to infection. Paucity of available allograft has restricted more such procedures to be carried out

  14. Waveband specific transcriptional control of select genetic pathways in vertebrate skin (Xiphophorus maculatus).

    Science.gov (United States)

    Walter, Ronald B; Boswell, Mikki; Chang, Jordan; Boswell, William T; Lu, Yuan; Navarro, Kaela; Walter, Sean M; Walter, Dylan J; Salinas, Raquel; Savage, Markita

    2018-05-10

    Evolution occurred exclusively under the full spectrum of sunlight. Conscription of narrow regions of the solar spectrum by specific photoreceptors suggests a common strategy for regulation of genetic pathways. Fluorescent light (FL) does not possess the complexity of the solar spectrum and has only been in service for about 60 years. If vertebrates evolved specific genetic responses regulated by light wavelengths representing the entire solar spectrum, there may be genetic consequences to reducing the spectral complexity of light. We utilized RNA-Seq to assess changes in the transcriptional profiles of Xiphophorus maculatus skin after exposure to FL ("cool white"), or narrow wavelength regions of light between 350 and 600 nm (i.e., 50 nm or 10 nm regions, herein termed "wavebands"). Exposure to each 50 nm waveband identified sets of genes representing discrete pathways that showed waveband specific transcriptional modulation. For example, 350-400 or 450-500 nm waveband exposures resulted in opposite regulation of gene sets marking necrosis and apoptosis (i.e., 350-400 nm; necrosis suppression, apoptosis activation, while 450-500 nm; apoptosis suppression, necrosis activation). Further investigation of specific transcriptional modulation employing successive 10 nm waveband exposures between 500 and 550 nm showed; (a) greater numbers of genes may be transcriptionally modulated after 10 nm exposures, than observed for 50 nm or FL exposures, (b) the 10 nm wavebands induced gene sets showing greater functional specificity than 50 nm or FL exposures, and (c) the genetic effects of FL are primarily due to 30 nm between 500 and 530 nm. Interestingly, many genetic pathways exhibited completely opposite transcriptional effects after different waveband exposures. For example, the epidermal growth factor (EGF) pathway exhibits transcriptional suppression after FL exposure, becomes highly active after 450-500 nm waveband exposure, and again, exhibits strong

  15. Predicting parenting stress in caregivers of children with brain tumours.

    Science.gov (United States)

    Bennett, Emily; English, Martin William; Rennoldson, Michael; Starza-Smith, Arleta

    2013-03-01

    The purpose of the study was to identify factors that contribute to parenting stress in caregivers of children diagnosed with brain tumours. The study was cross-sectional and recruited 37 participants from a clinical database at a specialist children's hospital. Parents were sent questionnaires, which were used to measure factors related to stress in caregivers of children diagnosed with a brain tumour. Stress levels were measured using the Parenting Stress Index-Short Form (PSI/SF). Correlation analysis and multiple linear regression were used to examine the associations between parenting stress and coping styles, locus of control, parent-perceived child disability and time since diagnosis. Results revealed that 51% of parents were experiencing clinically significant levels of stress. The mean stress level of parents in the study was significantly higher than the PSI/SF norms (t = 4.7, p parenting stress. Other styles of coping, child behaviour problems and the amount of time since diagnosis were not found to be predictive of levels of parenting stress. There was a high prevalence of parenting stress in caregivers of children with a brain tumour. An external locus of control and coping by accepting responsibility increased the likelihood of elevated levels of stress. Results emphasised the importance of ongoing support for parents of children with brain tumours. Intervention might helpfully be centred on strategies to increase parents' internal locus of control. Copyright © 2012 John Wiley & Sons, Ltd.

  16. The European quality of care pathways (EQCP study on the impact of care pathways on interprofessional teamwork in an acute hospital setting: study protocol: for a cluster randomised controlled trial and evaluation of implementation processes

    Directory of Open Access Journals (Sweden)

    Deneckere Svin

    2012-05-01

    Full Text Available Abstract Background Although care pathways are often said to promote teamwork, high-level evidence that supports this statement is lacking. Furthermore, knowledge on conditions and facilitators for successful pathway implementation is scarce. The objective of the European Quality of Care Pathway (EQCP study is therefore to study the impact of care pathways on interprofessional teamwork and to build up understanding on the implementation process. Methods/design An international post-test-only cluster Randomised Controlled Trial (cRCT, combined with process evaluations, will be performed in Belgium, Ireland, Italy, and Portugal. Teams caring for proximal femur fracture (PFF patients and patients hospitalized with an exacerbation of chronic obstructive pulmonary disease (COPD will be randomised into an intervention and control group. The intervention group will implement a care pathway for PFF or COPD containing three active components: a formative evaluation of the actual teams’ performance, a set of evidence-based key interventions, and a training in care pathway-development. The control group will provide usual care. A set of team input, process and output indicators will be used as effect measures. The main outcome indicator will be relational coordination. Next to these, process measures during and after pathway development will be used to evaluate the implementation processes. In total, 132 teams have agreed to participate, of which 68 were randomly assigned to the intervention group and 64 to the control group. Based on power analysis, a sample of 475 team members per arm is required. To analyze results, multilevel analysis will be performed. Discussion Results from our study will enhance understanding on the active components of care pathways. Through this, preferred implementation strategies can be defined. Trail registration NCT01435538

  17. The cross-pathway control system regulates production of the secondary metabolite toxin, sirodesmin PL, in the ascomycete, Leptosphaeria maculans

    Directory of Open Access Journals (Sweden)

    Fox Ellen M

    2011-07-01

    Full Text Available Abstract Background Sirodesmin PL is a secondary metabolite toxin made by the ascomycetous plant pathogen, Leptosphaeria maculans. The sirodesmin biosynthetic genes are clustered in the genome. The key genes are a non-ribosomal peptide synthetase, sirP, and a pathway-specific transcription factor, sirZ. Little is known about regulation of sirodesmin production. Results Genes involved in regulation of sirodesmin PL in L. maculans have been identified. Two hundred random insertional T-DNA mutants were screened with an antibacterial assay for ones producing low levels of sirodesmin PL. Three such mutants were isolated and each transcribed sirZ at very low levels. One of the affected genes had high sequence similarity to Aspergillus fumigatus cpcA, which regulates the cross-pathway control system in response to amino acid availability. This gene was silenced in L. maculans and the resultant mutant characterised. When amino acid starvation was artificially-induced by addition of 3-aminotriazole for 5 h, transcript levels of sirP and sirZ did not change in the wild type. In contrast, levels of sirP and sirZ transcripts increased in the silenced cpcA mutant. After prolonged amino acid starvation the silenced cpcA mutant produced much higher amounts of sirodesmin PL than the wild type. Conclusions Production of sirodesmin PL in L. maculans is regulated by the cross pathway control gene, cpcA, either directly or indirectly via the pathway-specific transcription factor, sirZ.

  18. Breast Carcinoma Progression and Tumour Vascular Markers Related to Apoptotic Mechanisms

    Directory of Open Access Journals (Sweden)

    Miroslava Bilecova-Rabajdova

    2014-01-01

    Full Text Available Background. In the last few years, the cancer research had tried to identify and characterize new biochemical and molecular pathways in which the inhibition induces prosurvival mechanisms. Our work describes the expression of two different members of apoptotic regulatory pathway and their relationship with a progression of breast carcinoma. Materials and Methods. We compared expression of genes related to apoptosis (DR6 and Gpm6B in the blood of patients suffering from stage I of breast cancer in different grades (I–IV, with healthy controls. After isolation of mRNA, transcription of mRNA into the cDNA was performed. The quantification of gene expression changes in DR6 and Gpm6B was detected by RT-PCR method. Analysis at the protein level was performed by the Western blot.Results. In statistical analysis of Dr6 mRNA level changes we detected significant increase starting in Grading 1 (G1 and reached maximal level in G3.This expression on mRNA levels was similar to protein levels, which copy rising tendency with maximal value in G3. The results of Gpm6B were significantly lower.Conclusion. This result showed that antiapoptotic signalling during neovascularization is increased significantly. It would be advisable in the future to study the influence of cytostatic treatment on the expression of genes related to apoptotic pathways and their relationship with progression of breast cancer tumours.

  19. 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

  20. Putative tumour-suppressor gene DAB2 is frequently down regulated by promoter hypermethylation in nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    Tong, Joanna H; Lo, Kwok W; To, Ka F; Ng, David C; Chau, Shuk L; So, Ken K; Leung, Patrick P; Lee, Tin L; Lung, Raymond W; Chan, Michael W; Chan, Anthony W

    2010-01-01

    Human Disabled-2 (DAB2), is a multi-function signalling molecule that it is frequently down-regulated in human cancers. We aimed to investigate the possible tumour suppressor effect of DAB2 in nasopharyngeal carcinoma (NPC). We studied the expression of DAB2 in NPC cell lines, xenografts and primary tumour samples. The status of promoter methylation was assessed by methylation specific PCR and bisulfite sequencing. The functional role of DAB2 in NPC was investigated by re-introducing DAB2 expression into NPC cell line C666-1. Decrease or absent of DAB2 transcript was observed in NPC cell lines and xenografts. Loss of DAB2 protein expression was seen in 72% (33/46) of primary NPC as demonstrated by immunohistochemistry. Aberrant DAB2 promoter methylation was detected in 65.2% (30/46) of primary NPC samples by methylation specific PCR. Treatment of the DAB2 negative NPC cell line C666-1 with 5-aza-2'-deoxycytidine resulted in restoration of DAB2 expression in a dose-dependent manner. Overexpression of DAB2 in NPC cell line C666-1 resulted in reduced growth rate and 35% reduction in anchorage-dependent colony formation, and inhibition of serum-induced c-Fos expression compared to vector-transfected controls. Over expression of DAB2 resulted in alterations of multiple pathways as demonstrated by expression profiling and functional network analysis, which confirmed the role of DAB2 as an adaptor molecule involved in multiple receptor-mediated signalling pathways. We report the frequent down regulation of DAB2 in NPC and the promoter hypermethylation contributes to the loss of expression of DAB2. This is the first study demonstrating frequent DAB2 promoter hypermethylation in human cancer. Our functional studies support the putative tumour suppressor effect of DAB2 in NPC cells

  1. Radiopharmaceutical therapy of brain tumours

    International Nuclear Information System (INIS)

    Riva, P.; Franceschi, G.; Frattarelli, M.; Casi, M.; Santimaria, M.; Cremonini, A.M.; Guiducci, G.; Riva, N.

    1999-01-01

    Full text: The loco-regional radioimmunotherapy (RIT) of high-grade malignant glioma may represent a further favourable therapeutic approach, able to ameliorate the ominous prognosis of these diseases. The anti-tenascin monoclonal antibodies (MAbs) are directly injected in the tumoral bed after the operation. In the first pilot study, 81 glioblastoma patients received the MAbs (BC2 and BC4) labelled with 131 I (mean dose 2035 MBq). The toxicity was absent. The median survival was prolonged up to 25 months and the response rate (PR + CR + NED: no evidence of disease in cases with minimal lesions after customary treatments) was 44%. More recently, 90 Y instead of 131 I was employed. The benzyl-DTPA chelator was utilized for 90 Y conjugation. A phase I study was performed in 20 glioblastoma patients, who previously received all conventional regimens, but with progressive tumour. They were intralesionally given escalating 90 Y doses (185, 370, 555, 740, 925 MBq), 4 cases were included in each incremental level. No change in haematology, liver and renal parameters were encountered. The brain MTD was 925 MBq. The radiopharmaceutical remained in high amount only in the neoplastic area and did not diffuse in normal brain region nor in normal organs. The radiation dose to the tumour was, on average, 0.54 Gy per MBq of 90 Y administered (about 4 times higher in comparison to 131 I). Now a phase II study has been initiated. 30 evaluable patients (23 glioblastoma and 7 anaplastic astrocytoma; 8 newly diagnosed and 22 recurrent tumours) who have been already treated with surgery and radiotherapy, underwent loco-regional RIT, by administering a mean 90 Y dose of 740 MBq; in many cases multiple cycles were given. The median survival of patients who had the antibody infusion when their tumour burden was reduced was 28 months. The objective response consisted of 8 PD, 5 SD, 11 PR, 1 CR and 4 NED. The global response rate (PR + CR + NED) was 53.3% (47.8% in glioblastoma and 75.7% in

  2. Modular endoprosthetic replacement for metastatic tumours of the proximal femur

    Directory of Open Access Journals (Sweden)

    Carter Simon R

    2008-11-01

    Full Text Available Abstract Background and aims Endoprosthetic replacements of the proximal femur are commonly required to treat destructive metastases with either impending or actual pathological fractures at this site. Modular prostheses provide an off the shelf availability and can be adapted to most reconstructive situations for proximal femoral replacements. The aim of this study was to assess the clinical and functional outcomes following modular tumour prosthesis reconstruction of the proximal femur in 100 consecutive patients with metastatic tumours and to compare them with the published results of patients with modular and custom made endoprosthetic replacements. Methods 100 consecutive patients who underwent modular tumour prosthetic reconstruction of the proximal femur for metastases using the METS system from 2001 to 2007 were studied. The patient, tumour and treatment factors in relation to overall survival, local control, implant survival and complications were analysed. Functional scores were obtained from surviving patients. Results and conclusion There were 45 male and 55 female patients. The mean age was 60.2 years. The indications were metastases. Seventy five patients presented with pathological fracture or with failed fixation and 25 patients were at a high risk of developing a fracture. The mean follow up was 15.9 months [range 0–77]. Three patients died within 2 weeks following surgery. 69 patients have died and 31 are alive. Of the 69 patients who were dead 68 did not need revision surgery indicating that the implant provided single definitive treatment which outlived the patient. There were three dislocations (2/5 with THR and 1/95 with unipolar femoral heads. 6 patients had deep infections. The estimated five year implant survival (Kaplan-Meier analysis was 83.1% with revision as end point. The mean TESS score was 64% (54%–82%. We conclude that METS modular tumour prosthesis for proximal femur provides versatility; low implant related

  3. Multiple interactions between maternally-activated signalling pathways control Xenopus nodal-related genes.

    Science.gov (United States)

    Rex, Maria; Hilton, Emma; Old, Robert

    2002-03-01

    We have investigated the induction of the six Xenopus nodal-related genes, Xnr1-Xnr6, by maternal determinants. The beta-catenin pathway was modelled by stimulation using Xwnt8, activin-like signalling was modelled by activin, and VegT action was studied by overexpression in animal cap explants. Combinations of factors were examined, and previously unrecognised interactions were revealed in animal caps and whole embryos. For the induction of Xnr5 and Xnr6 in whole embryos, using a beta-catenin antisense morpholino oligonucleotide or a dominant negative XTcf3, we have demonstrated an absolute permissive requirement for the beta-catenin/Tcf pathway, in addition to the requirement for VegT action. In animal caps Xnr5 and Xnr6 are induced in response to VegT overexpression, and this induction is dependent upon the concomitant activation of the beta-catenin pathway that VegT initiates in animal caps. For the induction of Xnr3, VegT interacts negatively so as to inhibit the induction otherwise observed with wnt-signalling alone. The negative effect of VegT is not the result of a general inhibition of wnt-signalling, and does not result from an inhibition of wnt-induced siamois expression. A 294 bp proximal promoter fragment of the Xnr3 gene is sufficient to mediate the negative effect of VegT. Further experiments, employing cycloheximide to examine the dependence of Xnr gene expression upon proteins translated after the mid-blastula stage, demonstrated that Xnrs 4, 5 and 6 are 'primary' Xnr genes whose expression in the late blastula is solely dependent upon factors present before the mid-blastula stage.

  4. Phosphoinositide-3 kinase-Akt pathway controls cellular entry of Ebola virus.

    Directory of Open Access Journals (Sweden)

    Mohammad F Saeed

    2008-08-01

    Full Text Available The phosphoinositide-3 kinase (PI3K pathway regulates diverse cellular activities related to cell growth, migration, survival, and vesicular trafficking. It is known that Ebola virus requires endocytosis to establish an infection. However, the cellular signals that mediate this uptake were unknown for Ebola virus as well as many other viruses. Here, the involvement of PI3K in Ebola virus entry was studied. A novel and critical role of the PI3K signaling pathway was demonstrated in cell entry of Zaire Ebola virus (ZEBOV. Inhibitors of PI3K and Akt significantly reduced infection by ZEBOV at an early step during the replication cycle. Furthermore, phosphorylation of Akt-1 was induced shortly after exposure of cells to radiation-inactivated ZEBOV, indicating that the virus actively induces the PI3K pathway and that replication was not required for this induction. Subsequent use of pseudotyped Ebola virus and/or Ebola virus-like particles, in a novel virus entry assay, provided evidence that activity of PI3K/Akt is required at the virus entry step. Class 1A PI3Ks appear to play a predominant role in regulating ZEBOV entry, and Rac1 is a key downstream effector in this regulatory cascade. Confocal imaging of fluorescently labeled ZEBOV indicated that inhibition of PI3K, Akt, or Rac1 disrupted normal uptake of virus particles into cells and resulted in aberrant accumulation of virus into a cytosolic compartment that was non-permissive for membrane fusion. We conclude that PI3K-mediated signaling plays an important role in regulating vesicular trafficking of ZEBOV necessary for cell entry. Disruption of this signaling leads to inappropriate trafficking within the cell and a block in steps leading to membrane fusion. These findings extend our current understanding of Ebola virus entry mechanism and may help in devising useful new strategies for treatment of Ebola virus infection.

  5. Electric-Field Control of Interfering Transport Pathways in a Single-Molecule Anthraquinone Transistor

    Science.gov (United States)

    Koole, Max; Thijssen, Jos M.; Valkenier, Hennie; Hummelen, Jan C.; Zant, Herre S. J. van der

    2015-08-01

    It is understood that molecular conjugation plays an important role in charge transport through single-molecule junctions. Here, we investigate electron transport through an anthraquinone based single-molecule three-terminal device. With the use of an electric-field induced by a gate electrode, the molecule is reduced resulting into a ten-fold increase in the off-resonant differential conductance. Theoretical calculations link the change in differential conductance to a reduction-induced change in conjugation, thereby lifting destructive interference of transport pathways.

  6. Targeting Chromosomal Instability and Tumour Heterogeneity in HER2-Positive Breast Cancer

    DEFF Research Database (Denmark)

    Burrell, Rebecca A.; Birkbak, Nicolai Juul; Johnston, Stephen R.

    2010-01-01

    Chromosomal instability (CIN) is a common cause of tumour heterogeneity and poor prognosis in solid tumours and describes cell-cell variation in chromosome structure or number across a tumour population. In this article we consider evidence suggesting that CIN may be targeted and may influence...... response to distinct chemotherapy regimens, using HER2-positive breast cancer as an example. Pre-clinical models have indicated a role for HER2 signalling in initiating CIN and defective cell-cycle control, and evidence suggests that HER2-targeting may attenuate this process. Anthracyclines and platinum...... agents may target tumours with distinct patterns of karyotypic complexity, whereas taxanes may have preferential activity in tumours with relative chromosomal stability. A greater understanding of karyotypic complexity and identification of methods to directly examine and target CIN may support novel...

