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Sample records for residue modulates conformational

  1. Intensity modulated conformal radiotherapy

    International Nuclear Information System (INIS)

    Noel, Georges; Moty-Monnereau, Celine; Meyer, Aurelia; David, Pauline; Pages, Frederique; Muller, Felix; Lee-Robin, Sun Hae; David, Denis Jean

    2006-12-01

    This publication reports the assessment of intensity-modulated conformal radiotherapy (IMCR). This assessment is based on a literature survey which focussed on indications, efficiency and safety on the short term, on the risk of radio-induced cancer on the long term, on the role in the therapeutic strategy, on the conditions of execution, on the impact on morbidity-mortality and life quality, on the impact on the health system and on public health policies and program. This assessment is also based on the opinion of a group of experts regarding the technical benefit of IMCR, its indications depending on the cancer type, safety in terms of radio-induced cancers, and conditions of execution. Before this assessment, the report thus indicates indications for which the use of IMCR can be considered as sufficient or not determined. It also proposes a technical description of IMCR and helical tomo-therapy, discusses the use of this technique for various pathologies or tumours, analyses the present situation of care in France, and comments the identification of this technique in foreign classifications

  2. Residues in the membrane-spanning domain core modulate conformation and fusogenicity of the HIV-1 envelope glycoprotein

    International Nuclear Information System (INIS)

    Shang Liang; Hunter, Eric

    2010-01-01

    The membrane-spanning domain (MSD) of human immunodeficiency virus type I (HIV-1) envelope glycoprotein (Env) is critical for its biological activity. Initial studies have defined an almost invariant 'core' structure in the MSD and demonstrated that it is crucial for anchoring Env in the membrane and virus entry. We show here that amino acid substitutions in the MSD 'core' do not influence specific virus-cell attachment, nor CD4 receptor and CXCR4 coreceptor recognition by Env. However, substitutions within the MSD 'core' delayed the kinetics and reduced the efficiency of cell-cell fusion mediated by Env. Although we observed no evidence that membrane fusion mediated by the MSD core mutants was arrested at a hemifusion stage, impaired Env fusogenicity was correlated with minor conformational changes in the V2, C1, and C5 regions in gp120 and the immunodominant loop in gp41. These changes could delay initiation of the conformational changes required in the fusion process.

  3. Potential clinical efficacy of intensity-modulated conformal therapy

    International Nuclear Information System (INIS)

    Meeks, Sanford L.; Buatti, John M.; Bova, Francis J.; Friedman, William A.; Mendenhall, William M.; Zlotecki, Robert A.

    1998-01-01

    Purpose: The purpose of this study was to examine the potential benefit of using intensity-modulated conformal therapy for a variety of lesions currently treated with stereotactic radiosurgery or conventional radiotherapy. Methods and Materials: Intensity-modulated conformal treatment plans were generated for small intracranial lesions, as well as head and neck, lung, breast, and prostate cases, using the Peacock Plan[reg] treatment-planning system (Nomos Corporation). For small intracranial lesions, intensity-modulated conformal treatment plans were compared with stereotactic radiosurgery treatment plans generated for patient treatment at the University of Florida Shands Cancer Center. For other sites (head and neck, lung, breast, and prostate), plans generated using the Peacock Plan[reg] were compared with conventional treatment plans, as well as beam's-eye-view conformal treatment plans. Plan comparisons were accomplished through conventional qualitative review of two-dimensional (2D) dose distributions in conjunction with quantitative techniques, such as dose-volume histograms, dosimetric statistics, normal tissue complication probabilities, tumor control probabilities, and objective numerical scoring. Results: For small intracranial lesions, there is little difference between intensity-modulated conformal treatment planning and radiosurgery treatment planning in the conformation of high isodose lines with the target volume. However, stereotactic treatment planning provides a steeper dose gradient outside the target volume and, hence, a lower normal tissue toxicity index. For extracranial sites, objective numerical scores for beam's-eye-view and intensity-modulated conformal planning techniques are superior to scores for conventional treatment plans. The beam's-eye-view planning technique prevents geographic target misses and better excludes healthy tissues from the treatment portal. Compared with scores for the beam's-eye-view planning technique, scores for

  4. Substantial conformational change mediated by charge-triad residues of the death effector domain in protein-protein interactions.

    Directory of Open Access Journals (Sweden)

    Edward C Twomey

    Full Text Available Protein conformational changes are commonly associated with the formation of protein complexes. The non-catalytic death effector domains (DEDs mediate protein-protein interactions in a variety of cellular processes, including apoptosis, proliferation and migration, and glucose metabolism. Here, using NMR residual dipolar coupling (RDC data, we report a conformational change in the DED of the phosphoprotein enriched in astrocytes, 15 kDa (PEA-15 protein in the complex with a mitogen-activated protein (MAP kinase, extracellular regulated kinase 2 (ERK2, which is essential in regulating ERK2 cellular distribution and function in cell proliferation and migration. The most significant conformational change in PEA-15 happens at helices α2, α3, and α4, which also possess the highest flexibility among the six-helix bundle of the DED. This crucial conformational change is modulated by the D/E-RxDL charge-triad motif, one of the prominent structural features of DEDs, together with a number of other electrostatic and hydrogen bonding interactions on the protein surface. Charge-triad motif promotes the optimal orientation of key residues and expands the binding interface to accommodate protein-protein interactions. However, the charge-triad residues are not directly involved in the binding interface between PEA-15 and ERK2.

  5. Identification of key residues for protein conformational transition using elastic network model.

    Science.gov (United States)

    Su, Ji Guo; Xu, Xian Jin; Li, Chun Hua; Chen, Wei Zu; Wang, Cun Xin

    2011-11-07

    Proteins usually undergo conformational transitions between structurally disparate states to fulfill their functions. The large-scale allosteric conformational transitions are believed to involve some key residues that mediate the conformational movements between different regions of the protein. In the present work, a thermodynamic method based on the elastic network model is proposed to predict the key residues involved in protein conformational transitions. In our method, the key functional sites are identified as the residues whose perturbations largely influence the free energy difference between the protein states before and after transition. Two proteins, nucleotide binding domain of the heat shock protein 70 and human/rat DNA polymerase β, are used as case studies to identify the critical residues responsible for their open-closed conformational transitions. The results show that the functionally important residues mainly locate at the following regions for these two proteins: (1) the bridging point at the interface between the subdomains that control the opening and closure of the binding cleft; (2) the hinge region between different subdomains, which mediates the cooperative motions between the corresponding subdomains; and (3) the substrate binding sites. The similarity in the positions of the key residues for these two proteins may indicate a common mechanism in their conformational transitions.

  6. Anion induced conformational preference of Cα NN motif residues in functional proteins.

    Science.gov (United States)

    Patra, Piya; Ghosh, Mahua; Banerjee, Raja; Chakrabarti, Jaydeb

    2017-12-01

    Among different ligand binding motifs, anion binding C α NN motif consisting of peptide backbone atoms of three consecutive residues are observed to be important for recognition of free anions, like sulphate or biphosphate and participate in different key functions. Here we study the interaction of sulphate and biphosphate with C α NN motif present in different proteins. Instead of total protein, a peptide fragment has been studied keeping C α NN motif flanked in between other residues. We use classical force field based molecular dynamics simulations to understand the stability of this motif. Our data indicate fluctuations in conformational preferences of the motif residues in absence of the anion. The anion gives stability to one of these conformations. However, the anion induced conformational preferences are highly sequence dependent and specific to the type of anion. In particular, the polar residues are more favourable compared to the other residues for recognising the anion. © 2017 Wiley Periodicals, Inc.

  7. Theoretical conformational analysis of the bovine adrenal medulla 12 residue peptide molecule

    Science.gov (United States)

    Akhmedov, N. A.; Tagiyev, Z. H.; Hasanov, E. M.; Akverdieva, G. A.

    2003-02-01

    The spatial structure and conformational properties of the bovine adrenal medulla 12 residue peptide Tyr1-Gly2-Gly3-Phe4-Met5-Arg6-Arg7-Val8-Gly9-Arg10-Pro11-Glu12 (BAM-12P) molecule were studied by theoretical conformational analysis. It is revealed that this molecule can exist in several stable states. The energy and geometrical parameters for the low-energy conformations are obtained. The conformationally rigid and labile segments of this molecule were revealed.

  8. Intensity-modulated three-dimensional conformal radiotherapy

    International Nuclear Information System (INIS)

    Mohan, Radhe

    1996-01-01

    Optimized intensity-modulated treatments one of the important advances in photon radiotherapy. Intensity modulation provides a greatly increased control over dose distributions. Such control can be maximally exploited to achieve significantly higher levels of conformation to the desired clinical objectives using sophisticated optimization techniques. Safe, rapid and efficient delivery of intensity-modulated treatments has become feasible using a dynamic multi-leaf collimator under computer control. The need for all other field shaping devices such as blocks, wedges and compensators is eliminated. Planning and delivery of intensity-modulated treatments is amenable to automation and development of class solutions for each treatment site and stage which can be implemented not only at major academic centers but on a wide scale. A typical treatment involving as many as 10 fields can be delivered in times shorter than much simpler conventional treatments. The main objective of the course is to give an overview of the current state of the art of planning and delivery methods of intensity-modulated treatments. Specifically, the following topics will be covered using representative optimized plans and treatments: 1. A typical procedure for planning and delivering an intensity-modulated treatment. 2. Quantitative definition of criteria (i.e., the objective function) of optimization of intensity-modulated treatments. Clinical relevance of objectives and the dependence of the quality of optimized intensity-modulated plans upon whether the objectives are stated purely in terms of simple dose or dose-volume criteria or whether they incorporate biological indices. 3. Importance of the lateral transport of radiation in the design of intensity-modulated treatments. Impact on dose homogeneity and the optimum choice of margins. 4. Use of intensity-modulated treatments in escalation of tumor dose for the same or lower normal tissue dose. Fractionation of intensity-modulated treatments

  9. Intensity-modulated three-dimensional conformal radiotherapy

    International Nuclear Information System (INIS)

    Mohan, Radhe

    1997-01-01

    Optimized intensity-modulated treatments one of the important advances in photon radiotherapy. Intensity modulation provides a greatly increased control over dose distributions. Such control can be maximally exploited to achieve significantly higher levels of conformation to the desired clinical objectives using sophisticated optimization techniques. Safe, rapid and efficient delivery of intensity-modulated treatments has become feasible using a dynamic multi-leaf collimator under computer control. The need for all other field shaping devices such as blocks, wedges and compensators is eliminated. Planning and delivery of intensity-modulated treatments is amenable to automation and development of class solutions for each treatment site and stage which can be implemented not only at major academic centers but on a wide scale. A typical treatment involving as many as 10 fields can be delivered in times shorter than much simpler conventional treatments. The main objective of the course is to give an overview of the current state of the art of planning and delivery methods of intensity-modulated treatments. Specifically, the following topics will be covered using representative optimized plans and treatments: 1. A typical procedure for planning and delivering an intensity-modulated treatment. 2. Quantitative definition of criteria (i.e., the objective function) of optimization of intensity-modulated treatments. Clinical relevance of objectives and the dependence of the quality of optimized intensity-modulated plans upon whether the objectives are stated purely in terms of simple dose or dose-volume criteria or whether they incorporate biological indices. 3. Importance of the lateral transport of radiation in the design of intensity-modulated treatments. Impact on dose homogeneity and the optimum choice of margins. 4. Use of intensity-modulated treatments in escalation of tumor dose for the same or lower normal tissue dose. Fractionation of intensity-modulated treatments

  10. Conformal radiotherapy by intensity modulation of pediatrics tumors

    International Nuclear Information System (INIS)

    Leseur, J.; Le Prise, E.; Carrie, C.; Bernier, V.; Beneyton, V.; Mahe, M.A.; Supiot, S.

    2009-01-01

    The objective of this study is to take stock on the validated and potential indications of the conformal radiotherapy with intensity modulation ( intensity modulated radiotherapy I.M.R.T.) in pediatrics and to propose recommendations for its use as well as the adapted dose constraints. About 40 to 50% of children treated for a cancer are irradiated. The I.M.R.T., by linear accelerator or helical tomo-therapy has for aim to give a homogenous dose to the target volume and to save organs at risk. Its use in pediatrics seems particularly interesting because of the complexity of target volumes and the closeness of organs at risk. In compensation for these positive elements, the importance of low doses irradiation given in big volumes makes fear event consequences on growth and an increased incidence of secondary cancers in children suffering from tumors with high cure rates and long life expectancy. (N.C.)

  11. Conformation of dehydropentapeptides containing four achiral amino acid residues – controlling the role of L-valine

    Directory of Open Access Journals (Sweden)

    Michał Jewgiński

    2014-03-01

    Full Text Available Structural studies of pentapeptides containing an achiral block, built from two dehydroamino acid residues (ΔZPhe and ΔAla and two glycines, as well as one chiral L-Val residue were performed using NMR spectroscopy. The key role of the L-Val residue in the generation of the secondary structure of peptides is discussed. The obtained results suggest that the strongest influence on the conformation of peptides arises from a valine residue inserted at the C-terminal position. The most ordered conformation was found for peptide Boc-Gly-ΔAla-Gly-ΔZPhe-Val-OMe (3, which adopts a right-handed helical conformation.

  12. Gas-Phase Hydrogen-Deuterium Exchange Labeling of Select Peptide Ion Conformer Types: a Per-Residue Kinetics Analysis.

    Science.gov (United States)

    Khakinejad, Mahdiar; Kondalaji, Samaneh Ghassabi; Tafreshian, Amirmahdi; Valentine, Stephen J

    2015-07-01

    The per-residue, gas-phase hydrogen deuterium exchange (HDX) kinetics for individual amino acid residues on selected ion conformer types of the model peptide KKDDDDDIIKIIK have been examined using ion mobility spectrometry (IMS) and HDX-tandem mass spectrometry (MS/MS) techniques. The [M + 4H](4+) ions exhibit two major conformer types with collision cross sections of 418 Å(2) and 446 Å(2); the [M + 3H](3+) ions also yield two different conformer types having collision cross sections of 340 Å(2) and 367 Å(2). Kinetics plots of HDX for individual amino acid residues reveal fast- and slow-exchanging hydrogens. The contributions of each amino acid residue to the overall conformer type rate constant have been estimated. For this peptide, N- and C-terminal K residues exhibit the greatest contributions for all ion conformer types. Interior D and I residues show decreased contributions. Several charge state trends are observed. On average, the D residues of the [M + 3H](3+) ions show faster HDX rate contributions compared with [M + 4H](4+) ions. In contrast the interior I8 and I9 residues show increased accessibility to exchange for the more elongated [M + 4H](4+) ion conformer type. The contribution of each residue to the overall uptake rate showed a good correlation with a residue hydrogen accessibility score model calculated using a distance from charge site and initial incorporation site for nominal structures obtained from molecular dynamic simulations (MDS).

  13. Driving Calmodulin Protein towards Conformational Shift by Changing Ionization States of Select Residues

    International Nuclear Information System (INIS)

    Negi, Sunita; Atilgan, Ali Rana; Atilgan, Canan

    2012-01-01

    Proteins are complex systems made up of many conformational sub-states which are mainly determined by the folded structure. External factors such as solvent type, temperature, pH and ionic strength play a very important role in the conformations sampled by proteins. Here we study the conformational multiplicity of calmodulin (CaM) which is a protein that plays an important role in calcium signaling pathways in the eukaryotic cells. CaM can bind to a variety of other proteins or small organic compounds, and mediates different physiological processes by activating various enzymes. Binding of calcium ions and proteins or small organic molecules to CaM induces large conformational changes that are distinct to each interacting partner. In particular, we discuss the effect of pH variation on the conformations of CaM. By using the pKa values of the charged residues as a basis to assign protonation states, the conformational changes induced in CaM by reducing the pH are studied by molecular dynamics simulations. Our current view suggests that at high pH, barrier crossing to the compact form is prevented by repulsive electrostatic interactions between the two lobes. At reduced pH, not only is barrier crossing facilitated by protonation of residues, but also conformations which are on average more compact are attained. The latter are in accordance with the fluorescence resonance energy transfer experiment results of other workers. The key events leading to the conformational change from the open to the compact conformation are (i) formation of a salt bridge between the N-lobe and the linker, stabilizing their relative motions, (ii) bending of the C-lobe towards the N-lobe, leading to a lowering of the interaction energy between the two-lobes, (iii) formation of a hydrophobic patch between the two lobes, further stabilizing the bent conformation by reducing the entropic cost of the compact form, (iv) sharing of a Ca +2 ion between the two lobes.

  14. Driving Calmodulin Protein towards Conformational Shift by Changing Ionization States of Select Residues

    Science.gov (United States)

    Negi, Sunita; Rana Atilgan, Ali; Atilgan, Canan

    2012-12-01

    Proteins are complex systems made up of many conformational sub-states which are mainly determined by the folded structure. External factors such as solvent type, temperature, pH and ionic strength play a very important role in the conformations sampled by proteins. Here we study the conformational multiplicity of calmodulin (CaM) which is a protein that plays an important role in calcium signaling pathways in the eukaryotic cells. CaM can bind to a variety of other proteins or small organic compounds, and mediates different physiological processes by activating various enzymes. Binding of calcium ions and proteins or small organic molecules to CaM induces large conformational changes that are distinct to each interacting partner. In particular, we discuss the effect of pH variation on the conformations of CaM. By using the pKa values of the charged residues as a basis to assign protonation states, the conformational changes induced in CaM by reducing the pH are studied by molecular dynamics simulations. Our current view suggests that at high pH, barrier crossing to the compact form is prevented by repulsive electrostatic interactions between the two lobes. At reduced pH, not only is barrier crossing facilitated by protonation of residues, but also conformations which are on average more compact are attained. The latter are in accordance with the fluorescence resonance energy transfer experiment results of other workers. The key events leading to the conformational change from the open to the compact conformation are (i) formation of a salt bridge between the N-lobe and the linker, stabilizing their relative motions, (ii) bending of the C-lobe towards the N-lobe, leading to a lowering of the interaction energy between the two-lobes, (iii) formation of a hydrophobic patch between the two lobes, further stabilizing the bent conformation by reducing the entropic cost of the compact form, (iv) sharing of a Ca+2 ion between the two lobes.

  15. A lipid-mediated conformational switch modulates the thermosensing activity of DesK.

    Science.gov (United States)

    Inda, María Eugenia; Vandenbranden, Michel; Fernández, Ariel; de Mendoza, Diego; Ruysschaert, Jean-Marie; Cybulski, Larisa Estefanía

    2014-03-04

    The thermosensor DesK is a multipass transmembrane histidine-kinase that allows the bacterium Bacillus subtilis to adjust the levels of unsaturated fatty acids required to optimize membrane lipid fluidity. The cytoplasmic catalytic domain of DesK behaves like a kinase at low temperature and like a phosphatase at high temperature. Temperature sensing involves a built-in instability caused by a group of hydrophilic residues located near the N terminus of the first transmembrane (TM) segment. These residues are buried in the lipid phase at low temperature and partially "buoy" to the aqueous phase at higher temperature with the thinning of the membrane, promoting the required conformational change. Nevertheless, the core question remains poorly understood: How is the information sensed by the transmembrane region converted into a rearrangement in the cytoplasmic catalytic domain to control DesK activity? Here, we identify a "linker region" (KSRKERERLEEK) that connects the TM sensor domain with the cytoplasmic catalytic domain involved in signal transmission. The linker adopts two conformational states in response to temperature-dependent membrane thickness changes: (i) random coiled and bound to the phospholipid head groups at the water-membrane interface, promoting the phosphatase state or (ii) unbound and forming a continuous helix spanning a region from the membrane to the cytoplasm, promoting the kinase state. Our results uphold the view that the linker is endowed with a helix/random coil conformational duality that enables it to behave like a transmission switch, with helix disruption decreasing the kinase/phosphatase activity ratio, as required to modulate the DesK output response.

  16. Polymorphisms at Amino Acid Residues 141 and 154 Influence Conformational Variation in Ovine PrP

    Science.gov (United States)

    Yang, Sujeong; Thackray, Alana M.; Hopkins, Lee; Monie, Tom P.; Burke, David F.; Bujdoso, Raymond

    2014-01-01

    Polymorphisms in ovine PrP at amino acid residues 141 and 154 are associated with susceptibility to ovine prion disease: Leu141Arg154 with classical scrapie and Phe141Arg154 and Leu141His154 with atypical scrapie. Classical scrapie is naturally transmissible between sheep, whereas this may not be the case with atypical scrapie. Critical amino acid residues will determine the range or stability of structural changes within the ovine prion protein or its functional interaction with potential cofactors, during conversion of PrPC to PrPSc in these different forms of scrapie disease. Here we computationally identified that regions of ovine PrP, including those near amino acid residues 141 and 154, displayed more conservation than expected based on local structural environment. Molecular dynamics simulations showed these conserved regions of ovine PrP displayed genotypic differences in conformational repertoire and amino acid side-chain interactions. Significantly, Leu141Arg154 PrP adopted an extended beta sheet arrangement in the N-terminal palindromic region more frequently than the Phe141Arg154 and Leu141His154 variants. We supported these computational observations experimentally using circular dichroism spectroscopy and immunobiochemical studies on ovine recombinant PrP. Collectively, our observations show amino acid residues 141 and 154 influence secondary structure and conformational change in ovine PrP that may correlate with different forms of scrapie. PMID:25126555

  17. General Conformity Training Module 2.5: Proactive Role for Federal Agencies

    Science.gov (United States)

    Module 2.5 explains how taking a proactive role will allow a federal agency to more effectively participate in newly promulgated programs under the General Conformity Regulations, such as the emission reduction credits and the emission budgets programs.

  18. Identification of intracellular residues in the dopamine transporter critical for regulation of transporter conformation and cocaine binding

    DEFF Research Database (Denmark)

    Loland, Claus Juul; Grånäs, Charlotta; Javitch, Jonathan A

    2004-01-01

    Recently we showed evidence that mutation of Tyr-335 to Ala (Y335A) in the human dopamine transporter (hDAT) alters the conformational equilibrium of the transport cycle. Here, by substituting, one at a time, 16 different bulky or charged intracellular residues, we identify three residues, Lys-26...

  19. 3D Pattern Synthesis of Time-Modulated Conformal Arrays with a Multiobjective Optimization Approach

    Directory of Open Access Journals (Sweden)

    Wentao Li

    2014-01-01

    Full Text Available This paper addresses the synthesis of the three-dimensional (3D radiation patterns of the time-modulated conformal arrays. Due to the nature of periodic time modulation, harmonic radiation patterns are generated at the multiples of the modulation frequency in time-modulated arrays. Thus, the optimization goal of the time-modulated conformal array includes the optimization of the sidelobe level at the operating frequency and the sideband levels (SBLs at the harmonic frequency, and the design can be regarded as a multiobjective problem. The multiobjective particle swarm optimization (MOPSO is applied to optimize the switch-on instants and pulse durations of the time-modulated conformal array. To significantly reduce the optimization variables, the modified Bernstein polynomial is employed in the synthesis process. Furthermore, dual polarized patch antenna is designed as radiator to achieve low cross-polarization level during the beam scanning. A 12 × 13 (156-element conical conformal microstrip array is simulated to demonstrate the proposed synthesis mechanism, and good results reveal the promising ability of the proposed algorithm in solving the synthesis of the time-modulated conformal arrays problem.

  20. Subnanomolar Inhibitor of Cytochrome bc1 Complex Designed via Optimizing Interaction with Conformationally Flexible Residues

    Science.gov (United States)

    Zhao, Pei-Liang; Wang, Le; Zhu, Xiao-Lei; Huang, Xiaoqin; Zhan, Chang-Guo; Wu, Jia-Wei; Yang, Guang-Fu

    2009-01-01

    Cytochrome bc1 complex (EC 1.10.2.2, bc1), an essential component of the cellular respiratory chain and the photosynthetic apparatus in photosynthetic bacteria, has been identified as a promising target for new drugs and agricultural fungicides. X-ray diffraction structures of the free bc1 complex and its complexes with various inhibitors revealed that the phenyl group of Phe274 in the binding pocket exhibited significant conformational flexibility upon different inhibitors binding to optimize respective π-π interactions, whereas the side chains of other hydrophobic residues showed conformational stability. Therefore, in the present study, a strategy of optimizing the π-π interaction with conformationally flexible residues was proposed to design and discover new bc1 inhibitors with a higher potency. Eight new compounds were designed and synthesized, among which compound 5c with a Ki value of 570 pM was identified as the most promising drug or fungicide candidate, significantly more potent than the commercially available bc1 inhibitors including azoxystrobin (AZ), kresoxim-methyl (KM), and pyraclostrobin (PY). To our knowledge, this is the first bc1 inhibitor discovered from structure-based design with a potency of subnanomolar Ki value. For all of the compounds synthesized and assayed, the calculated binding free energies correlated reasonably well with the binding free energies derived from the experimental Ki values with a correlation coefficient of r2 = 0.89. The further inhibitory kinetics studies revealed that compound 5c is a non-competitive inhibitor with respect to substrate cytochrome c, but is a competitive inhibitor with respect to substrate ubiquinol. Due to its subnanomolar Ki potency and slow dissociation rate constant (k−0 = 0.00358 s−1), compound 5c could be used as a specific probe for further elucidation of the mechanism of bc1 function and as a new lead compound for future drug discovery. PMID:19928849

  1. A proton beam delivery system for conformal therapy and intensity modulated therapy

    International Nuclear Information System (INIS)

    Yu Qingchang

    2001-01-01

    A scattering proton beam delivery system for conformal therapy and intensity modulated therapy is described. The beam is laterally spread out by a dual-ring double scattering system and collimated by a program-controlled multileaf collimator and patient specific fixed collimators. The proton range is adjusted and modulated by a program controlled binary filter and ridge filters

  2. Implementation of intensity-modulated conformational radiotherapy for cervical cancers at the Alexis Vautrin Centre

    International Nuclear Information System (INIS)

    Renard-Oldrini, Sophie

    2010-01-01

    As platinum salt based concomitant conformational radiotherapy and chemotherapy have been used as a standard treatment for cervical cancers but resulted in digestive and haematological toxicities, this research thesis reports the application of intensity-modulated conformational radiation therapy. After having recalled some epidemiological, anatomical aspects, diagnosis and treatments aspects regarding cervical cancer, the author presents this last treatment technique (principles, benefits, practical implementation). The author discusses results obtained by an experiment during which seven patients have been treated by simple conformational radiation therapy, and four by intensity-modulated conformational radiation therapy. Results are discussed in terms of volumes (clinical target volume, growth target volume, planned target volume), dosimetric results, toxicities (urine and skin), weight loss [fr

  3. A J-modulated protonless NMR experiment characterizes the conformational ensemble of the intrinsically disordered protein WIP

    Energy Technology Data Exchange (ETDEWEB)

    Rozentur-Shkop, Eva; Goobes, Gil; Chill, Jordan H., E-mail: Jordan.Chill@biu.ac.il [Bar Ilan University, Department of Chemistry (Israel)

    2016-12-15

    Intrinsically disordered proteins (IDPs) are multi-conformational polypeptides that lack a single stable three-dimensional structure. It has become increasingly clear that the versatile IDPs play key roles in a multitude of biological processes, and, given their flexible nature, NMR is a leading method to investigate IDP behavior on the molecular level. Here we present an IDP-tailored J-modulated experiment designed to monitor changes in the conformational ensemble characteristic of IDPs by accurately measuring backbone one- and two-bond J({sup 15}N,{sup 13}Cα) couplings. This concept was realized using a unidirectional (H)NCO {sup 13}C-detected experiment suitable for poor spectral dispersion and optimized for maximum coverage of amino acid types. To demonstrate the utility of this approach we applied it to the disordered actin-binding N-terminal domain of WASp interacting protein (WIP), a ubiquitous key modulator of cytoskeletal changes in a range of biological systems. One- and two-bond J({sup 15}N,{sup 13}Cα) couplings were acquired for WIP residues 2–65 at various temperatures, and in denaturing and crowding environments. Under native conditions fitted J-couplings identified in the WIP conformational ensemble a propensity for extended conformation at residues 16–23 and 45–60, and a helical tendency at residues 28–42. These findings are consistent with a previous study of the based upon chemical shift and RDC data and confirm that the WIP{sup 2–65} conformational ensemble is biased towards the structure assumed by this fragment in its actin-bound form. The effects of environmental changes upon this ensemble were readily apparent in the J-coupling data, which reflected a significant decrease in structural propensity at higher temperatures, in the presence of 8 M urea, and under the influence of a bacterial cell lysate. The latter suggests that crowding can cause protein unfolding through protein–protein interactions that stabilize the unfolded

  4. Influences of conformations of peptides on stereoinversions and/or isomerizations of aspartic acid residues.

    Science.gov (United States)

    Oda, Akifumi; Nakayoshi, Tomoki; Fukuyoshi, Shuichi; Kurimoto, Eiji; Takahashi, Ohgi

    2018-07-01

    Recently, non-enzymatic stereoinversions of aspartic acid (Asp) residues in proteins and peptides have been reported. Here, we performed replica exchange molecular dynamics (REMD) simulations of model peptides (exon 6, 26A-1, and 26A-2) extracted from elastin to investigate their structural features, thereby revealing the factor that influences stereoinversions. For REMD trajectories, we calculated distances between carboxyl carbon in Asp and amide nitrogen in the (n + 1) residue (CN distances). Because bond formation between carbon and nitrogen is indispensable to the formation of a succinimide intermediate the distance between them seems to play an important role in stereoinversion. Moreover, we calculated polar surface areas (PSAs) for the trajectories, finding that CN distances and PSA were different for each peptide, with the longest CN distance and smallest PSA observed for exon 6 peptide, where stereoinversion of Asp is the slowest. Although the average CN distance was shorter for exon 26A-1 peptide than for exon 26A-2 peptide, the number of conformations with CN distances acids: biology in the mirror, edited by Dr. Loredano Pollegioni, Dr. Jean-Pierre Mothet and Dr. Molla Gianluca. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Loop Electrostatics Asymmetry Modulates the Preexisting Conformational Equilibrium in Thrombin.