  7. DMPD: CSF-1 and cell cycle control in macrophages. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 8981359 CSF-1 and cell cycle control in macrophages. Hamilton JA. Mol Reprod Dev. 1...997 Jan;46(1):19-23. (.png) (.svg) (.html) (.csml) Show CSF-1 and cell cycle control in macrophages. PubmedI...D 8981359 Title CSF-1 and cell cycle control in macrophages. Authors Hamilton JA. Publication Mol Reprod Dev

  8. N-terminomics reveals control of Arabidopsis seed storage proteins and proteases by the Arg/N-end rule pathway.

    Science.gov (United States)

    Zhang, Hongtao; Gannon, Lucy; Hassall, Kirsty L; Deery, Michael J; Gibbs, Daniel J; Holdsworth, Michael J; van der Hoorn, Renier A L; Lilley, Kathryn S; Theodoulou, Frederica L

    2018-05-01

    The N-end rule pathway of targeted protein degradation is an important regulator of diverse processes in plants but detailed knowledge regarding its influence on the proteome is lacking. To investigate the impact of the Arg/N-end rule pathway on the proteome of etiolated seedlings, we used terminal amine isotopic labelling of substrates with tandem mass tags (TMT-TAILS) for relative quantification of N-terminal peptides in prt6, an Arabidopsis thaliana N-end rule mutant lacking the E3 ligase PROTEOLYSIS6 (PRT6). TMT-TAILS identified over 4000 unique N-terminal peptides representing c. 2000 protein groups. Forty-five protein groups exhibited significantly increased N-terminal peptide abundance in prt6 seedlings, including cruciferins, major seed storage proteins, which were regulated by Group VII Ethylene Response Factor (ERFVII) transcription factors, known substrates of PRT6. Mobilisation of endosperm α-cruciferin was delayed in prt6 seedlings. N-termini of several proteases were downregulated in prt6, including RD21A. RD21A transcript, protein and activity levels were downregulated in a largely ERFVII-dependent manner. By contrast, cathepsin B3 protein and activity were upregulated by ERFVIIs independent of transcript. We propose that the PRT6 branch of the pathway regulates protease activities in a complex manner and optimises storage reserve mobilisation in the transition from seed to seedling via control of ERFVII action. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

  9. Interacting signal pathways control defense gene expression in Arabidopsis in response to cell wall-degrading enzymes from Erwinia carotovora.

    Science.gov (United States)

    Norman-Setterblad, C; Vidal, S; Palva, E T

    2000-04-01

    We have characterized the role of salicylic acid (SA)-independent defense signaling in Arabidopsis thaliana in response to the plant pathogen Erwinia carotovora subsp. carotovora. Use of pathway-specific target genes as well as signal mutants allowed us to elucidate the role and interactions of ethylene, jasmonic acid (JA), and SA signal pathways in this response. Gene expression studies suggest a central role for both ethylene and JA pathways in the regulation of defense gene expression triggered by the pathogen or by plant cell wall-degrading enzymes (CF) secreted by the pathogen. Our results suggest that ethylene and JA act in concert in this regulation. In addition, CF triggers another, strictly JA-mediated response inhibited by ethylene and SA. SA does not appear to have a major role in activating defense gene expression in response to CF. However, SA may have a dual role in controlling CF-induced gene expression, by enhancing the expression of genes synergistically induced by ethylene and JA and repressing genes induced by JA alone.

  10. Pump-shaped dump optimal control reveals the nuclear reaction pathway of isomerization of a photoexcited cyanine dye.

    Science.gov (United States)

    Dietzek, Benjamin; Brüggemann, Ben; Pascher, Torbjörn; Yartsev, Arkady

    2007-10-31

    Using optimal control as a spectroscopic tool we decipher the details of the molecular dynamics of the essential multidimensional excited-state photoisomerization - a fundamental chemical reaction of key importance in biology. Two distinct nuclear motions are identified in addition to the overall bond-twisting motion: Initially, the reaction is dominated by motion perpendicular to the torsion coordinate. At later times, a second optically active vibration drives the system along the reaction path to the bottom of the excited-state potential. The time scales of the wavepacket motion on a different part of the excited-state potential are detailed by pump-shaped dump optimal control. This technique offers new means to control a chemical reaction far from the Franck-Condon point of absorption and to map details of excited-state reaction pathways revealing unique insights into the underlying reaction mechanism.

  11. Tuning complement activation and pathway through controlled molecular architecture of dextran chains in nanoparticle corona.

    Science.gov (United States)

    Coty, Jean-Baptiste; Eleamen Oliveira, Elquio; Vauthier, Christine

    2017-11-05

    The understanding of complement activation by nanomaterials is a key to a rational design of safe and efficient nanomedicines. This work proposed a systematic study investigating how molecular design of nanoparticle coronas made of dextran impacts on mechanisms that trigger complement activation. The nanoparticles used for this work consisted of dextran-coated poly(isobutylcyanoacrylate) (PIBCA) nanoparticles have already been thoroughly characterized. Their different capacity to trigger complement activation established on the cleavage of the protein C3 was also already described making these nanoparticles good models to investigate the relation between the molecular feature of their corona and the mechanism by which they triggered complement activation. Results of this new study show that complement activation pathways can be selected by distinct architectures formed by dextran chains composing the nanoparticle corona. Assumptions that explain the relation between complement activation mechanisms triggered by the nanoparticles and the nanoparticle corona molecular feature were proposed. These results are of interest to better understand how the design of dextran-coated nanomaterials will impact interactions with the complement system. It can open perspectives with regard to the selection of a preferential complement activation pathway or prevent the nanoparticles to activate the complement system, based on a rational choice of the corona configuration. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Control of seizures by ketogenic diet-induced modulation of metabolic pathways.

    Science.gov (United States)

    Clanton, Ryan M; Wu, Guoyao; Akabani, Gamal; Aramayo, Rodolfo

    2017-01-01

    Epilepsy is too complex to be considered as a disease; it is more of a syndrome, characterized by seizures, which can be caused by a diverse array of afflictions. As such, drug interventions that target a single biological pathway will only help the specific individuals where that drug's mechanism of action is relevant to their disorder. Most likely, this will not alleviate all forms of epilepsy nor the potential biological pathways causing the seizures, such as glucose/amino acid transport, mitochondrial dysfunction, or neuronal myelination. Considering our current inability to test every individual effectively for the true causes of their epilepsy and the alarming number of misdiagnoses observed, we propose the use of the ketogenic diet (KD) as an effective and efficient preliminary/long-term treatment. The KD mimics fasting by altering substrate metabolism from carbohydrates to fatty acids and ketone bodies (KBs). Here, we underscore the need to understand the underlying cellular mechanisms governing the KD's modulation of various forms of epilepsy and how a diverse array of metabolites including soluble fibers, specific fatty acids, and functional amino acids (e.g., leucine, D-serine, glycine, arginine metabolites, and N-acetyl-cysteine) may potentially enhance the KD's ability to treat and reverse, not mask, these neurological disorders that lead to epilepsy.

  13. Aminoacyl-tRNA quality control is required for efficient activation of the TOR pathway regulator Gln3p.

    Science.gov (United States)

    Mohler, Kyle; Mann, Rebecca; Kyle, Amanda; Reynolds, Noah; Ibba, Michael

    2017-09-14

    The aminoacylation status of the cellular tRNA pool regulates both general amino acid control (GAAC) and target of rapamycin (TOR) stress response pathways in yeast. Consequently, fidelity of translation at the level of aminoacyl-tRNA synthesis plays a central role in determining accuracy and sensitivity of stress responses. To investigate effects of translational quality control (QC) on cell physiology under stress conditions, phenotypic microarray analyses were used to identify changes in QC deficient cells. Nitrogen source growth assays showed QC deficient yeast grew differently compared to WT. The QC deficient strain was more tolerant to caffeine treatment than wild type through altered interactions with the TOR and GAAC pathways. Increased caffeine tolerance of the QC deficient strain was consistent with the observation that the activity of Gln3p, a transcription factor controlled by the TOR pathway, is decreased in the QC deficient strain compared to WT. GCN4 translation, which is typically repressed in the absence of nutritional stress, was enhanced in the QC deficient strain through TOR inhibition. QC did not impact cell cycle regulation; however, the chronological lifespan of QC deficient yeast strains decreased compared to wild type, likely due to translational errors and alteration of the TOR-associated regulon. These findings support the idea that changes in translational fidelity provide a mechanism of cellular adaptation by modulating TOR activity. This, in turn, supports a central role for aminoacyl-tRNA synthesis QC in the integrated stress response by maintaining the proper aa-tRNA pools necessary to coordinate the GAAC and TOR.

  14. Facultative or obligate anaerobic bacteria have the potential for multimodality therapy of solid tumours.

    Science.gov (United States)

    Wei, Ming Q; Ellem, Kay A O; Dunn, Paul; West, Malcolm J; Bai, Chun Xue; Vogelstein, Bert

    2007-02-01

    Recent understanding of the unique pathology of solid tumours has shed light on the difficult and disappointing nature of their clinical treatment. All solid tumours undergo angiogenesis that results in biological changes and adaptive metabolisms, i.e. formation of defective vessels, appearance of hypoxic areas, and emergence of an heterogeneous tumour cell population. This micro-milieu provides a haven for anaerobic bacteria. The strictly anaerobic clostridia have several advantages over other facultative anaerobes such as salmonella or lactic acid-producing, Gram-positive, obligate, anaerobic bifidobacteria. Both pathogenic and non-pathogenic clostridia have been demonstrated to specifically colonise and destroy solid tumours. Early trials of non-pathogenic strains in humans had shown plausible safety. Genetic modifications and adaptation of pathogenic and non-pathogenic strains have further created improved features. However, these manipulations rarely generate strains that resulted in complete tumour control alone. Combined modalities of therapies with chemo and radiation therapies, on the other hand, often perform better, including 'cure' of solid tumours in a high percentage of animals. Considering that clostridia have unlimited capacities for genetic improvement, we predict that designer clostridia forecast a promising future for the development of potent strains for tumour destruction, incorporating mechanisms such as immunotherapy to overcome immune suppression and to elicit strong anti-tumour responses.

  15. The effect of 6 and 15 MV on intensity-modulated radiation therapy prostate cancer treatment: plan evaluation, tumour control probability and normal tissue complication probability analysis, and the theoretical risk of secondary induced malignancies

    Science.gov (United States)

    Hussein, M; Aldridge, S; Guerrero Urbano, T; Nisbet, A

    2012-01-01

    Objective The aim of this study was to investigate the effect of 6 and 15-MV photon energies on intensity-modulated radiation therapy (IMRT) prostate cancer treatment plan outcome and to compare the theoretical risks of secondary induced malignancies. Methods Separate prostate cancer IMRT plans were prepared for 6 and 15-MV beams. Organ-equivalent doses were obtained through thermoluminescent dosemeter measurements in an anthropomorphic Aldersen radiation therapy human phantom. The neutron dose contribution at 15 MV was measured using polyallyl-diglycol-carbonate neutron track etch detectors. Risk coefficients from the International Commission on Radiological Protection Report 103 were used to compare the risk of fatal secondary induced malignancies in out-of-field organs and tissues for 6 and 15 MV. For the bladder and the rectum, a comparative evaluation of the risk using three separate models was carried out. Dose–volume parameters for the rectum, bladder and prostate planning target volume were evaluated, as well as normal tissue complication probability (NTCP) and tumour control probability calculations. Results There is a small increased theoretical risk of developing a fatal cancer from 6 MV compared with 15 MV, taking into account all the organs. Dose–volume parameters for the rectum and bladder show that 15 MV results in better volume sparing in the regions below 70 Gy, but the volume exposed increases slightly beyond this in comparison with 6 MV, resulting in a higher NTCP for the rectum of 3.6% vs 3.0% (p=0.166). Conclusion The choice to treat using IMRT at 15 MV should not be excluded, but should be based on risk vs benefit while considering the age and life expectancy of the patient together with the relative risk of radiation-induced cancer and NTCPs. PMID:22010028

  16. Malignant tumours of the kidney: imaging strategy

    International Nuclear Information System (INIS)

    Smets, Anne M.; Kraker, Jan de

    2010-01-01

    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.)

  17. Tumour regrowth after irradiation. An experimental approach

    Energy Technology Data Exchange (ETDEWEB)

    Yamaura, H; Matsuzawa, T [Tohoku Univ., Sendai (Japan). Research Inst. for Tuberculosis, Leprosy and Cancer

    1979-03-01

    Structural changes in irradiated tumours and their regrowth were studied in a rat hepatoma, AH109A, using histological and transparent-chamber techniques. The development of the tumour was examined by means of vascular morphometry as observed in the chamber. Schematically, the tumour tissue was divided into four isocentric layers according to vascular morphology and measurements of vessel volume, surface area, and length per mm/sup 3/ of tissue. The vascularity was greatest in the outermost region, decreased towards the inner parts and reached an absence of vascularity at the central necrosis. The tumours were gamma- or X-irradiated with various doses. The inside hypoxic region was destroyed completely after 300 rad, and regrowths started exclusively from the outermost area of the tumour where enhancement of the effect of radiation by oxygen was thought to be greatest. Possible mechanisms of tumour regrowth are discussed.

  18. Imaging of solid kidney tumours in children

    International Nuclear Information System (INIS)

    Hugosson, C.; Nyman, R.; Jacobsson, B.; Jorulf, H.; Sackey, K.; McDonald, P.

    1995-01-01

    Eighteen children aged 6 months to 12 years with 20 solid renal tumours; 13 Wilms' tumours (WT), 2 clear cell sarcomas of the kidney, 1 malignant rhabdoid tumour of the kidney and 2 cases of bilateral nephroblastomatosis with Wilms' tumour underwent evaluation with US, CT and MR imaging. Contrast-enhanced CT and non-enhanced MR were equally accurate in determining the size and origin of the tumour but were unreliable in separation of stages I, II and III. US could only accurately assess the size of the tumours. MR characteristics varied somewhat between WTs and non-WTs but contrast-enhanced MR imaging might be useful for separation of WTs from nephroblastomatosis. (orig.)

  19. Genetic variation in TLR or NFkappaB pathways and the risk of breast cancer: a case-control study

    International Nuclear Information System (INIS)

    Resler, Alexa J; Malone, Kathleen E; Johnson, Lisa G; Malkki, Mari; Petersdorf, Effie W; McKnight, Barbara; Madeleine, Margaret M

    2013-01-01

    Toll-like receptors (TLRs) and the transcription factor nuclear factor-κB (NFκB) are important in inflammation and cancer. We examined the association between breast cancer risk and 233 tagging single nucleotide polymorphisms within 31 candidate genes involved in TLR or NFκB pathways. This population-based study in the Seattle area included 845 invasive breast cancer cases, diagnosed between 1997 and 1999, and 807 controls aged 65–79. Variant alleles in four genes were associated with breast cancer risk based on gene-level tests: MAP3K1, MMP9, TANK, and TLR9. These results were similar when the risk of breast cancer was examined within ductal and luminal subtypes. Subsequent exploratory pathway analyses using the GRASS algorithm found no associations for genes in TLR or NFκB pathways. Using publicly available CGEMS GWAS data to validate significant findings (N = 1,145 cases, N = 1,142 controls), rs889312 near MAP3K1 was confirmed to be associated with breast cancer risk (P = 0.04, OR 1.15, 95% CI 1.01–1.30). Further, two SNPs in TANK that were significant in our data, rs17705608 (P = 0.05) and rs7309 (P = 0.04), had similar risk estimates in the CGEMS data (rs17705608 OR 0.83, 95% CI 0.72–0.96; CGEMS OR 0.90, 95% CI 0.80–1.01 and rs7309 OR 0.83, 95% CI 0.73–0.95; CGEMS OR 0.91, 95% CI 0.81–1.02). Our findings suggest plausible associations between breast cancer risk and genes in TLR or NFκB pathways. Given the few suggestive associations in our data and the compelling biologic rationale for an association between genetic variation in these pathways and breast cancer risk, further studies are warranted that examine these effects

  20. Ligand-free, protein-bound technetium-99m iron-dextran enhancement of technetium pyrophosphate uptake in tumours

    International Nuclear Information System (INIS)

    Pojer, P.M.; Jakovljevic, A.C.; Wise, K.N.

    1985-01-01

    The biodistribution of technetium-99m was studied in T-cell lymphoma and selected organs of iron-dextran treated and control mice given technetium-99m pyrophosphate. The results showed that high serum iron levels increased tumour uptake of technetium pyrophosphate. This supports the hypothesis that technetium, in common with other metal-based tumour seeking radiopharmaceuticals, is transported to tumours as a ligand-free protein-bound cation. (U.K.)

  1. Mobile phones and head tumours. The discrepancies in cause-effect relationships in the epidemiological studies - how do they arise?

    OpenAIRE

    Levis, Angelo G; Minicuci, Nadia; Ricci, Paolo; Gennaro, Valerio; Garbisa, Spiridione

    2011-01-01

    Abstract Background Whether or not there is a relationship between use of mobile phones (analogue and digital cellulars, and cordless) and head tumour risk (brain tumours, acoustic neuromas, and salivary gland tumours) is still a matter of debate; progress requires a critical analysis of the methodological elements necessary for an impartial evaluation of contradictory studies. Methods A close examination of the protocols and results from all case-control and cohort studies, pooled- and meta-...

  2. An unusual presentation of a glomus tumour.

    LENUS (Irish Health Repository)

    Nugent, N

    2011-02-01

    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.

  3. Surgical management of epithelial parotid tumours

    International Nuclear Information System (INIS)

    Obaid, M.A.; Yusuf, A.

    2004-01-01

    Objective: To describe the clinicopathological presentation and treatment options in epithelial parotid tumours with emphasis on surgery. Subjects and Methods: Epithelial parotid tumours diagnosed and operated by an ENT surgeon and a general surgeon in 10 years during their posting in different teaching hospitals were included in the study. Clinical presentation, preoperative investigations, operative procedure, histopathology report, postoperative complications and further management were recorded. The data was collected and reviewed from the records of all the patients maintained by the authors. Results: Fifty-two patients presented with parotid tumour. Average age was 38 years. Commonest presentation was painless lump over the parotid region (85%), pain (15%), facial palsy, and enlarged neck nodes. Majority of tumours were benign, only two were recurrent. Parotid pleomorphic Adenoma (PPA) was the commonest benign tumour, others being Warthin's tumour and monomorphic adenoma. Adenoid cystic carcinoma was the commonest malignant tumour 29% followed by mucoepidermoid carcinoma. Others were carcinoma in PPA squamous cell carcinoma, malignant mixed tumour, malignant Iymphoepithelioma and undifferentiated carcinoma. Superficial parotidectomy (SP) was the commonest operation performed in 69%. Other procedures were total conservative parotidectomy in 11%, total radical surgery in 9% and enucleation in only one patient earliest in the series. Neck node dissection was done in 2 patients. Except for one child, rest of the 13 patients received postoperative radiotherapy and one patient of Iymphoepithelioma received chemotherapy in addition. Commonest postoperative complication was temporary facial weakness in 35% (18/52). Permanent facial palsy occurred in 08 patients. Of these 07 had a malignant process and only one patient had excision biopsy. Conclusion: Benign and malignant epithelial parotid tumours can be diagnosed by there clinical presentation . supplemented with

  4. Comparison of metastatic disease after local tumour treatment with radiotherapy or surgery in various tumour models

    International Nuclear Information System (INIS)

    Ruiter, J. de; Cramer, S.J.; Lelieveld, P.; Putten, L.M. van

    1982-01-01

    Spontaneous metastases in lymph nodes and/or the lung were obtained after tumour cell inoculation of four mouse tumours and one rat tumour into the foot-pads of syngeneic animals or their F 1 hybrids. Following local radiotherapy with doses of 45-80 Gy, significantly more mice died with metastases than following local amputation of the tumour-bearing foot when the 2661 carcinoma was involved. No significant difference was observed after these treatments for the other tumours. The enhancement of metastatic growth after local radiotherapy in the 2661 carcinoma seems not to be due to incomplete killing of tumour cells in the foot. The presence of irradiated normal structures and tumour tissue after radiotherapy promoted the outgrowth of 2661 carcinoma cells which were outside the radiation field at the time of treatment. Evidently, even under similar experimental conditions, radiotherapy may enhance the growth of metastases from some tumours and not from others. (author)

  5. Nuclear medicine in childhood tumours

    International Nuclear Information System (INIS)

    Hoefnagel, C.A.

    2004-01-01

    Full text: In recent years the contribution of nuclear medicine has been of increasing interest to paediatric oncology, in particular in imaging for diagnosis, staging and follow-up, in quantitative function analysis of organs at risk during oncological therapy, as well as in radionuclide therapy. For tumour imaging a great number of tumour-seeking radiopharmaceuticals are available, exploiting various metabolic and biological properties of individual tumours; several of these agents can also be applied for radionuclide therapy. More recent tracers allow the characterization of tumours, highlighting features like hormone receptors, hypoxia, MDR and apoptosis. New techniques in paediatric oncology include PET and probe-guided surgery. As a functional modality, nuclear medicine is well suited to monitor the function of organs at risk during treatment in paediatric oncology, in particular cardiac, pulmonary, renal and salivary gland function. A summary of applications and major Indications will be presented. Osteosarcoma: In differentiated osteosarcoma bone scintigraphy/SPECT using 99m Tc-diphosphonate may, as a result of Its targeting the tumour-produced osteoid, visualize not only the primary bone tumour and skeletal metastases, but also the extraosseous metastases. For preoperative therapy nd palliation of metastases beta-emitting bone-seeking agents, such as 89 Sr-chloride, 186 Re-HEDP and 153 Sm-EDTMP, are available. Lymphoma: 67 Ga-citrate has been used for decades in the detection, staging and follow up of lymphoma, as well as for early recognition of response to therapy. 201 TI-chloride scintigraphy/SPECT and PET using 18 F-deoxyglucose can also be used for this purpose. 99m Tc- sestamibi and 99m Tc-tetrofosmin are associated with p-glycoprotein, playing a role in multidrug resistance. In adults with recurrent non Hodgkin lymphoma treatment with 131 l- or 90 Y labelled anti-CD20 antibodies is highly effective. Thyroid carcinoma. 201 TI-chloride scintigraphy

  6. Effect of combined irradiation and EGFR/Erb-B inhibition with BIBW 2992 on proliferation and tumour cure in cell lines and xenografts

    International Nuclear Information System (INIS)

    Gurtner, Kristin; Ebert, Nadja; Pfitzmann, Dorothee; Eicheler, Wolfgang; Zips, Daniel; Baumann, Michael; Krause, Mechthild

    2014-01-01

    In previous experiments an enhanced anti-proliterative effect of the EGFR/ErbB tyrosine kinase inhibitor (TKI) BIBW 2992 with single dose irradiation was observed in FaDu tumour xenografts. Aim of the present experiment was to determine if this effect can also be seen in combination with a fractionated radiotherapy. Secondly we investigate the efficacy of BIBW 2992 on local tumour control for UT-SCC-15. Tumour pieces of FaDu, UT-SCC-14, A431, UT-SCC-15 (squamous cell carcinomas) and A7 (glioma) tumour models were transplanted onto the right hind leg of NMRI (nu/nu) nude mice. For evaluation of tumour growth mice were either treated daily orally with BIBW 2992 (30 mg/kg body weight), or carrier up to a final tumour size of 15 mm or with a fractionated radiotherapy (15f/15d, 30 Gy) with simultaneous application of BIBW 2992 or carrier. For local tumour control UT-SCC-15 tumours were treated with a fractionated radiotherapy (30f/6weeks) or received 30f/6 weeks in combination with daily orally BIBW 2992 (22.5 mg/kg b.w.) during RT. A significant effect on tumour growth time was observed in all tumour models for BIBW 2992 application alone. However, substantial intertumoural heterogeneity could be seen. In the UT-SCC-14, UT-SCC-15 and A431 tumour models a total regression of the tumours and no recurrence during treatment time (73 days) were determined where as for the A7 tumour only a slight effect was noticeable. For the combined treatment of fractionated radiotherapy (15f/15d) and BIBW 2992 administration a significant effect on tumour growth time was seen compared to irradiation alone for A7, UT-SCC-15 and A431 (ER 1.2 – 3.7), this advantage could not be demonstrated for FaDu and UT-SCC-14. However, the local tumour control was not altered for the UT-SCC-15 tumour model when adding BIBW 2992 to fractionated irradiation (30f/6weeks). A heterogeneous effect on tumour growth time of BIBW 2992 alone as well as in combination with fractionated irradiation could be

  7. Targeted radiotherapy with {sup 177} Lu-DOTA-TATE in athymic mice with induced pancreatic malignant tumours

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, M. A de; Pedraza L, M. [Department of Nuclear Medicine, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico D.F. (Mexico); Rodriguez C, J. [Faculty of Medicine, UAEM, Toluca, Estado de Mexico (Mexico); Ferro F, G. [ININ, 52045 Estado de Mexico (Mexico); Murphy S, E. [Hospital Santelena, Mexico D.F. (Mexico)

    2006-07-01

    Malignant pancreas tumours induced in athymic mice are a good model for targeted radiotherapy. The objective of this research was to estimate pancreatic tumour absorbed radiation doses and to evaluate {sup 177}Lu-DOTA-TATE as a therapeutic radiopharmaceutical that could be used in humans. AR42J murine pancreas cancer cells, which over-express somatostatin receptors, were injected in athymic mice and 20 days later the mean tumour size was 3.08 square cm (n=3). A mean of 86.3 MBq {sup 177}Lu-DOTA-TATE, was injected in a tail vein and 19 days after therapy the size of the tumours was 0.81 square cm. There was a partial relapse and after 16 days, when sacrificed, the mean tumour size was 8.28 cubic cm. An epithelial and sarcoma mixed tumour in the kidney of one treated mouse was found. The tumour of the control mouse was 8.61 cubic cm when sacrificed 14 days after tumour induction. Radiotherapy estimates to the tumours was 35.9-39.7 Gy and the tumours might have been completely reduced with a second therapy dose. These preliminary studies justify further therapeutic and dosimetry estimations to ensure that Lu-{sup 177}-DOTA-TATE will act as expected in man, considering kidney radiation. (Author)

  8. Skeletal (stromal) stem cells: an update on intracellular signaling pathways controlling osteoblast differentiation.

    Science.gov (United States)

    Abdallah, Basem M; Jafari, Abbas; Zaher, Walid; Qiu, Weimin; Kassem, Moustapha

    2015-01-01

    Skeletal (marrow stromal) stem cells (BMSCs) are a group of multipotent cells that reside in the bone marrow stroma and can differentiate into osteoblasts, chondrocytes and adipocytes. Studying signaling pathways that regulate BMSC differentiation into osteoblastic cells is a strategy for identifying druggable targets for enhancing bone formation. This review will discuss the functions and the molecular mechanisms of action on osteoblast differentiation and bone formation; of a number of recently identified regulatory molecules: the non-canonical Notch signaling molecule Delta-like 1/preadipocyte factor 1 (Dlk1/Pref-1), the Wnt co-receptor Lrp5 and intracellular kinases. This article is part of a Special Issue entitled: Stem Cells and Bone. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Tumours of the pineal region in childhood

    International Nuclear Information System (INIS)

    Herrmann, H.D.; Schulte, F.J.; Winkler, D.; Mueller, D.

    1988-01-01

    36 patients with tumours in the pineal region were treated between 1980 and 1986, 19 of whom were under 20 years of age. Diagnosis was based on cranial CT, supplemented to by MRI as from 1986. Preoperative angiography was peformed on all patients to demonstrate tumour vascularization and type of vascular supply. Stereotactic biopsies were complemented by intraoperative ventriculography. Stereotactic biopsy only was performed in 13 patients out of the total group to verify tumour histology. 23 patients were directly operated on primarily. 3 of these died postoperative. In cases of germ-cell tumours and pineal blastomas the total brain and the vertebral canal were irradiated. (orig./MG) [de

  10. 131I-MIBG and neuroendocrine tumours

    International Nuclear Information System (INIS)

    Oliva Gonzalez, Juan Perfecto; Gonzalez Gonzalez, Joaquin Jorge; Calderon Marin, Carlos Fabian

    2012-01-01

    Neuroendocrine tumours are neoplasms that arise from various tissues closely linked to the neural crest by their common embryological origin. These tumours have the ability to synthesize neurotransmitter peptides and hormones, as well as to store catecholamines. Some of these tumours express somatostatin receptors at their membranes, what have allowed nuclear medicine to be involved in their diagnosis, treatment and monitoring. Since they arise from different and varied types of tissues, these tumours have a wide range of signs and symptoms different for every one of them. These signs and symptoms mainly depend on their biochemical characteristics, given by the substances they secrete, as well as by their location, and consequently, they also depend on the place where the tumour appears, its local infiltration, and potential long-distance metastasis resulting from the tumour). Neuroendocrine tumours are diagnosed by means of nuclear medicine images, which are obtained by using different techniques and radiopharmaceuticals such as 99 mTc dimercaptosuccinic acid (DMSA(V)), 99 mTc-methoxy-isobutyl-isonitrile (MIBI), metaiodobenzylguanidine (MIBG) labelled with 131 I or 123 I ( 131 I-MIBG or 123 I -MIBG), 111 In-labelled octreotide, positron emission tomography, using 68 Ga-labelled somatostatin analogues and carcinoembryonic antigen monoclonal antibodies. Nuclear medicine uses mainly somatostatin analogues labelled with 90 Y or 177 Lu for the treatment of these tumours. This paper is aimed at showing our experience in the use of 131 I-MIBG for the diagnosis and treatment of neuroendocrine tumours.(author)

  11. Peptide receptor radionuclide therapy of neuroendocrine tumours

    International Nuclear Information System (INIS)

    Bodei, L.; Giammarile, F.

    2009-01-01

    Neuroendocrine tumours are considered relatively rare tumours that have the characteristic property of secreting bioactive substances, such as amines and hormones. They constitute a heterogeneous group, characterized by good prognosis, but important disparities of the evolutionary potential. In the aggressive forms, the therapeutic strategies are limited. The metabolic or internal radiotherapy, using radiolabelled peptides, which can act at the same time on the primary tumour and its metastases, constitutes a tempting therapeutic alternative, currently in evolution. The prospects are related to the development of new radiopharmaceuticals, with the use of other peptide analogues whose applications will overflow the framework of the neuro-endocrine tumours. (authors)

  12. Computed tomography in malignant primary bone tumours

    International Nuclear Information System (INIS)

    Kersjes, W.; Harder, T.; Haeffner, P.

    1990-01-01

    The importance of computed tomography is examined in malignant primary bone tumours using a strongly defined examination group of 13 Patients (six Ewing's-sarcomas, five osteosarcomas, one chondrosarcoma and one spindle-shaped cell sarcoma). Computed tomography is judged superior compared to plain radiographs in recognition of bone marrow infiltration and presentation of parosteal tumour parts as well as in analysis of tissue components of tumours, CT is especially suitable for therapy planning and evaluating response to therapy. CT does not provide sufficient diagnostic information to determine dignity and exact diagnosis of bone tumours. (orig.) [de

  13. Elevated tumour marker: an indication for imaging?

    LENUS (Irish Health Repository)

    McMahon, Colm J

    2012-02-01

    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\\

  14. Treatment Of Brain Tumours In Childhood

    International Nuclear Information System (INIS)

    Stancokova, T.

    2007-01-01

    Children tumours are the second most common oncologic diseases in childhood (20 %) with highest incidence of mortality in children oncology. Brain tumours form a heterogenous group of tumours with their classification,diagnostic criteria and therapeutic modalities. General principles of treatment involve neurosurgery, which is a prognostic factor, its radicality depends on localization. Radiotherapy has limitations in children until 3 years for possible late effects. Chemotherapy is effective in tumours with high growing rate. These days challenge is to improve therapeutic outcomes and minimalize toxicity of therapy. (author)

  15. 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

    International Nuclear Information System (INIS)

    Bacman, David; Merkel, Susanne; Croner, Roland; Papadopoulos, Thomas; Brueckl, Wolfgang; Dimmler, Arno

    2007-01-01

    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. 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. 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 shorter survival. Stromal TGF-beta receptor 2

  16. 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

    2007-08-01

    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

  17. Control of cell proliferation, endoreduplication, cell size, and cell death by the retinoblastoma-related pathway in maize endosperm

    KAUST Repository

    Sabelli, Paolo A.

    2013-04-22

    The endospermof cereal grains is one of the most valuable products of modern agriculture. Cereal endosperm development comprises different phases characterized by mitotic cell proliferation, endoreduplication, the accumulation of storage compounds, and programmed cell death. Although manipulation of these processes could maximize grain yield, how they are regulated and integrated is poorly understood. We show that the Retinoblastoma-related (RBR) pathway controls key aspects of endosperm development in maize. Down-regulation of RBR1 by RNAi resulted in up-regulation of RBR3-type genes, as well as the MINICHROMOSOME MAINTENANCE 2-7 gene family and PROLIFERATING CELL NUCLEAR ANTIGEN, which encode essential DNA replication factors. Both the mitotic and endoreduplication cell cycles were stimulated. Developing transgenic endosperm contained 42-58% more cells and ~70% more DNA than wild type, whereas there was a reduction in cell and nuclear sizes. In addition, cell death was enhanced. The DNA content of mature endosperm increased 43% upon RBR1 downregulation, whereas storage protein content and kernel weight were essentially not affected. Down-regulation of both RBR1 and CYCLIN DEPENDENT KINASE A (CDKA);1 indicated that CDKA;1 is epistatic to RBR1 and controls endoreduplication through an RBR1- dependent pathway. However, the repressive activity of RBR1 on downstream targets was independent from CDKA;1, suggesting diversification of RBR1 activities. Furthermore, RBR1 negatively regulated CDK activity, suggesting the presence of a feedback loop. These results indicate that the RBR1 pathway plays a major role in regulation of different processes during maize endosperm development and suggest the presence of tissue/organlevel regulation of endosperm/seed homeostasis.

  18. The Azospirillum brasilense Che1 chemotaxis pathway controls swimming velocity, which affects transient cell-to-cell clumping.

    Science.gov (United States)

    Bible, Amber; Russell, Matthew H; Alexandre, Gladys

    2012-07-01

    The Che1 chemotaxis-like pathway of Azospirillum brasilense contributes to chemotaxis and aerotaxis, and it has also been found to contribute to regulating changes in cell surface adhesive properties that affect the propensity of cells to clump and to flocculate. The exact contribution of Che1 to the control of chemotaxis and flocculation in A. brasilense remains poorly understood. Here, we show that Che1 affects reversible cell-to-cell clumping, a cellular behavior in which motile cells transiently interact by adhering to one another at their nonflagellated poles before swimming apart. Clumping precedes and is required for flocculation, and both processes appear to be independently regulated. The phenotypes of a ΔaerC receptor mutant and of mutant strains lacking cheA1, cheY1, cheB1, or cheR1 (alone or in combination) or with che1 deleted show that Che1 directly mediates changes in the flagellar swimming velocity and that this behavior directly modulates the transient nature of clumping. Our results also suggest that an additional receptor(s) and signaling pathway(s) are implicated in mediating other Che1-independent changes in clumping identified in the present study. Transient clumping precedes the transition to stable clump formation, which involves the production of specific extracellular polysaccharides (EPS); however, production of these clumping-specific EPS is not directly controlled by Che1 activity. Che1-dependent clumping may antagonize motility and prevent chemotaxis, thereby maintaining cells in a metabolically favorable niche.

  19. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial

    NARCIS (Netherlands)

    Smolen, Josef S.; Kay, Jonathan; Doyle, Mittie K.; Landewé, Robert; Matteson, Eric L.; Wollenhaupt, Jürgen; Gaylis, Norman; Murphy, Frederick T.; Neal, Jeffrey S.; Zhou, Yiying; Visvanathan, Sudha; Hsia, Elizabeth C.; Rahman, Mahboob U.; Ahern, Michael John; Hall, Stephen; Nash, Peter Thomas; Graninger, Winfried; Ebner, Wolfgang; Machold, Klaus; Zamani, Omid; Atkins, Christopher; Beaulieu, André; Bell, Mary; Fitzcharles, Mary Ann; Keystone, Edward; Khraishi, Majed; McKendry, Robert J. R.; Rahman, Proton; Thomason, Glen T. D.; Thorne, J. Carter; Bookman, Arthur; Faraawi, Rafat; Hannonen, Pekka; Leirisalo-Repo, Marjetta; Järvinen, Pentti; Braun, Jürgen; Burmester, Gerd; Fiehn, Christoph; Gruenke, Mathias; Bäuerle, Michael; Hauer, Rolf-Walter; Kellner, Herbert; Rubbert, Andrea; Schewe, Stefan; Sieper, Joachim; Tony, Hans-Peter; Kekow, Jörn; Ching, Daniel Wai Tho; Jones, Peter Brian Barrie; Singh, Gagrath Pradeep

    2009-01-01

    Tumour necrosis factor alpha (TNFalpha) inhibitors are frequently used to treat rheumatoid arthritis, but whether use of a different TNFalpha inhibitor can improve patient response is unknown. We assess the efficacy and safety of the TNFalpha inhibitor golimumab in patients with active rheumatoid

  20. Survival pathways under stress

    Indian Academy of Sciences (India)

    First page Back Continue Last page Graphics. Survival pathways under stress. Bacteria survive by changing gene expression. pattern. Three important pathways will be discussed: Stringent response. Quorum sensing. Proteins performing function to control oxidative damage.

  1. Tumour Necrosis Factor-alpha and Nuclear Factor-kappa B Gene Variants in Sepsis.

    Science.gov (United States)

    Acar, Leyla; Atalan, Nazan; Karagedik, E Hande; Ergen, Arzu

    2018-01-20

    The humoral system is activated and various cytokines are released due to infections in tissues and traumatic damage. Nuclear factor-kappa B dimers are encoded by nuclear factor-kappa B genes and regulate transcription of several crucial proteins of inflammation such as tumour necrosis factor-alpha. To investigate the possible effect of polymorphisms on tumour necrosis factor-alpha serum levels with clinical and prognostic parameters of sepsis by determining the nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A) gene polymorphisms and tumour necrosis factor-alpha serum levels. Case-control study. Seventy-two patients with sepsis and 104 healthy controls were included in the study. In order to determine the polymorphisms of nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A), polymerase chain reaction-restriction fragment length polymorphism analysis was performed and serum tumour necrosis factor-alpha levels were determined using an enzyme-linked immunosorbent assay. We observed no significant differences in tumour necrosis factor-alpha serum levels between the study groups. In the patient group, an increase in the tumour necrosis factor-alpha serum levels in patients carrying the tumour necrosis factor-alpha (-308 G/A) A allele compared to those without the A allele was found to be statistically significant. Additionally, an increase in the tumour necrosis factor-alpha serum levels in patients carrying tumour necrosis factor-alpha (-308 G/A) AA genotype compared with patients carrying the AG or GG genotypes was statistically significant. No significant differences were found in these 2 polymorphisms between the patient and control groups (p>0.05). Our results showed the AA genotype and the A allele of the tumour necrosis factor-alpha (-308 G/A) polymorphism may be used as a predictor of elevated tumour necrosis factor-alpha levels in patients with sepsis.

  2. Diagnostic utility of Wilms′ tumour-1 protein (WT-1 immunostaining in paediatric renal tumours

    Directory of Open Access Journals (Sweden)

    Surbhi Goyal

    2016-01-01

    Interpretation & conclusions: WT1 helps to differentiate Wilms′ tumour from other paediatric renal tumours. It may help in differentiating the two subgroups of Wilms′ tumour which have distinct molecular pathogenesis and biological behaviour, however, further prospective studies are required for validation of this hypothesis.