    Science.gov (United States)

    Pozzi, Nicola; Zerbetto, Mirco; Acquasaliente, Laura; Tescari, Simone; Frezzato, Diego; Polimeno, Antonino; Gohara, David W; Di Cera, Enrico; De Filippis, Vincenzo

    2016-07-19

    Thrombin exists as an ensemble of active (E) and inactive (E*) conformations that differ in their accessibility to the active site. Here we show that redistribution of the E*-E equilibrium can be achieved by perturbing the electrostatic properties of the enzyme. Removal of the negative charge of the catalytic Asp102 or Asp189 in the primary specificity site destabilizes the E form and causes a shift in the 215-217 segment that compromises substrate entrance. Solution studies and existing structures of D102N document stabilization of the E* form. A new high-resolution structure of D189A also reveals the mutant in the collapsed E* form. These findings establish a new paradigm for the control of the E*-E equilibrium in the trypsin fold.

  6. Conformal intensity-modulated radiotherapy (IMRT) delivered by robotic linac-conformality versus efficiency of dose delivery

    International Nuclear Information System (INIS)

    Webb, Steve

    2000-01-01

    Intensity-modulated radiotherapy (IMRT) may be delivered with a high-energy-photon linac mounted on a robotic gantry and executing a complex trajectory. In a previous paper an inverse-planning technique was developed for such an application. Here the work is extended to demonstrate the dependence of conformality on the size of the elemental pencil beam, on the complexity of the trajectory and on the sampling of azimuth and elevation of the collimated source. The improved conformality of complex trajectories is demonstrated and benchmarked relative to simpler trajectories, more representative of existing non-robotic IMRT techniques. Specifically, by choosing a very fine pencil beam, exquisitely conformal dose distributions have been obtained. Important sampling considerations have been determined. Expressions have been derived for the dosimetry and monitor-unit efficiency of robotic IMRT. Equivalent trajectories were computed for executing the complex robotic trajectories instead by using a conventional linac. The work benchmarks an ideal in IMRT against which more practical and more common techniques may be measured. (author)

  7. Conformal radiation therapy with or without intensity modulation in the treatment of localized prostate cancer

    International Nuclear Information System (INIS)

    Maingon, P.; Truc, G.; Bosset, M.; Peignaux, K.; Ammor, A.; Bolla, M.

    2005-01-01

    Conformal radiation therapy has now to be considered as a standard treatment of localized prostatic adenocarcinomas. Using conformational methods and intensity modulated radiation therapy requires a rigorous approach for their implementation in routine, focused on the reproducibility of the treatment, target volume definitions, dosimetry, quality control, setup positioning. In order to offer to the largest number of patients high-dose treatment, the clinicians must integrate as prognostic factors accurate definition of microscopic extension as well as the tolerance threshold of critical organs. High-dose delivery is expected to be most efficient in intermediary risks and locally advanced diseases. Intensity modulated radiation therapy is specifically dedicated to dose escalation. Perfect knowledge of classical constraints of conformal radiation therapy is required. Using such an approach in routine needs a learning curve including the physicists and a specific quality assurance program. (author)

  8. Pancreatic cancer planning: Complex conformal vs modulated therapies

    International Nuclear Information System (INIS)

    Chapman, Katherine L.; Witek, Matthew E.; Chen, Hongyu; Showalter, Timothy N.; Bar-Ad, Voichita; Harrison, Amy S.

    2016-01-01

    To compare the roles of intensity-modulated radiation therapy (IMRT) and volumetric- modulated arc therapy (VMAT) therapy as compared to simple and complex 3-dimensional chemoradiotherpy (3DCRT) planning for resectable and borderline resectable pancreatic cancer. In all, 12 patients who received postoperative radiotherapy (8) or neoadjuvant concurrent chemoradiotherapy (4) were evaluated retrospectively. Radiotherapy planning was performed for 4 treatment techniques: simple 4-field box, complex 5-field 3DCRT, 5 to 6-field IMRT, and single-arc VMAT. All volumes were approved by a single observer in accordance with Radiation Therapy Oncology Group (RTOG) Pancreas Contouring Atlas. Plans included tumor/tumor bed and regional lymph nodes to 45 Gy; with tumor/tumor bed boosted to 50.4 Gy, at least 95% of planning target volume (PTV) received the prescription dose. Dose-volume histograms (DVH) for multiple end points, treatment planning, and delivery time were assessed. Complex 3DCRT, IMRT, and VMAT plans significantly (p < 0.05) decreased mean kidney dose, mean liver dose, liver (V 30 , V 35 ), stomach (D 10 %), stomach (V 45 ), mean right kidney dose, and right kidney (V 15 ) as compared with the simple 4-field plans that are most commonly reported in the literature. IMRT plans resulted in decreased mean liver dose, liver (V 35 ), and left kidney (V 15 , V 18 , V 20 ). VMAT plans decreased small bowel (D 10 %, D 15 %), small bowel (V 35 , V 45 ), stomach (D 10 %, D 15 %), stomach (V 35 , V 45 ), mean liver dose, liver (V 35 ), left kidney (V 15 , V 18 , V 20 ), and right kidney (V 18 , V 20 ). VMAT plans significantly decreased small bowel (D 10 %, D 15 %), left kidney (V 20 ), and stomach (V 45 ) as compared with IMRT plans. Treatment planning and delivery times were most efficient for simple 4-field box and VMAT. Excluding patient setup and imaging, average treatment delivery was within 10 minutes for simple and complex 3DCRT, IMRT, and VMAT treatments. This article

  9. Pancreatic cancer planning: Complex conformal vs modulated therapies

    Energy Technology Data Exchange (ETDEWEB)

    Chapman, Katherine L. [Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA (United States); Witek, Matthew E. [Department of Radiation Oncology, University of Wisconsin School of Medicine School of Medicine and Public Health, Madison, WI (United States); Chen, Hongyu [Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA (United States); Showalter, Timothy N. [Department of Radiation Oncology, University of Virginia, Charlottesville, VA (United States); Bar-Ad, Voichita [Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA (United States); Harrison, Amy S., E-mail: amy.harrison@jefferson.edu [Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA (United States)

    2016-07-01

    To compare the roles of intensity-modulated radiation therapy (IMRT) and volumetric- modulated arc therapy (VMAT) therapy as compared to simple and complex 3-dimensional chemoradiotherpy (3DCRT) planning for resectable and borderline resectable pancreatic cancer. In all, 12 patients who received postoperative radiotherapy (8) or neoadjuvant concurrent chemoradiotherapy (4) were evaluated retrospectively. Radiotherapy planning was performed for 4 treatment techniques: simple 4-field box, complex 5-field 3DCRT, 5 to 6-field IMRT, and single-arc VMAT. All volumes were approved by a single observer in accordance with Radiation Therapy Oncology Group (RTOG) Pancreas Contouring Atlas. Plans included tumor/tumor bed and regional lymph nodes to 45 Gy; with tumor/tumor bed boosted to 50.4 Gy, at least 95% of planning target volume (PTV) received the prescription dose. Dose-volume histograms (DVH) for multiple end points, treatment planning, and delivery time were assessed. Complex 3DCRT, IMRT, and VMAT plans significantly (p < 0.05) decreased mean kidney dose, mean liver dose, liver (V{sub 30}, V{sub 35}), stomach (D{sub 10}%), stomach (V{sub 45}), mean right kidney dose, and right kidney (V{sub 15}) as compared with the simple 4-field plans that are most commonly reported in the literature. IMRT plans resulted in decreased mean liver dose, liver (V{sub 35}), and left kidney (V{sub 15}, V{sub 18}, V{sub 20}). VMAT plans decreased small bowel (D{sub 10}%, D{sub 15}%), small bowel (V{sub 35}, V{sub 45}), stomach (D{sub 10}%, D{sub 15}%), stomach (V{sub 35}, V{sub 45}), mean liver dose, liver (V{sub 35}), left kidney (V{sub 15}, V{sub 18}, V{sub 20}), and right kidney (V{sub 18}, V{sub 20}). VMAT plans significantly decreased small bowel (D{sub 10}%, D{sub 15}%), left kidney (V{sub 20}), and stomach (V{sub 45}) as compared with IMRT plans. Treatment planning and delivery times were most efficient for simple 4-field box and VMAT. Excluding patient setup and imaging, average

  10. Modulation of the Conformational Dynamics of Apo-Adenylate Kinase through a π-Cation Interaction.

    Science.gov (United States)

    Halder, Ritaban; Manna, Rabindra Nath; Chakraborty, Sandipan; Jana, Biman

    2017-06-15

    Large-scale conformational transition from open to closed state of adenylate kinase (ADK) is essential for its catalytic cycle. Apo-ADK undergoes conformational transition in a way that closely resembles an open-to-closed conformational transition. Here, equilibrium simulations, free-energy simulations, and quantum mechanics/molecular mechanics (QM/MM) calculations in combination with several bioinformatics approaches have been used to explore the molecular origin of this conformational transition in apo-ADK. In addition to its conventional open state, Escherichia coli apo-ADK adopts conformations that resemble a closed-like intermediate, the "half-open-half-closed" (HOHC) state, and a π-cation interaction can account for the stability of this HOHC state. Energetics and the electronic properties of this π-cation interaction have been explored using QM/MM calculations. Upon rescinding the π-cation interaction, the conformational landscape of the apo-ADK changes completely. The apo-ADK population is shifted completely toward the open state. This π-cation interaction is highly conserved in bacterial ADK; the cationic guanidinium moiety of a conserved ARG interacts with the delocalized π-electron cloud of either PHE or TYR. Interestingly, this study demonstrates the modulation of a principal protein dynamics by a conserved specific π-cation interaction across different organisms.

  11. Electro-optic modulator with ultra-low residual amplitude modulation for frequency modulation and laser stabilization.

    Science.gov (United States)

    Tai, Zhaoyang; Yan, Lulu; Zhang, Yanyan; Zhang, Xiaofei; Guo, Wenge; Zhang, Shougang; Jiang, Haifeng

    2016-12-01

    The reduction of the residual amplitude modulation (RAM) induced by electro-optic modulation is essential for many applications of frequency modulation spectroscopy requiring a lower system noise floor. Here, we demonstrate a simple passive approach employing an electro-optic modulator (EOM) cut at Brewster's angle. The proposed EOM exhibits a RAM of a few parts per million, which is comparable with that achieved by a common EOM under critical active temperature and bias voltage controls. The frequency instability of a 10 cm cavity-stabilized laser induced by the RAM effect of the proposed EOM is below 3×10-17 for integration times from 1 to 1000 s, and below 4×10-16 for comprehensive noise contributions for integration times from 1 to 100 s.

  12. Measurement of conformational constraints in an elastin-mimetic protein by residue-pair selected solid-state NMR

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Mei [Iowa State University, Department of Chemistry (United States)], E-mail: mhong@iastate.edu; McMillan, R. Andrew; Conticello, Vincent P. [Emory University, Department of Chemistry (United States)

    2002-02-15

    We introduce a solid-state NMR technique for selective detection of a residue pair in multiply labeled proteins to obtain site-specific structural constraints. The method exploits the frequency-offset dependence of cross polarization to achieve {sup 13}CO{sub i} {sup {yields}} {sup 15}N{sub i} {sup {yields}} {sup 13}C{alpha}{sub i} transfer between two residues. A {sup 13}C, {sup 15}N-labeled elastin mimetic protein (VPGVG){sub n} is used to demonstrate the method. The technique selected the Gly3 C{alpha} signal while suppressing the Gly5 C{alpha} signal, and allowed the measurement of the Gly3 C{alpha} chemical shift anisotropy to derive information on the protein conformation. This residue-pair selection technique should simplify the study of protein structure at specific residues.

  13. Measurement of conformational constraints in an elastin-mimetic protein by residue-pair selected solid-state NMR

    International Nuclear Information System (INIS)

    Hong, Mei; McMillan, R. Andrew; Conticello, Vincent P.

    2002-01-01

    We introduce a solid-state NMR technique for selective detection of a residue pair in multiply labeled proteins to obtain site-specific structural constraints. The method exploits the frequency-offset dependence of cross polarization to achieve 13 CO i → 15 N i → 13 Cα i transfer between two residues. A 13 C, 15 N-labeled elastin mimetic protein (VPGVG) n is used to demonstrate the method. The technique selected the Gly3 Cα signal while suppressing the Gly5 Cα signal, and allowed the measurement of the Gly3 Cα chemical shift anisotropy to derive information on the protein conformation. This residue-pair selection technique should simplify the study of protein structure at specific residues

  14. Saturation Mutagenesis of the HIV-1 Envelope CD4 Binding Loop Reveals Residues Controlling Distinct Trimer Conformations.

    Directory of Open Access Journals (Sweden)

    Maria Duenas-Decamp

    2016-11-01

    Full Text Available The conformation of HIV-1 envelope (Env glycoprotein trimers is key in ensuring protection against waves of neutralizing antibodies generated during infection, while maintaining sufficient exposure of the CD4 binding site (CD4bs for viral entry. The CD4 binding loop on Env is an early contact site for CD4 while penetration of a proximal cavity by CD4 triggers Env conformational changes for entry. The role of residues in the CD4 binding loop in regulating the conformation of the trimer and trimer association domain (TAD was investigated using a novel saturation mutagenesis approach. Single mutations identified, resulted in distinct trimer conformations affecting CD4bs exposure, the glycan shield and the TAD across diverse HIV-1 clades. Importantly, mutations that improve access to the CD4bs without exposing the immunodominant V3 loop were identified. The different trimer conformations identified will affect the specificity and breadth of nabs elicited in vivo and are important to consider in design of Env immunogens for vaccines.

  15. Active cancellation of residual amplitude modulation in a frequency-modulation based Fabry-Perot interferometer.

    Science.gov (United States)

    Yu, Yinan; Wang, Yicheng; Pratt, Jon R

    2016-03-01

    Residual amplitude modulation (RAM) is one of the most common noise sources known to degrade the sensitivity of frequency modulation spectroscopy. RAM can arise as a result of the temperature dependent birefringence of the modulator crystal, which causes the orientation of the crystal's optical axis to shift with respect to the polarization of the incident light with temperature. In the fiber-based optical interferometer used on the National Institute of Standards and Technology calculable capacitor, RAM degrades the measured laser frequency stability and correlates with the environmental temperature fluctuations. We have demonstrated a simple approach that cancels out excessive RAM due to polarization mismatch between the light and the optical axis of the crystal. The approach allows us to measure the frequency noise of a heterodyne beat between two lasers individually locked to different resonant modes of a cavity with an accuracy better than 0.5 ppm, which meets the requirement to further determine the longitudinal mode number of the cavity length. Also, this approach has substantially mitigated the temperature dependency of the measurements of the cavity length and consequently the capacitance.

  16. Dynamic and Progressive Control of DNA Origami Conformation by Modulating DNA Helicity with Chemical Adducts.

    Science.gov (United States)

    Chen, Haorong; Zhang, Hanyu; Pan, Jing; Cha, Tae-Gon; Li, Shiming; Andréasson, Joakim; Choi, Jong Hyun

    2016-05-24

    DNA origami has received enormous attention for its ability to program complex nanostructures with a few nanometer precision. Dynamic origami structures that change conformation in response to environmental cues or external signals hold great promises in sensing and actuation at the nanoscale. The reconfiguration mechanism of existing dynamic origami structures is mostly limited to single-stranded hinges and relies almost exclusively on DNA hybridization or strand displacement. Here, we show an alternative approach by demonstrating on-demand conformation changes with DNA-binding molecules, which intercalate between base pairs and unwind DNA double helices. The unwinding effect modulates the helicity mismatch in DNA origami, which significantly influences the internal stress and the global conformation of the origami structure. We demonstrate the switching of a polymerized origami nanoribbon between different twisting states and a well-constrained torsional deformation in a monomeric origami shaft. The structural transformation is shown to be reversible, and binding isotherms confirm the reconfiguration mechanism. This approach provides a rapid and reversible means to change DNA origami conformation, which can be used for dynamic and progressive control at the nanoscale.

  17. Conformal radiotherapy by intensity modulation of pediatrics tumors; Radiotherapie conformationnelle par modulation d'intensite des tumeurs pediatriques

    Energy Technology Data Exchange (ETDEWEB)

    Leseur, J.; Le Prise, E. [Centre Eugene-Marquis, 35 - Rennes (France); Carrie, C. [Centre Leon Berard, 69 - Lyon (France); Bernier, V. [Centre Alexis-Vautrin, 54 - Nancy (France); Beneyton, V. [Centre Paul-Strauss, 67 - Strasbourg (France); Mahe, M.A.; Supiot, S. [Centre Rene-Gauducheau, 44 - Nantes (France)

    2009-10-15

    The objective of this study is to take stock on the validated and potential indications of the conformal radiotherapy with intensity modulation ( intensity modulated radiotherapy I.M.R.T.) in pediatrics and to propose recommendations for its use as well as the adapted dose constraints. About 40 to 50% of children treated for a cancer are irradiated. The I.M.R.T., by linear accelerator or helical tomo-therapy has for aim to give a homogenous dose to the target volume and to save organs at risk. Its use in pediatrics seems particularly interesting because of the complexity of target volumes and the closeness of organs at risk. In compensation for these positive elements, the importance of low doses irradiation given in big volumes makes fear event consequences on growth and an increased incidence of secondary cancers in children suffering from tumors with high cure rates and long life expectancy. (N.C.)

  18. Modulation of calmodulin lobes by different targets: an allosteric model with hemiconcerted conformational transitions.

    Directory of Open Access Journals (Sweden)

    Massimo Lai

    2015-01-01

    Full Text Available Calmodulin is a calcium-binding protein ubiquitous in eukaryotic cells, involved in numerous calcium-regulated biological phenomena, such as synaptic plasticity, muscle contraction, cell cycle, and circadian rhythms. It exibits a characteristic dumbell shape, with two globular domains (N- and C-terminal lobe joined by a linker region. Each lobe can take alternative conformations, affected by the binding of calcium and target proteins. Calmodulin displays considerable functional flexibility due to its capability to bind different targets, often in a tissue-specific fashion. In various specific physiological environments (e.g. skeletal muscle, neuron dendritic spines several targets compete for the same calmodulin pool, regulating its availability and affinity for calcium. In this work, we sought to understand the general principles underlying calmodulin modulation by different target proteins, and to account for simultaneous effects of multiple competing targets, thus enabling a more realistic simulation of calmodulin-dependent pathways. We built a mechanistic allosteric model of calmodulin, based on an hemiconcerted framework: each calmodulin lobe can exist in two conformations in thermodynamic equilibrium, with different affinities for calcium and different affinities for each target. Each lobe was allowed to switch conformation on its own. The model was parameterised and validated against experimental data from the literature. In spite of its simplicity, a two-state allosteric model was able to satisfactorily represent several sets of experiments, in particular the binding of calcium on intact and truncated calmodulin and the effect of different skMLCK peptides on calmodulin's saturation curve. The model can also be readily extended to include multiple targets. We show that some targets stabilise the low calcium affinity T state while others stabilise the high affinity R state. Most of the effects produced by calmodulin targets can be

  19. Retrospective evaluation of dosimetric quality for prostate carcinomas treated with 3D conformal, intensity modulated and volumetric modulated arc radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Crowe, Scott B [Science and Engineering Faculty, Queensland University of Technology, Brisbane, Queensland (Australia); Kairn, Tanya [Science and Engineering Faculty, Queensland University of Technology, Brisbane, Queensland (Australia); Premion, Wesley Medical Centre, Brisbane, Queensland (Australia); Middlebrook, Nigel; Hill, Brendan; Christie, David R H; Knight, Richard T [Premion, Wesley Medical Centre, Brisbane, Queensland (Australia); Kenny, John [Australian Clinical Dosimetry Services, Australian Radiation Protection and Nuclear Safety Agency, Melbourne, Victoria (Australia); Langton, Christian M; Trapp, Jamie V [Science and Engineering Faculty, Queensland University of Technology, Brisbane, Queensland (Australia)

    2013-12-15

    This study examines and compares the dosimetric quality of radiotherapy treatment plans for prostate carcinoma across a cohort of 163 patients treated across five centres: 83 treated with three-dimensional conformal radiotherapy (3DCRT), 33 treated with intensity modulated radiotherapy (IMRT) and 47 treated with volumetric modulated arc therapy (VMAT). Treatment plan quality was evaluated in terms of target dose homogeneity and organs at risk (OAR), through the use of a set of dose metrics. These included the mean, maximum and minimum doses; the homogeneity and conformity indices for the target volumes; and a selection of dose coverage values that were relevant to each OAR. Statistical significance was evaluated using two-tailed Welch's T-tests. The Monte Carlo DICOM ToolKit software was adapted to permit the evaluation of dose metrics from DICOM data exported from a commercial radiotherapy treatment planning system. The 3DCRT treatment plans offered greater planning target volume dose homogeneity than the other two treatment modalities. The IMRT and VMAT plans offered greater dose reduction in the OAR: with increased compliance with recommended OAR dose constraints, compared to conventional 3DCRT treatments. When compared to each other, IMRT and VMAT did not provide significantly different treatment plan quality for like-sized tumour volumes. This study indicates that IMRT and VMAT have provided similar dosimetric quality, which is superior to the dosimetric quality achieved with 3DCRT.

  20. Dosimetric comparison of three-dimensional conformal and intensity modulated radiotherapy in brain glioma

    International Nuclear Information System (INIS)

    Lu Jie; Zhang Guifang; Bai Tong; Yin Yong; Fan Tingyong; Wu Chaoxia

    2009-01-01

    Objective: To investigate the dosimetry advantages of intensity modulated radiotherapy (IMRT)of brain glioma compared with that of three-dimensional conformal radiotherapy (SD CRT). Methods: Ten patients with brain glioma were enrolled in this study. Three-dimensional conf0rmal and intensity modulated radiotherapy plans were performed for each patient. The dose distributions of target volume and normal tissues, conformal index (CI) and heterogeneous index (HI) were analyzed using the dose-volume histogram (DVH). The prescription dose was 60 Gy in 30 fractions. Results: IMRT plans decrease the maximum dose and volume of brainstem, mean dose of affected side parotid and maximum dose of spinal-cord. The CI for PTV of IMRT was superior to that of SD CRT, the HI for PTV has no statistical significance of the two model plans. Conclusions: IMRT plans can obviously decrease the dose and volume of brainstem. IMRT is a potential method in the treatment of brain glioma, and dose escalation was possible in patients with brain glioma. (authors)

  1. Elucidating Ligand-Modulated Conformational Landscape of GPCRs Using Cloud-Computing Approaches.

    Science.gov (United States)

    Shukla, Diwakar; Lawrenz, Morgan; Pande, Vijay S

    2015-01-01

    G-protein-coupled receptors (GPCRs) are a versatile family of membrane-bound signaling proteins. Despite the recent successes in obtaining crystal structures of GPCRs, much needs to be learned about the conformational changes associated with their activation. Furthermore, the mechanism by which ligands modulate the activation of GPCRs has remained elusive. Molecular simulations provide a way of obtaining detailed an atomistic description of GPCR activation dynamics. However, simulating GPCR activation is challenging due to the long timescales involved and the associated challenge of gaining insights from the "Big" simulation datasets. Here, we demonstrate how cloud-computing approaches have been used to tackle these challenges and obtain insights into the activation mechanism of GPCRs. In particular, we review the use of Markov state model (MSM)-based sampling algorithms for sampling milliseconds of dynamics of a major drug target, the G-protein-coupled receptor β2-AR. MSMs of agonist and inverse agonist-bound β2-AR reveal multiple activation pathways and how ligands function via modulation of the ensemble of activation pathways. We target this ensemble of conformations with computer-aided drug design approaches, with the goal of designing drugs that interact more closely with diverse receptor states, for overall increased efficacy and specificity. We conclude by discussing how cloud-based approaches present a powerful and broadly available tool for studying the complex biological systems routinely. © 2015 Elsevier Inc. All rights reserved.

  2. Pelvic Ewing sarcomas. Three-dimensional conformal vs. intensity-modulated radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Mounessi, F.S.; Lehrich, P.; Haverkamp, U.; Eich, H.T. [Muenster Univ. (Germany). Dept. of Radiation Oncology; Willich, N. [Muenster Univ. (Germany). Dept. of Radiation Oncology; Universitaetsklinikum Muenster (Germany). RiSK - Registry for the Evaluation of Late Side Effects after Radiotherapy in Childhood and Adolescence; Boelling, T. [Center for Radiation Oncology, Osnabrueck (Germany)

    2013-04-15

    The goal of the present work was to assess the potential advantage of intensity-modulated radiotherapy (IMRT) over three-dimensional conformal radiotherapy (3D-CRT) planning in pelvic Ewing's sarcoma. A total of 8 patients with Ewing sarcoma of the pelvis undergoing radiotherapy were analyzed. Plans for 3D-CRT and IMRT were calculated for each patient. Dose coverage of the planning target volume (PTV), conformity and homogeneity indices, as well as further parameters were evaluated. Results The average dose coverage values for PTV were comparable in 3D-CRT and IMRT plans. Both techniques had a PTV coverage of V{sub 95} > 98 % in all patients. Whereas the IMRT plans achieved a higher conformity index compared to the 3D-CRT plans (conformity index 0.79 {+-} 0.12 vs. 0.54 {+-} 0.19, p = 0.012), the dose distribution across the target volumes was less homogeneous with IMRT planning than with 3D-CRT planning. This difference was statistically significant (homogeneity index 0.11 {+-} 0.03 vs. 0.07 {+-} 0.0, p = 0.035). For the bowel, D{sub mean} and D{sub 1%}, as well as V{sub 2} to V{sub 60} were reduced in IMRT plans. For the bladder and the rectum, there was no significant difference in D{sub mean}. However, the percentages of volumes receiving at least doses of 30, 40, 45, and 50 Gy (V{sub 30} to V{sub 50}) were lower for the rectum in IMRT plans. The volume of normal tissue receiving at least 2 Gy (V{sub 2}) was significantly higher in IMRT plans compared with 3D-CRT, whereas at high dose levels (V{sub 30}) it was significantly lower. Compared to 3D-CRT, IMRT showed significantly better results regarding dose conformity (p = 0.012) and bowel sparing at dose levels above 30 Gy (p = 0.012). Thus, dose escalation in the radiotherapy of pelvic Ewing's sarcoma can be more easily achieved using IMRT. (orig.)

  3. Conformation-specific spectroscopy of capped glutamine-containing peptides: role of a single glutamine residue on peptide backbone preferences.

    Science.gov (United States)

    Walsh, Patrick S; Dean, Jacob C; McBurney, Carl; Kang, Hyuk; Gellman, Samuel H; Zwier, Timothy S

    2016-04-28

    The conformational preferences of a series of short, aromatic-capped, glutamine-containing peptides have been studied under jet-cooled conditions in the gas phase. This work seeks a bottom-up understanding of the role played by glutamine residues in directing peptide structures that lead to neurodegenerative diseases. Resonant ion-dip infrared (RIDIR) spectroscopy is used to record single-conformation infrared spectra in the NH stretch, amide I and amide II regions. Comparison of the experimental spectra with the predictions of calculations carried out at the DFT M05-2X/6-31+G(d) level of theory lead to firm assignments for the H-bonding architectures of a total of eight conformers of four molecules, including three in Z-Gln-OH, one in Z-Gln-NHMe, three in Ac-Gln-NHBn, and one in Ac-Ala-Gln-NHBn. The Gln side chain engages actively in forming H-bonds with nearest-neighbor amide groups, forming C8 H-bonds to the C-terminal side, C9 H-bonds to the N-terminal side, and an amide-stacked geometry, all with an extended (C5) peptide backbone about the Gln residue. The Gln side chain also stabilizes an inverse γ-turn in the peptide backbone by forming a pair of H-bonds that bridge the γ-turn and stabilize it. Finally, the entire conformer population of Ac-Ala-Gln-NHBn is funneled into a single structure that incorporates the peptide backbone in a type I β-turn, stabilized by the Gln side chain forming a C7 H-bond to the central amide group in the β-turn not otherwise involved in a hydrogen bond. This β-turn backbone structure is nearly identical to that observed in a series of X-(AQ)-Y β-turns in the protein data bank, demonstrating that the gas-phase structure is robust to perturbations imposed by the crystalline protein environment.

  4. Accuracy of Real-time Couch Tracking During 3-dimensional Conformal Radiation Therapy, Intensity Modulated Radiation Therapy, and Volumetric Modulated Arc Therapy for Prostate Cancer

    International Nuclear Information System (INIS)

    Wilbert, Juergen; Baier, Kurt; Hermann, Christian; Flentje, Michael; Guckenberger, Matthias

    2013-01-01

    Purpose: To evaluate the accuracy of real-time couch tracking for prostate cancer. Methods and Materials: Intrafractional motion trajectories of 15 prostate cancer patients were the basis for this phantom study; prostate motion had been monitored with the Calypso System. An industrial robot moved a phantom along these trajectories, motion was detected via an infrared camera system, and the robotic HexaPOD couch was used for real-time counter-steering. Residual phantom motion during real-time tracking was measured with the infrared camera system. Film dosimetry was performed during delivery of 3-dimensional conformal radiation therapy (3D-CRT), step-and-shoot intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT). Results: Motion of the prostate was largest in the anterior–posterior direction, with systematic (∑) and random (σ) errors of 2.3 mm and 2.9 mm, respectively; the prostate was outside a threshold of 5 mm (3D vector) for 25.0%±19.8% of treatment time. Real-time tracking reduced prostate motion to ∑=0.01 mm and σ = 0.55 mm in the anterior–posterior direction; the prostate remained within a 1-mm and 5-mm threshold for 93.9%±4.6% and 99.7%±0.4% of the time, respectively. Without real-time tracking, pass rates based on a γ index of 2%/2 mm in film dosimetry ranged between 66% and 72% for 3D-CRT, IMRT, and VMAT, on average. Real-time tracking increased pass rates to minimum 98% on average for 3D-CRT, IMRT, and VMAT. Conclusions: Real-time couch tracking resulted in submillimeter accuracy for prostate cancer, which transferred into high dosimetric accuracy independently of whether 3D-CRT, IMRT, or VMAT was used.

  5. Elimination of residual amplitude modulation in tunable diode laser wavelength modulation spectroscopy using an optical fiber delay line.

    Science.gov (United States)

    Chakraborty, Arup Lal; Ruxton, Keith; Johnstone, Walter; Lengden, Michael; Duffin, Kevin

    2009-06-08

    A new fiber-optic technique to eliminate residual amplitude modulation in tunable diode laser wavelength modulation spectroscopy is presented. The modulated laser output is split to pass in parallel through the gas measurement cell and an optical fiber delay line, with the modulation frequency / delay chosen to introduce a relative phase shift of pi between them. The two signals are balanced using a variable attenuator and recombined through a fiber coupler. In the absence of gas, the direct laser intensity modulation cancels, thereby eliminating the high background. The presence of gas induces a concentration-dependent imbalance at the coupler's output from which the absolute absorption profile is directly recovered with high accuracy using 1f detection.

  6. Modular design of synthetic protein mimics. Characterization of the helical conformation of a 13-residue peptide in crystals

    International Nuclear Information System (INIS)

    Karle, I.L.; Flippen-Anderson, J.L.; Uma, K.; Balaram, P.

    1989-01-01

    The incorporation of α-aminoisobutyryl (Aib) residues into peptide sequences facilitates helical folding. Aib-containing sequences have been chosen for the design of rigid helical segments in a modular approach to the construction of a synthetic protein mimic. The helical conformation of the synthetic peptide Boc-Aib-(Val-Ala-Leu-Aib) 3 -OMe in crystals is established by X-ray diffraction. The 13-residue apolar peptide adopts a helical form in the crystal with seven α-type hydrogen bonds in the middle and 3 10 -type hydrogen bonds at either end. The helices stack in columns, zigzag rather than linear, by means of direct NH hor-ellipsis OC head to tail hydrogen bonds. Leucyl side chains are extended on one side of the helix and valyl side chains on the other side. Water molecules form hydrogen bonds with several backbone carbonyl oxygens that also participate in α-helix hydrogen bonds. There is no apparent distortion of the helix caused by hydration

  7. Effects of the substitution of amino acid residues, through chemical synthesis, on the conformation and activity of antimicrobial peptides

    Directory of Open Access Journals (Sweden)

    Regina C. Adão

    2012-06-01

    Full Text Available Antimicrobial peptides make up an assorted group of molecules which contain from 12 to 50 amino acid residues and which may be produced by microorganisms, plants and animals. From the discovery that these biomolecules are lethal to bacteria, inhibiting the pathogenic organism’s growth, and are also related to innate and adapted defense mechanisms, the investigation of such molecules came to be an emergent research field, in which more than 1800 antimicrobial peptides have so far been discovered throughout the last three decades. These molecules are potential representatives of a new generation of antibiotic agents and the main motivation for such use is their activity against a wide variety of pathogens, including Gram-positive and Gram-negative bacteria as well as fungi and viruses. An important class of comprising some of these peptides may be found in anurans, from which it has been isolated, a considerable number of antimicrobial peptides with diverse sequences and structures, including linear and dimeric ones. In this work monomeric chains (CH1 e CH2 of the heterodimeric antimicrobial peptide distinctin (isolated in 1999 from Phyllomedusa distincta anurans, as well as its mutated monomers (CH1-S and CH2-S and the heterodimer itself were synthesized. The distinctin is the peptide with two chains of different sequences (Table 1 bound each other by disulfide bond from the cystein residues constituting the heterodimer. To investigate the effects on the biological activity by amino acids substitution at normal distinctin CH1 and CH2 chains, both were synthesized as well as their similar chains (CH1-S and CH2-S in which the cystein (Fig.1 a residues of each chain were changed by serin residues (Fig. 1 b. The new chains were named mutants. The synthesis was carried out in solid phase, using Fmoc strategy. The heterodimer distinctin was obtained from CH1 and CH2 chains coupling through cystein residues air oxidation. The results from HPLC

  8. Minimising contralateral breast dose in post-mastectomy intensity-modulated radiotherapy by incorporating conformal electron irradiation

    NARCIS (Netherlands)

    van der Laan, Hans Paul; Korevaar, Erik W; Dolsma, Willemtje; Maduro, John H; Langendijk, Johannes A

    PURPOSE: To assess the potential benefit of incorporating conformal electron irradiation in intensity-modulated radiotherapy (IMRT) for loco-regional post-mastectomy RT. PATIENTS AND METHODS: Ten consecutive patients that underwent left-sided mastectomy were selected for this comparative planning

  9. Anal wall sparing effect of an endorectal balloon in 3D conformal and intensity-modulated prostate radiotherapy.

    NARCIS (Netherlands)

    Smeenk, R.J.; Lin, E.N.J.T. van; Kollenburg, P. van; Kunze-Busch, M.C.; Kaanders, J.H.A.M.

    2009-01-01

    BACKGROUND AND PURPOSE: To investigate the anal wall (Awall) sparing effect of an endorectal balloon (ERB) in 3D conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) for prostate cancer. MATERIALS AND METHODS: In 24 patients with localized prostate carcinoma, two planning

  10. Cardiac Exposure in the Dynamic Conformal Arc Therapy, Intensity-Modulated Radiotherapy and Volumetric Modulated Arc Therapy of Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Xin Ming

    Full Text Available To retrospectively evaluate the cardiac exposure in three cohorts of lung cancer patients treated with dynamic conformal arc therapy (DCAT, intensity-modulated radiotherapy (IMRT, or volumetric modulated arc therapy (VMAT at our institution in the past seven years.A total of 140 lung cancer patients were included in this institutional review board approved study: 25 treated with DCAT, 70 with IMRT and 45 with VMAT. All plans were generated in a same commercial treatment planning system and have been clinically accepted and delivered. The dose distribution to the heart and the effects of tumor laterality, the irradiated heart volume and the beam-to-heart distance on the cardiac exposure were investigated.The mean dose to the heart among all 140 plans was 4.5 Gy. Specifically, the heart received on average 2.3, 5.2 and 4.6 Gy in the DCAT, IMRT and VMAT plans, respectively. The mean heart doses for the left and right lung tumors were 4.1 and 4.8 Gy, respectively. No patients died with evidence of cardiac disease. Three patients (2% with preexisting cardiac condition developed cardiac disease after treatment. Furthermore, the cardiac exposure was found to increase linearly with the irradiated heart volume while decreasing exponentially with the beam-to-heart distance.Compared to old technologies for lung cancer treatment, modern radiotherapy treatment modalities demonstrated better heart sparing. But the heart dose in lung cancer radiotherapy is still higher than that in the radiotherapy of breast cancer and Hodgkin's disease where cardiac complications have been extensively studied. With strong correlations of mean heart dose with beam-to-heart distance and irradiated heart volume, cautions should be exercised to avoid long-term cardiac toxicity in the lung cancer patients undergoing radiotherapy.

  11. Identification of potential small molecule allosteric modulator sites on IL-1R1 ectodomain using accelerated conformational sampling method.

    Directory of Open Access Journals (Sweden)

    Chao-Yie Yang

    Full Text Available The interleukin-1 receptor (IL-1R is the founding member of the interleukin 1 receptor family which activates innate immune response by its binding to cytokines. Reports showed dysregulation of cytokine production leads to aberrant immune cells activation which contributes to auto-inflammatory disorders and diseases. Current therapeutic strategies focus on utilizing antibodies or chimeric cytokine biologics. The large protein-protein interaction interface between cytokine receptor and cytokine poses a challenge in identifying binding sites for small molecule inhibitor development. Based on the significant conformational change of IL-1R type 1 (IL-1R1 ectodomain upon binding to different ligands observed in crystal structures, we hypothesized that transient small molecule binding sites may exist when IL-1R1 undergoes conformational transition and thus suitable for inhibitor development. Here, we employed accelerated molecular dynamics (MD simulation to efficiently sample conformational space of IL-1R1 ectodomain. Representative IL-1R1 ectodomain conformations determined from the hierarchy cluster analysis were analyzed by the SiteMap program which leads to identify small molecule binding sites at the protein-protein interaction interface and allosteric modulator locations. The cosolvent mapping analysis using phenol as the probe molecule further confirms the allosteric modulator site as a binding hotspot. Eight highest ranked fragment molecules identified from in silico screening at the modulator site were evaluated by MD simulations. Four of them restricted the IL-1R1 dynamical motion to inactive conformational space. The strategy from this study, subject to in vitro experimental validation, can be useful to identify small molecule compounds targeting the allosteric modulator sites of IL-1R and prevent IL-1R from binding to cytokine by trapping IL-1R in inactive conformations.

  12. Rational Modulation of the Induced-Fit Conformational Change for Slow-Onset Inhibition in Mycobacterium tuberculosis InhA.

    Science.gov (United States)

    Lai, Cheng-Tsung; Li, Huei-Jiun; Yu, Weixuan; Shah, Sonam; Bommineni, Gopal R; Perrone, Victoria; Garcia-Diaz, Miguel; Tonge, Peter J; Simmerling, Carlos

    2015-08-04

    Slow-onset enzyme inhibitors are the subject of considerable interest as an approach to increasing the potency of pharmaceutical compounds by extending the residence time of the inhibitor on the target (the lifetime of the drug-receptor complex). However, rational modulation of residence time presents significant challenges because it requires additional mechanistic insight, such as the nature of the transition state for postbinding isomerization. Our previous work, based on X-ray crystallography, enzyme kinetics, and molecular dynamics simulation, suggested that the slow step in inhibition of the Mycobacterium tuberculosis enoyl-ACP reductase InhA involves a change in the conformation of the substrate binding loop from an open state in the initial enzyme-inhibitor complex to a closed state in the final enzyme-inhibitor complex. Here, we use multidimensional free energy landscapes for loop isomerization to obtain a computational model for the transition state. The results suggest that slow-onset inhibitors crowd key side chains on helices that slide past each other during isomerization, resulting in a steric clash. The landscapes become significantly flatter when residues involved in the steric clash are replaced with alanine. Importantly, this lower barrier can be increased by rational inhibitor redesign to restore the steric clash. Crystallographic studies and enzyme kinetics confirm the predicted effects on loop structure and flexibility, as well as inhibitor residence time. These loss and regain of function studies validate our mechanistic hypothesis for interactions controlling substrate binding loop isomerization, providing a platform for the future design of inhibitors with longer residence times and better in vivo potency. Similar opportunities for slow-onset inhibition via the same mechanism are identified in other pathogens.

  13. Modulation of constitutive activity and signaling bias of the ghrelin receptor by conformational constraint in the second extracellular loop

    DEFF Research Database (Denmark)

    Mokrosinski, Jacek; Frimurer, Thomas M; Sivertsen, Bjoern

    2012-01-01

    Based on a rare, natural Glu for Ala204(C+6) variant located six residues after the conserved Cys residue in extracellular loop 2 (ECL2b) associated with selective elimination of the high constitutive signaling of the ghrelin receptor, this loop was subjected to a detailed structure functional....... Moreover, the constitutive activity of the receptor was inhibited by Zn(2+) binding in an engineered metal-ion site stabilizing an a-helical conformation of this loop segment. It is concluded that the high constitutive activity of the ghrelin receptor is dependent upon flexibility in the C-terminal segment...

  14. Estimating the costs of intensity-modulated and 3-dimensional conformal radiotherapy in Ontario.

    Science.gov (United States)

    Yong, J H E; McGowan, T; Redmond-Misner, R; Beca, J; Warde, P; Gutierrez, E; Hoch, J S

    2016-06-01

    Radiotherapy is a common treatment for many cancers, but up-to-date estimates of the costs of radiotherapy are lacking. In the present study, we estimated the unit costs of intensity-modulated radiotherapy (imrt) and 3-dimensional conformal radiotherapy (3D-crt) in Ontario. An activity-based costing model was developed to estimate the costs of imrt and 3D-crt in prostate cancer. It included the costs of equipment, staff, and supporting infrastructure. The framework was subsequently adapted to estimate the costs of radiotherapy in breast cancer and head-and-neck cancer. We also tested various scenarios by varying the program maturity and the use of volumetric modulated arc therapy (vmat) alongside imrt. From the perspective of the health care system, treating prostate cancer with imrt and 3D-crt respectively cost $12,834 and $12,453 per patient. The cost of radiotherapy ranged from $5,270 to $14,155 and was sensitive to analytic perspective, radiation technique, and disease site. Cases of head-and-neck cancer were the most costly, being driven by treatment complexity and fractions per treatment. Although imrt was more costly than 3D-crt, its cost will likely decline over time as programs mature and vmat is incorporated. Our costing model can be modified to estimate the costs of 3D-crt and imrt for various disease sites and settings. The results demonstrate the important role of capital costs in studies of radiotherapy cost from a health system perspective, which our model can accommodate. In addition, our study established the need for future analyses of imrt cost to consider how vmat affects time consumption.

  15. Head and neck cancers: clinical benefits of three-dimensional conformal radiotherapy and of intensity-modulated radiotherapy

    International Nuclear Information System (INIS)

    Giraud, P.; Jaulerry, C.; Brunin, F.; Zefkili, S.; Helfre, S.; Chauvet, I.; Rosenwald, J.C.; Cosset, J.M.

    2002-01-01

    The conformal radiotherapy approach, three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT), is based on modern imaging modalities, efficient 3-D treatment planning systems, sophisticated immobilization systems and rigorous quality assurance and treatment verification. The central objective of conformal radiotherapy is to ensure a high dose distribution tailored to the limits of the target volume while reducing exposure of normal tissues. These techniques would then allow further tumor dose escalation. Head-and-neck tumors are some of the most attractive localizations to test conformal radiotherapy. They combine ballistic difficulties due to particularly complex shapes (nasopharynx, ethmoid) and problems due to the number and low tolerance of neighbouring organs like parotids, eyes, brainstem and spinal cord. The therapeutic irradiation of head-and-neck tumors thus remains a challenge for the radiation oncologist. Conformal radiotherapy does have a significant potential for improving local control and reducing toxicity when compared to standard radiotherapy. However, in the absence of prospective randomized trials, it is somewhat difficult at present to evaluate the real benefits drawn from 3DCRT and IMRT. The published clinical reports on the use of conformal radiotherapy are essentially dealing with dosimetric comparisons on relatively small numbers of patients. Recently, a few publications have emphasized the clinical experience several precursor teams with a suitable follow-up. This paper describes the current state-of-the-art of 3DCRT and IMRT in order to evaluate the impact of these techniques on head-and-neck cancers irradiation. (authors)

  16. Carcinoma of the anal canal: Intensity modulated radiation therapy (IMRT) versus three-dimensional conformal radiation therapy (3DCRT)

    Science.gov (United States)

    Sale, Charlotte; Moloney, Phillip; Mathlum, Maitham

    2013-01-01

    Introduction Patients with anal canal carcinoma treated with standard conformal radiotherapy frequently experience severe acute and late toxicity reactions to the treatment area. Roohipour et al. (Dis Colon Rectum 2008; 51: 147–53) stated a patient's tolerance of chemoradiation to be an important prediction of treatment success. A new intensity modulated radiation therapy (IMRT) technique for anal carcinoma cases has been developed at the Andrew Love Cancer Centre aimed at reducing radiation to surrounding healthy tissue. Methods A same-subject repeated measures design was used for this study, where five anal carcinoma cases at the Andrew Love Cancer Centre were selected. Conformal and IMRT plans were generated and dosimetric evaluations were performed. Each plan was prescribed a total of 54 Gray (Gy) over a course of 30 fractions to the primary site. Results The IMRT plans resulted in improved dosimetry to the planning target volume (PTV) and reduction in radiation to the critical structures (bladder, external genitalia and femoral heads). Statistically there was no difference between the IMRT and conformal plans in the dose to the small and large bowel; however, the bowel IMRT dose–volume histogram (DVH) doses were consistently lower. Conclusion The IMRT plans were superior to the conformal plans with improved dose conformity and reduced radiation to the surrounding healthy tissue. Anecdotally it was found that patients tolerated the IMRT treatment better than the three-dimensional (3D) conformal radiation therapy. This study describes and compares the planning techniques. PMID:26229623

  17. Carcinoma of the anal canal: Intensity modulated radiation therapy (IMRT) versus three-dimensional conformal radiation therapy (3DCRT)

    International Nuclear Information System (INIS)

    Sale, Charlotte; Moloney, Phillip; Mathlum, Maitham

    2013-01-01

    Patients with anal canal carcinoma treated with standard conformal radiotherapy frequently experience severe acute and late toxicity reactions to the treatment area. Roohipour et al. (Dis Colon Rectum 2008; 51: 147–53) stated a patient's tolerance of chemoradiation to be an important prediction of treatment success. A new intensity modulated radiation therapy (IMRT) technique for anal carcinoma cases has been developed at the Andrew Love Cancer Centre aimed at reducing radiation to surrounding healthy tissue. A same-subject repeated measures design was used for this study, where five anal carcinoma cases at the Andrew Love Cancer Centre were selected. Conformal and IMRT plans were generated and dosimetric evaluations were performed. Each plan was prescribed a total of 54 Gray (Gy) over a course of 30 fractions to the primary site. The IMRT plans resulted in improved dosimetry to the planning target volume (PTV) and reduction in radiation to the critical structures (bladder, external genitalia and femoral heads). Statistically there was no difference between the IMRT and conformal plans in the dose to the small and large bowel; however, the bowel IMRT dose–volume histogram (DVH) doses were consistently lower. The IMRT plans were superior to the conformal plans with improved dose conformity and reduced radiation to the surrounding healthy tissue. Anecdotally it was found that patients tolerated the IMRT treatment better than the three-dimensional (3D) conformal radiation therapy. This study describes and compares the planning techniques

  18. Carcinoma of the anal canal: Intensity modulated radiation therapy (IMRT) versus three-dimensional conformal radiation therapy (3DCRT).

    Science.gov (United States)

    Sale, Charlotte; Moloney, Phillip; Mathlum, Maitham

    2013-12-01

    Patients with anal canal carcinoma treated with standard conformal radiotherapy frequently experience severe acute and late toxicity reactions to the treatment area. Roohipour et al. (Dis Colon Rectum 2008; 51: 147-53) stated a patient's tolerance of chemoradiation to be an important prediction of treatment success. A new intensity modulated radiation therapy (IMRT) technique for anal carcinoma cases has been developed at the Andrew Love Cancer Centre aimed at reducing radiation to surrounding healthy tissue. A same-subject repeated measures design was used for this study, where five anal carcinoma cases at the Andrew Love Cancer Centre were selected. Conformal and IMRT plans were generated and dosimetric evaluations were performed. Each plan was prescribed a total of 54 Gray (Gy) over a course of 30 fractions to the primary site. The IMRT plans resulted in improved dosimetry to the planning target volume (PTV) and reduction in radiation to the critical structures (bladder, external genitalia and femoral heads). Statistically there was no difference between the IMRT and conformal plans in the dose to the small and large bowel; however, the bowel IMRT dose-volume histogram (DVH) doses were consistently lower. The IMRT plans were superior to the conformal plans with improved dose conformity and reduced radiation to the surrounding healthy tissue. Anecdotally it was found that patients tolerated the IMRT treatment better than the three-dimensional (3D) conformal radiation therapy. This study describes and compares the planning techniques.

  19. Carcinoma of the anal canal: Intensity modulated radiation therapy (IMRT) versus three-dimensional conformal radiation therapy (3DCRT)

    Energy Technology Data Exchange (ETDEWEB)

    Sale, Charlotte; Moloney, Phillip; Mathlum, Maitham [Andrew Love Cancer Centre, Geelong Hospital, Geelong, Victoria (Australia)

    2013-12-15

    Patients with anal canal carcinoma treated with standard conformal radiotherapy frequently experience severe acute and late toxicity reactions to the treatment area. Roohipour et al. (Dis Colon Rectum 2008; 51: 147–53) stated a patient's tolerance of chemoradiation to be an important prediction of treatment success. A new intensity modulated radiation therapy (IMRT) technique for anal carcinoma cases has been developed at the Andrew Love Cancer Centre aimed at reducing radiation to surrounding healthy tissue. A same-subject repeated measures design was used for this study, where five anal carcinoma cases at the Andrew Love Cancer Centre were selected. Conformal and IMRT plans were generated and dosimetric evaluations were performed. Each plan was prescribed a total of 54 Gray (Gy) over a course of 30 fractions to the primary site. The IMRT plans resulted in improved dosimetry to the planning target volume (PTV) and reduction in radiation to the critical structures (bladder, external genitalia and femoral heads). Statistically there was no difference between the IMRT and conformal plans in the dose to the small and large bowel; however, the bowel IMRT dose–volume histogram (DVH) doses were consistently lower. The IMRT plans were superior to the conformal plans with improved dose conformity and reduced radiation to the surrounding healthy tissue. Anecdotally it was found that patients tolerated the IMRT treatment better than the three-dimensional (3D) conformal radiation therapy. This study describes and compares the planning techniques.

  20. High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design.

    Directory of Open Access Journals (Sweden)

    Antonella Paladino

    2017-01-01

    Full Text Available Understanding how binding events modulate functional motions of multidomain proteins is a major issue in chemical biology. We address several aspects of this problem by analyzing the differential dynamics of αvβ3 integrin bound to wild type (wtFN10, agonist or high affinity (hFN10, antagonist mutants of fibronectin. We compare the dynamics of complexes from large-scale domain motions to inter-residue coordinated fluctuations to characterize the distinctive traits of conformational evolution and shed light on the determinants of differential αvβ3 activation induced by different FN sequences. We propose an allosteric model for ligand-based integrin modulation: the conserved integrin binding pocket anchors the ligand, while different residues on the two FN10's act as the drivers that reorganize relevant interaction networks, guiding the shift towards inactive (hFN10-bound or active states (wtFN10-bound. We discuss the implications of results for the design of integrin inhibitors.