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

    LENUS (Irish Health Repository)

    Aquilina, K

    2012-02-03

    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. Evidence for an excitatory amino acid pathway in the brainstem and for its involvement in cardiovascular control.

    Science.gov (United States)

    Somogyi, P; Minson, J B; Morilak, D; Llewellyn-Smith, I; McIlhinney, J R; Chalmers, J

    1989-09-04

    The source and possible role of excitatory amino acid projections to areas of the ventrolateral medulla (VLM) involved in cardiovascular control were studied. Following the injection of [3H]D-aspartate ([3H]D-Asp), a selective tracer for excitatory amino acid pathways, into vasopressor or vasodepressor areas of the VLM in rats, more than 90% of retrogradely labelled neurones were found in the nucleus of the solitary tract (NTS). Very few of the [3H]D-Asp-labelled cells were immunoreactive for tyrosine hydroxylase, none for phenylethanolamine-N-methyltransferase or gamma-aminobutyric acid. The density of labelled cells in the NTS was similar to that obtained with the non-selective tracers wheat germ agglutinin-horseradish peroxidase (WGA-HRP) and WGA-colloidal gold, but these tracers also labelled other cell groups in the medulla. Furthermore, the decrease in blood pressure, caused by pharmacological activation of neurones in the NTS of rats, or by electrical stimulation of the aortic depressor nerve in rabbits could be blocked by the selective N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate injected into the caudal vasodepressor area of the VLM. This area corresponds to the termination of [3H]D-Asp transporting NTS neurones. These results provide evidence that a population of NTS neurones projecting to the VLM use excitatory amino acids as transmitters. Among other possible functions, this pathway may mediate tonic and reflex control of blood pressure via NMDA receptors in the VLM.

  5. Passive accumulation of Au nanoparticles in tumours in mice

    International Nuclear Information System (INIS)

    Kempson, I.M.; Wang, C.H.; Lai, S.F.; Cai, X.; Hwu, Y.; Yang, C.S.; Margaritondo, G.

    2011-01-01

    Full text: Enhance biocompatibility and passive accumulation of gold nanoparticles into tumours in vivo. Improved biocompatible nanoparticles synthesized by radical synthesis in solution by X-ray irradiation (5,000 Gy/sec). As an alternative to the use of chemical reducing agents, irradiation solutions can cause the reduction of dissolved ions to form nuclei form in sub-second times and growth is easily controlled by physically the X-ray intensity. The intensity can be used to manipulate growth rates for different applications and in the information of spherical and rod-structures. Size is easily controlled by exposure time and capping agents and provides high reproducibility with small size distributions. Resulting body burden in subcutaneous tumour mouse models was determined in various organs with ICP-MS. Cellular distributions were analysed with transmission x-ray Microscopy and conventional histology. The resulting nanoparticle sols were highly concentrated. naturally sterile, have high temperature stability and synthesised with fewer chemical reactants; providing greater chemical and biological adaptability. The results demonstrated that a passivated biocompatible surface, minimizing physiological clearance from the animal allows non-specific accumulation of large concentrations of nanoparticles into tumour tissues and significant penetration and circumnavigation of the binding site barrier effect. Concentrations of gold reached ∼ 25 times greater than surrounding muscle tissue and were retained for many hours. Physicochemical properties of nanoparticles impart significant influence on their ability to penetrate and accumulate in tumour tissues. Effective synthesis enables high concentrations of gold nanoparticles to accumulate in tumour tissues which could be applied to development in radiation oncology applications.

  6. Redox status evaluation in dogs affected by mast cell tumour.

    Science.gov (United States)

    Finotello, R; Pasquini, A; Meucci, V; Lippi, I; Rota, A; Guidi, G; Marchetti, V

    2014-06-01

    Oxidative stress status has been evaluated in depth in human medicine and its role in carcinogenesis has been clearly established. The purpose of this prospective study was to evaluate antioxidant concentrations and oxidative stress in dogs with mast cell tumours (MCTs) that had received no previous treatments, and to compare them to healthy controls. In 23 dogs with mast cell tumour and 10 healthy controls, oxidative status was assessed using the Reactive Oxygen Metabolites-derived compounds (d-ROMs) test, antioxidant activity was measured by the Biological Antioxidant Potential (BAP) test, and α-tocopherol levels were evaluated using high-performance liquid chromatography and ultraviolet analysis. At baseline, dogs with MCT had significantly higher d-ROMs (P defence barrier are altered in dogs with newly diagnosed MCT compared with control dogs. Future studies are needed in order to assess the prognostic role of oxidative stress and to evaluate the impact of different therapeutic approaches. © 2012 John Wiley & Sons Ltd.

  7. Bioactive albumin-based carriers for tumour chemotherapy.

    Science.gov (United States)

    Shahzad, Yasser; Khan, Ikram Ullah; Hussain, Talib; Alamgeer; Serra, Christophe A; Rizvi, Syed A A; Gerber, Minja; du Plessis, Jeanetta

    2014-01-01

    Proteins are posed as the natural counterpart of the synthetic polymers for the development of drug delivery systems and few of them, have been regarded safe for drug delivery purposes by the United States Food and Drug Administration (FDA). Serum albumin is the most abundant protein in human blood. Interest in the exploration of pharmaceutical applications of albumin-based drug delivery carriers, especially for the delivery of chemotherapeutic agents, has increased in recent years. Albumin has several advantages over synthetic polymers, as it is biocompatible, biodegradable, has low cytotoxicity and has an excellent binding capacity with various drugs. Micro- and nano-carriers not only protect active pharmaceutical ingredients against degradation, but also offer a prolonged release of drugs in a controlled fashion. Since existing tumour chemotherapeutic agents neither target tumour cells, nor are they specific to tumour cells, a slow release of drugs from carriers would be beneficial in targeting carcinogenic cells intracellularly. This article aims at providing an overview of pharmaceutical applications of albumin as a drug delivery carrier in tumour chemotherapy.

  8. Hypothesis: solid tumours behave as systemic metabolic dictators.

    Science.gov (United States)

    Lee, Yang-Ming; Chang, Wei-Chun; Ma, Wen-Lung

    2016-06-01

    Current knowledge regarding mechanisms of carcinogenesis in human beings centres around the accumulation of genetic instability, amplified cellular signalling, disturbed cellular energy metabolism and microenvironmental regulation governed by complicated cell-cell interactions. In this article, we provide an alternative view of cancer biology. We propose that cancer behaves as a systemic dictator that interacts with tissues throughout the body to control their metabolism and eventually homeostasis. The mechanism of development of this endocrine organ-like tumour (EOLT) tissue might be the driving force for cancer progression. Here, we review the literature that led to the development of this hypothesis. The EOLT phenotype can be defined as a tumour that alters systemic homeostasis. The literature indicates that the EOLT phenotype is present throughout cancer progression. The feedback mechanism that governs the interaction between tumours and various organs is unknown. We believe that investigating the mechanism of EOLT development may advance the current knowledge of regulation within the tumour macroenvironment and consequently lead to new diagnostic methods and therapy. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  9. Targeted radiotherapy with Sm-153-EDTMP in nine cases of canine primary bone tumours

    Directory of Open Access Journals (Sweden)

    R.J. Milner

    1998-07-01

    Full Text Available Nine dogs with primary bone tumours were treated with Samarium-153-EDTMP (Sm-153- EDTMP. Conventional treatment protocols were precluded by the size of the dogs and the owners' refusal of limb amputation. All the tumours were of the appendicular skeleton; 4 were confirmed osteosarcomas. The other 5 tumours were radiologically suspect for osteosarcoma. Bone scans were performed on all dogs using Technetium-99m-methylene diphosphonate (Tc-99m-MDP before administration of Sm-153-EDTMP. Regions of interest were identified over the contralateral limb at the same site as the tumour and counts per pixel were recorded for the tumour and contralateral limb and expressed as a ratio. The dogs were given 1 injection of 37 MBq/kg (1 mCi/kg of Sm-153-EDTMP intravenously. Thoracic and primary tumour site radiographs were taken at monthly or 2-monthly intervals to monitor progression of the primary tumour and search for evidence of metastasis. Two dogs showed no response to treatment, with an increase in bone pain, and were euthanased within 1 month. In 1 dog, a tumour of the scapula underwent complete involution and the dog is considered free of disease at 20 months post Sm-153-EDTMP treatment. The overall tumourcidal effect of a single dose of Sm-153-EDTMP on primary bone tumours was difficult to evaluate in this group of dogs, as, with one exception, all the primary tumours progressed over time and the dogs were euthanased. Pain control, for which Sm-155-EDTMP is used in man, was not evident, except in the dog that responded completely to treatment.

  10. 2-Acetylpyridine N4-Phenyl- Thiosemicarbazone as a new tool for tumour diagnosis

    International Nuclear Information System (INIS)

    Soares, Marcella Araugio; Pesquero, Jorge Luiz

    2009-01-01

    The aim of this work was to determine in vivo biodistribution of radiolabelled 2-acetylpyridine N4 phenyl thiosemicarbazone (Ph) and to evaluate its applicability for tumour diagnosis. Ph was labelled with 125 I using lactoperoxidase method and radiochemical analysis was performed by chromatography. 125 I-Ph production was successful with 86 ± 9.2% of radiochemical purity and high specific activity (17.6 TBq /mmol). 125 I-Ph was used for biodistribution and pharmacokinetics studies on Swiss mice bearing Ehrlich solid tumour. 125 I-Ph presented a rapid blood clearance (T 1/2 = 97.2 min.) and the kidneys were the main excretion pathway (CL0.01 mL/min). 125 I-Ph uptake was significant in tumour (2.5%ID/g) and tumour-to-normal tissue uptake was more than 20-fold higher depending on the organ. The uptake by the organs like heart, lungs, stomach and liver followed the blood perfusion. Our results suggest that 125 I-Ph possess indispensable characteristics for an efficient radiopharmaceutical for tumour diagnosis. The next step will be to evaluate the quality of tumour SPECT images provided by 131 I-Ph. (author)

  11. 2-Acetylpyridine N4-Phenyl- Thiosemicarbazone as a new tool for tumour diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Soares, Marcella Araugio; Pesquero, Jorge Luiz [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Dept. de Fisiologia e Biofisica], e-mail: marcellaaraugio@yahoo.com.br; Costa, Pryscila R. da; Mendes, Isolda M.C.; Beraldo, Heloisa; Santos, Raquel Gouvea dos [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil)], e-mail: santosr@cdtn.br

    2009-07-01

    The aim of this work was to determine in vivo biodistribution of radiolabelled 2-acetylpyridine N4 phenyl thiosemicarbazone (Ph) and to evaluate its applicability for tumour diagnosis. Ph was labelled with {sup 125}I using lactoperoxidase method and radiochemical analysis was performed by chromatography. {sup 125}I-Ph production was successful with 86 {+-} 9.2% of radiochemical purity and high specific activity (17.6 TBq /mmol). {sup 125}I-Ph was used for biodistribution and pharmacokinetics studies on Swiss mice bearing Ehrlich solid tumour. {sup 125}I-Ph presented a rapid blood clearance (T{sub 1/2}= 97.2 min.) and the kidneys were the main excretion pathway (CL0.01 mL/min). {sup 125}I-Ph uptake was significant in tumour (2.5%ID/g) and tumour-to-normal tissue uptake was more than 20-fold higher depending on the organ. The uptake by the organs like heart, lungs, stomach and liver followed the blood perfusion. Our results suggest that {sup 125}I-Ph possess indispensable characteristics for an efficient radiopharmaceutical for tumour diagnosis. The next step will be to evaluate the quality of tumour SPECT images provided by {sup 131}I-Ph. (author)

  12. Malignant tumours of the vulva

    International Nuclear Information System (INIS)

    Simonsen, E.

    1983-01-01

    The thesis analyses 317 patients with vulvar malignancies treated at the University Hospital, Lund, during 1960-1979. The three most common histological types of malignancy have been analysed. The oncological clinic in Lund has since the 1960's used a surgical technique where the primary tumour and the regional lymph nodes are operated on in two separate surgical seances. The vulvectomy is performed with tarm knife technique, and the wound is left open. The 5-year crude survival rate for the entire patient material treated with curative intention was over 60 %, which agrees well with reports from other centres. Our surgical approach using two separate seances has, however, much lower rates of postoperative complications and mortality than the rates in other reports. The overall most important prognostic factors for the patients with invasive vulvar malignancies are the presence of lymphatic metastases at the time of surgery, and the surgical radicality of the primary surgery. The treatment at most stages of tumour development and most histological types should include total vulvectomy preoperative irradiation of the inguinal lymph nodes, and inguinal lymphadenectomy. Only local extirpation and hemivulvectomy are, however, indicated for small microinvasively growing squamous cell carcinoma and basal cell carcinoma. Samll invasive onesided squamous cell carcinoma is best treated with ipsilateral surgery combined with preoperative irradiation of the inguinal lymph nodes. Patients with metastases in the inguinal lymph nodes should receive additional irradiation of the inguinal and pelvic lymph node stations. (Author)

  13. Assessment of the response of tumours to radiation: clinical and experimental studies

    International Nuclear Information System (INIS)

    Suit, H.D.; Walker, A.M.

    1980-01-01

    There is an important and active research programme at the laboratory and clinical level to develop indicators of the ultimate local response of tumours to radiation. In order to be of great value clinically indicators should yield a high true positivity and a low false positivity so that revisions of therapeutic strategy will be made only when there is a real need for such a change. The available data in the literature from the clinical studies, when analysed in terms of the true and false positive rates, indicate that the extent of regression at the completion of external beam therapy is not a useful prognostic indicator. This pertains to populations of tumour of a specific histopathological type, tumour size and anatomic site. Studies of laboratory animal tumour models have shown that regression patterns may be useful prognostic indicators for a tumour which is characterized by moderate immunogenicity and where there is close correlation between complete regression and permanent control. In contrast for tumours which are weakly or nonimmunogenic and which regress completely even at low tumour control probabilities, the pattern of regression has not been demonstrated to be of prognostic value. (author)

  14. Growth of extrapulmonary tumours after inhalation of small doses of plutonium oxide by rats

    International Nuclear Information System (INIS)

    Nolibe, D.; Masse, R.; L'Hullier, I.; Metivier, H.; Lafuma, J.

    1983-01-01

    After inhalation of plutonium oxide ( 239 PuO 2 ) involving initial lung burdens ranging from 74 to 103 Bq, male rats of the Wistar strain are kept in conditions allowing maximum survival; tumour incidences for the target organ (lung) and for the rest of the organs are calculated separately after the death of the animals. In the outbred Wistar rat the incidence of lung tumours is 18.5% for an initial lung burden of 74 Bq. The mean survival time of animals having such tumours is 973 days after inhalation. For an initial burden of 103 Bq syngenetic Wistar AG rats show a lower frequency of lung tumours (6.1%), but also a much reduced mean survival time, namely 757 days. Compared with the frequencies observed in the corresponding control groups, the frequency of non-pulmonary tumours is twice as high (12%) in consanguineous rats and six times as high (25.9%) in conventional rats. A supralinear dose-effect relationship at very low doses seems improbable in view of the dose delivered ( -3 Gy in the most exposed organs, such as the liver) and, in particular, because there is no correlation between the dose delivered to the organs and the location of the tumours. The exposed animals show, on the one hand, no specificity of organs for the surplus extrapulmonary tumours observed, and on the other, an inhibition by about 45% in the natural cytotoxic activity (natural killers) measured one year after inhalation. These observations suggest the hypothesis that an anti-tumour control mechanism is affected, perhaps as a result of the irradiation experienced during the circulation of blood cells in the lung capillaries. The failure of this system would in that case allow the expression of neoplastic characters as ageing progresses. A non-specific BCG immunotherapy does not restore this anti-tumour control system. (author)

  15. Fast growth associated with aberrant vasculature and hypoxia in fibroblast growth factor 8b (FGF8b) over-expressing PC-3 prostate tumour xenografts

    International Nuclear Information System (INIS)

    Tuomela, Johanna; Solin, Olof; Minn, Heikki; Härkönen, Pirkko L; Grönroos, Tove J; Valta, Maija P; Sandholm, Jouko; Schrey, Aleksi; Seppänen, Jani; Marjamäki, Päivi; Forsback, Sarita; Kinnunen, Ilpo

    2010-01-01

    Prostate tumours are commonly poorly oxygenated which is associated with tumour progression and development of resistance to chemotherapeutic drugs and radiotherapy. Fibroblast growth factor 8b (FGF8b) is a mitogenic and angiogenic factor, which is expressed at an increased level in human prostate tumours and is associated with a poor prognosis. We studied the effect of FGF8b on tumour oxygenation and growth parameters in xenografts in comparison with vascular endothelial growth factor (VEGF)-expressing xenografts, representing another fast growing and angiogenic tumour model. Subcutaneous tumours of PC-3 cells transfected with FGF8b, VEGF or empty (mock) vectors were produced and studied for vascularity, cell proliferation, glucose metabolism and oxygenation. Tumours were evaluated by immunohistochemistry (IHC), flow cytometry, use of radiolabelled markers of energy metabolism ([ 18 F]FDG) and hypoxia ([ 18 F]EF5), and intratumoral polarographic measurements of pO 2 . Both FGF8b and VEGF tumours grew rapidly in nude mice and showed highly vascularised morphology. Perfusion studies, pO 2 measurements, [ 18 F]EF5 and [ 18 F]FDG uptake as well as IHC staining for glucose transport protein (GLUT1) and hypoxia inducible factor (HIF) 1 showed that VEGF xenografts were well-perfused and oxygenised, as expected, whereas FGF8b tumours were as hypoxic as mock tumours. These results suggest that FGF8b-induced tumour capillaries are defective. Nevertheless, the growth rate of hypoxic FGF8b tumours was highly increased, as that of well-oxygenised VEGF tumours, when compared with hypoxic mock tumour controls. FGF8b is able to induce fast growth in strongly hypoxic tumour microenvironment whereas VEGF-stimulated growth advantage is associated with improved perfusion and oxygenation of prostate tumour xenografts

  16. Convective Influence and Transport Pathways Controlling the Tropical Distribution of Carbon Monoxide at 100 Hpa

    Science.gov (United States)

    Jensen, Eric; Bergman, John; Pfister, Leonard; Ueyama, Rei; Kinnison, Doug

    2014-01-01

    Trajectory calculations with convective influence diagnosed from geostationary-satellite cloud measurements are used to evaluate the relative importance of different Tropical Tropopause Layer (TTL) transport pathways for establishing the distribution of carbon monoxide (CO) at 100 hPa as observed by the Microwave Limb Sounder (MLS) on board the Aura satellite. Carbon monoxide is a useful tracer for investigating TTL transport and convective influence because the CO lifetime is comparable to the time require for slow ascent through the TTL (a couple of months). Offline calculations of TTL radiative heating are used to determine the vertical motion field. The simple trajectory model does a reasonable job of reproducing the MLS CO distributions during Boreal wintertime and summertime. The broad maximum in CO concentration over the Pacific is primarily a result of the strong radiative heating (indicating upward vertical motion) associated with the abundant TTL cirrus in this region. Sensitivity tests indicate that the distinct CO maximum in the Asian monsoon anticyclone is strongly impacted by extreme convective systems with detrainment of polluted air above 360 K potential temperature. The relative importance of different CO source regions will also be discussed.