  1. A comparison of morbidity following conformal versus intensity-modulated radiotherapy for urinary bladder cancer.

    Science.gov (United States)

    Søndergaard, Jimmi; Holmberg, Mats; Jakobsen, Annette Ross; Agerbæk, Mads; Muren, Ludvig Paul; Høyer, Morten

    2014-10-01

    In radiotherapy (RT) of urinary bladder cancer, the use of intensity-modulated RT (IMRT) opens for sparing of considerable intestinal volumes. The purpose of the present study was to investigate the acute and late toxicities following either conformal RT (CRT) or IMRT for bladder cancer, and to correlate the toxicities to dose-volume parameters. The study included 116 consecutively treated patients with muscle-invasive bladder cancer who received either CRT (n = 66) or IMRT (n = 50) during 2007-2010. Acute side effects were retrospectively collected whereas late effects were assessed by a cross-sectional evaluation by telephone interview of 44 recurrence-free patients. Acute and late toxicities were scored according to the Common Terminology Criteria for Adverse Event (CTCAE) version 3.0. Acute diarrhoea grade ≥ 2 was more frequent in patients treated by CRT (56%) compared to IMRT (30%) (p = 0.008). Logistic regression analysis showed a correlation between acute diarrhoea and bowel cavity dose-volume parameters in the 10-50 Gy range. Severe late toxicity (grade ≥ 3) was recorded in 10% of the total cohort, with no statistical difference between the IMRT and CRT groups. Patients treated with IMRT for bladder cancer had significantly less acute diarrhoea compared to those treated with CRT, but there was no significant difference in late morbidity between the groups. The risk of acute diarrhoea was related to the volume of bowel irradiated.

  2. Conformal intensity-modulated radiotherapy (IMRT) delivered by robotic linac - testing IMRT to the limit?

    International Nuclear Information System (INIS)

    Webb, S.

    1999-01-01

    In this paper it is proposed that intensity-modulated radiotherapy (IMRT) could be delivered optimally by a short-length linac mounted on a robotic arm. The robot would allow the linac to 'plant' narrow pencils of photon radiation with any orientation (excluding zones within which the linac and couch might collide) relative to the planning target volume (PTV). The treatment is specified by the trajectory of the robot and by the number of monitor units (MUs) delivered at each robotic orientation. An inverse-planning method to determine the optimum robotic trajectory is presented. It is shown that for complex PTVs, specifically those with concavities in their outline, the conformality of the treatment is improved by the use of a complex trajectory in comparison with a less complex constrained trajectory and this improvement is quantified. It is concluded that robotic linac delivery would lead to a great flexibility in those IMRT treatments requiring very complicated dose distributions with complex 3D shapes. However, even using very fast computers, the goal of determining whether robotic linac delivery is the ultimate IMRT cannot be conclusively reached at present. (author)

  3. Electroabsorption spectra of carotenoid isomers: Conformational modulation of polarizability vs. induced dipole moments

    International Nuclear Information System (INIS)

    Krawczyk, Stanislaw; Jazurek, Beata; Luchowski, Rafal; Wiacek, Dariusz

    2006-01-01

    Electroabsorption spectra of all-trans, 13-cis and 15-cis isomers of carotenoids violaxanthin and β-carotene frozen in organic solvents were analysed in terms of changes in permanent dipole moment, Δμ, and in the linear polarizability, Δα, on electronic excitation. The spectral range investigated covered the two carotenoid absorption bands in the VIS and UV, known to originate from differently oriented transition dipole moments. In contrast with the collinearity of the apparent Δμ with Δα in the lowest-energy allowed (VIS) transition 1A g - ->1B u + , the axis of the largest polarizability change in the UV transition 1A g - ->1A g + (''cis band'') was found to make a large angle with the transition moment, while the direction of Δμ appears to be much closer to it. These data support the view that Δμ's inferred from electrochromic spectra of carotenoids are apparent and are not induced by the local matrix field in the solvent cavity, but merely result from conformational modulation of molecular polarizability

  4. Disease Control After Reduced Volume Conformal and Intensity Modulated Radiation Therapy for Childhood Craniopharyngioma

    Energy Technology Data Exchange (ETDEWEB)

    Merchant, Thomas E., E-mail: thomas.merchant@stjude.org [St Jude Children' s Research Hospital, Radiological Sciences, Memphis, Tennessee (United States); Kun, Larry E.; Hua, Chia-Ho [St Jude Children' s Research Hospital, Radiological Sciences, Memphis, Tennessee (United States); Wu, Shengjie; Xiong, Xiaoping [St Jude Children' s Research Hospital, Biostatistics, Memphis, Tennessee (United States); Sanford, Robert A.; Boop, Frederick A. [Semmes Murphey Neurologic and Spine Institute, Neurosurgery, Memphis, Tennessee (United States)

    2013-03-15

    Purpose: To estimate the rate of disease control after conformal radiation therapy using reduced clinical target volume (CTV) margins and to determine factors that predict for tumor progression. Methods and Materials: Eighty-eight children (median age, 8.5 years; range, 3.2-17.6 years) received conformal or intensity modulated radiation therapy between 1998 and 2009. The study group included those prospectively treated from 1998 to 2003, using a 10-mm CTV, defined as the margin surrounding the solid and cystic tumor targeted to receive the prescription dose of 54 Gy. The CTV margin was subsequently reduced after 2003, yielding 2 groups of patients: those treated with a CTV margin greater than 5 mm (n=26) and those treated with a CTV margin less than or equal to 5 mm (n=62). Disease progression was estimated on the basis of additional variables including sex, race, extent of resection, tumor interventions, target volume margins, and frequency of weekly surveillance magnetic resonance (MR) imaging during radiation therapy. Median follow-up was 5 years. Results: There was no difference between progression-free survival rates based on CTV margins (>5 mm vs ≤5 mm) at 5 years (88.1% ± 6.3% vs 96.2% ± 4.4% [P=.6386]). There were no differences based on planning target volume (PTV) margins (or combined CTV plus PTV margins). The PTV was systematically reduced from 5 to 3 mm during the time period of the study. Factors predictive of superior progression-free survival included Caucasian race (P=.0175), no requirement for cerebrospinal fluid shunting (P=.0066), and number of surveillance imaging studies during treatment (P=.0216). Patients whose treatment protocol included a higher number of weekly surveillance MR imaging evaluations had a lower rate of tumor progression. Conclusions: These results suggest that targeted volume reductions for radiation therapy using smaller margins are feasible and safe but require careful monitoring. We are currently investigating

  5. Transition from 2-D radiotherapy to 3-D conformal and intensity modulated radiotherapy

    International Nuclear Information System (INIS)

    2008-05-01

    Cancer is one of the leading causes of death globally and radiotherapy is currently an essential component in the management of cancer patients, either alone or in combination with surgery or chemotherapy, both for cure or palliation. It is now recognized that safe and effective radiotherapy service needs not only substantial capital investment in radiotherapy equipment and specially designed facilities but also continuous investment in maintenance and upgrading of the equipment to comply with the technical progress, but also in training the staff. The recent IAEA-TECDOC publication 'Setting up a Radiotherapy Programme: Clinical, Medical Physics, Radiation Protection and Safety Aspects' provides general guidelines for designing and implementing radiotherapy services in Member States. Advances in computer technology have enabled the possibility of transitioning from basic 2- dimensional treatment planning and delivery (2-D radiotherapy) to a more sophisticated approach with 3-dimensional conformal radiotherapy (3-D CRT). Whereas 2-D radiotherapy can be applied with simple equipment, infrastructure and training, transfer to 3-D conformal treatments requires more resources in technology, equipment, staff and training. A novel radiation treatment approach using Intensity Modulated Radiation Therapy (IMRT) that optimizes the delivery of radiation to irregularly shaped tumour volumes demands even more sophisticated equipment and seamless teamwork, and consequentially more resources, advanced training and more time for treatment planning and verification of dose delivery than 3-D CRT. Whereas 3-D CRT can be considered as a standard, IMRT is still evolving. Due to the increased interest of Member States to the modern application of radiotherapy the IAEA has received a number of requests for guidance coming from radiotherapy departments that wish to upgrade their facilities to 3-D CRT and IMRT through Technical Cooperation programme. These requests are expected to increase

  6. Carcinoma of the anal canal: Intensity modulated radiation therapy (IMRT) versus three-dimensional conformal radiation therapy (3DCRT)

    OpenAIRE

    Sale, Charlotte; Moloney, Phillip; Mathlum, Maitham

    2013-01-01

    Introduction Patients with anal canal carcinoma treated with standard conformal radiotherapy frequently experience severe acute and late toxicity reactions to the treatment area. Roohipour et al. (Dis Colon Rectum 2008; 51: 147–53) stated a patient's tolerance of chemoradiation to be an important prediction of treatment success. A new intensity modulated radiation therapy (IMRT) technique for anal carcinoma cases has been developed at the Andrew Love Cancer Centre aimed at reducing radiation ...

  7. Concerted motions in HIV-1 TAR RNA may allow access to bound state conformations: RNA dynamics from NMR residual dipolar couplings.

    Science.gov (United States)

    Al-Hashimi, Hashim M; Gosser, Yuying; Gorin, Andrey; Hu, Weidong; Majumdar, Ananya; Patel, Dinshaw J

    2002-01-11

    Ground-state dynamics in RNA is a critical precursor for structural adaptation observed ubiquitously in protein-RNA recognition. A tertiary conformational analysis of the stem-loop structural element in the transactivation response element (TAR) from human immunodeficiency virus type 1 (HIV-I) RNA is presented using recently introduced NMR methods that rely on the measurement of residual dipolar couplings (RDC) in partially oriented systems. Order matrix analysis of RDC data provides evidence for inter-helical motions that are of amplitude 46(+/-4) degrees, of random directional character, and that are executed about an average conformation with an inter-helical angle between 44 degrees and 54 degrees. The generated ensemble of TAR conformations have different organizations of functional groups responsible for interaction with the trans-activator protein Tat, including conformations similar to the previously characterized bound-state conformation. These results demonstrate the utility of RDC-NMR for simultaneously characterizing RNA tertiary dynamics and average conformation, and indicate an avenue for TAR complex formation involving tertiary structure capture. Copyright 2001 Academic Press.

  8. Outcomes After Intensity-Modulated Versus Conformal Radiotherapy in Older Men With Nonmetastatic Prostate Cancer

    International Nuclear Information System (INIS)

    Bekelman, Justin E.; Mitra, Nandita; Efstathiou, Jason; Liao Kaijun; Sunderland, Robert; Yeboa, Deborah N.; Armstrong, Katrina

    2011-01-01

    Purpose: There is little evidence comparing complications after intensity-modulated (IMRT) vs. three-dimensional conformal radiotherapy (CRT) for prostate cancer. The study objective was to test the hypothesis that IMRT, compared with CRT, is associated with a reduction in bowel, urinary, and erectile complications in elderly men with nonmetastatic prostate cancer. Methods and Materials: We undertook an observational cohort study using registry and administrative claims data from the SEER-Medicare database. We identified men aged 65 years or older diagnosed with nonmetastatic prostate cancer in the United States between 2002 and 2004 who received IMRT (n = 5,845) or CRT (n = 6,753). The primary outcome was a composite measure of bowel complications. Secondary outcomes were composite measures of urinary and erectile complications. We also examined specific subsets of bowel (proctitis/hemorrhage) and urinary (cystitis/hematuria) events within the composite complication measures. Results: IMRT was associated with reductions in composite bowel complications (24-month cumulative incidence 18.8% vs. 22.5%; hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.79–0.93) and proctitis/hemorrhage (HR 0.78; 95% CI, 0.64–0.95). IMRT was not associated with rates of composite urinary complications (HR 0.93; 95% CI, 0.83–1.04) or cystitis/hematuria (HR 0.94; 95% CI, 0.83–1.07). The incidence of erectile complications involving invasive procedures was low and did not differ significantly between groups, although IMRT was associated with an increase in new diagnoses of impotence (HR 1.27, 95% CI, 1.14–1.42). Conclusion: IMRT is associated with a small reduction in composite bowel complications and proctitis/hemorrhage compared with CRT in elderly men with nonmetastatic prostate cancer.

  9. Impact of inter- and intrafraction deviations and residual set-up errors on PTV margins. Different alignment techniques in 3D conformal prostate cancer radiotherapy

    International Nuclear Information System (INIS)

    Langsenlehner, T.; Doeller, C.; Winkler, P.; Kapp, K.S.; Galle, G.

    2013-01-01

    The aim of this work was to analyze interfraction and intrafraction deviations and residual set-up errors (RSE) after online repositioning to determine PTV margins for 3 different alignment techniques in prostate cancer radiotherapy. The present prospective study included 44 prostate cancer patients with implanted fiducials treated with three-dimensional (3D) conformal radiotherapy. Daily localization was based on skin marks followed by marker detection using kilovoltage (kV) imaging and subsequent patient repositioning. Additionally, in-treatment megavoltage (MV) images were obtained for each treatment field. In an off-line analysis of 7,273 images, interfraction prostate motion, RSE after marker-based prostate localization, prostate position during each treatment session, and the effect of treatment time on intrafraction deviations were analyzed to evaluate PTV margins. Margins accounting for interfraction deviation, RSE and intrafraction motion were 14.1, 12.9, and 15.1 mm in anterior-posterior (AP), superior-inferior (SI), and left-right (LR) direction for skin mark alignment and 9.6, 8.7, and 2.6 mm for bony structure alignment, respectively. Alignment to implanted markers required margins of 4.6, 2.8, and 2.5 mm. As margins to account for intrafraction motion increased with treatment prolongation PTV margins could be reduced to 3.9, 2.6, and 2.4 mm if treatment time was ≤ 4 min. With daily online correction and repositioning based on implanted fiducials, a significant reduction of PTV margins can be achieved. The use of an optimized workflow with faster treatment techniques such as volumetric modulated arc techniques (VMAT) could allow for a further decrease. (orig.)

  10. Comparative dosimetric study of three-dimensional conformal, dynamic conformal arc, and intensity-modulated radiotherapy for brain tumor treatment using Novalis system

    International Nuclear Information System (INIS)

    Ding Meisong; Newman, Francis M.S.; Kavanagh, Brian D.; Stuhr, Kelly M.S.; Johnson, Tim K.; Gaspar, Laurie E.

    2006-01-01

    Purpose: To investigate the dosimetric differences among three-dimensional conformal radiotherapy (3D-CRT), dynamic conformal arc therapy (DCAT), and intensity-modulated radiotherapy (IMRT) for brain tumor treatment. Methods and Materials: Fifteen patients treated with Novalis were selected. We performed 3D-CRT, DCAT, and IMRT plans for all patients. The margin for the planning target volume (PTV) was 1 mm, and the specific prescription dose was 90% for all plans. The target coverage at the prescription dose, conformity index (CI), and heterogeneity index were analyzed for all plans. Results: For small tumors (PTV ≤2 cm 3 ), the three dosimetric parameters had approximate values for both 3D-CRT and DCAT plans. The CI for the IMRT plans was high. For medium tumors (PTV >2 to ≤100 cm 3 ), the three plans were competitive with each other. The IMRT plans had a greater CI, better target coverage at the prescription dose, and a better heterogeneity index. For large tumors (PTV >100 cm 3 ), the IMRT plan had good target coverage at the prescription dose and heterogeneity index and approximate CI values as those in the 3D-CRT and DCAT plans. Conclusion: The results of our study have shown that DCAT is suitable for most cases in the treatment of brain tumors. For a small target, 3D-CRT is useful, and IMRT is not recommended. For larger tumors, IMRT is superior to 3D-CRT and very competitive in sparing critical structures, especially for big tumors

  11. Effect of No-Clean Flux Residues on the Performance of Acrylic Conformal Coating in Aggressive Environments

    DEFF Research Database (Denmark)

    Rathinavelu, Umadevi; Jellesen, Morten S.; Møller, Per

    2012-01-01

    at various temperatures was quantified using ion chromatography by extracting the residue, and surface morphology of the residues was investigated using optical microscopy. The flux residue in general consists of both resin and activator components such as carboxylic acids. Coated samples with flux residues...

  12. Multiple native-like conformations trapped via self-association-induced hydrophobic collapse of the 33-residue beta-sheet domain from platelet factor 4.

    OpenAIRE

    Ilyina, E; Mayo, K H

    1995-01-01

    Native platelet factor 4 (PF4) (70 residues) has a hydrophobic three-stranded anti-parallel beta-sheet domain on to which is folded an amphipathic C-terminal alpha-helix and an aperiodic N-terminal domain. The 33-amino acid beta-sheet domain from PF4 (residues 23-55) has been synthesized and studied by c.d. and n.m.r. At 10 degrees C and low concentration, peptide 23-55 appears to exist in aqueous solution in a random-coil distribution of highly flexible conformational states. Some preferred ...

  13. Quantitative conformational analysis of the core region of N-glycans using residual dipolar couplings, aqueous molecular dynamics, and steric alignment

    International Nuclear Information System (INIS)

    Almond, Andrew; Duus, Jens O.

    2001-01-01

    A method is described for quantitatively investigating the dynamic conformation of small oligosaccharides containing an α(1 → 6) linkage. It was applied to the oligosaccharide Man-α(1 → 3) {Man-α (1 → 6)}Man-α-O-Me, which is a core region frequently observed in N-linked glycans. The approach tests an aqueous molecular dynamics simulation, capable of predicting microscopic dynamics, against experimental residual dipolar couplings, by assuming that alignment is caused purely by steric hindrance. The experimental constraints were heteronuclear and homonuclear residual dipolar couplings, and in particular those within the α(1 → 6) linkage itself. Powerful spin-state-selective pulse sequences and editing schemes were used to obtain the most relevant couplings for testing the model. Molecular dynamics simulations in water over a period of 50 ns were not able to predict the correct rotamer population at the α(1 → 6) linkage to agree with the experimental data. However, this sampling problem could be corrected using a simple maximum likelihood optimisation, indicating that the simulation was modelling local dynamics correctly. The maximum likelihood prediction of the residual dipolar couplings was found to be an almost equal population of the gg and gt rotamer conformations at the α(1 → 6) linkage, and the tg conformation was predicted to be unstable and unpopulated in aqueous solution. In this case all twelve measured residual dipolar couplings could be satisfied. This conformer population could also be used to make predictions of scalar couplings with the use of a previously derived empirical equation, and is qualitatively in agreement with previous predictions based on NMR, X-ray crystallography and optical data

  14. Delivery confirmation of bolus electron conformal therapy combined with intensity modulated x-ray therapy

    International Nuclear Information System (INIS)

    Kavanaugh, James A.; Hogstrom, Kenneth R.; Fontenot, Jonas P.; Henkelmann, Gregory; Chu, Connel; Carver, Robert A.

    2013-01-01

    Purpose: The purpose of this study was to demonstrate that a bolus electron conformal therapy (ECT) dose plan and a mixed beam plan, composed of an intensity modulated x-ray therapy (IMXT) dose plan optimized on top of the bolus ECT plan, can be accurately delivered. Methods: Calculated dose distributions were compared with measured dose distributions for parotid and chest wall (CW) bolus ECT and mixed beam plans, each simulated in a cylindrical polystyrene phantom that allowed film dose measurements. Bolus ECT plans were created for both parotid and CW PTVs (planning target volumes) using 20 and 16 MeV beams, respectively, whose 90% dose surface conformed to the PTV. Mixed beam plans consisted of an IMXT dose plan optimized on top of the bolus ECT dose plan. The bolus ECT, IMXT, and mixed beam dose distributions were measured using radiographic films in five transverse and one sagittal planes for a total of 36 measurement conditions. Corrections for film dose response, effects of edge-on photon irradiation, and effects of irregular phantom optical properties on the Cerenkov component of the film signal resulted in high precision measurements. Data set consistency was verified by agreement of depth dose at the intersections of the sagittal plane with the five measured transverse planes. For these same depth doses, results for the mixed beam plan agreed with the sum of the individual depth doses for the bolus ECT and IMXT plans. The six mean measured planar dose distributions were compared with those calculated by the treatment planning system for all modalities. Dose agreement was assessed using the 4% dose difference and 0.2 cm distance to agreement. Results: For the combined high-dose region and low-dose region, pass rates for the parotid and CW plans were 98.7% and 96.2%, respectively, for the bolus ECT plans and 97.9% and 97.4%, respectively, for the mixed beam plans. For the high-dose gradient region, pass rates for the parotid and CW plans were 93.1% and 94

  15. FM-to-AM modulations induced by a weak residual reflection stack of sine-modulated pulses in inertial confinement fusion laser systems

    Science.gov (United States)

    Huang, Xiaoxia; Deng, Xuewei; Zhou, Wei; Hu, Dongxia; Guo, Huaiwen; Wang, Yuancheng; Zhao, Bowang; Zhong, Wei; Deng, Wu

    2018-02-01

    We report on frequency to amplitude modulation (FM-to-AM) conversion induced by a weak residual reflection stack of sine-modulated pulses in a complex laser system. Theoretical and experimental investigations reveal that when weak residual reflected pulses stack on the main pulse, the spectral intensity changes in the stacked region, which then converts to obvious AM. This kind of FM-to-AM effect often occurs in the tail of the pulse and cannot be eliminated by common compensation methods, which even enhance the modulation depth. Furthermore, the actual intensity modulation frequency and depth induced by the residual reflection stack are much higher and deeper than observed on the oscilloscope, which is harmful for safe operation of the laser facility and the driving power balance during inertial confinement fusion. To eliminate this kind of FM-to-AM effect, any possible on-axis and near-axis residual reflection in laser systems must be avoided.

  16. A comparison of conformal and intensity-modulated techniques for oesophageal radiotherapy

    International Nuclear Information System (INIS)

    Nutting, Christopher M.; Bedford, James L.; Cosgrove, Vivian P.; Tait, Diana M.; Dearnaley, David P.; Webb, Steve

    2001-01-01

    Background and purpose: To investigate the potential of intensity-modulated radiotherapy (IMRT) to reduce lung irradiation in the treatment of oesophageal carcinoma with radical radiotherapy. Materials and methods: A treatment planning study was performed to compare two-phase conformal radiotherapy (CFRT) with IMRT in five patients. The CFRT plans consisted of anterior, posterior and bilateral posterior oblique fields, while the IMRT plans consisted of either nine equispaced fields (9F), or four fields (4F) with orientations equal to the CFRT plans. IMRT plans with seven, five or three equispaced fields were also investigated in one patient. Treatment plans were compared using dose-volume histograms and normal tissue complication probabilities. Results: The 9F IMRT plan was unable to improve on the homogeneity of dose to the planning target volume (PTV), compared with the CFRT plan (dose range, 16.9±4.5 (1 SD) vs. 12.4±3.9%; P=0.06). Similarly, the 9F IMRT plan was unable to reduce the mean lung dose (11.7±3.2 vs. 11.0±2.9 Gy; P=0.2). Similar results were obtained for seven, five and three equispaced fields in the single patient studied. The 4F IMRT plan provided comparable PTV dose homogeneity with the CFRT plan (11.8±3.3 vs. 12.4±3.9%; P=0.6), with reduced mean lung dose (9.5±2.3 vs 11.0±2.9 Gy; P=0.001). Conclusions: IMRT using nine equispaced fields provided no improvement over CFRT. This was because the larger number of fields in the IMRT plan distributed a low dose over the entire lung. In contrast, IMRT using four fields equal to the CFRT fields offered an improvement in lung sparing. Thus, IMRT with a few carefully chosen field directions may lead to a modest reduction in pneumonitis, or allow tumour dose escalation within the currently accepted lung toxicity

  17. Effect of solder flux residue on the performance of silicone conformal coatings on printed circuit board assemblies

    DEFF Research Database (Denmark)

    Rathinavelu, Umadevi; Jellesen, Morten Stendahl; Ambat, Rajan

    2013-01-01

    Conformal coatings are applied on printed circuit board assemblies (PCBAs) in order to protect the assembly from environmental influence and silicone-based coating is commonly used. A systematic study on the performance of silicone conformal coating in connection with process-related contaminants...

  18. Dosimetry comparison of irradiation with conformal radiotherapy, intensity modulated radiotherapy, conformal radiotherapy in stereotactic conditions and robotic stereotactic radiotherapy for benign brain tumours

    International Nuclear Information System (INIS)

    Spasic, E.; Noel, A.; Buchheit, I.; Bernier, V.

    2011-01-01

    Purpose. - To compare several techniques in order to determine the best treatment for benign brain tumours. Methods and patients. - A retrospective study was performed for five patients who received 3D-conformal radiotherapy, intensity modulated radiotherapy or CyberKnife R . These patients had a meningioma, a pituitary tumour, a cranio-pharyngioma or a neurinoma. In each case, these treatment plans were optimised and compared with the three other dosimetries. Radiobiological or positioning parameters were evaluated, as well as dosimetric parameters, in order to compare treatments with different characteristics. Results. - The dosimetric parameters showed that the choice of treatment seemed to be determined mostly by tumour size, shape and proximity with organs at risk (not tumour localisation). Whereas the results showed no significant deviations with regards to the radiobiological parameters. Therefore, with these parameters, it was difficult to give priority to a treatment. Conclusions. - With regards to benign brain tumours of medium or large size, intensity modulated radiotherapy seemed the recommended treatment. It enabled to obtain a good ratio between efficacy and toxicity for tumours that are really close to organs at risk. Concerning small benign brain tumours, the CyberKnife R was probably the best treatment. (authors)

  19. Bladder radiotherapy treatment: A retrospective comparison of 3-dimensional conformal radiotherapy, intensity-modulated radiation therapy, and volumetric-modulated arc therapy plans

    Energy Technology Data Exchange (ETDEWEB)

    Pasciuti, Katia, E-mail: k.pasciuti@virgilio.it [Department of Radiotherapy Physics, Royal Free Hospital, London (United Kingdom); Kuthpady, Shrinivas [Department of Radiotherapy, Royal Free Hospital, London (United Kingdom); Anderson, Anne; Best, Bronagh [Department of Radiotherapy Physics, Royal Free Hospital, London (United Kingdom); Waqar, Saleem; Chowdhury, Subhra [Department of Radiotherapy, Royal Free Hospital, London (United Kingdom)

    2017-04-01

    To examine tumor's and organ's response when different radiotherapy plan techniques are used. Ten patients with confirmed bladder tumors were first treated using 3-dimensional conformal radiotherapy (3DCRT) and subsequently the original plans were re-optimized using the intensity-modulated radiation treatment (IMRT) and volumetric-modulated arc therapy (VMAT)-techniques. Targets coverage in terms of conformity and homogeneity index, TCP, and organs' dose limits, including integral dose analysis were evaluated. In addition, MUs and treatment delivery times were compared. Better minimum target coverage (1.3%) was observed in VMAT plans when compared to 3DCRT and IMRT ones confirmed by a statistically significant conformity index (CI) results. Large differences were observed among techniques in integral dose results of the femoral heads. Even if no statistically significant differences were reported in rectum and tissue, a large amount of energy deposition was observed in 3DCRT plans. In any case, VMAT plans provided better organs and tissue sparing confirmed also by the normal tissue complication probability (NTCP) analysis as well as a better tumor control probability (TCP) result. Our analysis showed better overall results in planning using VMAT techniques. Furthermore, a total time reduction in treatment observed among techniques including gantry and collimator rotation could encourage using the more recent one, reducing target movements and patient discomfort.

  20. Dosimetric and Radiobiologic Comparison of 3D Conformal Versus Intensity Modulated Planning Techniques for Prostate Bed Radiotherapy

    International Nuclear Information System (INIS)

    Koontz, Bridget F.; Das, Shiva; Temple, Kathy; Bynum, Sigrun; Catalano, Suzanne; Koontz, Jason I.; Montana, Gustavo S.; Oleson, James R.