  17. Targeting Plant Ethylene Responses by Controlling Essential Protein-Protein Interactions in the Ethylene Pathway.

    Science.gov (United States)

    Bisson, Melanie M A; Groth, Georg

    2015-08-01

    The gaseous plant hormone ethylene regulates many processes of high agronomic relevance throughout the life span of plants. A central element in ethylene signaling is the endoplasmic reticulum (ER)-localized membrane protein ethylene insensitive2 (EIN2). Recent studies indicate that in response to ethylene, the extra-membranous C-terminal end of EIN2 is proteolytically processed and translocated from the ER to the nucleus. Here, we report that the conserved nuclear localization signal (NLS) mediating nuclear import of the EIN2 C-terminus provides an important domain for complex formation with ethylene receptor ethylene response1 (ETR1). EIN2 lacking the NLS domain shows strongly reduced affinity for the receptor. Interaction of EIN2 and ETR1 is also blocked by a synthetic peptide of the NLS motif. The corresponding peptide substantially reduces ethylene responses in planta. Our results uncover a novel mechanism and type of inhibitor interfering with ethylene signal transduction and ethylene responses in plants. Disruption of essential protein-protein interactions in the ethylene signaling pathway as shown in our study for the EIN2-ETR1 complex has the potential to guide the development of innovative ethylene antagonists for modern agriculture and horticulture. Copyright © 2015 The Author. Published by Elsevier Inc. All rights reserved.

  18. A new pathway in the control of the initiation of puberty: the MKRN3 gene.

    Science.gov (United States)

    Abreu, Ana Paula; Macedo, Delanie B; Brito, Vinicius N; Kaiser, Ursula B; Latronico, Ana Claudia

    2015-06-01

    Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. The role of MKRN3, an imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-13), in pubertal initiation was first described in 2013 after the identification of deleterious MKRN3 mutations in five families with central precocious puberty (CPP) using whole-exome sequencing analysis. Since then, additional loss-of-function mutations of MKRN3 have been associated with the inherited premature sexual development phenotype in girls and boys from different ethnic groups. In all of these families, segregation analysis clearly demonstrated autosomal dominant inheritance with complete penetrance, but with exclusive paternal transmission, consistent with the monoallelic expression of MKRN3 (a maternally imprinted gene). Interestingly, the hypothalamic Mkrn3 mRNA expression pattern in mice correlated with a putative inhibitory input on puberty initiation. Indeed, the initiation of puberty depends on a decrease in factors that inhibit the release of GnRH combined with an increase in stimulatory factors. These recent human and animal findings suggest that MKRN3 plays an inhibitory role in the reproductive axis to represent a new pathway in pubertal regulation. © 2015 Society for Endocrinology.

  19. The role of choline (Cho) in the diagnostics and differentiation of brain tumours with HMRS technique

    International Nuclear Information System (INIS)

    Sobiecka, B.; Urbanik, A.

    2009-01-01

    Background: The aim of the research was a comprehensive analysis of Cho concentration and Cho/Cr, NAA/Cho, NAA/Cho+Cr ratios for the purposes of the diagnostics and differentiation of brain tumours (the type of the pathological lesion in patients with brain tumours) with the use of HMRS technique. Material/Methods: The HMRS examinations were performed with the use of the MRI Signa Excite 1.5 T system, in PRESS technique (TR = 1500 ms, TE = 35 ms) and involved 100 patients with brain tumours (age range: 18 to 81 yrs, mean age 50.61). Spectra were taken from three different locations: tumour centre, the tumour edge and contralateral unchanged cerebral tissue. All patients underwent surgery followed by histopathological analysis, on the basis of which two groups were separated (benign tumours, malignant tumours - 50 cases each). Additionally, 30 healthy volunteers in the age of 20 to 79 years (mean age 40.8) were examined. Results: The comparison of the examined patients with the control group revealed significantly higher Cho concentrations in patients with brain tumours. The analysis of Cho concentration was also performed with consideration of the age factor (under and over 60 years of age). Significantly lower mean Cho concentrations were discovered in a group of patients under 60 years of age. The analysis of Cho concentrations and Cho/Cr ratios reveled statistical significance for two factors: voxel location factor and the type of the pathological lesion. The average of Cho concentration and Cho/Cr ratios were higher in the group of patients with malignant tumours. The highest Cho concentrations and Cho/Cr ratios were observed in the tumour centre. The relative NAA/Cho and NAA/Cho+Cr ratios were statistically significant when taking into consideration the voxel location factor only. The results received from contralateral normal cerebral tissue (the internal model) were compared with control group (the external model). Mean values of Cho concentration were

  20. REPORT OF SEVEN CASES OF METASTATIC TUMOURS

    African Journals Online (AJOL)

    Major Adebayo

    Metastatic lesions may mimic odontogenic infections and other disease conditions in the oral cavity in presentation leading to late diagnosis by the unwary clinician. In Nigeria, reports on jaw tumours from metastasis elsewhere are quite scarce. This report presents a series of histologically verified metastatic tumours to the ...

  1. Second primary tumours in oral cancer

    NARCIS (Netherlands)

    van der Waal, I.; de Bree, R.

    2010-01-01

    Second primary tumours in patients treated for oral cancer occur at a rate of 3% to 7% per year. The majority of these tumours show up at least six months after the detection of the primary and are often located in the upper aerodigestive tract. Cessation of smoking habits may reduce the risk of the

  2. Tumour cell expansion in bladder epithelium

    NARCIS (Netherlands)

    J.M.J. Rebel (Annemarie)

    1995-01-01

    textabstractBladder cancer is common in western society. The major problem of patients with superficial bladder cancer is the high recurrence rate and multifocality of these tumours. In 70 % of the patients superficial bladder cancer recurs after local resection of the tumour within 15 years. The

  3. Tumour screening by means of tomography methods

    International Nuclear Information System (INIS)

    Diederich, S.

    2005-01-01

    Tomography methods such as computer tomography (CT), magnetic resonance tomography (MRT), and sonography/ultrasound examinations make it possible to detect small asymptomatic tumours, thus potentially preventing their manifestation at an advanced stage and improving survival prospects for the patients concerned. There are data available on various common tumours which show that modern tomography methods are capable of detecting not only small asymptomatic tumours but also their benign precursors (e.g. polyps of the large intestine). This has been demonstrated for lung cancer, colon cancer and breast cancer. However, it has not been possible to date to show for any tomography method or any type of tumour that the systematic use of such diagnostic procedures does anything to lower the mortality rate for that tumour. For other types of tumour (pancreatic cancer, kidney cancer, ovary cancer) the above named methods are either not sufficiently sensitive or the body of data that has accumulated on their respective use is too small to judge the benefit of tomography screenings. Current technical developments make it appear probable that for many types of cancer the reliability with which small tumours can be detected will improve in future. Studies aimed at clarifying the potential of screenings for reducing mortality rates are already underway for lung cancer and would be worthwhile performing for other tumour types

  4. CASE REPORT Paraspinal primitive neuroectodermal tumour (PNET)

    African Journals Online (AJOL)

    could be confirmed on the lateral lumbar spine X-ray. The T11 inter- pedicular distance was ... Department of Diagnostic Radiology, University of Limpopo, Medunsa Campus. CASE REPORT. 18. SA JOURNAL OF ... tumours from neural crest origin.1-4,6 PNET and ES are classified together into the Ewing family of tumours ...

  5. Maternal sensitivity and latency to positive emotion following challenge: pathways through effortful control.

    Science.gov (United States)

    Conway, Anne; McDonough, Susan C; Mackenzie, Michael; Miller, Alison; Dayton, Carolyn; Rosenblum, Katherine; Muzik, Maria; Sameroff, Arnold

    2014-01-01

    The ability to self-generate positive emotions is an important component of emotion regulation. In this study, we focus on children's latency to express positive emotions following challenging situations and assess whether this ability operates through early maternal sensitivity and children's effortful control. Longitudinal relations between maternal sensitivity, infant negative affect, effortful control, and latency to positive emotion following challenge were examined in 156 children who were 33 months of age. Structural equation models supported the hypothesis that maternal sensitivity during infancy predicted better effortful control and, in turn, shorter latencies to positive emotions following challenge at 33 months. Directions for future research are discussed. © 2014 Michigan Association for Infant Mental Health.

  6. Distinct Cell Guidance Pathways Controlled by the Rac and Rho GEF Domains of UNC-73/TRIO in Caenorhabditis elegans

    Science.gov (United States)

    Marcus-Gueret, Nancy; Schmidt, Kristopher L.; Stringham, Eve G.

    2012-01-01

    The cytoskeleton regulator UNC-53/NAV2 is required for both the anterior and posterior outgrowth of several neurons as well as that of the excretory cell while the kinesin-like motor VAB-8 is essential for most posteriorly directed migrations in Caenorhabditis elegans. Null mutations in either unc-53 or vab-8 result in reduced posterior excretory canal outgrowth, while double null mutants display an enhanced canal extension defect, suggesting the genes act in separate pathways to control this posteriorly directed outgrowth. Genetic analysis of putative interactors of UNC-53 or VAB-8, and cell-specific rescue experiments suggest that VAB-8, SAX-3/ROBO, SLT-1/Slit, and EVA-1 are functioning together in the outgrowth of the excretory canals, while UNC-53 appears to function in a parallel pathway with UNC-71/ADAM. The known VAB-8 interactor, the Rac/Rho GEF UNC-73/TRIO operates in both pathways, as isoform specific alleles exhibit enhancement of the phenotype in double-mutant combination with either unc-53 or vab-8. On the basis of these results, we propose a bipartite model for UNC-73/TRIO activity in excretory canal extension: a cell autonomous function that is mediated by the Rho-specific GEF domain of the UNC-73E isoform in conjunction with UNC-53 and UNC-71 and a cell nonautonomous function that is mediated by the Rac-specific GEF domain of the UNC-73B isoform, through partnering with VAB-8 and the receptors SAX-3 and EVA-1. PMID:21996675

  7. Evidence for a Chk2-BRCA1-BRCA2 pathway in controlling homologous recombination

    International Nuclear Information System (INIS)

    Powell, S.N.

    2003-01-01

    The BRCA2 protein is thought to play a role as a supportive protein for the assembly of Rad51 filaments at the sites of DNA damage or stalled DNA replication, and thereby facilitates the process of homologous recombination (HR). We provide direct evidence that the interaction of BRCA2 and Rad51, via the BRC repeat motifs of BRCA2, is the key to its function in HR. Furthermore, the BRCA2's role to facilitate HR is dependent on a replicating DNA template, closely linking the process of HR to DNA replication. To date, no other role for BRCA2 has been elucidated in-vivo. BRCA1, by contrast, has a complex series of functions including a supportive role in HR, a possible role in non-homologous recombination (NHR), transcriptional co-activation and E3 ubiquitin ligase activity. The protein undergoes extensive post-translational modification, principally by phosphorylation, in both S-phase and in response to DNA damage. We show that ATM-dependent modifications of BRCA1 are important for S-phase and G2/M checkpoints, but have no direct impact on DNA repair. However, a chk2 dependent modification of BRCA1 at serine-988, appears critical for the promotion of Rad51-dependent HR and the inhibition of Mre11/Rad50/NBS1- dependent repair. Direct modification of chk2 kinase activity, by over-expression of a kinase-dead chk2, results in an identical phenotype as seen with the S988A mutation of BRCA1. Taken together, these results suggest that a chk2-BRCA1-BRCA2 dependent pathway promotes error-free HR, suppresses error-prone NHR and thereby maintains genomic stability

  8. Gene expression profile and genomic alterations in colonic tumours induced by 1,2-dimethylhydrazine (DMH) in rats

    International Nuclear Information System (INIS)

    Femia, Angelo Pietro; Luceri, Cristina; Toti, Simona; Giannini, Augusto; Dolara, Piero; Caderni, Giovanna

    2010-01-01

    Azoxymethane (AOM) or 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats shares many phenotypical similarities with human sporadic colon cancer and is a reliable model for identifying chemopreventive agents. Genetic mutations relevant to human colon cancer have been described in this model, but comprehensive gene expression and genomic analysis have not been reported so far. Therefore, we applied genome-wide technologies to study variations in gene expression and genomic alterations in DMH-induced colon cancer in F344 rats. For gene expression analysis, 9 tumours (TUM) and their paired normal mucosa (NM) were hybridized on 4 × 44K Whole rat arrays (Agilent) and selected genes were validated by semi-quantitative RT-PCR. Functional analysis on microarray data was performed by GenMAPP/MappFinder analysis. Array-comparative genomic hybridization (a-CGH) was performed on 10 paired TUM-NM samples hybridized on Rat genome arrays 2 × 105K (Agilent) and the results were analyzed by CGH Analytics (Agilent). Microarray gene expression analysis showed that Defcr4, Igfbp5, Mmp7, Nos2, S100A8 and S100A9 were among the most up-regulated genes in tumours (Fold Change (FC) compared with NM: 183, 48, 39, 38, 36 and 32, respectively), while Slc26a3, Mptx, Retlna and Muc2 were strongly down-regulated (FC: -500; -376, -167, -79, respectively). Functional analysis showed that pathways controlling cell cycle, protein synthesis, matrix metalloproteinases, TNFα/NFkB, and inflammatory responses were up-regulated in tumours, while Krebs cycle, the electron transport chain, and fatty acid beta oxidation were down-regulated. a-CGH analysis showed that four TUM out of ten had one or two chromosomal aberrations. Importantly, one sample showed a deletion on chromosome 18 including Apc. The results showed complex gene expression alterations in adenocarcinomas encompassing many altered pathways. While a-CGH analysis showed a low degree of genomic imbalance, it is interesting to

  9. Drosophila insulin and target of rapamycin (TOR pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo

    Directory of Open Access Journals (Sweden)

    Parisi Federica

    2011-09-01

    Full Text Available Abstract Background Genetic studies in Drosophila melanogaster reveal an important role for Myc in controlling growth. Similar studies have also shown how components of the insulin and target of rapamycin (TOR pathways are key regulators of growth. Despite a few suggestions that Myc transcriptional activity lies downstream of these pathways, a molecular mechanism linking these signaling pathways to Myc has not been clearly described. Using biochemical and genetic approaches we tried to identify novel mechanisms that control Myc activity upon activation of insulin and TOR signaling pathways. Results Our biochemical studies show that insulin induces Myc protein accumulation in Drosophila S2 cells, which correlates with a decrease in the activity of glycogen synthase kinase 3-beta (GSK3β a kinase that is responsible for Myc protein degradation. Induction of Myc by insulin is inhibited by the presence of the TOR inhibitor rapamycin, suggesting that insulin-induced Myc protein accumulation depends on the activation of TOR complex 1. Treatment with amino acids that directly activate the TOR pathway results in Myc protein accumulation, which also depends on the ability of S6K kinase to inhibit GSK3β activity. Myc upregulation by insulin and TOR pathways is a mechanism conserved in cells from the wing imaginal disc, where expression of Dp110 and Rheb also induces Myc protein accumulation, while inhibition of insulin and TOR pathways result in the opposite effect. Our functional analysis, aimed at quantifying the relative contribution of Myc to ommatidial growth downstream of insulin and TOR pathways, revealed that Myc activity is necessary to sustain the proliferation of cells from the ommatidia upon Dp110 expression, while its contribution downstream of TOR is significant to control the size of the ommatidia. Conclusions Our study presents novel evidence that Myc activity acts downstream of insulin and TOR pathways to control growth in Drosophila. At

  10. Drosophila insulin and target of rapamycin (TOR) pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo.

    Science.gov (United States)

    Parisi, Federica; Riccardo, Sara; Daniel, Margaret; Saqcena, Mahesh; Kundu, Nandini; Pession, Annalisa; Grifoni, Daniela; Stocker, Hugo; Tabak, Esteban; Bellosta, Paola

    2011-09-27

    Genetic studies in Drosophila melanogaster reveal an important role for Myc in controlling growth. Similar studies have also shown how components of the insulin and target of rapamycin (TOR) pathways are key regulators of growth. Despite a few suggestions that Myc transcriptional activity lies downstream of these pathways, a molecular mechanism linking these signaling pathways to Myc has not been clearly described. Using biochemical and genetic approaches we tried to identify novel mechanisms that control Myc activity upon activation of insulin and TOR signaling pathways. Our biochemical studies show that insulin induces Myc protein accumulation in Drosophila S2 cells, which correlates with a decrease in the activity of glycogen synthase kinase 3-beta (GSK3β ) a kinase that is responsible for Myc protein degradation. Induction of Myc by insulin is inhibited by the presence of the TOR inhibitor rapamycin, suggesting that insulin-induced Myc protein accumulation depends on the activation of TOR complex 1. Treatment with amino acids that directly activate the TOR pathway results in Myc protein accumulation, which also depends on the ability of S6K kinase to inhibit GSK3β activity. Myc upregulation by insulin and TOR pathways is a mechanism conserved in cells from the wing imaginal disc, where expression of Dp110 and Rheb also induces Myc protein accumulation, while inhibition of insulin and TOR pathways result in the opposite effect. Our functional analysis, aimed at quantifying the relative contribution of Myc to ommatidial growth downstream of insulin and TOR pathways, revealed that Myc activity is necessary to sustain the proliferation of cells from the ommatidia upon Dp110 expression, while its contribution downstream of TOR is significant to control the size of the ommatidia. Our study presents novel evidence that Myc activity acts downstream of insulin and TOR pathways to control growth in Drosophila. At the biochemical level we found that both these pathways

  11. Parotid gland tumours: a six years experience

    International Nuclear Information System (INIS)

    Malik, K.A.

    2006-01-01

    To find out the different types of Parotid tumours in out setup and their prevalence in different age groups. All patients admitted with Parotid swellings, irrespective of age and sex. The detailed data of the patients was collected and analyzed. A total of 27 patients, 15 males and 12 females, with ages ranging from 15 to 65 years were included in the study. Most of the patients were in the 31-50 years of age group. Pleomorphic adenoma was the commonest benign tumour with an incidence of 66.6%, while Mucoepidermoid Carcinoma with an incidence of 11.11% was the most common malignant tumour. Parotid gland is the principal site of salivary gland tumours. Males are affected more and Pleomorphic adenoma is the most common benign and Mucoepidermoid carcinoma the most common malignant tumour. (author)

  12. Molecular pathology of bone tumours: diagnostic implications.

    Science.gov (United States)

    Puls, Florian; Niblett, Angela J; Mangham, D Chas

    2014-03-01

    Alongside histomorphology and immunohistochemistry, molecular pathology is now established as one of the cornerstones in the tissue diagnosis of bone tumours. We describe the principal molecular pathological techniques employed, and each of the bone tumour entities where their identified characteristic molecular pathological changes can be detected to support and confirm the suspected histological diagnosis. Tumours discussed include fibrous dysplasia, classical and subtype osteosarcomas, central and surface cartilaginous tumours, Ewing's sarcoma, vascular tumours, aneurysmal bone cyst, chordoma, myoepithelioma, and angiomatoid fibrous histiocytoma. This is a rapidly evolving field with discoveries occurring every few months, and some of the newer entities (the Ewing's-like sarcomas), which are principally identified by their molecular pathology characteristics, are discussed. © 2013 John Wiley & Sons Ltd.

  13. Musculoskeletal desmoid tumours: Diagnostic imaging appearances

    International Nuclear Information System (INIS)

    Liu, Daniel; Perera, Warren; Schlicht, Stephen; Choong, Peter; Slavin, John; Pianta, Marcus

    2015-01-01

    This study aimed to discuss the role medical imaging has on diagnosis of musculoskeletal desmoid tumours and to describe their radiological appearances on various imaging modalities. Imaging of histologically proven cases of desmoid tumours at St. Vincent's Hospital Melbourne were obtained via picture archiving communication system (PACS) and then assessed by two musculoskeletal radiologists. Suitable imagings were obtained from PACS. All imaging chosen was de-identified. Desmoid tumours can occur in many areas of the body. Imaging plays an important role in the diagnosis of these tumours and magnetic resonance imaging has been the gold standard for imaging and is the most accurate in terms of assessing tumour margins and involvement of surrounding structure.