    2009-01-01

    Adjuvant radiotherapy for locally advanced prostate cancer improves biochemical and clinical disease-free survival. While comparisons in intact prostate cancer show a benefit for intensity modulated radiation therapy (IMRT) over 3D conformal planning, this has not been studied for post-prostatectomy radiotherapy (RT). This study compares normal tissue and target dosimetry and radiobiological modeling of IMRT vs. 3D conformal planning in the postoperative setting. 3D conformal plans were designed for 15 patients who had been treated with IMRT planning for salvage post-prostatectomy RT. The same computed tomography (CT) and target/normal structure contours, as well as prescription dose, was used for both IMRT and 3D plans. Normal tissue complication probabilities (NTCPs) were calculated based on the dose given to the bladder and rectum by both plans. Dose-volume histogram and NTCP data were compared by paired t-test. Bladder and rectal sparing were improved with IMRT planning compared to 3D conformal planning. The volume of the bladder receiving at least 75% (V75) and 50% (V50) of the dose was significantly reduced by 28% and 17%, respectively (p = 0.002 and 0.037). Rectal dose was similarly reduced, V75 by 33% and V50 by 17% (p = 0.001 and 0.004). While there was no difference in the volume of rectum receiving at least 65 Gy (V65), IMRT planning significant reduced the volume receiving 40 Gy or more (V40, p = 0.009). Bladder V40 and V65 were not significantly different between planning modalities. Despite these dosimetric differences, there was no significant difference in the NTCP for either bladder or rectal injury. IMRT planning reduces the volume of bladder and rectum receiving high doses during post-prostatectomy RT. Because of relatively low doses given to the bladder and rectum, there was no statistically significant improvement in NTCP between the 3D conformal and IMRT plans.

  1. Dosimetric and radiobiologic comparison of 3D conformal versus intensity modulated planning techniques for prostate bed radiotherapy.

    Science.gov (United States)

    Koontz, Bridget F; Das, Shiva; Temple, Kathy; Bynum, Sigrun; Catalano, Suzanne; Koontz, Jason I; Montana, Gustavo S; Oleson, James R

    2009-01-01

    Adjuvant radiotherapy for locally advanced prostate cancer improves biochemical and clinical disease-free survival. While comparisons in intact prostate cancer show a benefit for intensity modulated radiation therapy (IMRT) over 3D conformal planning, this has not been studied for post-prostatectomy radiotherapy (RT). This study compares normal tissue and target dosimetry and radiobiological modeling of IMRT vs. 3D conformal planning in the postoperative setting. 3D conformal plans were designed for 15 patients who had been treated with IMRT planning for salvage post-prostatectomy RT. The same computed tomography (CT) and target/normal structure contours, as well as prescription dose, was used for both IMRT and 3D plans. Normal tissue complication probabilities (NTCPs) were calculated based on the dose given to the bladder and rectum by both plans. Dose-volume histogram and NTCP data were compared by paired t-test. Bladder and rectal sparing were improved with IMRT planning compared to 3D conformal planning. The volume of the bladder receiving at least 75% (V75) and 50% (V50) of the dose was significantly reduced by 28% and 17%, respectively (p = 0.002 and 0.037). Rectal dose was similarly reduced, V75 by 33% and V50 by 17% (p = 0.001 and 0.004). While there was no difference in the volume of rectum receiving at least 65 Gy (V65), IMRT planning significant reduced the volume receiving 40 Gy or more (V40, p = 0.009). Bladder V40 and V65 were not significantly different between planning modalities. Despite these dosimetric differences, there was no significant difference in the NTCP for either bladder or rectal injury. IMRT planning reduces the volume of bladder and rectum receiving high doses during post-prostatectomy RT. Because of relatively low doses given to the bladder and rectum, there was no statistically significant improvement in NTCP between the 3D conformal and IMRT plans.

  2. Modulation of Amyloid-β Conformation by Charge State of N-Terminal Disordered Region

    International Nuclear Information System (INIS)

    Xi Wen-Hui; Li Wen-Fei; Wang Wei

    2012-01-01

    Based on molecular dynamics simulations, we show that variations of the charge states of the histidines, which are the main effects of pH-value change and metal binding, can lead to a drastic change of the intra-peptide interactions of the segment 17–42 and the conformational distribution of the monomeric amyloid-β (Aβ). Since we already knew that the conformational distribution of monomeric Aβ can largely affect Aβ fibrillar aggregation, our results suggest that the pH value change and metal binding can affect the Aβ aggregation by much more complex mechanism than just affecting the inter-peptide interactions. To fully understand the mechanism of metal binding and pH-value induced Aβ aggregation, we also need to consider their effects on the conformational distribution of monomeric Aβ. (cross-disciplinary physics and related areas of science and technology)

  3. A novel conformity index for intensity modulated radiation therapy plan evaluation

    International Nuclear Information System (INIS)

    Cheung, Fion W. K.; Law, Maria Y. Y.

    2012-01-01

    Purpose: Intensity modulated radiation therapy (IMRT) has gained popularity in the treatment of cancers. Manual evaluation of IMRT plans for head-and-neck cancers has been especially challenging necessitating efficient and objective assessment tools. In this work, the authors address this issue by developing a personalized conformity index (CI) for comparison of IMRT plans for head-and-neck cancers and evaluating its plan quality discerning power in comparison with other widely used CIs. Methods: A two-dimensional CI with dose and distance incorporated (CI DD ) was developed using the MATLAB program language, to quantify the planning target volume (PTV) coverage. Valuable information contained in the digital imaging and communication in medicine (DICOM) RT objects were harvested for computation of each of the CI DD components. Apart from the dose penalty factor, a distance-based exponential function was employed by varying the penalty weight associated with the location of cold spots within the PTV. With the goal of deriving a customized penalty factor, the distances between individual pixel and its nearest PTV boundary was found. Using the exponential function, the impact of distance penalty was substantially larger for cold spots closer to the PTV centroid but petered out quickly wherever they were situated in the vicinity of PTV border. In order to evaluate the CI DD scoring system, three CT image data sets of nasopharyngeal carcinoma (NPC) patients were collected. Ten IMRT plans with degrading qualities were generated from each dataset and were ranked based on CI DD and other existing indices. The coefficient of variance was calculated for each dataset to compare the degree of variation. Results: The CI DD scoring system that considered spatial importance of each voxel within the PTV was successfully developed. The results demonstrated that the CI DD including four discrete factors could provide accurate rankings of plan quality by examining the relative

  4. A novel conformity index for intensity modulated radiation therapy plan evaluation.

    Science.gov (United States)

    Cheung, Fion W K; Law, Maria Y Y

    2012-09-01

    Intensity modulated radiation therapy (IMRT) has gained popularity in the treatment of cancers. Manual evaluation of IMRT plans for head-and-neck cancers has been especially challenging necessitating efficient and objective assessment tools. In this work, the authors address this issue by developing a personalized conformity index (CI) for comparison of IMRT plans for head-and-neck cancers and evaluating its plan quality discerning power in comparison with other widely used CIs. A two-dimensional CI with dose and distance incorporated (CI(DD)) was developed using the MATLAB program language, to quantify the planning target volume (PTV) coverage. Valuable information contained in the digital imaging and communication in medicine (DICOM) RT objects were harvested for computation of each of the CI(DD) components. Apart from the dose penalty factor, a distance-based exponential function was employed by varying the penalty weight associated with the location of cold spots within the PTV. With the goal of deriving a customized penalty factor, the distances between individual pixel and its nearest PTV boundary was found. Using the exponential function, the impact of distance penalty was substantially larger for cold spots closer to the PTV centroid but petered out quickly wherever they were situated in the vicinity of PTV border. In order to evaluate the CI(DD) scoring system, three CT image data sets of nasopharyngeal carcinoma (NPC) patients were collected. Ten IMRT plans with degrading qualities were generated from each dataset and were ranked based on CI(DD) and other existing indices. The coefficient of variance was calculated for each dataset to compare the degree of variation. The CI(DD) scoring system that considered spatial importance of each voxel within the PTV was successfully developed. The results demonstrated that the CI(DD) including four discrete factors could provide accurate rankings of plan quality by examining the relative importance of each cold spot

  5. A remote palm domain residue of RB69 DNA polymerase is critical for enzyme activity and influences the conformation of the active site.

    Directory of Open Access Journals (Sweden)

    Agata Jacewicz

    Full Text Available Non-conserved amino acids that are far removed from the active site can sometimes have an unexpected effect on enzyme catalysis. We have investigated the effects of alanine replacement of residues distant from the active site of the replicative RB69 DNA polymerase, and identified a substitution in a weakly conserved palm residue (D714A, that renders the enzyme incapable of sustaining phage replication in vivo. D714, located several angstroms away from the active site, does not contact the DNA or the incoming dNTP, and our apoenzyme and ternary crystal structures of the Pol(D714A mutant demonstrate that D714A does not affect the overall structure of the protein. The structures reveal a conformational change of several amino acid side chains, which cascade out from the site of the substitution towards the catalytic center, substantially perturbing the geometry of the active site. Consistent with these structural observations, the mutant has a significantly reduced k pol for correct incorporation. We propose that the observed structural changes underlie the severe polymerization defect and thus D714 is a remote, non-catalytic residue that is nevertheless critical for maintaining an optimal active site conformation. This represents a striking example of an action-at-a-distance interaction.

  6. Target volume delineation and field setup. A practical guide for conformal and intensity-modulated radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Nancy Y. [Memorial Sloan-Kettering Cancer Center, New York, NY (United States). Radiation Oncology; Lu, Jiade J. (eds.) [National Univ. Health System, Singapore (Singapore). Dept. of Radiation Oncology; National Univ. of Singapore (Singapore). Dept. of Medicine

    2013-03-01

    Practical handbook on selection and delineation of tumor volumes and fields for conformal radiation therapy, including IMRT. Helpful format facilitating use on a step-by-step basis in daily practice. Designed to ensure accurate coverage of commonly encountered tumors along their routes of spread. This handbook is designed to enable radiation oncologists to appropriately and confidently delineate tumor volumes/fields for conformal radiation therapy, including intensity-modulated radiation therapy (IMRT), in patients with commonly encountered cancers. The orientation of this handbook is entirely practical, in that the focus is on the illustration of clinical target volume (CTV) delineation for each major malignancy. Each chapter provides guidelines and concise knowledge on CTV selection for a particular disease, explains how the anatomy of lymphatic drainage shapes the selection of the target volume, and presents detailed illustrations of volumes, slice by slice, on planning CT images. While the emphasis is on target volume delineation for three-dimensional conformal therapy and IMRT, information is also provided on conventional radiation therapy field setup and planning for certain malignancies for which IMRT is not currently suitable.

  7. Limited Advantages of Intensity-Modulated Radiotherapy Over 3D Conformal Radiation Therapy in the Adjuvant Management of Gastric Cancer

    International Nuclear Information System (INIS)

    Alani, Shlomo; Soyfer, Viacheslav; Strauss, Natan; Schifter, Dan; Corn, Benjamin W.

    2009-01-01

    Purpose: Although chemoradiotherapy was considered the standard adjuvant treatment for gastric cancer, a recent Phase III trial (Medical Research Council Adjuvant Gastric Infusional Chemotherapy [MAGIC]) did not include radiotherapy in the randomization scheme because it was considered expendable. Given radiotherapy's potential, efforts needed to be made to optimize its use for treating gastric cancer. We assessed whether intensity-modulated radiotherapy (IMRT) could improve upon our published results in patients treated with three-dimensional (3D) conformal therapy. Methods and Materials: Fourteen patients with adenocarcinoma of the stomach were treated with adjuvant chemoradiotherapy using a noncoplanar four-field arrangement. Subsequently, a nine-field IMRT plan was designed using a CMS Xio IMRT version 4.3.3 module. Two IMRT beam arrangements were evaluated: beam arrangement 1 consisted of gantry angles of 0 deg., 53 deg., 107 deg., 158 deg., 204 deg., 255 deg., and 306 deg.. Beam arrangement 2 consisted of gantry angles of 30 deg., 90 deg., 315 deg., and 345 deg.; a gantry angle of 320 deg./couch, 30 deg.; and a gantry angle of 35 o /couch, 312 o . Both the target volume coverage and the dose deposition in adjacent critical organs were assessed in the plans. Dose-volume histograms were generated for the clinical target volume, kidneys, spine, and liver. Results: Comparison of the clinical target volumes revealed satisfactory coverage by the 95% isodose envelope using either IMRT or 3D conformal therapy. However, IMRT was only marginally better than 3D conformal therapy at protecting the spine and kidneys from radiation. Conclusions: IMRT confers only a marginal benefit in the adjuvant treatment of gastric cancer and should be used only in the small subset of patients with risk factors for kidney disease or those with a preexisting nephropathy.

  8. Limited advantages of intensity-modulated radiotherapy over 3D conformal radiation therapy in the adjuvant management of gastric cancer.

    Science.gov (United States)

    Alani, Shlomo; Soyfer, Viacheslav; Strauss, Natan; Schifter, Dan; Corn, Benjamin W

    2009-06-01

    Although chemoradiotherapy was considered the standard adjuvant treatment for gastric cancer, a recent Phase III trial (Medical Research Council Adjuvant Gastric Infusional Chemotherapy [MAGIC]) did not include radiotherapy in the randomization scheme because it was considered expendable. Given radiotherapy's potential, efforts needed to be made to optimize its use for treating gastric cancer. We assessed whether intensity-modulated radiotherapy (IMRT) could improve upon our published results in patients treated with three-dimensional (3D) conformal therapy. Fourteen patients with adenocarcinoma of the stomach were treated with adjuvant chemoradiotherapy using a noncoplanar four-field arrangement. Subsequently, a nine-field IMRT plan was designed using a CMS Xio IMRT version 4.3.3 module. Two IMRT beam arrangements were evaluated: beam arrangement 1 consisted of gantry angles of 0 degrees , 53 degrees , 107 degrees , 158 degrees , 204 degrees , 255 degrees , and 306 degrees . Beam arrangement 2 consisted of gantry angles of 30 degrees , 90 degrees , 315 degrees , and 345 degrees ; a gantry angle of 320 degrees /couch, 30 degrees ; and a gantry angle of 35 degrees /couch, 312 degrees . Both the target volume coverage and the dose deposition in adjacent critical organs were assessed in the plans. Dose-volume histograms were generated for the clinical target volume, kidneys, spine, and liver. Comparison of the clinical target volumes revealed satisfactory coverage by the 95% isodose envelope using either IMRT or 3D conformal therapy. However, IMRT was only marginally better than 3D conformal therapy at protecting the spine and kidneys from radiation. IMRT confers only a marginal benefit in the adjuvant treatment of gastric cancer and should be used only in the small subset of patients with risk factors for kidney disease or those with a preexisting nephropathy.

  9. Modulation of the disordered conformational ensembles of the p53 transactivation domain by cancer-associated mutations.

    Directory of Open Access Journals (Sweden)

    Debabani Ganguly

    2015-04-01

    Full Text Available Intrinsically disordered proteins (IDPs are frequently associated with human diseases such as cancers, and about one-fourth of disease-associated missense mutations have been mapped into predicted disordered regions. Understanding how these mutations affect the structure-function relationship of IDPs is a formidable task that requires detailed characterization of the disordered conformational ensembles. Implicit solvent coupled with enhanced sampling has been proposed to provide a balance between accuracy and efficiency necessary for systematic and comparative assessments of the effects of mutations as well as post-translational modifications on IDP structure and interaction. Here, we utilize a recently developed replica exchange with guided annealing enhanced sampling technique to calculate well-converged atomistic conformational ensembles of the intrinsically disordered transactivation domain (TAD of tumor suppressor p53 and several cancer-associated mutants in implicit solvent. The simulations are critically assessed by quantitative comparisons with several types of experimental data that provide structural information on both secondary and tertiary levels. The results show that the calculated ensembles reproduce local structural features of wild-type p53-TAD and the effects of K24N mutation quantitatively. On the tertiary level, the simulated ensembles are overly compact, even though they appear to recapitulate the overall features of transient long-range contacts qualitatively. A key finding is that, while p53-TAD and its cancer mutants sample a similar set of conformational states, cancer mutants could introduce both local and long-range structural modulations to potentially perturb the balance of p53 binding to various regulatory proteins and further alter how this balance is regulated by multisite phosphorylation of p53-TAD. The current study clearly demonstrates the promise of atomistic simulations for detailed characterization of IDP

  10. Conserved Residues Lys57 and Lys401 of Protein Disulfide Isomerase Maintain an Active Site Conformation for Optimal Activity: Implications for Post-Translational Regulation

    Directory of Open Access Journals (Sweden)

    Cody Caba

    2018-02-01

    Full Text Available Despite its study since the 1960's, very little is known about the post-translational regulation of the multiple catalytic activities performed by protein disulfide isomerase (PDI, the primary protein folding catalyst of the cell. This work identifies a functional role for the highly conserved CxxC-flanking residues Lys57 and Lys401 of human PDI in vitro. Mutagenesis studies have revealed these residues as modulating the oxidoreductase activity of PDI in a pH-dependent manner. Non-conservative amino acid substitutions resulted in enzyme variants upwards of 7-fold less efficient. This attenuated activity was found to translate into a 2-fold reduction of the rate of electron shuttling between PDI and the intraluminal endoplasmic reticulum oxidase, ERO1α, suggesting a functional significance to oxidative protein folding. In light of this, the possibility of lysine acetylation at residues Lys57 and Lys401 was assessed by in vitro treatment using acetylsalicylic acid (aspirin. A total of 28 acetyllysine residues were identified, including acLys57 and acLys401. The kinetic behavior of the acetylated protein form nearly mimicked that obtained with a K57/401Q double substitution variant providing an indication that acetylation of the active site-flanking lysine residues can act to reversibly modulate PDI activity.

  11. Conserved Residues Lys57 and Lys401 of Protein Disulfide Isomerase Maintain an Active Site Conformation for Optimal Activity: Implications for Post-Translational Regulation.

    Science.gov (United States)

    Caba, Cody; Ali Khan, Hyder; Auld, Janeen; Ushioda, Ryo; Araki, Kazutaka; Nagata, Kazuhiro; Mutus, Bulent

    2018-01-01

    Despite its study since the 1960's, very little is known about the post-translational regulation of the multiple catalytic activities performed by protein disulfide isomerase (PDI), the primary protein folding catalyst of the cell. This work identifies a functional role for the highly conserved CxxC-flanking residues Lys 57 and Lys 401 of human PDI in vitro . Mutagenesis studies have revealed these residues as modulating the oxidoreductase activity of PDI in a pH-dependent manner. Non-conservative amino acid substitutions resulted in enzyme variants upwards of 7-fold less efficient. This attenuated activity was found to translate into a 2-fold reduction of the rate of electron shuttling between PDI and the intraluminal endoplasmic reticulum oxidase, ERO1α, suggesting a functional significance to oxidative protein folding. In light of this, the possibility of lysine acetylation at residues Lys 57 and Lys 401 was assessed by in vitro treatment using acetylsalicylic acid (aspirin). A total of 28 acetyllysine residues were identified, including acLys 57 and acLys 401 . The kinetic behavior of the acetylated protein form nearly mimicked that obtained with a K57/401Q double substitution variant providing an indication that acetylation of the active site-flanking lysine residues can act to reversibly modulate PDI activity.

  12. 3D-Conformal Versus Intensity-Modulated Postoperative Radiotherapy of Vaginal Vault: A Dosimetric Comparison

    International Nuclear Information System (INIS)

    Cilla, Savino; Macchia, Gabriella; Digesu, Cinzia; Deodato, Francesco; Romanella, Michele; Ferrandina, Gabriella; Padula, Gilbert; Picardi, Vincenzo; Scambia, Giovanni; Piermattei, Angelo; Morganti, Alessio Giuseppe

    2010-01-01

    We evaluated a step-and-shoot IMRT plan in the postoperative irradiation of the vaginal vault compared with equispaced beam arrangements (3-5) 3D-radiotherapy (RT) optimized plans. Twelve patients were included in this analysis. Four plans for each patient were compared in terms of dose-volume histograms, homogeneity index (HI), and conformity index (CI): (1) 3 equispaced beam arrangement 3D-RT; (2) 4 equispaced beam arrangement 3D-RT; (3) 5 equispaced beam arrangement 3D-RT; (4) step-and-shoot IMRT technique. CI showed a good discrimination between the four plans. The mean scores of CI were 0.58 (range: 0.38-0.67) for the 3F-CRT plan, 0.58 (range: 0.41-0.66) for 4F-CRT, 0.62 (range: 0.43-0.68) for 5F-CRT and 0.69 (range: 0.58-0.78) for the IMRT plan. A significant improvement of the conformity was reached by the IMRT plan (p mean , V90%, V95%, V100% was recorded for rectal and bladder irradiation with the IMRT plan. Surprisingly, IMRT supplied a significant dose reduction also for rectum and bladder V30% and V50%. A significant dosimetric advantage of IMRT over 3D-RT in the adjuvant treatment of vaginal vault alone in terms of treatment conformity and rectum and bladder sparing is shown.

  13. The field-matching problem as it applies to the peacock three dimensional conformal system for intensity modulation

    International Nuclear Information System (INIS)

    Carol, Mark; Grant, Walter H.; Bleier, Alan R.; Kania, Alex A.; Targovnik, Harris S.; Butler, E. Brian; Shiao, W. Woo

    1996-01-01

    Purpose: Intensity modulated beam systems have been developed as a means of creating a high-dose region that closely conforms to the prescribed target volume while also providing specific sparing of organs at risk within complex treatment geometries. The slice-by-slice treatment paradigm used by one such system for delivering intensity modulated fields introduces regions of dose nonuniformity where each pair of treatment slices abut. A study was designed to evaluate whether or not the magnitude of the nonuniformity that results from this segmental delivery paradigm is significant relative to the overall dose nonuniformity present in the intensity modulation technique itself. An assessment was also made as to the increase in nonuniformity that would result if errors were made in indexing during treatment delivery. Methods and Materials: Treatment plans were generated to simulate correctly indexed and incorrectly indexed treatments of 4, 10, and 18 cm diameter targets. Indexing errors of from 0.1 to 2.0 mm were studied. Treatment plans were also generated for targets of the same diameter but of lengths that did not require indexing of the treatment couch. Results: The nonuniformity that results from the intensity modulation delivery paradigm is 11-16% for targets where indexing is not required. Correct indexing of the couch adds an additional 1-2% in nonuniformity. However, a couch indexing error of as little as 1 mm can increase the total nonuniformity to as much as 25%. All increases in nonuniformity from indexing are essentially independent of target diameter. Conclusions: The dose nonuniformity introduced by the segmental strip delivery paradigm is small relative to the nonuniformity present in the intensity modulation paradigm itself. A positioning accuracy of better than 0.5 mm appears to be required when implementing segmental intensity modulated treatment plans

  14. Alternative SAIL-Trp for robust aromatic signal assignment and determination of the {chi}{sub 2} conformation by intra-residue NOEs

    Energy Technology Data Exchange (ETDEWEB)

    Miyanoiri, Yohei; Takeda, Mitsuhiro [Nagoya University, Graduate School of Science, Structural Biology Research Center (Japan); Jee, JunGoo; Ono, Akira M.; Okuma, Kosuke; Terauchi, Tsutomu [Tokyo Metropolitan University, Center for Priority Areas (Japan); Kainosho, Masatsune, E-mail: kainosho@nagoya-u.jp [Nagoya University, Graduate School of Science, Structural Biology Research Center (Japan)

    2011-12-15

    Tryptophan (Trp) residues are frequently found in the hydrophobic cores of proteins, and therefore, their side-chain conformations, especially the precise locations of the bulky indole rings, are critical for determining structures by NMR. However, when analyzing [U-{sup 13}C,{sup 15}N]-proteins, the observation and assignment of the ring signals are often hampered by excessive overlaps and tight spin couplings. These difficulties have been greatly alleviated by using stereo-array isotope labeled (SAIL) proteins, which are composed of isotope-labeled amino acids optimized for unambiguous side-chain NMR assignment, exclusively through the {sup 13}C-{sup 13}C and {sup 13}C-{sup 1}H spin coupling networks (Kainosho et al. in Nature 440:52-57, 2006). In this paper, we propose an alternative type of SAIL-Trp with the [{zeta}2,{zeta}3-{sup 2}H{sub 2}; {delta}1,{epsilon}3,{eta}2-{sup 13}C{sub 3}; {epsilon}1-{sup 15}N]-indole ring ([{sup 12}C{sub {gamma},}{sup 12}C{sub {epsilon}2}] SAIL-Trp), which provides a more robust way to correlate the {sup 1}H{sub {beta}}, {sup 1}H{sub {alpha}}, and {sup 1}H{sub N} to the {sup 1}H{sub {delta}1} and {sup 1}H{sub {epsilon}3} through the intra-residue NOEs. The assignment of the {sup 1}H{sub {delta}1}/{sup 13}C{sub {delta}1} and {sup 1}H{sub {epsilon}3}/{sup 13}C{sub {epsilon}3} signals can thus be transferred to the {sup 1}H{sub {epsilon}1}/{sup 15}N{sub {epsilon}1} and {sup 1}H{sub {eta}2}/{sup 13}C{sub {eta}2} signals, as with the previous type of SAIL-Trp, which has an extra {sup 13}C at the C{sub {gamma}} of the ring. By taking advantage of the stereospecific deuteration of one of the prochiral {beta}-methylene protons, which was {sup 1}H{sub {beta}2} in this experiment, one can determine the side-chain conformation of the Trp residue including the {chi}{sub 2} angle, which is especially important for Trp residues, as they can adopt three preferred conformations. We demonstrated the usefulness of [{sup 12}C{sub {gamma}},{sup 12}C

  15. Alternative SAIL-Trp for robust aromatic signal assignment and determination of the χ2 conformation by intra-residue NOEs

    International Nuclear Information System (INIS)

    Miyanoiri, Yohei; Takeda, Mitsuhiro; Jee, JunGoo; Ono, Akira M.; Okuma, Kosuke; Terauchi, Tsutomu; Kainosho, Masatsune

    2011-01-01

    Tryptophan (Trp) residues are frequently found in the hydrophobic cores of proteins, and therefore, their side-chain conformations, especially the precise locations of the bulky indole rings, are critical for determining structures by NMR. However, when analyzing [U– 13 C, 15 N]-proteins, the observation and assignment of the ring signals are often hampered by excessive overlaps and tight spin couplings. These difficulties have been greatly alleviated by using stereo-array isotope labeled (SAIL) proteins, which are composed of isotope-labeled amino acids optimized for unambiguous side-chain NMR assignment, exclusively through the 13 C– 13 C and 13 C– 1 H spin coupling networks (Kainosho et al. in Nature 440:52–57, 2006). In this paper, we propose an alternative type of SAIL-Trp with the [ζ2,ζ3- 2 H 2 ; δ1,ε3,η2- 13 C 3 ; ε1- 15 N]-indole ring ([ 12 C γ, 12 C ε2 ] SAIL-Trp), which provides a more robust way to correlate the 1 H β , 1 H α , and 1 H N to the 1 H δ1 and 1 H ε3 through the intra-residue NOEs. The assignment of the 1 H δ1 / 13 C δ1 and 1 H ε3 / 13 C ε3 signals can thus be transferred to the 1 H ε1 / 15 N ε1 and 1 H η2 / 13 C η2 signals, as with the previous type of SAIL-Trp, which has an extra 13 C at the C γ of the ring. By taking advantage of the stereospecific deuteration of one of the prochiral β-methylene protons, which was 1 H β2 in this experiment, one can determine the side-chain conformation of the Trp residue including the χ 2 angle, which is especially important for Trp residues, as they can adopt three preferred conformations. We demonstrated the usefulness of [ 12 C γ , 12 C ε2 ] SAIL-Trp for the 12 kDa DNA binding domain of mouse c-Myb protein (Myb-R2R3), which contains six Trp residues.