  14. Cooperative tumour cell membrane targeted phototherapy

    Science.gov (United States)

    Kim, Heegon; Lee, Junsung; Oh, Chanhee; Park, Ji-Ho

    2017-06-01

    The targeted delivery of therapeutics using antibodies or nanomaterials has improved the precision and safety of cancer therapy. However, the paucity and heterogeneity of identified molecular targets within tumours have resulted in poor and uneven distribution of targeted agents, thus compromising treatment outcomes. Here, we construct a cooperative targeting system in which synthetic and biological nanocomponents participate together in the tumour cell membrane-selective localization of synthetic receptor-lipid conjugates (SR-lipids) to amplify the subsequent targeting of therapeutics. The SR-lipids are first delivered selectively to tumour cell membranes in the perivascular region using fusogenic liposomes. By hitchhiking with extracellular vesicles secreted by the cells, the SR-lipids are transferred to neighbouring cells and further spread throughout the tumour tissues where the molecular targets are limited. We show that this tumour cell membrane-targeted delivery of SR-lipids leads to uniform distribution and enhanced phototherapeutic efficacy of the targeted photosensitizer.

  15. Identification of connectivity in human motor control: exciting the afferent pathways

    NARCIS (Netherlands)

    Campfens, S.F.

    2014-01-01

    Motor control involves various parts of the central nervous system (CNS) and requires the exchange of information between neural populations in the CNS. Information exchange in facilitated by the formation of functional networks between populations of was localized at the sensorimotor area

  16. Studies on the pathways and effects of cadmium in controlled ecosystem enclosures

    Energy Technology Data Exchange (ETDEWEB)

    Kremling, K; Piuze, J; Von Brockel, K; Wong, C S

    1978-01-01

    Research report:At Controlled Ecosystem Pollution Experiment (CEPEX) at Saanich Inlet on Vancouver Island, Canada, cadmium was added to sea water enclosed in moored plastic containers to assess the metal's effect on marine phytoplankton. The test containers received 1.3

  17. A Genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation

    NARCIS (Netherlands)

    Paul, Petra; van den Hoorn, Tineke; Jongsma, Marlieke L. M.; Bakker, Mark J.; Hengeveld, Rutger; Janssen, Lennert; Cresswell, Peter; Egan, David A.; van Ham, Marieke; ten Brinke, Anja; Ovaa, Huib; Beijersbergen, Roderick L.; Kuijl, Coenraad; Neefjes, Jacques

    2011-01-01

    MHC class II molecules (MHC-II) present peptides to T helper cells to facilitate immune responses and are strongly linked to autoimmune diseases. To unravel processes controlling MHC-II antigen presentation, we performed a genome-wide flow cytometry-based RNAi screen detecting MHC-II expression and

  18. WIP-YAP/TAZ as A New Pro-Oncogenic Pathway in Glioma

    Directory of Open Access Journals (Sweden)

    Sergio Rivas

    2018-06-01

    Full Text Available Wild-type p53 (wtp53 is described as a tumour suppressor gene, and mutations in p53 occur in many human cancers. Indeed, in high-grade malignant glioma, numerous molecular genetics studies have established central roles of RTK-PI3K-PTEN and ARF-MDM2-p53 INK4a-RB pathways in promoting oncogenic capacity. Deregulation of these signalling pathways, among others, drives changes in the glial/stem cell state and environment that permit autonomous growth. The initially transformed cell may undergo subsequent modifications, acquiring a more complete tumour-initiating phenotype responsible for disease advancement to stages that are more aggressive. We recently established that the oncogenic activity of mutant p53 (mtp53 is driven by the actin cytoskeleton-associated protein WIP (WASP-interacting protein, correlated with tumour growth, and more importantly that both proteins are responsible for the tumour-initiating cell phenotype. We reported that WIP knockdown in mtp53-expressing glioblastoma greatly reduced proliferation and growth capacity of cancer stem cell (CSC-like cells and decreased CSC-like markers, such as hyaluronic acid receptor (CD44, prominin-1 (CD133, yes-associated protein (YAP and transcriptional co-activator with PDZ-binding motif (TAZ. We thus propose a new CSC signalling pathway downstream of mtp53 in which Akt regulates WIP and controls YAP/TAZ stability. WIP drives a mechanism that stimulates growth signals, promoting YAP/TAZ and β-catenin stability in a Hippo-independent fashion, which allows cells to coordinate processes such as proliferation, stemness and invasiveness, which are key factors in cancer progression. Based on this multistep tumourigenic model, it is tantalizing to propose that WIP inhibitors may be applied as an effective anti-cancer therapy.

  19. Activation of the Canonical Wnt/β-Catenin Signalling Pathway is Rare in Canine Malignant Melanoma Tissue and Cell Lines

    Science.gov (United States)

    Chon, E.; Thompson, V.; Schmid, S.; Stein, T. J.

    2012-01-01

    Summary Canine malignant melanoma is a highly aggressive tumour associated with a poor overall survival rate due to both local disease recurrence and its highly metastatic nature. Similar to advanced melanoma in man, canine oral melanoma is poorly responsive to conventional anti-cancer therapies. The lack of sustainable disease control warrants investigation of novel therapies, preferably targeting features specific to the tumour and different from normal cells. The Wnt signalling pathway is known to contribute to melanocytic lineage development in vertebrates and perturbation of the Wnt/β-catenin pathway has been implicated in numerous cancer types. Alterations of the Wnt/β-catenin pathway are suggested to occur in a subset of human melanomas, although the precise role of the Wnt/β-catenin pathway in melanoma is yet to be defined. This study investigates the activation status of the canonical Wnt/β-catenin pathway in canine malignant melanoma and its potential as a therapeutic target for treating this disease. The data indicate canonical Wnt/β-catenin pathway activation is a rare event in canine oral malignant melanoma tissue and canine malignant melanoma cell lines. PMID:22901430

  20. Growth of the Developing Cerebral Cortex Is Controlled by MicroRNA-7 through the p53 Pathway

    Directory of Open Access Journals (Sweden)

    Andrew Pollock

    2014-05-01

    Full Text Available Proper growth of the mammalian cerebral cortex is crucial for normal brain functions and is controlled by precise gene-expression regulation. Here, we show that microRNA-7 (miR-7 is highly expressed in cortical neural progenitors and describe miR-7 sponge transgenic mice in which miR-7-silencing activity is specifically knocked down in the embryonic cortex. Blocking miR-7 function causes microcephaly-like brain defects due to reduced intermediate progenitor (IP production and apoptosis. Upregulation of miR-7 target genes, including those implicated in the p53 pathway, such as Ak1 and Cdkn1a (p21, is responsible for abnormalities in neural progenitors. Furthermore, ectopic expression of Ak1 or p21 and specific blockade of miR-7 binding sites in target genes using protectors in vivo induce similarly reduced IP production. Using conditional miRNA sponge transgenic approaches, we uncovered an unexpected role for miR-7 in cortical growth through its interactions with genes in the p53 pathway.

  1. Amyloid domains in the cell nucleus controlled by nucleoskeletal protein lamin B1 reveal a new pathway of mercury neurotoxicity

    Science.gov (United States)

    Arnhold, Florian; Gührs, Karl-Heinz

    2015-01-01

    Mercury (Hg) is a bioaccumulating trace metal that globally circulates the atmosphere and waters in its elemental, inorganic and organic chemical forms. While Hg represents a notorious neurotoxicant, the underlying cellular pathways are insufficiently understood. We identify amyloid protein aggregation in the cell nucleus as a novel pathway of Hg-bio-interactions. By mass spectrometry of purified protein aggregates, a subset of spliceosomal components and nucleoskeletal protein lamin B1 were detected as constituent parts of an Hg-induced nuclear aggregome network. The aggregome network was located by confocal imaging of amyloid-specific antibodies and dyes to amyloid cores within splicing-speckles that additionally recruit components of the ubiquitin-proteasome system. Hg significantly enhances global proteasomal activity in the nucleus, suggesting that formation of amyloid speckles plays a role in maintenance of protein homeostasis. RNAi knock down showed that lamin B1 for its part regulates amyloid speckle formation and thus likewise participates in nuclear protein homeostasis. As the Hg-induced cascade of interactions between the nucleoskeleton and protein homeostasis reduces neuronal signalling, amyloid fibrillation in the cell nucleus is introduced as a feature of Hg-neurotoxicity that opens new avenues of future research. Similar to protein aggregation events in the cytoplasm that are controlled by the cytoskeleton, amyloid fibrillation of nuclear proteins may be driven by the nucleoskeleton. PMID:25699204

  2. Tumour location within the breast: Does tumour site have prognostic ability?

    Science.gov (United States)

    Rummel, Seth; Hueman, Matthew T; Costantino, Nick; Shriver, Craig D; Ellsworth, Rachel E

    2015-01-01

    Tumour location within the breast varies with the highest frequency in the upper outer quadrant (UOQ) and lowest frequency in the lower inner quadrant (LIQ). Whether tumour location is prognostic is unclear. To determine whether tumour location is prognostic, associations between tumour site and clinicopathological characteristics were evaluated. All patients enrolled in the Clinical Breast Care Project whose tumour site-UOQ, upper inner quadrant (UIQ), central, LIQ, lower outer quadrant (LOQ)-was determined by a single, dedicated breast pathologist were included in this study. Patients with multicentric disease (n = 122) or tumours spanning multiple quadrants (n = 381) were excluded from further analysis. Clinicopathological characteristics were analysed using chi-square tests for univariate analysis with multivariate analysis performed using principal components analysis (PCA) and multiple logistic regression. Significance was defined as P location, 30 had bilateral disease. Tumour location in the UOQ (51.5%) was significantly higher than in the UIQ (15.6%), LOQ (14.2%), central (10.6%), or LIQ (8.1%). Tumours in the central quadrant were significantly more likely to have higher tumour stage (P = 0.003) and size (P location as a prognostic factor revealed that although tumours in the central region are associated with less favourable outcome, these associations are not independent of location but rather driven by larger tumour size. Tumours in the central region are more difficult to detect mammographically, resulting in larger tumour size at diagnosis and thus less favourable prognosis. Together, these data demonstrate that tumour location is not an independent prognostic factor.

  3. MMP9 expression in oesophageal adenocarcinoma is upregulated with visceral obesity and is associated with poor tumour differentiation.

    LENUS (Irish Health Repository)

    Allott, Emma H

    2011-11-28

    Overweight and obesity is linked to increased incidence and mortality of many cancer types. Of all cancers, oesophageal adenocarcinoma (OAC) displays one of the strongest epidemiological links with obesity, accounting for up to 40% of cases, but molecular pathways driving this association remain largely unknown. This study aimed to elucidate mechanisms underpinning the association of obesity and cancer, and to determine if visceral obesity is associated with aggressive tumour biology in OAC. Following co-culture with visceral adipose tissue explants, expression of genes involved in tumour cell invasion and metastasis (matrix metalloproteinase (MMP)2 and MMP9) were upregulated between 10-fold (MMP2) and 5000-fold (MMP9), and expression of tumour suppressor p53 was downregulated 2-fold in OAC cell lines. Western blotting confirmed these results at the protein level, while zymographic analysis detected increased activity of MMPs in OAC cell lines following co-culture with adipose tissue explants. When OAC cell lines were cultured with adipose tissue conditioned media (ACM) from visceral adipose tissue, increased proliferative, migratory and invasive capacity of tumour cells was observed. In OAC patient tumour biopsies, elevated gene expression of MMP9 was associated with visceral obesity, measured by visceral fat area, while increased gene expression of MMP9 and decreased gene expression of tumour suppressor p53 was associated with poor tumour differentiation. These novel data highlight an important role for visceral obesity in upregulation of pro-tumour pathways contributing to aggressive tumour biology, and may ultimately lead to development of stratified treatment for viscerally obese OAC patients. © 2011 Wiley Periodicals, Inc.

  4. Directing Reaction Pathways through Controlled Reactant Binding at Pd-TiO2 Interfaces.

    Science.gov (United States)

    Zhang, Jing; Wang, Bingwen; Nikolla, Eranda; Medlin, J Will

    2017-06-01

    Recent efforts to design selective catalysts for multi-step reactions, such as hydrodeoxygenation (HDO), have emphasized the preparation of active sites at the interface between two materials having different properties. However, achieving precise control over interfacial properties, and thus reaction selectivity, has remained a challenge. Here, we encapsulated Pd nanoparticles (NPs) with TiO 2 films of regulated porosity to gain a new level of control over catalyst performance, resulting in essentially 100 % HDO selectivity for two biomass-derived alcohols. This catalyst also showed exceptional reaction specificity in HDO of furfural and m-cresol. In addition to improving HDO activity by maximizing the interfacial contact between the metal and metal oxide sites, encapsulation by the nanoporous oxide film provided a significant selectivity boost by restricting the accessible conformations of aromatics on the surface. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Lck/PLCγ control migration and proliferation of interleukin (IL)-2-stimulated T cells via the Rac1 GTPase/glycogen phosphorylase pathway.

    Science.gov (United States)

    Llavero, Francisco; Artaso, Alain; Lacerda, Hadriano M; Parada, Luis A; Zugaza, José L

    2016-11-01

    Recently, we have reported that the IL-2-stimulated T cells activate PKCθ in order to phosphorylate the serine residues of αPIX-RhoGEF, and to switch on the Rac1/PYGM pathway resulting in T cell migration and proliferation. However, the molecular mechanism connecting the activated IL-2-R with the PKCθ/αPIX/Rac1/PYGM pathway is still unknown. In this study, the use of a combined pharmacological and genetic approach identified Lck, a Src family member, as the tyrosine kinase phosphorylating PLCγ leading to Rac1 and PYGM activation in the IL-2-stimulated Kit 225 T cells via the PKCθ/αPIX pathway. The PLCγ tyrosine phosphorylation was required to activate first PKCθ, and then αPIX and Rac1/PYGM. The results presented here delineate a novel signalling pathway ranking equally in importance to the three major pathways controlled by the IL-2-R, i.e. PI3K, Ras/MAPK and JAK/STAT pathways. The overall evidence strongly indicates that the central biological role of the novel IL-2-R/Lck/PLCγ/PKCθ/αPIX/Rac1/PYGM signalling pathway is directly related to the control of fundamental cellular processes such as T cell migration and proliferation. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Tumour-induced osteomalacia’

    Science.gov (United States)

    Munoz, Javier; Michel Ortega, Rosa; Celzo, Florence; Donthireddy, Vijayalakshmi

    2012-01-01

    A 60-year-old man presented 2 years before his diagnosis with long-standing muscle cramping, progressive generalised weakness and chronic hip pain. The patient was found to have bilateral femoral neck pathologic fractures therefore, underwent reamed intramedullary nailing of both femurs. Laboratory studies showed hypophosphataemia. Bone marrow biopsy was negative for malignancy. Positron emission tomography demonstrated fludeoxyglucose uptake only in the posterior neck. Bone scan showed innumerable foci of increased activity throughout the skeleton consistent with pseudofractures seen in osteomalacia. Fine needle aspiration from the mass in the neck revealed a phosphaturic mesenchymal tumour of mixed connective tissue type. Resection of the mass in the neck resulted in resolution of generalised complaints with no evidence of recurrence with a follow-up of 12 months. PMID:22736784

  7. The roles of the olivocerebellar pathway in motor learning and motor control. A consensus paper

    Science.gov (United States)

    Lang, Eric J.; Apps, Richard; Bengtsson, Fredrik; Cerminara, Nadia L.; De Zeeuw, Chris I.; Ebner, Timothy J.; Heck, Detlef H.; Jaeger, Dieter; Jörntell, Henrik; Kawato, Mitsuo; Otis, Thomas S.; Ozyildirim, Ozgecan; Popa, Laurentiu S.; Reeves, Alexander M.B.; Schweighofer, Nicolas; Sugihara, Izumi; Xiao, Jianqiang

    2016-01-01

    For many decades the predominant view in the cerebellar field has been that the olivocerebellar system's primary function is to induce plasticity in the cerebellar cortex, specifically, at the parallel fiber-Purkinje cell synapse. However, it has also long been proposed that the olivocerebellar system participates directly in motor control by helping to shape ongoing motor commands being issued by the cerebellum. Evidence consistent with both hypotheses exists; however, they are often investigated as mutually exclusive alternatives. In contrast, here we take the perspective that the olivocerebellar system can contribute to both the motor learning and motor control functions of the cerebellum, and might also play a role in development. We then consider the potential problems and benefits of its having multiple functions. Moreover, we discuss how its distinctive characteristics (e.g., low firing rates, synchronization, variable complex spike waveform) make it more or less suitable for one or the other of these functions, and why its having a dual role makes sense from an evolutionary perspective. We did not attempt to reach a consensus on the specific role(s) the olivocerebellar system plays in different types of movements, as that will ultimately be determined experimentally; however, collectively, the various contributions highlight the flexibility of the olivocerebellar system, and thereby suggest it has the potential to act in both the motor learning and motor control functions of the cerebellum. PMID:27193702

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

    Directory of Open Access Journals (Sweden)

    Maini PK

    2010-04-01

    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

  9. Multiscale biomechanics of brain tumours favours cancer invasion by cell softening and tissue stiffening

    Science.gov (United States)

    Kas, Josef; Fritsch, Anatol; Grosser, Steffen; Friebe, Sabrina; Reiss-Zimmermann, Martin; Müller, Wolf; Hoffmann, Karl-Titus; Sack, Ingolf

    Cancer progression needs two contradictory mechanical prerequisites. For metastasis individual cancer cells or small clusters have to flow through the microenvironment by overcoming the yield stress exerted by the surrounding. On the other hand a tumour has to behave as a solid to permit cell proliferation and spreading of the tumour mass against its surrounding. We determine that the high mechanical adaptability of cancer cells and the scale controlled viscoelastic properties of tissues reconcile both conflicting properties, fluid and solid, simultaneously in brain tumours. We resolve why different techniques that assess cell and tissue mechanics have produced apparently conflicting results by our finding that tumours generate different viscoelastic behaviours on different length scales, which are in concert optimal for tumour spreading and metastasis. Single cancer cells become very soft in their elastic behavior which promotes cell unjamming. On the level of direct cell-to-cell interactions cells feel their micro-environment as rigid elastic substrate that stimulates cancer on the molecular level. All over a tumour has predominately a stiff elastic character in terms of viscoelastic behaviour caused by a solid backbone. Simultaneously, the tumour mass is characterized by a large local variability in the storage and loss modulus that is caused by areas of a more fluid nature.

  10. Prolactin, TNF alpha and nitric oxide expression in nitroso-N-methylurea-induced-mammary tumours

    Directory of Open Access Journals (Sweden)

    Vegh Irene

    2007-11-01

    Full Text Available Abstract Background The N-Nitrosomethylurea breast cancer model induced in rats is used for the study of carcinogenesis in mammary cancer, prostate, pancreas, etc. This model is very similar to human neoplastic disease. Methods The present experimental study was designed to assess whether metoclopramide administration has any effect on development of MNU-induced tumours, and evaluate the treatment of goserelin acetate on PRL, TNF alpha and NO expression. NMU was administered to female Wistar rats on 2 occasions (5 mg/100 g body w/rat. PRL and TNF alpha were performed by immune-assay. Nitric Oxide by semi automated-assay and ploidy analyses by flow cytometry. Results The administration of metoclopramide made the induction time shorter and increased the incidence and average of tumours per rat. Tumours development was inhibited by a goserelin chronic administration. The ploidy of adenocarcinoma was polyploid-aneuploid type (average S = 60%. It was higher basal PRL plasma levels in rats with NMU induced tumours than in basal controls without tumour (p Conclusion The increase of blood PRL levels in NMU-induced rats may be an indicator of a poor prognosis of mammary cancer evolution. The metoclopramide administration accelerates tumour growth. However goserelin administration achieves regression in tumour development associated to inhibition PRL, TNF alpha and NO expression.