  16. Alternative SAIL-Trp for robust aromatic signal assignment and determination of the χ(2) conformation by intra-residue NOEs.

    Science.gov (United States)

    Miyanoiri, Yohei; Takeda, Mitsuhiro; Jee, JunGoo; Ono, Akira M; Okuma, Kosuke; Terauchi, Tsutomu; Kainosho, Masatsune

    2011-12-01

    Tryptophan (Trp) residues are frequently found in the hydrophobic cores of proteins, and therefore, their side-chain conformations, especially the precise locations of the bulky indole rings, are critical for determining structures by NMR. However, when analyzing [U-(13)C,(15)N]-proteins, the observation and assignment of the ring signals are often hampered by excessive overlaps and tight spin couplings. These difficulties have been greatly alleviated by using stereo-array isotope labeled (SAIL) proteins, which are composed of isotope-labeled amino acids optimized for unambiguous side-chain NMR assignment, exclusively through the (13)C-(13)C and (13)C-(1)H spin coupling networks (Kainosho et al. in Nature 440:52-57, 2006). In this paper, we propose an alternative type of SAIL-Trp with the [ζ2,ζ3-(2)H(2); δ1,ε3,η2-(13)C(3); ε1-(15)N]-indole ring ([(12)C (γ,) ( 12) C(ε2)] SAIL-Trp), which provides a more robust way to correlate the (1)H(β), (1)H(α), and (1)H(N) to the (1)H(δ1) and (1)H(ε3) through the intra-residue NOEs. The assignment of the (1)H(δ1)/(13)C(δ1) and (1)H(ε3)/(13)C(ε3) signals can thus be transferred to the (1)H(ε1)/(15)N(ε1) and (1)H(η2)/(13)C(η2) signals, as with the previous type of SAIL-Trp, which has an extra (13)C at the C(γ) of the ring. By taking advantage of the stereospecific deuteration of one of the prochiral β-methylene protons, which was (1)H(β2) in this experiment, one can determine the side-chain conformation of the Trp residue including the χ(2) angle, which is especially important for Trp residues, as they can adopt three preferred conformations. We demonstrated the usefulness of [(12)C(γ),(12)C(ε2)] SAIL-Trp for the 12 kDa DNA binding domain of mouse c-Myb protein (Myb-R2R3), which contains six Trp residues.

  17. A Study of Residual Amplitude Modulation Suppression in Injection Locked Quantum Cascade Lasers Based on a Simplified Rate Equation Model

    International Nuclear Information System (INIS)

    Webb, J F; Yong, K S C; Haldar, M K

    2015-01-01

    Using results that come out of a simplified rate equation model, the suppression of residual amplitude modulation in injection locked quantum cascade lasers with the master laser modulated by its drive current is investigated. Quasi-static and dynamic expressions for intensity modulation are used. The suppression peaks at a specific value of the injection ratio for a given detuning and linewidth enhancement factor. The intensity modulation suppression remains constant over a range of frequencies. The effects of injection ratio, detuning, coupling efficiency and linewidth enhancement factor are considered. (paper)

  18. In silico analysis of conformational changes induced by mutation of aromatic binding residues: consequences for drug binding in the hERG K+ channel.

    Directory of Open Access Journals (Sweden)

    Kirsten Knape

    Full Text Available Pharmacological inhibition of cardiac hERG K(+ channels is associated with increased risk of lethal arrhythmias. Many drugs reduce hERG current by directly binding to the channel, thereby blocking ion conduction. Mutation of two aromatic residues (F656 and Y652 substantially decreases the potency of numerous structurally diverse compounds. Nevertheless, some drugs are only weakly affected by mutation Y652A. In this study we utilize molecular dynamics simulations and docking studies to analyze the different effects of mutation Y652A on a selected number of hERG blockers. MD simulations reveal conformational changes in the binding site induced by mutation Y652A. Loss of π-π-stacking between the two aromatic residues induces a conformational change of the F656 side chain from a cavity facing to cavity lining orientation. Docking studies and MD simulations qualitatively reproduce the diverse experimentally observed modulatory effects of mutation Y652A and provide a new structural interpretation for the sensitivity differences.

  19. Quality controls in intensity-modulated conformational radiotherapy. S.F.P.M. report nr 26, January 2010

    International Nuclear Information System (INIS)

    Valinta, Danielle; Poinsignon, Anne; Caron, Jerome; Dejean, Catherine; Corsetti, Dominique; Marcie, Serge; Mazurier, Jocelyne; Naudy, Suzanne; Aget, Helene; Marchesi, Vincent; Vieillevigne, Laure; Dedieu, Veronique; Bramoule, Celine; Caselles, Olivier; Lacaze, Brigitte; Mazurier, Jocelyne

    2009-08-01

    This report proposes a comprehensive presentation of the different controls which can be performed for the implementation of 3D intensity-modulated conformal radiation therapy (IMCR). The authors first present the IMCR principle by describing modes of production of modulated beams, the practical realisation of intensity modulation with Multi Leaf Collimator (MLC), multi leaf collimators, and the inverse planning system. They present the quality control of the accelerator (pre-requisites, linearity of the monitor chamber, symmetry and homogeneity), the quality control of multi leaf collimators (prerequisites, leaf absolute calibration, static mode, dynamic mode), the quality control of the treatment planning system (prerequisites, tests specific to IMCR, example in dynamic mode with the chair test), the quality control of the treatment plan (objective, necessary equipment and software solutions, measurement of point absolute dose, control of dose distribution, independent calculation of the number of monitor units), and the treatment verification (pre-treatment verification, patient repositioning during treatment). Finally, they indicate human means required for IMCR implementation, and formulate some recommendations for this implementation

  20. Dosimetric comparison of the related parameters between simultaneous integrated boost intensity-modulated radiotherapy and sequential boost conformal radiotherapy for postoperative malignant glioma of the brain

    International Nuclear Information System (INIS)

    Shao Qian; Lu Jie; Li Jianbin; Sun Tao; Bai Tong; Liu Tonghai; Yin Yong

    2011-01-01

    Objective: To compare the dosimetric of different parameter of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) with sequential boost conformal radiotherapy (SB-CRT) for postoperative malignant glioma of the brain. Methods: Ten patients with malignant glioma of brain were selected to study. Each patient was simulated all by CT and MRI, and the imagings of CT and MRI were all sent to Pinnacle 3 planning system. The fusion technology with MR-CT imaging was used on Pinnacle 3 planning system. The target volume was delineated and defined based on MRI. The postoperative residual lesion and resection cavity were defined as gross tumor volume (GTV) and expanded GTV some scope was defined as clinical target volume (CTV). The margins of GTV expanded 10 mm and 25 mm were defined as CTV1 and CTV2 respectively. CTV1 and CTV2 all enlarged 5 mm were defined as PTV1 and PTV2 respectively. The plans of simultaneous integrated boost intensity-modulated radiotherapy and sequential boost conformal radiotherapy were respectively designed for each patient using Pinnacle 3 planning system and the dosimetric of different parameter was compared. The prescribe dose of SIB-IMRT was PTV1: 62.5 Gy/25 f, PTV2: 50.0 Gy/25 f; and SB-CRT was PTV1: 66.0 Gy/33 f, PTV2: 50.0 Gy/25 f. The dosimetries of different parameters of SIB-IMRT and SB-CRT were compared by using Paired-Samples T Test. Results: The maximum and mean dose of PTV1, PTV2, and brainstem were of significant difference (P 0.05). Conclusion: The SIB-IMRT plan is better than the SB-CRT plan. The CI and HI of SIB-IMRT are superior to SB-CRT. At the same time, it can preserve the important organs such as brainstem and reduce the mean dose of whole brain. On the other hand it can shorten the total period of therapy time. (authors)

  1. On the near UV photophysics of a phenylalanine residue: conformation-dependent ππ* state deactivation revealed by laser spectroscopy of isolated neutral dipeptides.

    Science.gov (United States)

    Loquais, Yohan; Gloaguen, Eric; Alauddin, Mohammad; Brenner, Valérie; Tardivel, Benjamin; Mons, Michel

    2014-10-28

    The primary step of the near UV photophysics of a phenylalanine residue is investigated in one- and two-color pump-probe R2PI nanosecond experiments carried out on specific conformers of the Ac-Gly-Phe-NH2 molecule and related neutral compounds isolated in a supersonic expansion. Compared to toluene, whose ππ* state photophysics is dominated by intersystem crossing with a lifetime of ∼80 ns at the origin, the first ππ* state of Phe in the peptide environment is systematically found to be shorter-lived. The lifetime at the origin of transition is found to be significantly shortened in the presence of a primary amide (-CONH2) group (20-60 ns, depending on the conformer considered), demonstrating the existence of an additional non-radiative relaxation channel related to this chemical group. The quenching effect induced by the peptide environment is still more remarkable beyond the origin of the ππ* state, since vibronic bands of one of the 4 conformers observed (the 27-ribbon conformation) become barely detectable in the ns R2PI experiment, suggesting a significant conformer-selective lifetime shortening (below 100 ps). These results on dipeptides, which extend previous investigations on shorter Phe-containing molecules (N-Ac-Phe-NH2 and N-Ac-Phe-NH-Me), confirm the existence of conformer-dependent non-radiative deactivation processes, whose characteristic timescales range from tens of ns down to hundreds of ps or below. This dynamics is assigned to two distinct mechanisms: a first one, consistent with an excitation energy transfer from the optically active ππ* state to low-lying amide nπ* excited states accessed through conical intersections, especially in the presence of a C-terminal primary amide group (-CONH2); a second one, responsible for the short lifetimes in 2(7) ribbon structures, would be more specifically triggered by phenyl ring vibrational excitations. Implications in terms of spectroscopic probing of Phe in a peptide environment, especially

  2. Role of Rhodobacter sphaeroides photosynthetic reaction center residue M214 in the composition, absorbance properties, and conformations of H(A) and B(A) cofactors.

    Science.gov (United States)

    Saer, Rafael G; Hardjasa, Amelia; Rosell, Federico I; Mauk, A Grant; Murphy, Michael E P; Beatty, J Thomas

    2013-04-02

    In the native reaction center (RC) of Rhodobacter sphaeroides, the side chain of (M)L214 projects orthogonally toward the plane and into the center of the A branch bacteriopheophytin (BPhe) macrocycle. The possibility that this side chain is responsible for the dechelation of the central Mg(2+) of bacteriochlorophyll (BChl) was investigated by replacement of (M)214 with residues possessing small, nonpolar side chains that can neither coordinate nor block access to the central metal ion. The (M)L214 side chain was also replaced with Cys, Gln, and Asn to evaluate further the requirements for assembly of the RC with BChl in the HA pocket. Photoheterotrophic growth studies showed no difference in growth rates of the (M)214 nonpolar mutants at a low light intensity, but the growth of the amide-containing mutants was impaired. The absorbance spectra of purified RCs indicated that although absorbance changes are associated with the nonpolar mutations, the nonpolar mutant RC pigment compositions are the same as in the wild-type protein. Crystal structures of the (M)L214G, (M)L214A, and (M)L214N mutants were determined (determined to 2.2-2.85 Å resolution), confirming the presence of BPhe in the HA pocket and revealing alternative conformations of the phytyl tail of the accessory BChl in the BA site of these nonpolar mutants. Our results demonstrate that (i) BChl is converted to BPhe in a manner independent of the aliphatic side chain length of nonpolar residues replacing (M)214, (ii) BChl replaces BPhe if residue (M)214 has an amide-bearing side chain, (iii) (M)214 side chains containing sulfur are not sufficient to bind BChl in the HA pocket, and (iv) the (M)214 side chain influences the conformation of the phytyl tail of the BA BChl.

  3. A dosimetric comparison of 3D conformal vs intensity modulated vs volumetric arc radiation therapy for muscle invasive bladder cancer

    Directory of Open Access Journals (Sweden)

    Foroudi Farshad

    2012-07-01

    Full Text Available Abstract Background To compare 3 Dimensional Conformal radiotherapy (3D-CRT with Intensity Modulated Radiotherapy (IMRT with Volumetric-Modulated Arc Therapy (VMAT for bladder cancer. Methods Radiotherapy plans for 15 patients with T2-T4N0M0 bladder cancer were prospectively developed for 3-DCRT, IMRT and VMAT using Varian Eclipse planning system. The same radiation therapist carried out all planning and the same clinical dosimetric constraints were used. 10 of the patients with well localised tumours had a simultaneous infield boost (SIB of the primary tumour planned for both IMRT and VMAT. Tumour control probabilities and normal tissue complication probabilities were calculated. Results Mean planning time for 3D-CRT, IMRT and VMAT was 30.0, 49.3, and 141.0 minutes respectively. The mean PTV conformity (CI index for 3D-CRT was 1.32, for IMRT 1.05, and for VMAT 1.05. The PTV Homogeneity (HI index was 0.080 for 3D-CRT, 0.073 for IMRT and 0.086 for VMAT. Tumour control and normal tissue complication probabilities were similar for 3D-CRT, IMRT and VMAT. The mean monitor units were 267 (range 250–293 for 3D-CRT; 824 (range 641–1083 for IMRT; and 403 (range 333–489 for VMAT (P  Conclusions VMAT is associated with similar dosimetric advantages as IMRT over 3D-CRT for muscle invasive bladder cancer. VMAT is associated with faster delivery times and less number of mean monitor units than IMRT. SIB is feasible in selected patients with localized tumours.

  4. Chemotherapy and intensity modulated conformational radiotherapy for locally advanced pancreas cancers

    International Nuclear Information System (INIS)

    Huguet, F.; Wu, A.; Zhang, Z.; Winston, C.; Reidy, D.; Ho, A.; Allen, P.; Karyn, G.

    2011-01-01

    The authors report a retrospective study of the tolerance and survival of 48 patients who have been treated by a chemotherapy followed by a chemotherapy concomitant with an intensity-modulated radiotherapy for a locally advanced pancreas cancer. Results are discussed in terms of toxicity, cancer response, operability, survival rate. Tolerance is good. Local control rates, global survival rates and secondary resection rates are promising. Short communication

  5. Chest wall desmoid tumours treated with definitive radiotherapy: a plan comparison of 3D conformal radiotherapy, intensity-modulated radiotherapy and volumetric-modulated arc radiotherapy

    International Nuclear Information System (INIS)

    Liu, Jia; Ng, Diana; Lee, James; Stalley, Paul; Hong, Angela

    2016-01-01

    Definitive radiotherapy is often used for chest wall desmoid tumours due to size or anatomical location. The delivery of radiotherapy is challenging due to the large size and constraints of normal surrounding structures. We compared the dosimetry of 3D conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc radiotherapy (VMAT) to evaluate the best treatment option. Ten consecutive patients with inoperable chest wall desmoid tumours (PTV range 416–4549 cm 3 ) were selected. For each patient, 3DCRT, IMRT and VMAT plans were generated and the Conformity Index (CI), organ at risk (OAR) doses and monitor unit (MU) were evaluated. The Wilcoxon signed-rank test was used to compare dose delivered to both target and OARs. The mean number of fields for 3DCRT and IMRT were 6.3 ± 2.1, 7.2 ± 1.8. The mean number of arcs for VMAT was 3.7 ± 1.1. The mean conformity index of VMAT (0.98 ± 0.14) was similar to that of IMRT (1.03 ± 0.13), both of which were significantly better than 3DCRT (1.35 ± 0.20; p = 0.005). The mean dose to lung was significantly higher for 3DCRT (11.9Gy ± 7.9) compared to IMRT (9.4Gy ± 5.4, p = 0.014) and VMAT (8.9Gy ± 4.5, p = 0.017). For the 3 females, the low dose regions in the ipsilateral breast for VMAT were generally less with VMAT. IMRT plans required 1427 ± 532 MU per fraction which was almost 4-fold higher than 3DCRT (313 ± 112, P = 0.005). Compared to IMRT, VMAT plans required 60 % less MU (570 ± 285, P = 0.005). For inoperable chest wall desmoid tumours, VMAT delivered equivalent target coverage when compared to IMRT but required 60 % less MU. Both VMAT and IMRT were superior to 3DCRT in terms of better PTV coverage and sparing of lung tissue

  6. Conformation radiotherapy and conformal radiotherapy

    International Nuclear Information System (INIS)

    Morita, Kozo

    1999-01-01

    In order to coincide the high dose region to the target volume, the 'Conformation Radiotherapy Technique' using the multileaf collimator and the device for 'hollow-out technique' was developed by Prof. S. Takahashi in 1960. This technique can be classified a type of 2D-dynamic conformal RT techniques. By the clinical application of this technique, the late complications of the lens, the intestine and the urinary bladder after radiotherapy for the maxillary cancer and the cervical cancer decreased. Since 1980's the exact position and shape of the tumor and the surrounding normal tissues can be easily obtained by the tremendous development of the CT/MRI imaging technique. As a result, various kinds of new conformal techniques such as the 3D-CRT, the dose intensity modulation, the tomotherapy have been developed since the beginning of 1990'. Several 'dose escalation study with 2D-/3D conformal RT' is now under way to improve the treatment results. (author)

  7. A Slow Conformational Switch in the BMAL1 Transactivation Domain Modulates Circadian Rhythms.

    Science.gov (United States)

    Gustafson, Chelsea L; Parsley, Nicole C; Asimgil, Hande; Lee, Hsiau-Wei; Ahlbach, Christopher; Michael, Alicia K; Xu, Haiyan; Williams, Owen L; Davis, Tara L; Liu, Andrew C; Partch, Carrie L

    2017-05-18

    The C-terminal transactivation domain (TAD) of BMAL1 (brain and muscle ARNT-like 1) is a regulatory hub for transcriptional coactivators and repressors that compete for binding and, consequently, contributes to period determination of the mammalian circadian clock. Here, we report the discovery of two distinct conformational states that slowly exchange within the dynamic TAD to control timing. This binary switch results from cis/trans isomerization about a highly conserved Trp-Pro imide bond in a region of the TAD that is required for normal circadian timekeeping. Both cis and trans isomers interact with transcriptional regulators, suggesting that isomerization could serve a role in assembling regulatory complexes in vivo. Toward this end, we show that locking the switch into the trans isomer leads to shortened circadian periods. Furthermore, isomerization is regulated by the cyclophilin family of peptidyl-prolyl isomerases, highlighting the potential for regulation of BMAL1 protein dynamics in period determination. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Computational study of the activity, dynamics, energetics and conformations of insulin analogues using molecular dynamics simulations: Application to hyperinsulinemia and the critical residue B26

    Directory of Open Access Journals (Sweden)

    Anastasios Papaioannou

    2017-09-01

    Full Text Available Due to the increasing prevalence of diabetes, finding therapeutic analogues for insulin has become an urgent issue. While many experimental studies have been performed towards this end, they have limited scope to examine all aspects of the effect of a mutation. Computational studies can help to overcome these limitations, however, relatively few studies that focus on insulin analogues have been performed to date. Here, we present a comprehensive computational study of insulin analogues—three mutant insulins that have been identified with hyperinsulinemia and three mutations on the critical B26 residue that exhibit similar binding affinity to the insulin receptor—using molecular dynamics simulations with the aim of predicting how mutations of insulin affect its activity, dynamics, energetics and conformations. The time evolution of the conformers is studied in long simulations. The probability density function and potential of mean force calculations are performed on each insulin analogue to unravel the effect of mutations on the dynamics and energetics of insulin activation. Our conformational study can decrypt the key features and molecular mechanisms that are responsible for an enhanced or reduced activity of an insulin analogue. We find two key results: 1 hyperinsulinemia may be due to the drastically reduced activity (and binding affinity of the mutant insulins. 2 Y26BS and Y26BE are promising therapeutic candidates for insulin as they are more active than WT-insulin. The analysis in this work can be readily applied to any set of mutations on insulin to guide development of more effective therapeutic analogues.

  9. Conformation-Specific IR and UV Spectroscopy of the Amino Acid Glutamine: Amide-Stacking and Hydrogen Bonding in AN Important Residue in Neurodegenerative Diseases

    Science.gov (United States)

    Walsh, Patrick S.; Dean, Jacob C.; Zwier, Timothy S.

    2014-06-01

    Glutamine plays an important role in several neurodegenerative diseases including Huntington's disease (HD) and Alzheimer's disease (AD). An intriguing aspect of the structure of glutamine is its incorporation of an amide group in its side chain, thereby opening up the possibility of forming amide-amide H-bonds between the peptide backbone and side chain. In this study the conformational preferences of two capped gluatamines Z(carboxybenzyl)-Glutamine-X (X=OH, NHMe) are studied under jet-cooled conditions in the gas phase in order to unlock the intrinsic structural motifs that are favored by this flexible sidechain. Conformational assignments are made by comparing the hydride stretch ( 3100-3700 cm-1) and amide I and II ( 1400-1800 cm-1) resonant ion-dip infrared spectra with predictions from harmonic frequency calculations. Assigned structures will be compared to previously published results on both natural and unnatural residues. Particular emphasis will be placed on the comparison between glutamine and unconstrained γ-peptides due to the similar three-carbon spacing between backbone and side chain in glutamine to the backbone spacing in γ-peptides. The ability of the glutamine side-chain to form amide stacked conformations will be a main focus, along with the prevalence of extended backbone type structures. W. H. James, III, C W. Müller, E. G. Buchanan, M. G. D. Nix, L. Guo, L. Roskop, M. S. Gordon, L. V. Slipchenko, S. H. Gellman, and T. S. Zwier, J. Am. Chem. Soc., 2009, 131(40), 14243-14245.

  10. Helical tomo-therapy in the anal canal cancer: dosimetric comparison with conformal radiotherapy with intensity modulation and classical conformal radiotherapy

    International Nuclear Information System (INIS)

    Ozsahin, M.; Ugurluer, G.; Ballerini, G.; Letenneur, G.; Zouhair, A.; Mirimanoff, R.O.

    2009-01-01

    A dosimetry comparison was made between helical tomo-therapy, I.M.R.T. and classical conformal three dimensional radiotherapy for twelve first patients that received a image guided radiotherapy, the toxicity was tackled with a minimum follow-up of fourteen months. In conclusion, the CT-guided radiotherapy allows to save organs at risks superior to I.M.R.T. and conformal radiotherapy and a best homogeneity in the target volume. the toxicity is moderated and the break time is limited. (N.C.)

  11. Mutation in the β-hairpin of the Bordetella pertussis adenylate cyclase toxin modulates N-lobe conformation in calmodulin

    International Nuclear Information System (INIS)

    Springer, Tzvia I.; Goebel, Erich; Hariraju, Dinesh; Finley, Natosha L.

    2014-01-01

    Highlights: • Bordetella pertussis adenylate cyclase toxin modulates bi-lobal structure of CaM. • The structure and stability of the complex rely on intermolecular associations. • A novel mode of CaM-dependent activation of the adenylate cyclase toxin is proposed. - Abstract: Bordetella pertussis, causative agent of whooping cough, produces an adenylate cyclase toxin (CyaA) that is an important virulence factor. In the host cell, the adenylate cyclase domain of CyaA (CyaA-ACD) is activated upon association with calmodulin (CaM), an EF-hand protein comprised of N- and C-lobes (N-CaM and C-CaM, respectively) connected by a flexible tether. Maximal CyaA-ACD activation is achieved through its binding to both lobes of intact CaM, but the structural mechanisms remain unclear. No high-resolution structure of the intact CaM/CyaA-ACD complex is available, but crystal structures of isolated C-CaM bound to CyaA-ACD shed light on the molecular mechanism by which this lobe activates the toxin. Previous studies using molecular modeling, biochemical, and biophysical experiments demonstrate that CyaA-ACD’s β-hairpin participates in site-specific interactions with N-CaM. In this study, we utilize nuclear magnetic resonance (NMR) spectroscopy to probe the molecular association between intact CaM and CyaA-ACD. Our results indicate binding of CyaA-ACD to CaM induces large conformational perturbations mapping to C-CaM, while substantially smaller structural changes are localized primarily to helices I, II, and IV, and the metal-binding sites in N-CaM. Site-specific mutations in CyaA-ACD’s β-hairpin structurally modulate N-CaM, resulting in conformational perturbations in metal binding sites I and II, while no significant structural modifications are observed in C-CaM. Moreover, dynamic light scattering (DLS) analysis reveals that mutation of the β-hairpin results in a decreased hydrodynamic radius (R h ) and reduced thermal stability in the mutant complex. Taken together

  12. Mutation in the β-hairpin of the Bordetella pertussis adenylate cyclase toxin modulates N-lobe conformation in calmodulin

    Energy Technology Data Exchange (ETDEWEB)

    Springer, Tzvia I.; Goebel, Erich; Hariraju, Dinesh [Department of Microbiology, Miami University, Oxford, OH 45056 (United States); Finley, Natosha L., E-mail: finleynl@miamioh.edu [Department of Microbiology, Miami University, Oxford, OH 45056 (United States); Cell, Molecular, and Structural Biology Program, Miami University, Oxford, OH 45056 (United States)

    2014-10-10

    Highlights: • Bordetella pertussis adenylate cyclase toxin modulates bi-lobal structure of CaM. • The structure and stability of the complex rely on intermolecular associations. • A novel mode of CaM-dependent activation of the adenylate cyclase toxin is proposed. - Abstract: Bordetella pertussis, causative agent of whooping cough, produces an adenylate cyclase toxin (CyaA) that is an important virulence factor. In the host cell, the adenylate cyclase domain of CyaA (CyaA-ACD) is activated upon association with calmodulin (CaM), an EF-hand protein comprised of N- and C-lobes (N-CaM and C-CaM, respectively) connected by a flexible tether. Maximal CyaA-ACD activation is achieved through its binding to both lobes of intact CaM, but the structural mechanisms remain unclear. No high-resolution structure of the intact CaM/CyaA-ACD complex is available, but crystal structures of isolated C-CaM bound to CyaA-ACD shed light on the molecular mechanism by which this lobe activates the toxin. Previous studies using molecular modeling, biochemical, and biophysical experiments demonstrate that CyaA-ACD’s β-hairpin participates in site-specific interactions with N-CaM. In this study, we utilize nuclear magnetic resonance (NMR) spectroscopy to probe the molecular association between intact CaM and CyaA-ACD. Our results indicate binding of CyaA-ACD to CaM induces large conformational perturbations mapping to C-CaM, while substantially smaller structural changes are localized primarily to helices I, II, and IV, and the metal-binding sites in N-CaM. Site-specific mutations in CyaA-ACD’s β-hairpin structurally modulate N-CaM, resulting in conformational perturbations in metal binding sites I and II, while no significant structural modifications are observed in C-CaM. Moreover, dynamic light scattering (DLS) analysis reveals that mutation of the β-hairpin results in a decreased hydrodynamic radius (R{sub h}) and reduced thermal stability in the mutant complex. Taken

  13. A dosimetric comparison of 3D conformal vs intensity modulated vs volumetric arc radiation therapy for muscle invasive bladder cancer

    International Nuclear Information System (INIS)

    Foroudi, Farshad; Kron, Tomas; Wilson, Lesley; Bressel, Mathias; Haworth, Annette; Hornby, Colin; Pham, Daniel; Cramb, Jim; Gill, Suki; Tai, Keen Hun