  11. lmmunohistochemical study of effect of ionizing radiation on human malignant tumours

    International Nuclear Information System (INIS)

    Adomaitiene, D. I.; Aleknavicius, E.; Valuckas, K. and others

    2000-01-01

    Cell proliferation-associated tumour markers are considered to have a valuable clinical significance. The current study was designed to investigate changes in immunohistochemical (IH) expression of proliferating cell nuclear antigen PCNA in human malignant tumour tissue samples obtained before and after preoperative radiotherapy. Tumour tissue samples were obtained from 26 patients with rectal carcinoma, from 22 patients with carcinoma corporis uteri and from 82 patients with breast cancer. Tumour samples were processed for IH examination by using monoclonal antibodies (MoAbs) PC10 against PCNA. IH analysis of histological specimens of carcinoma corporis uteri and rectal carcinoma obtained before and after preoperative radiotherapy has revealed heterogeneity of biological response to irradiation. The great majority of tumour specimens after irradiation showed a high PCNA expression level in cell population. Only minority of tumour specimens (15-20%) exhibited reduced immunoreactivity with MoAbs PC10. PCNA positivity rate in breast cancer specimens obtained during surgery from 55 patients after preoperative radiotherapy in comparison to biomarker expression pattern in tumour specimens from 27 unirradiated patients (control group) was found to be tended to decrease. These in vivo findings are discussed in terms of radiation-induced cell death, followed after proliferation, and PCNA role in DNA repair. (author)

  12. Sparing effect of x-ray fractionation in mammary tumours and skin reactions of mice

    International Nuclear Information System (INIS)

    Fowler, J.F.; Denekamp, J.; Sheldon, P.W.; Smith, A.M.; Begg, A.C.; Harris, S.R.; Page, A.L.

    1975-01-01

    The increase in total dose with number of fractions of x-rays between 2 and 15 was found to be similar for local control of tumours (TCD 50 ) and for skin reactions. This result could be explained if the gain from reoxygenation of hypoxic tumour cells was the same for two fractions as for larger numbers, and the dose-sparing effect of repair and repopulation was similar for the tumour and for skin. In addition, a split-dose experiment was carried out with the tumours clamped off to make them acutely hypoxic during irradiation. The resulting value of (D 2 -D 1 )sub(24h) was not significantly smaller than the value previously found for skin reactions. 1290 rad was found in anoxic conditions, corresponding to a dose increment for repair in oxygenated conditions of 430 to 520 rad, assuming an oxygen enhancement ratio of 3 to 2.5. Reduced values have been found from regrowth experiments on two other types of tumour in mice. These results are consistent with no significant difference in the sparing effect of x-ray fractionation on skin or C 3 H mammary tumours in mice for up to 15 equal fractions given in 18 days; but reduced repair plus more proliferation in tumours than in skin cannot be excluded. (author)

  13. 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.

  14. Targeting of liver tumour in rats by selective delivery of holmium-166 loaded microspheres: a biodistribution study

    Energy Technology Data Exchange (ETDEWEB)

    Nijsen, F.; Rook, D.; Zonnenberg, B.; Klerk, J. de; Rijk, P. van; Schip, F. van het [Dept. of Nuclear Medicine, University Medical Center, Utrecht (Netherlands); Brandt, C. [Animal Inst., Utrecht Univ. (Netherlands); Meijer, R. [Dept. of Radiology, Univ. Medical Center, Utrecht (Netherlands); Dullens, H. [Dept. of Pathology, Univ. Medical Center, Utrecht (Netherlands); Hennink, W. [Dept. of Pharmaceutics, Utrecht Univ. (Netherlands)

    2001-06-01

    Intra-arterial administration of beta-emitting particles that become trapped in the vascular bed of a tumour and remain there while delivering high doses, represents a unique approach in the treatment of both primary and metastatic liver tumours. Studies on selective internal radiation therapy of colorectal liver metastases using yttrium-90 glass microspheres have shown encouraging results. This study describes the biodistribution of 40-{mu}m poly lactic acid microspheres loaded with radioactive holmium-166, after intra-arterial administration into the hepatic artery of rats with implanted liver tumours. Radioactivity measurements showed >95% retention of injected activity in the liver and its resident tumour. The average activity detected in other tissues was {<=}0.1%ID/g, with incidental exceptions in the lungs and stomach. Very little {sup 166}Ho activity was detected in kidneys (<0.1%ID/g), thereby indicating the stability of the microspheres in vivo. Tumour targeting was very effective, with a mean tumour to liver ratio of 6.1{+-}2.9 for rats with tumour (n=15) versus 0.7{+-}0.5 for control rats (n=6; P<0.001). These ratios were not significantly affected by the use of adrenaline. Histological analysis showed that five times as many large (>10) and medium-sized (4-9) clusters of microspheres were present within tumour and peritumoural tissue, compared with normal liver. Single microspheres were equally dispersed throughout the tumour, as well as normal liver parenchyma. (orig.)

  15. NMR metabolomics of human lung tumours reveals distinct metabolic signatures for adenocarcinoma and squamous cell carcinoma

    OpenAIRE

    Rocha, CM; Barros, AS; Goodfellow, BJ; Carreira, IM; Gomes, AA; Sousa, V; Bernardo, J; Carvalho, L; Gil, AM; Duarte, IF

    2015-01-01

    Lung tumour subtyping, particularly the distinction between adenocarcinoma (AdC) and squamous cell carcinoma (SqCC), is a critical diagnostic requirement. In this work, the metabolic signatures of lung carcinomas were investigated through (1)H NMR metabolomics, with a view to provide additional criteria for improved diagnosis and treatment planning. High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (NMR) spectroscopy was used to analyse matched tumour and adjacent control tissue...

  16. Precision controlled atomic resolution scanning transmission electron microscopy using spiral scan pathways

    Science.gov (United States)

    Sang, Xiahan; Lupini, Andrew R.; Ding, Jilai; Kalinin, Sergei V.; Jesse, Stephen; Unocic, Raymond R.

    2017-03-01

    Atomic-resolution imaging in an aberration-corrected scanning transmission electron microscope (STEM) can enable direct correlation between atomic structure and materials functionality. The fast and precise control of the STEM probe is, however, challenging because the true beam location deviates from the assigned location depending on the properties of the deflectors. To reduce these deviations, i.e. image distortions, we use spiral scanning paths, allowing precise control of a sub-Å sized electron probe within an aberration-corrected STEM. Although spiral scanning avoids the sudden changes in the beam location (fly-back distortion) present in conventional raster scans, it is not distortion-free. “Archimedean” spirals, with a constant angular frequency within each scan, are used to determine the characteristic response at different frequencies. We then show that such characteristic functions can be used to correct image distortions present in more complicated constant linear velocity spirals, where the frequency varies within each scan. Through the combined application of constant linear velocity scanning and beam path corrections, spiral scan images are shown to exhibit less scan distortion than conventional raster scan images. The methodology presented here will be useful for in situ STEM imaging at higher temporal resolution and for imaging beam sensitive materials.

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

    International Nuclear Information System (INIS)

    Satoh, H.; Kurisu, K.

    1995-01-01

    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

  18. Phase congruency map driven brain tumour segmentation

    Science.gov (United States)

    Szilágyi, Tünde; Brady, Michael; Berényi, Ervin

    2015-03-01

    Computer Aided Diagnostic (CAD) systems are already of proven value in healthcare, especially for surgical planning, nevertheless much remains to be done. Gliomas are the most common brain tumours (70%) in adults, with a survival time of just 2-3 months if detected at WHO grades III or higher. Such tumours are extremely variable, necessitating multi-modal Magnetic Resonance Images (MRI). The use of Gadolinium-based contrast agents is only relevant at later stages of the disease where it highlights the enhancing rim of the tumour. Currently, there is no single accepted method that can be used as a reference. There are three main challenges with such images: to decide whether there is tumour present and is so localize it; to construct a mask that separates healthy and diseased tissue; and to differentiate between the tumour core and the surrounding oedema. This paper presents two contributions. First, we develop tumour seed selection based on multiscale multi-modal texture feature vectors. Second, we develop a method based on a local phase congruency based feature map to drive level-set segmentation. The segmentations achieved with our method are more accurate than previously presented methods, particularly for challenging low grade tumours.

  19. The amygdalo-motor pathway and the control of facial expressions

    Directory of Open Access Journals (Sweden)

    Katalin M Gothard

    2014-03-01

    Full Text Available Facial expressions reflect decisions about the perceived meaning of social stimuli emitted by others and the expected socio-emotional outcome of the reciprocating expression. The decision to produce a facial expression emerges from the joint activity of a network of structures that include the amygdala and multiple, interconnected cortical and subcortical motor areas. Reciprocal transformations between sensory and motor signals give rise to distinct brain states that promote, or impede the production of facial expressions. The muscles of the upper and lower face are controlled by anatomically distinct motor areas and thus require distinct patterns of motor commands. Concomitantly multiple areas, including the amygdala, monitor the ongoing overt behavior (the expression of self and the covert, autonomic responses that accompany emotional expressions. Interoceptive signals and visceral states, therefore, should be incorporated into the formalisms of decision making in order account for decisions that govern the receiving-emitting cycle of facial expressions.

  20. Activation of the Ca2+/calcineurin/NFAT2 pathway controls smooth muscle cell differentiation

    International Nuclear Information System (INIS)

    Larrieu, Daniel; Thiebaud, Pierre; Duplaa, Cecile; Sibon, Igor; Theze, Nadine; Lamaziere, Jean-Marie Daniel

    2005-01-01

    Cellular mechanisms controlling smooth muscle cells (SMCs) phenotypic modulation are largely unknown. Intracellular Ca 2+ movements are essential to ensure SMC functions; one of the roles of Ca 2+ is to regulate calcineurin, which in turn induces nuclear localization of the nuclear factor of activated T-cell (NFAT). In order to investigate, during phenotypic differentiation of SMCs, the effect of calcineurin inhibition on NFAT 2 nuclear translocation, we used a culture model of SMC differentiation in serum-free conditions. We show that the treatment of cultured SMC with the calcineurin inhibitor cyclosporine A induced their dedifferentiation while preventing their differentiation. These findings suggest that nuclear translocation of NFAT 2 is dependent of calcineurin activity during the in vitro SMC differentiation kinetic and that the nuclear presence of NFAT 2 is critical in the acquisition and maintenance of SMC differentiation

  1. Human Migratory Meniscus Progenitor Cells Are Controlled via the TGF-β Pathway

    Science.gov (United States)

    Muhammad, Hayat; Schminke, Boris; Bode, Christa; Roth, Moritz; Albert, Julius; von der Heyde, Silvia; Rosen, Vicki; Miosge, Nicolai

    2014-01-01

    Summary Degeneration of the knee joint during osteoarthritis often begins with meniscal lesions. Meniscectomy, previously performed extensively after meniscal injury, is now obsolete because of the inevitable osteoarthritis that occurs following this procedure. Clinically, meniscus self-renewal is well documented as long as the outer, vascularized meniscal ring remains intact. In contrast, regeneration of the inner, avascular meniscus does not occur. Here, we show that cartilage tissue harvested from the avascular inner human meniscus during the late stages of osteoarthritis harbors a unique progenitor cell population. These meniscus progenitor cells (MPCs) are clonogenic and multipotent and exhibit migratory activity. We also determined that MPCs are likely to be controlled by canonical transforming growth factor β (TGF-β) signaling that leads to an increase in SOX9 and a decrease in RUNX2, thereby enhancing the chondrogenic potential of MPC. Therefore, our work is relevant for the development of novel cell biological, regenerative therapies for meniscus repair. PMID:25418724

  2. The Hippo pathway: key interaction and catalytic domains in organ growth control, stem cell self-renewal and tissue regeneration.

    Science.gov (United States)

    Cherrett, Claire; Furutani-Seiki, Makoto; Bagby, Stefan

    2012-01-01

    The Hippo pathway is a conserved pathway that interconnects with several other pathways to regulate organ growth, tissue homoeostasis and regeneration, and stem cell self-renewal. This pathway is unique in its capacity to orchestrate multiple processes, from sensing to execution, necessary for organ expansion. Activation of the Hippo pathway core kinase cassette leads to cytoplasmic sequestration of the nuclear effectors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), consequently disabling their transcriptional co-activation function. Components upstream of the core kinase cassette have not been well understood, especially in vertebrates, but are gradually being elucidated and include cell polarity and cell adhesion proteins.

  3. Reduced in-hospital mortality for heart failure with clinical pathways: the results of a cluster randomised controlled trial.

    Science.gov (United States)

    Panella, M; Marchisio, S; Demarchi, M L; Manzoli, L; Di Stanislao, F

    2009-10-01

    Hospital treatment of heart failure (HF) frequently does not follow published guidelines, potentially contributing to HF high morbidity, mortality and economic cost. The Experimental Prospective Study on the Effectiveness and Efficiency of the Implementation of Clinical Pathways was undertaken to determine how clinical pathways (CP) for hospital treatment of HF affected care variability, guidelines adherence, in-hospital mortality and outcomes at discharge. Methods/ Two-arm, cluster-randomised trial. Fourteen community hospitals were randomised either to the experimental arm (CP: appropriate therapeutic guidelines use, new organisation and procedures, patient education) or to the control arm (usual care). The main outcome was in-hospital mortality; secondary outcomes were length and appropriateness of the stay, rate of unscheduled readmissions, customer satisfaction, usage of diagnostic and therapeutic procedures during hospital stay and quality indicators at discharge. All outcomes were measured using validated instruments available in literature. In-hospital mortality was 5.6% in the experimental arm (n = 12); 15.4% in controls (n = 33, p = 0.001). In CP and usual care groups, the mean rates of unscheduled readmissions were 7.9% and 13.9%, respectively. Adjusting for age, smoking, New York Heart Association score, hypertension and source of referral, patients in the CP group, as compared to controls, had a significantly lower risk of in-hospital death (OR 0.18; 95% CI 0.07 to 0.46) and unscheduled readmissions (OR 0.42; 95% CI 0.20 to 0.87). No differences were found between CP and control with respect to the appropriateness of the stay, costs and patient's satisfaction. Except for electrocardiography, all recommended diagnostic procedures were used more in the CP group. Similarly, pharmaceuticals use was significantly greater in CP, with the exception of diuretics and anti-platelets agents. The introduction of a specifically tailored CP for the hospital

  4. MRI appearances of borderline ovarian tumours

    Energy Technology Data Exchange (ETDEWEB)

    Bent, C.L. [Department of Diagnostic Imaging, St Bartholomew' s Hospital, West Smithfield, London (United Kingdom)], E-mail: clare.bent@bartsandthelondon.nhs.uk; Sahdev, A.; Rockall, A.G. [Department of Diagnostic Imaging, St Bartholomew' s Hospital, West Smithfield, London (United Kingdom); Singh, N. [Department of Pathology, St Bartholomew' s Hospital, West Smithfield, London (United Kingdom); Sohaib, S.A. [Department of Radiology, Royal Marsden Hospital, London (United Kingdom); Reznek, R.H. [Cancer Imaging, St Bartholomew' s Hospital, West Smithfield, London (United Kingdom)

    2009-04-15

    This review was performed to describe the range of magnetic resonance imaging (MRI) appearances of borderline ovarian tumours. The MRI findings in 26 patients with 31 borderline ovarian tumours (mean age: 40.1 years, range: 14-85 years) were retrospectively reviewed. For each tumour, site, size, MRI characteristics, and enhancement following gadolinium administration were recorded. There were 20 serous and 11 mucinous borderline ovarian subtypes. Nine of 26 patients demonstrated bilateral disease on MRI; synchronous contralateral ovarian disease included three benign, five serous borderline, and one serous invasive tumour. A history of a metachronous mucinous borderline tumour was identified in one patient. MRI appearances were classified into four morphological categories: group 1 (6/31, 19%), unilocular cysts; group 2 (6/31, 19%), minimally septate cysts with papillary projections; group 3 (14/31, 45%), markedly septate lesions with plaque-like excrescences; and group 4 (5/31, 16%), predominantly solid with exophytic papillary projections, all of serous subtype. There was a significant difference in mean volume between serous (841.5 cm{sup 3}) and mucinous (6358.2 cm{sup 3}) subtypes (p = 0.009). All tumours demonstrated at least one MRI feature suggestive of malignancy. The present review demonstrates the variable MRI appearances of borderline ovarian tumours along with imaging features suggestive of tumour subtype. In patients in whom the clinical features are suggestive of a borderline ovarian tumour (young age and normal or minimally elevated CA125), the ability to predict a borderline disease using morphological features observed on MRI would be extremely helpful in surgical planning, with the potential to offer fertility or ovary-preserving surgery. Future studies are required to further this aim.

  5. Radiopharmaceuticals as probes to characterize tumour tissue

    International Nuclear Information System (INIS)

    Alam, Israt S.; Arshad, Mubarik A.; Nguyen, Quang-De; Aboagye, Eric O.

    2015-01-01

    Tumour cells exhibit several properties that allow them to grow and divide. A number of these properties are detectable by nuclear imaging methods. We discuss crucial tumour properties that can be described by current radioprobe technologies, further discuss areas of emerging radioprobe development, and finally articulate need areas that our field should aspire to develop. The review focuses largely on positron emission tomography and draws upon the seminal 'Hallmarks of Cancer' review article by Hanahan and Weinberg in 2011 placing into context the present and future roles of radiotracer imaging in characterizing tumours. (orig.)

  6. Carcinoid tumour of the middle ear

    LENUS (Irish Health Repository)

    Baig, Salman

    2012-09-01

    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.

  7. ZRF1 controls the retinoic acid pathway and regulates leukemogenic potential in acute myeloid leukemia.

    Science.gov (United States)

    Demajo, S; Uribesalgo, I; Gutiérrez, A; Ballaré, C; Capdevila, S; Roth, M; Zuber, J; Martín-Caballero, J; Di Croce, L

    2014-11-27

    Acute myeloid leukemia (AML) is frequently linked to epigenetic abnormalities and deregulation of gene transcription, which lead to aberrant cell proliferation and accumulation of undifferentiated precursors. ZRF1, a recently characterized epigenetic factor involved in transcriptional regulation, is highly overexpressed in human AML, but it is not known whether it plays a role in leukemia progression. Here, we demonstrate that ZRF1 depletion decreases cell proliferation, induces apoptosis and enhances cell differentiation in human AML cells. Treatment with retinoic acid (RA), a differentiating agent currently used to treat certain AMLs, leads to a functional switch of ZRF1 from a negative regulator to an activator of differentiation. At the molecular level, ZRF1 controls the RA-regulated gene network through its interaction with the RA receptor α (RARα) and its binding to RA target genes. Our genome-wide expression study reveals that ZRF1 regulates the transcription of nearly half of RA target genes. Consistent with our in vitro observations that ZRF1 regulates proliferation, apoptosis, and differentiation, ZRF1 depletion strongly inhibits leukemia progression in a xenograft mouse model. Finally, ZRF1 knockdown cooperates with RA treatment in leukemia suppression in vivo. Taken together, our data reveal that ZRF1 is a key transcriptional regulator in leukemia progression and suggest that ZRF1 inhibition could be a novel strategy to be explored for AML treatment.