    2012-01-01

    To compare 3 Dimensional Conformal radiotherapy (3D-CRT) with Intensity Modulated Radiotherapy (IMRT) with Volumetric-Modulated Arc Therapy (VMAT) for bladder cancer. Radiotherapy plans for 15 patients with T2-T4N0M0 bladder cancer were prospectively developed for 3-DCRT, IMRT and VMAT using Varian Eclipse planning system. The same radiation therapist carried out all planning and the same clinical dosimetric constraints were used. 10 of the patients with well localised tumours had a simultaneous infield boost (SIB) of the primary tumour planned for both IMRT and VMAT. Tumour control probabilities and normal tissue complication probabilities were calculated. Mean planning time for 3D-CRT, IMRT and VMAT was 30.0, 49.3, and 141.0 minutes respectively. The mean PTV conformity (CI) index for 3D-CRT was 1.32, for IMRT 1.05, and for VMAT 1.05. The PTV Homogeneity (HI) index was 0.080 for 3D-CRT, 0.073 for IMRT and 0.086 for VMAT. Tumour control and normal tissue complication probabilities were similar for 3D-CRT, IMRT and VMAT. The mean monitor units were 267 (range 250–293) for 3D-CRT; 824 (range 641–1083) for IMRT; and 403 (range 333–489) for VMAT (P < 0.05). Average treatment delivery time were 2:25min (range 2:01–3:09) for 3D-CRT; 4:39 (range 3:41–6:40) for IMRT; and 1:14 (range 1:13–1:14) for VMAT. In selected patients, the SIB did not result in a higher dose to small bowel or rectum. VMAT is associated with similar dosimetric advantages as IMRT over 3D-CRT for muscle invasive bladder cancer. VMAT is associated with faster delivery times and less number of mean monitor units than IMRT. SIB is feasible in selected patients with localized tumours

  14. Dosimetric Comparison of Three-Dimensional Conformal Proton Radiotherapy, Intensity-Modulated Proton Therapy, and Intensity-Modulated Radiotherapy for Treatment of Pediatric Craniopharyngiomas

    Energy Technology Data Exchange (ETDEWEB)

    Boehling, Nicholas S. [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Grosshans, David R., E-mail: dgrossha@mdanderson.org [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Bluett, Jaques B. [Department of Radiation Physics, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Palmer, Matthew T. [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Song, Xiaofei; Amos, Richard A.; Sahoo, Narayan [Department of Radiation Physics, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Meyer, Jeffrey J.; Mahajan, Anita; Woo, Shiao Y. [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States)

    2012-02-01

    Purpose: Cranial irradiation in pediatric patients is associated with serious long-term adverse effects. We sought to determine whether both three-dimensional conformal proton radiotherapy (3D-PRT) and intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiotherapy (IMRT) decrease integral dose to brain areas known to harbor neuronal stem cells, major blood vessels, and other normal brain structures for pediatric patients with craniopharyngiomas. Methods and Materials: IMRT, forward planned, passive scattering proton, and IMPT plans were generated and optimized for 10 pediatric patients. The dose was 50.4 Gy (or cobalt Gy equivalent) delivered in 28 fractions with the requirement for planning target volume (PTV) coverage of 95% or better. Integral dose data were calculated from differential dose-volume histograms. Results: The PTV target coverage was adequate for all modalities. IMRT and IMPT yielded the most conformal plans in comparison to 3D-PRT. Compared with IMRT, 3D-PRT and IMPT plans had a relative reduction of integral dose to the hippocampus (3D-PRT, 20.4; IMPT, 51.3%{sup Asterisk-Operator }), dentate gyrus (27.3, 75.0%{sup Asterisk-Operator }), and subventricular zone (4.5, 57.8%{sup Asterisk-Operator }). Vascular organs at risk also had reduced integral dose with the use of proton therapy (anterior cerebral arteries, 33.3{sup Asterisk-Operator }, 100.0%{sup Asterisk-Operator }; middle cerebral arteries, 25.9%{sup Asterisk-Operator }, 100%{sup Asterisk-Operator }; anterior communicating arteries, 30.8{sup Asterisk-Operator }, 41.7%{sup Asterisk-Operator }; and carotid arteries, 51.5{sup Asterisk-Operator }, 77.6{sup Asterisk-Operator }). Relative reduction of integral dose to the infratentorial brain (190.7{sup Asterisk-Operator }, 109.7%{sup Asterisk-Operator }), supratentorial brain without PTV (9.6, 26.8%{sup Asterisk-Operator }), brainstem (45.6, 22.4%{sup Asterisk-Operator }), and whole brain without PTV (19.4{sup Asterisk

  15. Accurate Determination of Leucine and Valine Side-chain Conformations using U-[15N/13C/2H]/[1H-(methine/methyl)-Leu/Val] Isotope Labeling, NOE Pattern Recognition, and Methine Cγ-Hγ/Cβ-Hβ Residual Dipolar Couplings

    International Nuclear Information System (INIS)

    Tang, Chun; Iwahara, Junji; Clore, G. Marius

    2005-01-01

    An isotope labeling scheme is described in which specific protonation of methine and methyl protons of leucine and valine is obtained on a 15 N/ 13 C labeled background with uniform deuteration of all other non-exchangeable protons. The presence of a protonated methine group has little effect on the favorable relaxation properties of the methyl protons of Leu and Val. This labeling scheme permits the rotameric state of leucine side-chains to be readily determined by simple inspection of the pattern of Hγ(i)-H N (i) and Hγ(i)-H N (i+1) NOEs in a 3D 15 N-separated NOE spectrum free of complications arising from spectral overlap and spin-diffusion. In addition, one-bond residual dipolar couplings for the methine 13 C- 1 H bond vectors of Leu and Val can be accurately determined from an intensity J-modulated constant-time HCCH-COSY experiment and used to accurately orient the side-chains of Leu and Val. Incorporation of these data into structure refinement improves the accuracy with which the conformations of Leu and Val side-chains can be established. This is important to ensure optimal packing both within the protein core and at intermolecular interfaces. The impact of the method on protein structure determination is illustrated by application to enzyme IIA Chitobiose , a 34 kDa homotrimeric phosphotransferase protein

  16. Contribution of the residue at position 4 within classical nuclear localization signals to modulating interaction with importins and nuclear targeting.

    Science.gov (United States)

    Smith, Kate M; Di Antonio, Veronica; Bellucci, Luca; Thomas, David R; Caporuscio, Fabiana; Ciccarese, Francesco; Ghassabian, Hanieh; Wagstaff, Kylie M; Forwood, Jade K; Jans, David A; Palù, Giorgio; Alvisi, Gualtiero

    2018-08-01

    Nuclear import involves the recognition by importin (IMP) superfamily members of nuclear localization signals (NLSs) within protein cargoes destined for the nucleus, the best understood being recognition of classical NLSs (cNLSs) by the IMPα/β1 heterodimer. Although the cNLS consensus [K-(K/R)-X-(K/R) for positions P2-P5] is generally accepted, recent studies indicated that the contribution made by different residues at the P4 position can vary. Here, we apply a combination of microscopy, molecular dynamics, crystallography, in vitro binding, and bioinformatics approaches to show that the nature of residues at P4 indeed modulates cNLS function in the context of a prototypical Simian Virus 40 large tumor antigen-derived cNLS (KKRK, P2-5). Indeed, all hydrophobic substitutions in place of R impaired binding to IMPα and nuclear targeting, with the largest effect exerted by a G residue at P4. Substitution of R with neutral hydrophobic residues caused the loss of electrostatic and van der Waals interactions between the P4 residue side chains and IMPα. Detailed bioinformatics analysis confirmed the importance of the P4 residue for cNLS function across the human proteome, with specific residues such as G being associated with low activity. Furthermore, we validate our findings for two additional cNLSs from human cytomegalovirus (HCMV) DNA polymerase catalytic subunit UL54 and processivity factor UL44, where a G residue at P4 results in a 2-3-fold decrease in NLS activity. Our results thus showed that the P4 residue makes a hitherto poorly appreciated contribution to nuclear import efficiency, which is essential to determining the precise nuclear levels of cargoes. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. Anal wall sparing effect of an endorectal balloon in 3D conformal and intensity-modulated prostate radiotherapy

    International Nuclear Information System (INIS)

    Smeenk, Robert Jan; Lin, Emile N.J.Th. van; Kollenburg, Peter van; Kunze-Busch, Martina; Kaanders, Johannes H.A.M.

    2009-01-01

    Background and purpose: To investigate the anal wall (Awall) sparing effect of an endorectal balloon (ERB) in 3D conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) for prostate cancer. Materials and methods: In 24 patients with localized prostate carcinoma, two planning CT-scans were performed: with and without ERB. A prostate planning target volume (PTV) was defined, and the Awall was delineated, using two different methods. Three-field and 4-field 3D-CRT plans, and IMRT plans were generated with a prescription dose of 78 Gy. In 144 treatment plans, the minimum dose (D min ), maximum dose (D max ), and mean dose (D mean ) to the Awall were calculated, as well as the Awall volumes exposed to doses ranging from ≥20 Gy to ≥70 Gy (V 20 - V 70 , respectively). Results: In the 3D-CRT plans, an ERB significantly reduced D mean , D max , and V 30 - V 70 . For IMRT all investigated dose parameters were significantly reduced by the ERB. The absolute reduction of D mean was 12 Gy in 3D-CRT and was 7.5 Gy in IMRT for both methods of Awall delineation. Conclusions: Application of an ERB showed a significant Awall sparing effect in both 3D-CRT and IMRT. This may lead to reduced late anal toxicity in prostate radiotherapy.

  18. Anal wall sparing effect of an endorectal balloon in 3D conformal and intensity-modulated prostate radiotherapy.

    Science.gov (United States)

    Smeenk, Robert Jan; van Lin, Emile N J Th; van Kollenburg, Peter; Kunze-Busch, Martina; Kaanders, Johannes H A M

    2009-10-01

    To investigate the anal wall (Awall) sparing effect of an endorectal balloon (ERB) in 3D conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) for prostate cancer. In 24 patients with localized prostate carcinoma, two planning CT-scans were performed: with and without ERB. A prostate planning target volume (PTV) was defined, and the Awall was delineated, using two different methods. Three-field and 4-field 3D-CRT plans, and IMRT plans were generated with a prescription dose of 78Gy. In 144 treatment plans, the minimum dose (D(min)), maximum dose (D(max)), and mean dose (D(mean)) to the Awall were calculated, as well as the Awall volumes exposed to doses ranging from >or=20Gy to >or=70Gy (V(20)-V(70), respectively). In the 3D-CRT plans, an ERB significantly reduced D(mean), D(max), and V(30)-V(70). For IMRT all investigated dose parameters were significantly reduced by the ERB. The absolute reduction of D(mean) was 12Gy in 3D-CRT and was 7.5Gy in IMRT for both methods of Awall delineation. Application of an ERB showed a significant Awall sparing effect in both 3D-CRT and IMRT. This may lead to reduced late anal toxicity in prostate radiotherapy.

  19. Intensity-Modulated Radiotherapy versus 3-Dimensional Conformal Radiotherapy Strategies for Locally Advanced Non-Small-Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Uğur Selek

    2014-12-01

    Full Text Available Chemoradiotherapy is the current standard of care in patients with advanced inoperable stage IIIA or IIIB non-small cell lung cancer (NSCLC. Three-dimensional radiotherapy (3DCRT has been a trusted method for a long time and has well-known drawbacks, most of which could be improved by Intensity Modulated Radiotherapy (IMRT. IMRT is not currently the standard treatment of locally advanced NSCLC, but almost all patients could benefit to a degree in organ at risk sparing, dose coverage conformality, or dose escalation. The most critical step for a radiation oncology department is to strictly evaluate its own technical and physical capabilities to determine the ability of IMRT to deliver an optimal treatment plan. This includes calculating the internal tumor motion (ideally 4DCT or equivalent techniques, treatment planning software with an up-to-date heterogeneity correction algorithm, and daily image guidance. It is crucial to optimise and individualise the therapeutic ratio for each patient during the decision of 3DCRT versus IMRT. The current literature rationalises the increasing use of IMRT, including 4D imaging plus PET/CT, and encourages the applicable knowledge-based and individualised dose escalation using advanced daily image-guided radiotherapy.

  20. Intensity-modulated conformal radiotherapy in the anal canal cancer. Report of technological assessment. Updating of the 2006 report

    International Nuclear Information System (INIS)

    2015-07-01

    As intensity-modulated conformal radiotherapy (IMCR) has already been technologically assessed in 2006 with a positive opinion for some treatments and a negative one for others, and as this technique displays some interesting properties for the treatment of pelvic cancers (optimisation of dose distribution, preservation of sane tissues, reduction of secondary effects during irradiation), this report proposes an assessment of clinical safety and efficiency of IMCR in the treatment of an anal canal cancer. After a discussion of generalities, of histological and epidemiological data, and of knowledge regarding treatment and follow-up of this cancer, the report presents the IMCR technique, some regulatory aspects, and its applications to the considered cancer. The methodology adopted for this assessment is then presented. Based on various studies and clinical results, the IMCR clinical safety and efficiency in the treatment of the anal canal cancer are discussed and assessed. Recommendations produced by different medical professional bodies are reported. Opinion of experts and a synthesis of stakeholders are then proposed

  1. Dosimetric comparison of field in field intensity-modulated radiotherapy technique with conformal radiotherapy techniques in breast cancer

    International Nuclear Information System (INIS)

    Ercan, T.; Alco, G.; Zengin, F.; Atilla, S.; Dincer, M.; Igdem, S.; Okkan, S.

    2010-01-01

    The aim of this study was to be able to implement the field-in-field intensity-modulated radiotherapy (FiF) technique in our daily practice for breast radiotherapy. To do this, we performed a dosimetric comparison. Treatment plans were produced for 20 consecutive patients. FiF plans and conformal radiotherapy (CRT) plans were compared for doses in the planning target volume (PTV), the dose homogeneity index (DHI), doses in irradiated soft tissue outside the target volume (SST), ipsilateral lung and heart doses for left breast irradiation, and the monitor unit counts (MU) required for treatment. Averaged values were compared using Student's t-test. With FiF, the DHI is improved 7.0% and 5.7%, respectively (P<0.0001) over the bilateral and lateral wedge CRT techniques. When the targeted volumes received 105% and 110% of the prescribed dose in the PTV were compared, significant decreases are found with the FiF technique. With the 105% dose, the SST, heart, and ipsilateral lung doses and the MU counts were also significantly lower with the FiF technique. The FiF technique, compared to CRT, for breast radiotherapy enables significantly better dose distribution in the PTV. Significant differences are also found for soft tissue volume, the ipsilateral lung dose, and the heart dose. Considering the decreased MUs needed for treatment, the FiF technique is preferred over tangential CRT. (author)

  2. Dosimetric Evaluation of Intensity Modulated Radiotherapy and 4-Field 3-D Conformal Radiotherapy in Prostate Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Bora Uysal

    2013-03-01

    Full Text Available Objective: The purpose of this dosimetric study is the targeted dose homogeneity and critical organ dose comparison of 7-field Intensity Modulated Radiotherapy (IMRT and 3-D 4-field conformal radiotherapy. Study Design: Cross sectional study. Material and Methods: Twenty patients with low and moderate risk prostate cancer treated at Gülhane Military Medical School Radiation Oncology Department between January 2009 and December 2009 are included in this study. Two seperate dosimetric plans both for 7-field IMRT and 3D-CRT have been generated for each patient to comparatively evaluate the dosimetric status of both techniques and all the patients received 7-field IMRT. Results: Dose-comparative evaluation of two techniques revealed the superiority of IMRT technique with statistically significantly lower femoral head doses along with reduced critical organ dose-volume parameters of bladder V60 (the volume receiving 60 Gy and rectal V40 (the volume receiving 40 Gy and V60. Conclusion: It can be concluded that IMRT is an effective definitive management tool for prostate cancer with improved critical organ sparing and excellent dose homogenization in target organs of prostate and seminal vesicles.

  3. A Comparison of Helical Intensity-Modulated Radiotherapy, Intensity-Modulated Radiotherapy, and 3D-Conformal Radiation Therapy for Pancreatic Cancer

    International Nuclear Information System (INIS)

    Poppe, Matthew M.; Narra, Venkat; Yue, Ning J.; Zhou Jinghao; Nelson, Carl; Jabbour, Salma K.

    2011-01-01

    We assessed dosimetric differences in pancreatic cancer radiotherapy via helical intensity-modulated radiotherapy (HIMRT), linac-based IMRT, and 3D-conformal radiation therapy (3D-CRT) with regard to successful plan acceptance and dose to critical organs. Dosimetric analysis was performed in 16 pancreatic cases that were planned to 54 Gy; both post-pancreaticoduodenectomy (n = 8) and unresected (n = 8) cases were compared. Without volume modification, plans met constraints 75% of the time with HIMRT and IMRT and 13% with 3D-CRT. There was no statistically significantly improvement with HIMRT over conventional IMRT in reducing liver V35, stomach V45, or bowel V45. HIMRT offers improved planning target volume (PTV) dose homogeneity compared with IMRT, averaging a lower maximum dose and higher volume receiving the prescription dose (D100). HIMRT showed an increased mean dose over IMRT to bowel and liver. Both HIMRT and IMRT offer a statistically significant improvement over 3D-CRT in lowering dose to liver, stomach, and bowel. The results were similar for both unresected and resected patients. In pancreatic cancer, HIMRT offers improved dose homogeneity over conventional IMRT and several significant benefits to 3D-CRT. Factors to consider before incorporating IMRT into pancreatic cancer therapy are respiratory motion, dose inhomogeneity, and mean dose.

  4. Involved-Site Image-Guided Intensity Modulated Versus 3D Conformal Radiation Therapy in Early Stage Supradiaphragmatic Hodgkin Lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Filippi, Andrea Riccardo, E-mail: andreariccardo.filippi@unito.it [Department of Oncology, University of Torino, Torino (Italy); Ciammella, Patrizia [Radiation Therapy Unit, Department of Oncology and Advanced Technology, ASMN Hospital IRCCS, Reggio Emilia (Italy); Piva, Cristina; Ragona, Riccardo [Department of Oncology, University of Torino, Torino (Italy); Botto, Barbara [Hematology, Città della Salute e della Scienza, Torino (Italy); Gavarotti, Paolo [Hematology, University of Torino and Città della Salute e della Scienza, Torino (Italy); Merli, Francesco [Hematology Unit, ASMN Hospital IRCCS, Reggio Emilia (Italy); Vitolo, Umberto [Hematology, Città della Salute e della Scienza, Torino (Italy); Iotti, Cinzia [Radiation Therapy Unit, Department of Oncology and Advanced Technology, ASMN Hospital IRCCS, Reggio Emilia (Italy); Ricardi, Umberto [Department of Oncology, University of Torino, Torino (Italy)

    2014-06-01

    Purpose: Image-guided intensity modulated radiation therapy (IG-IMRT) allows for margin reduction and highly conformal dose distribution, with consistent advantages in sparing of normal tissues. The purpose of this retrospective study was to compare involved-site IG-IMRT with involved-site 3D conformal RT (3D-CRT) in the treatment of early stage Hodgkin lymphoma (HL) involving the mediastinum, with efficacy and toxicity as primary clinical endpoints. Methods and Materials: We analyzed 90 stage IIA HL patients treated with either involved-site 3D-CRT or IG-IMRT between 2005 and 2012 in 2 different institutions. Inclusion criteria were favorable or unfavorable disease (according to European Organization for Research and Treatment of Cancer criteria), complete response after 3 to 4 cycles of an adriamycin- bleomycin-vinblastine-dacarbazine (ABVD) regimen plus 30 Gy as total radiation dose. Exclusion criteria were chemotherapy other than ABVD, partial response after ABVD, total radiation dose other than 30 Gy. Clinical endpoints were relapse-free survival (RFS) and acute toxicity. Results: Forty-nine patients were treated with 3D-CRT (54.4%) and 41 with IG-IMRT (45.6%). Median follow-up time was 54.2 months for 3D-CRT and 24.1 months for IG-IMRT. No differences in RFS were observed between the 2 groups, with 1 relapse each. Three-year RFS was 98.7% for 3D-CRT and 100% for IG-IMRT. Grade 2 toxicity events, mainly mucositis, were recorded in 32.7% of 3D-CRT patients (16 of 49) and in 9.8% of IG-IMRT patients (4 of 41). IG-IMRT was significantly associated with a lower incidence of grade 2 acute toxicity (P=.043). Conclusions: RFS rates at 3 years were extremely high in both groups, albeit the median follow-up time is different. Acute tolerance profiles were better for IG-IMRT than for 3D-CRT. Our preliminary results support the clinical safety and efficacy of advanced RT planning and delivery techniques in patients affected with early stage HL, achieving complete

  5. Treatment Planning Study to Determine Potential Benefit of Intensity-Modulated Radiotherapy Versus Conformal Radiotherapy for Unresectable Hepatic Malignancies

    International Nuclear Information System (INIS)

    Eccles, Cynthia L.; Bissonnette, Jean-Pierre; Craig, Tim; Taremi, Mojgan; Wu Xia; Dawson, Laura A.

    2008-01-01

    Purpose: To compare intensity-modulated radiotherapy (IMRT) with conformal RT (CRT) for hypofractionated isotoxicity liver RT and explore dose escalation using IMRT for the same/improved nominal risk of liver toxicity in a treatment planning study. Methods and Materials: A total of 26 CRT plans were evaluated. Prescription doses (24-54 Gy within six fractions) were individualized on the basis of the effective liver volume irradiated maintaining ≤5% risk of radiation-induced liver disease. The dose constraints included bowel (0.5 cm 3 ) and stomach (0.5 cm 3 ) to ≤30 Gy, spinal cord to ≤25 Gy, and planning target volume (PTV) to ≤140% of the prescribed dose. Two groups were evaluated: (1) PTV overlapping or directly adjacent to serial functioning normal tissues (n = 14), and (2) the liver as the dose-limiting normal tissue (n = 12). IMRT plans using direct machine parameter optimization maintained the CRT plan beam arrangements, an estimated radiation-induced liver disease risk of 5%, and underwent dose escalation, if all normal tissue constraints were maintained. Results: IMRT improved PTV coverage in 19 of 26 plans (73%). Dose escalation was feasible in 9 cases by an average of 3.8 Gy (range, 0.6-13.2) in six fractions. Three of seven plans without improved PTV coverage had small gross tumor volumes (≤105 cm 3 ) already receiving 54 Gy, the maximal prescription dose allowed. In the remaining cases, the PTV range was 9.6-689 cm 3 ; two had overlapped organs at risk; and one had four targets. IMRT did not improve these plans owing to poor target coverage (n = 2) and nonliver (n = 2) dose limits. Conclusion: Direct machine parameter optimization IMRT improved PTV coverage while maintaining normal tissue tolerances in most CRT liver plans. Dose escalation was possible in a minority of patients

  6. Cost-Effectiveness Analysis of Intensity Modulated Radiation Therapy Versus 3-Dimensional Conformal Radiation Therapy for Anal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Hodges, Joseph C., E-mail: joseph.hodges@utsouthwestern.edu [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Beg, Muhammad S. [Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Das, Prajnan [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Meyer, Jeffrey [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States)

    2014-07-15

    Purpose: To compare the cost-effectiveness of intensity modulated radiation therapy (IMRT) and 3-dimensional conformal radiation therapy (3D-CRT) for anal cancer and determine disease, patient, and treatment parameters that influence the result. Methods and Materials: A Markov decision model was designed with the various disease states for the base case of a 65-year-old patient with anal cancer treated with either IMRT or 3D-CRT and concurrent chemotherapy. Health states accounting for rates of local failure, colostomy failure, treatment breaks, patient prognosis, acute and late toxicities, and the utility of toxicities were informed by existing literature and analyzed with deterministic and probabilistic sensitivity analysis. Results: In the base case, mean costs and quality-adjusted life expectancy in years (QALY) for IMRT and 3D-CRT were $32,291 (4.81) and $28,444 (4.78), respectively, resulting in an incremental cost-effectiveness ratio of $128,233/QALY for IMRT compared with 3D-CRT. Probabilistic sensitivity analysis found that IMRT was cost-effective in 22%, 47%, and 65% of iterations at willingness-to-pay thresholds of $50,000, $100,000, and $150,000 per QALY, respectively. Conclusions: In our base model, IMRT was a cost-ineffective strategy despite the reduced acute treatment toxicities and their associated costs of management. The model outcome was sensitive to variations in local and colostomy failure rates, as well as patient-reported utilities relating to acute toxicities.

  7. Effects of three-dimensional conformal radiotherapy, indensity modulated radiotherapy, and conventional radiotherapy ON treatment of esophageal cancer

    Directory of Open Access Journals (Sweden)

    Jian-Jun Han

    2016-07-01

    Full Text Available Objective: To compare the irradiation volume, short-term and long-term efficacy of conventional radiotherapy (CR, three-dimensional conformal radiotherapy (3D-CRT, and indensity modulated radiotherapy (IMRT in the treatment of esophageal cancer. Methods: A retrospective analysis method was adopted. The patients were divided into CR group (n=42, 3D-CRT group (n=45, and IMRT group (n=40. A follow-up visit was paid to collect the short-term and long-term efficacy, and the occurrence of adverse reactions. The gross tumor voluem (GTV, clinical target volume (CTV, planning target volume (PTV, and irradiation volume of organs (bilateral lungs, spinal cord, and heart at risk (OAR in the three groups were compared. Results: It was found by target volume comparison that the mean values of GTV, CTV, and PTV in the three groups were significantly increased (P0.05. The occurrence rate of adverse reactions in 3D-CRT group and IMRT group was significantly lower than that in CR group (P0.05. The difference of 1-year survival rate among the three groups was not statistically significant (P=0.144, but 3-year and 5-year survival rates in 3D-CRT group and IMRT group were significantly higher than those in CR group (P<0.05. Conclusions: 3D-CRT and IMRT can significantly enhance the short-term and long-term efficacy for esophageal cancer patients, and alleviate the radioactive damage; therefore, they are deserved to be widely recommended in the clinic.

  8. Comparison of intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy as adjuvant therapy for gastric cancer.

    Science.gov (United States)

    Minn, A Yuriko; Hsu, Annie; La, Trang; Kunz, Pamela; Fisher, George A; Ford, James M; Norton, Jeffrey A; Visser, Brendan; Goodman, Karyn A; Koong, Albert C; Chang, Daniel T

    2010-08-15

    The current study was performed to compare the clinical outcomes and toxicity in patients treated with postoperative chemoradiotherapy for gastric cancer using intensity-modulated radiotherapy (IMRT) versus 3-dimensional conformal radiotherapy (3D CRT). Fifty-seven patients with gastric or gastroesophageal junction cancer were treated postoperatively: 26 with 3D CRT and 31 with IMRT. Concurrent chemotherapy was capecitabine (n=31), 5-fluorouracil (5-FU) (n=25), or none (n=1). The median radiation dose was 45 Gy. Dose volume histogram parameters for kidney and liver were compared between treatment groups. The 2-year overall survival rates for 3D CRT versus IMRT were 51% and 65%, respectively (P=.5). Four locoregional failures occurred each in the 3D CRT (15%) and the IMRT (13%) patients. Grade>or=2 acute gastrointestinal toxicity was found to be similar between the 3D CRT and IMRT patients (61.5% vs 61.2%, respectively) but more treatment breaks were needed (3 vs 0, respectively). The median serum creatinine from before radiotherapy to most recent creatinine was unchanged in the IMRT group (0.80 mg/dL) but increased in the 3D CRT group from 0.80 mg/dL to 1.0 mg/dL (P=.02). The median kidney mean dose was higher in the IMRT versus the 3D CRT group (13.9 Gy vs 11.1 Gy; P=.05). The median kidney V20 was lower for the IMRT versus the 3D CRT group (17.5% vs 22%; P=.17). The median liver mean dose for IMRT and 3D CRT was 13.6 Gy and 18.6 Gy, respectively (P=.19). The median liver V30 was 16.1% and 28%, respectively (PCancer Society.