  8. DREAM Controls the On/Off Switch of Specific Activity-Dependent Transcription Pathways

    Science.gov (United States)

    Mellström, Britt; Sahún, Ignasi; Ruiz-Nuño, Ana; Murtra, Patricia; Gomez-Villafuertes, Rosa; Savignac, Magali; Oliveros, Juan C.; Gonzalez, Paz; Kastanauskaite, Asta; Knafo, Shira; Zhuo, Min; Higuera-Matas, Alejandro; Errington, Michael L.; Maldonado, Rafael; DeFelipe, Javier; Jefferys, John G. R.; Bliss, Tim V. P.; Dierssen, Mara

    2014-01-01

    Changes in nuclear Ca2+ homeostasis activate specific gene expression programs and are central to the acquisition and storage of information in the brain. DREAM (downstream regulatory element antagonist modulator), also known as calsenilin/KChIP-3 (K+ channel interacting protein 3), is a Ca2+-binding protein that binds DNA and represses transcription in a Ca2+-dependent manner. To study the function of DREAM in the brain, we used transgenic mice expressing a Ca2+-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Using genome-wide analysis, we show that DREAM regulates the expression of specific activity-dependent transcription factors in the hippocampus, including Npas4, Nr4a1, Mef2c, JunB, and c-Fos. Furthermore, DREAM regulates its own expression, establishing an autoinhibitory feedback loop to terminate activity-dependent transcription. Ablation of DREAM does not modify activity-dependent transcription because of gene compensation by the other KChIP family members. The expression of daDREAM in the forebrain resulted in a complex phenotype characterized by loss of recurrent inhibition and enhanced long-term potentiation (LTP) in the dentate gyrus and impaired learning and memory. Our results indicate that DREAM is a major master switch transcription factor that regulates the on/off status of specific activity-dependent gene expression programs that control synaptic plasticity, learning, and memory. PMID:24366545

  9. Randomised controlled trial of tumour necrosis factor inhibitors against combination intensive therapy with conventional disease-modifying antirheumatic drugs in established rheumatoid arthritis: the TACIT trial and associated systematic reviews.

    Science.gov (United States)

    Scott, David L; Ibrahim, Fowzia; Farewell, Vern; O'Keeffe, Aidan G; Ma, Margaret; Walker, David; Heslin, Margaret; Patel, Anita; Kingsley, Gabrielle

    2014-10-01

    Rheumatoid arthritis (RA) is initially treated with methotrexate and other disease-modifying antirheumatic drugs (DMARDs). Active RA patients who fail such treatments can receive tumour necrosis factor inhibitors (TNFis), which are effective but expensive. We assessed whether or not combination DMARDs (cDMARDs) give equivalent clinical benefits at lower costs in RA patients eligible for TNFis. An open-label, 12-month, pragmatic, randomised, multicentre, two-arm trial [Tumour necrosis factor inhibitors Against Combination Intensive Therapy (TACIT)] compared these treatment strategies. We then systematically reviewed all comparable published trials. The TACIT trial involved 24 English rheumatology clinics. Active RA patients eligible for TNFis. The TACIT trial compared cDMARDs with TNFis plus methotrexate or another DMARD; 6-month non-responders received (a) TNFis if in the cDMARD group; and (b) a second TNFi if in the TNFi group. The Heath Assessment Questionnaire (HAQ) was the primary outcome measure. The European Quality of Life-5 Dimensions (EQ-5D), joint damage, Disease Activity Score for 28 Joints (DAS28), withdrawals and adverse effects were secondary outcome measures. Economic evaluation linked costs, HAQ changes and quality-adjusted life-years (QALYs). In total, 432 patients were screened; 104 started on cDMARDs and 101 started on TNFis. The initial demographic and disease assessments were similar between the groups. In total, 16 patients were lost to follow-up (nine in the cDMARD group, seven in the TNFi group) and 42 discontinued their intervention but were followed up (23 in the cDMARD group and 19 in the TNFi group). Intention-to-treat analysis with multiple imputation methods used for missing data showed greater 12-month HAQ score reductions with initial cDMARDs than with initial TNFis [adjusted linear regression coefficient 0.15, 95% confidence interval (CI) -0.003 to 0.31; p = 0.046]. Increases in 12-month EQ-5D scores were greater with initial c

  10. Functional analysis of 14 genes that constitute the purine catabolic pathway in Bacillus subtilis and evidence for a novel regulon controlled by the PucR transcription activator

    DEFF Research Database (Denmark)

    Schultz, Anna Charlotte; Nygaard, P.; Saxild, Hans Henrik

    2001-01-01

    The soil bacterium Bacillus subtilis has developed a highly controlled system for the utilization of a diverse array of low molecular-weight compounds as a nitrogen source when the preferred nitrogen sources, e.g., glutamate plus ammonia, are exhausted. We have identified such a system...... for the utilization of purines as nitrogen source in B. subtilis. Based on growth studies of strains with knockout mutations in genes, complemented with enzyme analysis, we could ascribe functions to 14 genes encoding enzymes or proteins of the purine degradation pathway. A functional xanthine dehydrogenase requires......ABCDE unit was decreased 16-fold, while expression of pucR was decreased 4-fold in the presence of allantoin. We have identified genes of the purine degradation pathway in B. subtilis and showed that their expression is subject to both general nitrogen catabolite control and pathway-specific control....

  11. Olfactory neural tumours - the role of external beam radiotherapy

    International Nuclear Information System (INIS)

    Slevin, N.J.; Irwin, C.J.R.; Banerjee, S.S.; Path, F.R.C.; Gupta, N.K.; Farrington, W.T.

    1996-01-01

    Olfactory neuroblastoma is an uncommon tumour arising in the nasal cavity or paranasal sinuses. We report the management of nine cases treated with external beam radiotherapy subsequent to surgery, either attempted definitive removal or biopsy only. Recent refinements in pathological evaluation of these tumours are discussed. Seven cases were deemed classical olfactory neuroblastoma whilst two were classified as neuroendocrine carcinoma. The clinical features, radiotherapy technique and variable natural history are presented. Seven of eight patients treated radically were controlled locally, with a minimum follow-up of two years. Three patients developed cervical lymph node disease and three patients died of systemic metastatic disease. Suggestions are made as to which patients should have en-bloc resection rather than definitive radiotherapy. (author)

  12. Targeted radionuclide therapy for neuroendocrine tumours: principles and application.

    Science.gov (United States)

    Druce, Maralyn R; Lewington, Val; Grossman, Ashley B

    2010-01-01

    Neuroendocrine tumours comprise a group of neoplasms with variable clinical behaviour. Their growth and spread is often very slow and initially asymptomatic, and thus they are often metastatic at the time of diagnosis and incurable by surgery. An exciting therapeutic strategy for cytoreduction, both for stabilisation of tumour growth and inhibition of hormone production, is the use of targeted radionuclide therapy. Evidence from large-scale, randomised, placebo-controlled trials is very difficult to obtain in these rare diseases, but current data appear promising. It is timely to review the principles underlying the use of these therapies, together with the clinical outcomes to date and potential directions for future research. Copyright 2009 S. Karger AG, Basel.

  13. A forgotten facial nerve tumour: granular cell tumour of the parotid and its implications for treatment.

    Science.gov (United States)

    Lerut, B; Vosbeck, J; Linder, T E

    2011-04-01

    We present a rare case of a facial nerve granular cell tumour in the right parotid gland, in a 10-year-old boy. A parotid or neurogenic tumour was suspected, based on magnetic resonance imaging. Intra-operatively, strong adhesions to surrounding structures were found, and a midfacial nerve branch had to be sacrificed for complete tumour removal. Recent reports verify that granular cell tumours arise from Schwann cells of peripheral nerve branches. The rarity of this tumour within the parotid gland, its origin from peripheral nerves, its sometimes misleading imaging characteristics, and its rare presentation with facial weakness and pain all have considerable implications on the surgical strategy and pre-operative counselling. Fine needle aspiration cytology may confirm the neurogenic origin of this lesion. When resecting the tumour, the surgeon must anticipate strong adherence to the facial nerve and be prepared to graft, or sacrifice, certain branches of this nerve.

  14. Is the gene encoding Chibby implicated as a tumour suppressor in colorectal cancer ?

    International Nuclear Information System (INIS)

    Gad, Sophie; Teboul, David; Lièvre, Astrid; Goasguen, Nicolas; Berger, Anne; Beaune, Philippe; Laurent-Puig, Pierre

    2004-01-01

    A novel member of the Wnt signalling pathway, Chibby, was recently identified. This protein inhibits Wnt/β-catenin mediated transcriptional activation by competing with Lef-1 (the transcription factor and target of β-catenin) to bind to β-catenin. This suggests that Chibby could be a tumour suppressor protein. The C22orf2 gene coding Chibby is located on chromosome 22, a region recurrently lost in colorectal cancer. Activation of the Wnt pathway is a major feature of colorectal cancer and occurs through inactivation of APC or activation of β-catenin. All of this led us to analyse the possible implication of Chibby in colorectal carcinogenesis. First, 36 tumour and matched normal colonic mucosa DNA were genotyped with five microsatellite markers located on chromosome 22 to search for loss of heterozygosity. Then, mutation screening of the C22orf2 coding sequence and splice sites was performed in the 36 tumour DNA. Finally, expression of Chibby was analysed by quantitative RT-PCR on 10 patients, 4 with loss of heterozygosity (LOH) on chromosome 22. Loss of heterozygosity involving the C22orf2 region was detected in 11 out of 36 patients (30%). Sequencing analysis revealed a known variant, rs3747174, in exon 5: T321C leading to a silent amino acid polymorphism A107A. Allelic frequencies were 0.69 and 0.31 for T and C variants respectively. No other mutation was detected. Among the 10 patients studied, expression analysis revealed that Chibby is overexpressed in 2 tumours and underexpressed in 1. No correlations were found with 22q LOH status. As no somatic mutation was detected in C22orf2 in 36 colorectal tumour DNA, our results do not support the implication of Chibby as a tumour suppressor in colorectal carcinogenesis. This was supported by the absence of underexpression of Chibby among the tumour samples with 22q LOH. The implication of other Wnt pathway members remains to be identified to explain the part of colorectal tumours without mutation in APC and β-catenin

  15. Eggs early in complementary feeding increase choline pathway biomarkers and DHA: a randomized controlled trial in Ecuador.

    Science.gov (United States)

    Iannotti, Lora L; Lutter, Chessa K; Waters, William F; Gallegos Riofrío, Carlos Andres; Malo, Carla; Reinhart, Gregory; Palacios, Ana; Karp, Celia; Chapnick, Melissa; Cox, Katherine; Aguirre, Santiago; Narvaez, Luis; López, Fernando; Sidhu, Rohini; Kell, Pamela; Jiang, Xuntian; Fujiwara, Hideji; Ory, Daniel S; Young, Rebecca; Stewart, Christine P

    2017-12-01

    Background: Choline status has been associated with stunting among young children. Findings from this study showed that an egg intervention improved linear growth by a length-for-age z score of 0.63. Objective: We aimed to test the efficacy of eggs introduced early in complementary feeding on plasma concentrations of biomarkers in choline pathways, vitamins B-12 and A, and essential fatty acids. Design: A randomized controlled trial, the Lulun ("egg" in Kichwa) Project, was conducted in a rural indigenous population of Ecuador. Infants aged 6-9 mo were randomly assigned to treatment (1 egg/d for 6 mo; n = 80) and control (no intervention; n = 83) groups. Socioeconomic data, anthropometric measures, and blood samples were collected at baseline and endline. Household visits were made weekly for morbidity surveillance. We tested vitamin B-12 plasma concentrations by using chemiluminescent competitive immunoassay and plasma concentrations of choline, betaine, dimethylglycine, retinol, essential fatty acids, methionine, dimethylamine (DMA), trimethylamine, and trimethylamine- N -oxide (TMAO) with the use of liquid chromatography-tandem mass spectrometry. Results: Socioeconomic factors and biomarker concentrations were comparable at baseline. Of infants, 11.4% were vitamin B-12 deficient and 31.7% marginally deficient at baseline. In adjusted generalized linear regression modeling, the egg intervention increased plasma concentrations compared with control by the following effect sizes: choline, 0.35 (95% CI: 0.12, 0.57); betaine, 0.29 (95% CI: 0.01, 0.58); methionine, 0.31 (95% CI: 0.03, 0.60); docosahexaenoic acid, 0.43 (95% CI: 0.13, 0.73); DMA, 0.37 (95% CI: 0.37, 0.69); and TMAO, 0.33 (95% CI: 0.08, 0.58). No significant group differences were found for vitamin B-12, retinol, linoleic acid (LA), α-linolenic acid (ALA), or ratios of betaine to choline and LA to ALA. Conclusion: The findings supported our hypothesis that early introduction of eggs significantly

  16. RAD9, RAD17; RAD24, and RAD53 control one pathway of resistance to γ irradiation in Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Koltovaya, N.A.; Nikulushkina, Yu.V.; Roshina, M.P.; Devin, A.B.

    2009-01-01

    Mechanisms for the genetic control of the cell cycle transition (checkpoint control) have been studied in more detail in yeast Saccharomyces cerevisiae. To clarify tho role of the RAD9, RAD17, RAD24, and RAD53 checkpoint genes in cell radioresistance, diploid double mutants were analyzed for cell sensitivity to ionizing radiation. All mutations in combination with rad9Δ were shown to manifest the epistatic type of interaction. Our results suggest that the RAD9, RAD17, RAD24, and RAD53 checkpoint genes belong to a single epistasis group called the RAD9 group and participate in the same pathway. RAD9 and RAD53 have a positive effect on sensitivity to γ irradiation, whereas RAD17 and RAD24 have a negative effect. For haploid interactions between mutations may differ in the case of γ or UV irradiation, mutations - for example, rad9Δ and rad24Δ - were shown to have an additive effect in the first case and epistatic - in the second. The analyzed genes can also participate in minor mechanisms of radioresistance that are relatively independent of the above major mechanism

  17. Coherently-enabled environmental control of optics and energy transfer pathways of hybrid quantum dot-metallic nanoparticle systems.

    Science.gov (United States)

    Hatef, Ali; Sadeghi, Seyed M; Fortin-Deschênes, Simon; Boulais, Etienne; Meunier, Michel

    2013-03-11

    It is well-known that optical properties of semiconductor quantum dots can be controlled using optical cavities or near fields of localized surface plasmon resonances (LSPRs) of metallic nanoparticles. In this paper we study the optics, energy transfer pathways, and exciton states of quantum dots when they are influenced by the near fields associated with plasmonic meta-resonances. Such resonances are formed via coherent coupling of excitons and LSPRs when the quantum dots are close to metallic nanorods and driven by a laser beam. Our results suggest an unprecedented sensitivity to the refractive index of the environment, causing significant spectral changes in the Förster resonance energy transfer from the quantum dots to the nanorods and in exciton transition energies. We demonstrate that when a quantum dot-metallic nanorod system is close to its plasmonic meta-resonance, we can adjust the refractive index to: (i) control the frequency range where the energy transfer from the quantum dot to the metallic nanorod is inhibited, (ii) manipulate the exciton transition energy shift of the quantum dot, and (iii) disengage the quantum dot from the metallic nanoparticle and laser field. Our results show that near meta-resonances the spectral forms of energy transfer and exciton energy shifts are strongly correlated to each other.

  18. Medical exposure to ionising radiation and the risk of brain tumours

    DEFF Research Database (Denmark)

    Blettner, Maria; Schlehofer, Brigitte; Samkange-Zeeb, Florence

    2007-01-01

    BACKGROUND: The role of exposure to low doses of ionising radiation in the aetiology of brain tumours has yet to be clarified. The objective of this study was to investigate the association between medically or occupationally related exposure to ionising radiation and brain tumours. METHODS: We...... used self-reported medical and occupational data collected during the German part of a multinational case-control study on mobile phone use and the risk of brain tumours (Interphone study) for the analyses. RESULTS: For any exposure to medical ionising radiation we found odds ratios (ORs) of 0.63 (95...... regions. CONCLUSION: We did not find any significant increased risk of brain tumours for exposure to medical ionising radiation....

  19. Biochemical and Cytological Comparison of Keratocystic Odontogenic Tumours to Nonkeratinising Odontogenic Cysts Fluid.

    Science.gov (United States)

    Patidar, Madhvika; Shetty, Pushparaj; Patidar, Nitesh; Mittal, Sugandh; Singh, Hanspal; Chethna

    2015-07-01

    To evaluate the levels of albumin, prealbumin, total protein, inorganic phosphate and presence of keratinocytes in the cystic fluid for the diagnosis and appropriate treatment planning of keratocystic odontogenic tumours and other non keratinizing odontogenic cysts. Fifteen keratocystic odontogenic tumour and 15 controls were studied. The cystic fluid was aspirated and analysed to determine the levels of albumin, prealbumin, total protein, inorganic phosphate and the presence of keratinocytes. The data collected was statistically evaluated using Mann Whitney U-Test and Student's t-test. A highly significant difference (pkeratocystic odontogenic tumour and non keratinizing odontogenic cysts. The presence of albumin also showed a significant difference (pkeratocystic odontogenic tumour in a minimally invasive and highly accurate fashion.

  20. Egfr Amplification Specific Gene Expression in Phyllodes Tumours of the Breast

    Directory of Open Access Journals (Sweden)

    Konstantin Agelopoulos

    2007-01-01

    Full Text Available Background: Recently, we were able to show that amplifications of the epidermal growth factor receptor (egfr gene and the overexpression of EGFR were associated with the initiation and progression of phyllodes tumours. Methods: In order to gain further insights into regulation mechanisms associated with egfr amplifications and EGFR expression in phyllodes tumours, we performed global gene expression analysis (Affymetrix A133.2 on a series of 10 phyllodes tumours, of these three with and seven without amplifications of an important regulatory repeat in intron 1 of egfr (CA-SSR I. The results were verified and extended by means of immunohistochemistry using the tissue microarray method on an extensively characterized series of 58 phyllodes tumours with antibodies against caveolin-1, eps15, EGF, TGF-α, pErk, pAkt and mdm2. Results: We were able to show that the presence of egfr CA-SSR I amplifications in phyllodes tumours was associated with 230 differentially expressed genes. Caveolin-1 and eps15, involved in EGFR turnover and signalling, were regulated differentially on the RNA and protein level proportionally to egfr gene dosage. Further immunohistochemical analysis revealed that the expression of caveolin-1 and eps15 were also significantly correlated with the expression of pAkt (p < 0.05, pERK (p < 0.05, mdm2 (p < 0.01 and EGF (p < 0.001 for caveolin-1. Eps15 and pERK were further associated with tumour grade (p < 0.01 and p < 0.001, respectively. Conclusion: Our results show that amplifications within regulatory sequences of egfr are associated with the expression of eps15 and caveolin-1, indicating an increased turnover of EGFR. The interplay between EGFR and caveolin-1, eps15, pAkt, mdm2 and pERK therefore seems to present a major molecular pathway in carcinogenesis and progression of breast phyllodes tumours.

  1. Radiological diagnosis of malignant tumours in patients with renal transplants

    Energy Technology Data Exchange (ETDEWEB)

    Raaijmakers, P A.M.; Rosenbusch, G; Hoitsma, A J; Boetes, C; Strijk, S P; Koene, R A.P.

    1984-12-01

    17 of 400 patients with a total of 537 renal transplantations developed a malignant tumour (4,2%). 3 patients had a tumour of the skin or lips, 5 a solid lymphoma, 2 a hepatocellular carcinoma and 7 each another tumour. The radiologic findings of the patients are described. The problems around the diagnostics of malignant tumours in patients with renal transplantations are discussed.

  2. Primitive neuroectodermal tumour of the kidney: radiologic-pathological correlations.

    Science.gov (United States)

    Chea, Y W; Agrawal, Rashi; Poh, Angeline C C

    2008-06-01

    A primitive neuroectodermal tumour of the kidney is a rare malignancy. We report the computed tomographic features and the histopathological correlation of such a tumour occurring in a middle-aged man. Although the radiological appearance has significant overlap with other renal tumours, this tumour should be included in the differential diagnosis of a large renal mass in younger patients.