  9. Comparison of conformal and intensity modulated radiation therapy techniques for treatment of pelvic tumors. Analysis of acute toxicity

    International Nuclear Information System (INIS)

    Ferrigno, Robson; Santos, Adriana; Martins, Lidiane C; Weltman, Eduardo; Chen, Michael J; Sakuraba, Roberto; Lopes, Cleverson P; Cruz, José C

    2010-01-01

    This retrospective analysis reports on the comparative outcome of acute gastrointestinal (GI) and genitourinary (GU) toxicities between conformal radiation therapy (CRT) and intensity modulated radiation therapy (IMRT) techniques in the treatment of patients with pelvic tumors. From January 2002 to December 2008, 69 patients with pelvic tumors underwent whole pelvic CRT and 65 underwent whole pelvic IMRT to treat pelvic lymph nodes and primary tumor regions. Total dose to the whole pelvis ranged from 50 to 50.4 Gy in 25 to 28 daily fractions. Chemotherapy (CT) regimen, when employed, was based upon primary tumor. Acute GI and GU toxicities were graded by RTOG/EORTC acute radiation morbidity criteria. Absence of GI symptoms during radiotherapy (grade 0) was more frequently observed in the IMRT group (43.1% versus 8.7; p < 0.001) and medication for diarrhea (Grade 2) was more frequently used in the CRT group (65.2% versus 38.5%; p = 0.002). Acute GI grade 1 and 3 side effects incidence was similar in both groups (18.5% versus 18.8%; p = 0.95 and 0% versus 7.2%; p = 0.058, respectively). Incidence of GU toxicity was similar in both groups (grade 0: 61.5% versus 66.6%, p = 0.54; grade 1: 20% versus 8.7%, p = 0.06; grade 2: 18.5% versus 23.5%, p = 0.50 and grade 3: 0% versus 1.5%, p > 0.99). This comparative case series shows less grade 2 acute GI toxicity in patients treated with whole pelvic IMRT in comparison with those treated with CRT. Incidence of acute GU toxicity was similar in both groups

  10. Cost-Effectiveness Analysis of Intensity Modulated Radiation Therapy Versus 3-Dimensional Conformal Radiation Therapy for Anal Cancer

    International Nuclear Information System (INIS)

    Hodges, Joseph C.; Beg, Muhammad S.; Das, Prajnan; Meyer, Jeffrey

    2014-01-01

    Purpose: To compare the cost-effectiveness of intensity modulated radiation therapy (IMRT) and 3-dimensional conformal radiation therapy (3D-CRT) for anal cancer and determine disease, patient, and treatment parameters that influence the result. Methods and Materials: A Markov decision model was designed with the various disease states for the base case of a 65-year-old patient with anal cancer treated with either IMRT or 3D-CRT and concurrent chemotherapy. Health states accounting for rates of local failure, colostomy failure, treatment breaks, patient prognosis, acute and late toxicities, and the utility of toxicities were informed by existing literature and analyzed with deterministic and probabilistic sensitivity analysis. Results: In the base case, mean costs and quality-adjusted life expectancy in years (QALY) for IMRT and 3D-CRT were $32,291 (4.81) and $28,444 (4.78), respectively, resulting in an incremental cost-effectiveness ratio of $128,233/QALY for IMRT compared with 3D-CRT. Probabilistic sensitivity analysis found that IMRT was cost-effective in 22%, 47%, and 65% of iterations at willingness-to-pay thresholds of $50,000, $100,000, and $150,000 per QALY, respectively. Conclusions: In our base model, IMRT was a cost-ineffective strategy despite the reduced acute treatment toxicities and their associated costs of management. The model outcome was sensitive to variations in local and colostomy failure rates, as well as patient-reported utilities relating to acute toxicities

  11. Outcome of three-dimensional conformal radiation therapy and intensity-modulated radiation therapy for inoperable locally advanced pancreatic cancer

    International Nuclear Information System (INIS)

    Lu Ningning; Jin Jing; Li Yexiong; Yu Zihao; Liu Xinfan; Wang Weihu; Wang Shulian; Song Yongwen; Liu Yuping

    2009-01-01

    Objective: To evaluate the outcome of radiotherapy for locally advanced pancreatic cancer. Methods: From January 2000 to December 2007, 41 patients with inoperable locally advanced (stage III) pancreatic cancer were treated with three-dimensional conformal radiation therapy(3DCRT) or intensity-modulated radiation therapy (IMRT). Among these patients, 30 received concurrent radio-chemo-therapy. Results: The median survival time(MST) and 1-year overall survival were 9.2 months and 23%. Patients with pretreatment KPS ≥ 80, no regional lymph nodes metastasis, and CR/PR after radiotherapy had better prognosis. The corresponding MSTs were 11.1 months vs 5.8 months (χ 2 =7.50, P=0.006), 10.8 months vs 6.5 months(χ 2 =5.67, P=0.017), and 19.5 months vs 9.1 months (χ 2 =7.28, P=0.007), respectively. Concurrent radio-chemotherapy tended to improve the overall survival(χ 2 =3.25, P=0.072). After radiotherapy, 18 patients had clinical benefit response, mainly being abdominal pain relief. Neither grade 4 hematologic nor grade 3 non-hematologic toxicities were observed. Conclusions: For patients with locally advanced pancreatic cancer, both 3DCRT and IMRT are effective in alleviation of disease-related symptoms. Patients with better performance status before treatment, no regional lymph nodes metastasis, and better response to radiotherapy may have better prognosis. Concurrent radio-chemotherapy trend to improve overall survival when compared with radiotherapy alone. (authors)

  12. Comparison of acute and subacute genitourinary and gastrointestinal adverse events of radiotherapy for prostate cancer using intensity-modulated radiation therapy, three-dimensional conformal radiation therapy, permanent implant brachytherapy and high-dose-rate brachytherapy

    NARCIS (Netherlands)

    Morimoto, Masahiro; Yoshioka, Yasuo; Konishi, Koji; Isohashi, Fumiaki; Takahashi, Yutaka; Ogata, Toshiyuki; Koizumi, Masahiko; Teshima, Teruki; Bijl, Henk P; van der Schaaf, Arjen; Langendijk, Johannes A; Ogawa, Kazuhiko

    2014-01-01

    AIMS AND BACKGROUND: To examine acute and subacute urinary and rectal toxicity in patients with localized prostate cancer monotherapeutically treated with the following four radiotherapeutic techniques: intensity-modulated radiation therapy, three-dimensional conformal radiation therapy,

  13. Intensity modulated radiotherapy in early stage Hodgkin lymphoma patients: Is it better than three dimensional conformal radiotherapy?

    International Nuclear Information System (INIS)

    De Sanctis, Vitaliana; Chiacchiararelli, Laura; Enrici, Riccardo Maurizi; Bolzan, Chiara; D’Arienzo, Marco; Bracci, Stefano; Fanelli, Alessandro; Cox, Maria Christina; Valeriani, Maurizio; Osti, Mattia F; Minniti, Giuseppe

    2012-01-01

    Cure rate of early Hodgkin Lymphoma are high and avoidance of late toxicities is of paramount importance. This comparative study aims to assess the normal tissue sparing capability of intensity-modulated radiation therapy (IMRT) versus standard three-dimensional conformal radiotherapy (3D-CRT) in terms of dose-volume parameters and normal tissue complication probability (NTCP) for different organs at risk in supradiaphragmatic Hodgkin Lymphoma (HL) patients. Ten HL patients were actually treated with 3D-CRT and all treatments were then re-planned with IMRT. Dose-volume parameters for thyroid, oesophagus, heart, coronary arteries, lung, spinal cord and breast were evaluated. Dose-volume histograms generated by TPS were analyzed to predict the NTCP for the considered organs at risk, according to different endpoints. Regarding dose-volume parameters no statistically significant differences were recorded for heart and origin of coronary arteries. We recorded statistically significant lower V30 with IMRT for oesophagus (6.42 vs 0.33, p = 0.02) and lungs (4.7 vs 0.1 p = 0.014 for the left lung and 2.59 vs 0.1 p = 0.017 for the right lung) and lower V20 for spinal cord (17.8 vs 7.2 p = 0.02). Moreover the maximum dose to the spinal cord was lower with IMRT (30.2 vs 19.9, p <0.001). Higher V10 with IMRT for thyroid (64.8 vs 95, p = 0.0019) and V5 for lungs (30.3 vs 44.8, p = 0.03, for right lung and 28.9 vs 48.1, p = 0.001 for left lung) were found, respectively. Higher V5 and V10 for breasts were found with IMRT (V5: 4.14 vs 20.6, p = 0.018 for left breast and 3.3 vs 17, p = 0.059 for right breast; V10: 2.5 vs 13.6 p = 0.035 for left breast and 1.7 vs 11, p = 0.07 for the right breast.) As for the NTCP, our data point out that IMRT is not always likely to significantly increase the NTCP to OARs. In HL male patients IMRT seems feasible and accurate while for women HL patients IMRT should be used with caution

  14. A comparative dosimetric study of conventional, conformal and intensity-modulated radiotherapy in postoperative pelvic irradiation of cervical cancer

    International Nuclear Information System (INIS)

    Li Bin; An Jusheng; Wu Lingying; Huang Manni; Gao Juzhen; Xu Yingjie; Dai Jianrong

    2008-01-01

    Objective: To evaluate target-volume coverage and organ at risk (OAR) protection achieved with conventional radiotherapy (CRT), three dimensional conformal radiotherapy (3DCRT), and intensity-modulated radiotherapy(IMRT) through dosimetric comparison in patients with cervical cancer after hysterectomy. Methods: The planning CT scans of 10 patients treated with pelvic radiation after hysterectomy for cervical cancer were used to generate CRT, 3DCRT and IMRT plans for this study. Clinical target volume(CTV) was contoured on the individual axial CT slices of every patient. The CTV was then uniformly expanded by 1.0 cm to create the planning target volume (PTV). The small bowel, rectum, bladder, bone marrow, ovaries, and femoral heads were outlined for the organ at risk (OAR) evaluation. The CRT, 3DCRT and IMRT plans were generated using commercial planning software. CRT plan was prescribed to deliver 45 Gy to the reference point, while IMRT and 3DCRT plans were 45 Gy to 95% of the PTV. Isodose line and dose volume histograms(DVH) were used to evaluate the dose distribution in CTV and OAR. Results: For 10 patients, the average volume of CTV receiving the prescribed dose of CRT was significantly lower than 3DCRT(Q=8.27, P<0.01) and IMRT(Q=8.37, P<0.01), respectively. Comparing with the CRT plan, the 3DCRT and IMRT plans notably reduced the volume of bowel at 30 and 45 Gy levels. The IMRT plan significantly spared rectum and bladder at 30 and 45 Gy levels comparing with the CRT (P<0.01) and 3DCRT(P<0.05) plans, while the 3DCRT plan significantly spared rectum and bladder at 45 Gy level comparing with the CRT(P<0.01) plans. For 4 patients with ovarian transposition, the average doses of ovary over 3 Gy were 2 patients with the 3 DCRT and IMRT plans, and 2 with all three plans. Conclusions: IMRT and 3DCRT are superior to CRT in improving dose coverage of target volume and sparing of OAR, while IMRT being the best. The superiority of IMRT and 3DCRT is obvious in sparing

  15. pH-induced conformational change of IscU at low pH correlates with protonation/deprotonation of two conserved histidine residues.

    Science.gov (United States)

    Dai, Ziqi; Kim, Jin Hae; Tonelli, Marco; Ali, Ibrahim K; Markley, John L

    2014-08-19

    IscU, the scaffold protein for the major iron-sulfur cluster biosynthesis pathway in microorganisms and mitochondria (ISC pathway), plays important roles in the formation of [2Fe-2S] and [4Fe-4S] clusters and their delivery to acceptor apo-proteins. Our laboratory has shown that IscU populates two distinct, functionally relevant conformational states, a more structured state (S) and a more dynamic state (D), that differ by cis/trans isomerizations about two peptidyl-prolyl peptide bonds [Kim, J. H., Tonelli, M., and Markley, J. L. (2012) Proc. Natl. Acad. Sci. U.S.A., 109, 454-459. Dai Z., Tonelli, M., and Markley, J. L. (2012) Biochemistry, 51, 9595-9602. Cai, K., Frederick, R. O., Kim, J. H., Reinen, N. M., Tonelli, M., and Markley, J. L. (2013) J. Biol. Chem., 288, 28755-28770]. Here, we report our findings on the pH dependence of the D ⇄ S equilibrium for Escherichia coli IscU in which the D-state is stabilized at low and high pH values. We show that the lower limb of the pH dependence curve results from differences in the pKa values of two conserved histidine residues (His10 and His105) in the two states. The net proton affinity of His10 is about 50 times higher and that of His105 is 13 times higher in the D-state than in the S-state. The origin of the high limb of the D ⇄ S pH dependence remains to be determined. These results show that changes in proton inventory need to be taken into account in the steps in iron-sulfur cluster assembly and transfer that involve transitions of IscU between its S- and D-states.

  16. Intensity-modulated proton therapy, volumetric-modulated arc therapy, and 3D conformal radiotherapy in anaplastic astrocytoma and glioblastoma. A dosimetric comparison

    Energy Technology Data Exchange (ETDEWEB)

    Adeberg, S.; Debus, J. [Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg (Germany); Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg (Germany); University Hospital Heidelberg, Department of Radiation Oncology, Heidelberg (Germany); German Cancer Research Center (DKFZ), Clinical Cooperation Unit Radiation Oncology, Heidelberg (Germany); Harrabi, S.B.; Bougatf, N.; Rieber, J.; Koerber, S.A.; Herfarth, K.; Rieken, S. [Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg (Germany); Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg (Germany); University Hospital Heidelberg, Department of Radiation Oncology, Heidelberg (Germany); Bernhardt, D.; Syed, M.; Sprave, T.; Mohr, A. [Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg (Germany); University Hospital Heidelberg, Department of Radiation Oncology, Heidelberg (Germany); Abdollahi, A. [University Hospital Heidelberg, Department of Radiation Oncology, Heidelberg (Germany); Haberer, T. [Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg (Germany); Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg (Germany); Combs, S.E. [Technische Universitaet Muenchen, Department of Radiation Oncology, Muenchen (Germany); Helmholtz Zentrum Muenchen, Institut fuer Innovative Radiotherapie (iRT), Department of Radiation Sciences (DRS), Neuherberg (Germany)

    2016-11-15

    The prognosis for high-grade glioma (HGG) patients is poor; thus, treatment-related side effects need to be minimized to conserve quality of life and functionality. Advanced techniques such as proton radiation therapy (PRT) and volumetric-modulated arc therapy (VMAT) may potentially further reduce the frequency and severity of radiogenic impairment. We retrospectively assessed 12 HGG patients who had undergone postoperative intensity-modulated proton therapy (IMPT). VMAT and 3D conformal radiotherapy (3D-CRT) plans were generated and optimized for comparison after contouring crucial neuronal structures important for neurogenesis and neurocognitive function. Integral dose (ID), homogeneity index (HI), and inhomogeneity coefficient (IC) were calculated from dose statistics. Toxicity data were evaluated. Target volume coverage was comparable for all three modalities. Compared to 3D-CRT and VMAT, PRT showed statistically significant reductions (p < 0.05) in mean dose to whole brain (-20.2 %, -22.7 %); supratentorial (-14.2 %, -20,8 %) and infratentorial (-91.0 %, -77.0 %) regions; brainstem (-67.6 %, -28.1 %); pituitary gland (-52.9 %, -52.5 %); contralateral hippocampus (-98.9 %, -98.7 %); and contralateral subventricular zone (-62.7 %, -66.7 %, respectively). Fatigue (91.7 %), radiation dermatitis (75.0 %), focal alopecia (100.0 %), nausea (41.7 %), cephalgia (58.3 %), and transient cerebral edema (16.7 %) were the most common acute toxicities. Essential dose reduction while maintaining equal target volume coverage was observed using PRT, particularly in contralaterally located critical neuronal structures, areas of neurogenesis, and structures of neurocognitive functions. These findings were supported by preliminary clinical results confirming the safety and feasibility of PRT in HGG. (orig.) [German] Die Prognose bei ''High-grade''-Gliomen (HGG) ist infaust. Gerade bei diesen Patienten sollten therapieassoziierte Nebenwirkungen minimiert werden

  17. Intensity-modulated radiotherapy (IMRT) and conventional three-dimensional conformal radiotherapy for high-grade gliomas: Does IMRT increase the integral dose to normal brain?

    International Nuclear Information System (INIS)

    Hermanto, Ulrich; Frija, Erik K.; Lii, MingFwu J.; Chang, Eric L.; Mahajan, Anita; Woo, Shiao Y.

    2007-01-01

    Purpose: To determine whether intensity-modulated radiotherapy (IMRT) treatment increases the total integral dose of nontarget tissue relative to the conventional three-dimensional conformal radiotherapy (3D-CRT) technique for high-grade gliomas. Methods and Materials: Twenty patients treated with 3D-CRT for glioblastoma multiforme were selected for a comparative dosimetric evaluation with IMRT. Original target volumes, organs at risk (OAR), and dose-volume constraints were used for replanning with IMRT. Predicted isodose distributions, cumulative dose-volume histograms of target volumes and OAR, normal tissue integral dose, target coverage, dose conformity, and normal tissue sparing with 3D-CRT and IMRT planning were compared. Statistical analyses were performed to determine differences. Results: In all 20 patients, IMRT maintained equivalent target coverage, improved target conformity (conformity index [CI] 95% 1.52 vs. 1.38, p mean by 19.8% and D max by 10.7%), optic chiasm (D mean by 25.3% and D max by 22.6%), right optic nerve (D mean by 37.3% and D max by 28.5%), and left optic nerve (D mean by 40.6% and D max by 36.7%), p ≤ 0.01. This was achieved without increasing the total nontarget integral dose by greater than 0.5%. Overall, total integral dose was reduced by 7-10% with IMRT, p < 0.001, without significantly increasing the 0.5-5 Gy low-dose volume. Conclusions: These results indicate that IMRT treatment for high-grade gliomas allows for improved target conformity, better critical tissue sparing, and importantly does so without increasing integral dose and the volume of normal tissue exposed to low doses of radiation

  18. Radiotherapy for Adult Medulloblastoma: Evaluation of Helical Tomotherapy, Volumetric Intensity Modulated Arc Therapy, and Three-Dimensional Conformal Radiotherapy and the Results of Helical Tomotherapy Therapy

    Directory of Open Access Journals (Sweden)

    Sun Zong-wen

    2018-01-01

    Full Text Available Introduction. All adult medulloblastoma (AMB patients should be treated with craniospinal irradiation (CSI postoperatively. Because of the long irradiation range, multiple radiation fields must be designed for conventional radiotherapy technology. CSI can be completed in only one session with helical tomotherapy (HT. We evaluated the dose of HT, volumetric intensity modulated arc therapy (VMAT, and three-dimensional conformal radiotherapy (3D-CRT of AMB and the results of 5 cases of AMB treated with HT. Methods. Complete craniospinal and posterior cranial fossa irradiation with HT, VMAT, and 3D-CRT and dose evaluation were performed. And results of 5 cases of AMB treated with HT were evaluated. Results. A large volume of tissue was exposed to low dose radiation in the organs at risk (OAR, while a small volume was exposed to high dose radiation with HT. The conformity and uniformity of the targets were good with HT and VMAT, and the volume of targets exposed to high dose with VMAT was larger than that of HT. The uniformity of 3D-CRT was also good, but the dose conformity was poor. The main toxicity was hematologic toxicity, without 4th-degree bone marrow suppression. There was 3rd-degree inhibition in the white blood cells, hemoglobin, and platelets. The three female patients suffered menstrual disorders during the course of radiation. Two female patients with heavy menstruation suffered 3rd-degree anemia inhibition, and 2 patients suffered amenorrhea after radiotherapy. Although menstrual cycle was normal, the third patient was not pregnant. Conclusion. CSI with HT is convenient for clinical practice, and the side effects are mild. With good conformity and uniformity, VMAT can also be used for selection in CSI. For poor conformity, 3D-CRT should not be the priority selection for CSI. In female patients, the ovaries should be protected.

  19. An investigation into the effects of residual water on the glass transition temperature of polylactide microspheres using modulated temperature DSC.

    Science.gov (United States)

    Passerini, N; Craig, D Q

    2001-05-18

    The objective of the study was to ascertain residual water levels in polylactide and polylactide-co-glycolide microspheres prepared using the solvent evaporation technique and to investigate the effects of that water on the glass transitional behaviour of the microspheres. Microspheres were prepared from polylactic acid (PLA) and polylactide-co-glycolide (PLGA) 50:50 and 75:25 using a standard solvent evaporation technique. The glass transition was measured as a function of drying conditions using modulated temperature DSC. The microspheres were found to contain very low levels of dichloromethane, while residual water levels of up to circa 3% w/w were noted after freeze or oven drying, these levels being higher for microspheres containing higher glycolic acid levels. The residual water was found to lower the T(g) following the Gordon-Taylor relationship. The data indicate that the microparticles may retain significant water levels following standard preparation and drying protocols and that this drying may markedly lower the T(g) of the spheres.

  20. Local Order in the Unfolded State: Conformational Biases and Nearest Neighbor Interactions

    Directory of Open Access Journals (Sweden)

    Siobhan Toal

    2014-07-01

    Full Text Available The discovery of Intrinsically Disordered Proteins, which contain significant levels of disorder yet perform complex biologically functions, as well as unwanted aggregation, has motivated numerous experimental and theoretical studies aimed at describing residue-level conformational ensembles. Multiple lines of evidence gathered over the last 15 years strongly suggest that amino acids residues display unique and restricted conformational preferences in the unfolded state of peptides and proteins, contrary to one of the basic assumptions of the canonical random coil model. To fully understand residue level order/disorder, however, one has to gain a quantitative, experimentally based picture of conformational distributions and to determine the physical basis underlying residue-level conformational biases. Here, we review the experimental, computational and bioinformatic evidence for conformational preferences of amino acid residues in (mostly short peptides that can be utilized as suitable model systems for unfolded states of peptides and proteins. In this context particular attention is paid to the alleged high polyproline II preference of alanine. We discuss how these conformational propensities may be modulated by peptide solvent interactions and so called nearest-neighbor interactions. The relevance of conformational propensities for the protein folding problem and the understanding of IDPs is briefly discussed.

  1. Radiobiologic comparison of helical tomotherapy, intensity modulated radiotherapy, and conformal radiotherapy in treating lung cancer accounting for secondary malignancy risks

    Energy Technology Data Exchange (ETDEWEB)

    Komisopoulos, Georgios [Department of Medical Physics, Medical School, University of Patras, Patras (Greece); Mavroidis, Panayiotis, E-mail: mavroidis@uthscsa.edu [Department of Radiation Oncology, University of Texas Health Sciences Center at San Antonio, San Antonio, TX (United States); Department of Medical Radiation Physics, Karolinska Institutet and Stockholm University, Stockholm (Sweden); Rodriguez, Salvador; Stathakis, Sotirios; Papanikolaou, Nikos [Department of Radiation Oncology, University of Texas Health Sciences Center at San Antonio, San Antonio, TX (United States); Nikiforidis, Georgios C.; Sakellaropoulos, Georgios C. [Department of Medical Physics, Medical School, University of Patras, Patras (Greece)

    2014-01-01

    The aim of the present study is to examine the importance of using measures to predict the risk of inducing secondary malignancies in association with the clinical effectiveness of treatment plans in terms of tumor control and normal tissue complication probabilities. This is achieved by using radiobiologic parameters and measures, which may provide a closer association between clinical outcome and treatment delivery. Overall, 4 patients having been treated for lung cancer were examined. For each of them, 3 treatment plans were developed based on the helical tomotherapy (HT), multileaf collimator-based intensity modulated radiation therapy (IMRT), and 3-dimensional conformal radiation therapy (CRT) modalities. The different plans were evaluated using the complication-free tumor control probability (p{sub +}), the overall probability of injury (p{sub I}), the overall probability of control/benefit (p{sub B}), and the biologically effective uniform dose (D{sup ¯¯}). These radiobiologic measures were used to develop dose-response curves (p-D{sup ¯¯} diagram), which can help to evaluate different treatment plans when used in conjunction with standard dosimetric criteria. The risks for secondary malignancies in the heart and the contralateral lung were calculated for the 3 radiation modalities based on the corresponding dose-volume histograms (DVHs) of each patient. Regarding the overall evaluation of the different radiation modalities based on the p{sub +} index, the average values of the HT, IMRT, and CRT are 67.3%, 61.2%, and 68.2%, respectively. The corresponding average values of p{sub B} are 75.6%, 70.5%, and 71.0%, respectively, whereas the average values of p{sub I} are 8.3%, 9.3%, and 2.8%, respectively. Among the organs at risk (OARs), lungs show the highest probabilities for complications, which are 7.1%, 8.0%, and 1.3% for the HT, IMRT, and CRT modalities, respectively. Similarly, the biologically effective prescription doses (D{sub B}{sup ¯¯}) for the

  2. Identification of key amino acid residues modulating intracellular and in vitro microcin E492 amyloid formation

    Directory of Open Access Journals (Sweden)

    Paulina eAguilera

    2016-01-01

    Full Text Available Microcin E492 (MccE492 is a pore-forming bacteriocin produced and exported by Klebsiella pneumoniae RYC492. Besides its antibacterial activity, excreted MccE492 can form amyloid fibrils in vivo as well as in vitro. It has been proposed that bacterial amyloids can be functional playing a biological role, and in the particular case of MccE492 it would control the antibacterial activity. MccE492 amyloid fibril’s morphology and formation kinetics in vitro have been well characterized, however it is not known which amino acid residues determine its amyloidogenic propensity, nor if it forms intracellular amyloid inclusions as has been reported for other bacterial amyloids. In this work we found the conditions in which MccE492 forms intracellular amyloids in E. coli cells, that were visualized as round-shaped inclusion bodies recognized by two amyloidophillic probes, 2-4´-methylaminophenyl benzothiazole and thioflavin-S. We used this property to perform a flow cytometry-based assay to evaluate the aggregation propensity of MccE492 mutants, that were designed using an in silico prediction of putative aggregation hotspots. We established that the predicted amino acid residues 54-63, effectively act as a pro-amyloidogenic stretch. As in the case of other amyloidogenic proteins, this region presented two gatekeeper residues (P57 and P59, which disfavor both intracellular and in vitro MccE492 amyloid formation, preventing an uncontrolled aggregation. Mutants in each of these gatekeeper residues showed faster in vitro aggregation and bactericidal inactivation kinetics, and the two mutants were accumulated as dense amyloid inclusions in more than 80% of E. coli cells expressing these variants. In contrast, the MccE492 mutant lacking residues 54-63 showed a significantly lower intracellular aggregation propensity and slower in vitro polymerization kinetics. Electron microscopy analysis of the amyloids formed in vitro by these mutants revealed that, although

  3. Construction of hevein (Hev b 6.02) with reduced allergenicity for immunotherapy of latex allergy by comutation of six amino acid residues on the conformational IgE epitopes.

    Science.gov (United States)

    Karisola, Piia; Mikkola, Jari; Kalkkinen, Nisse; Airenne, Kari J; Laitinen, Olli H; Repo, Susanna; Pentikäinen, Olli T; Reunala, Timo; Turjanmaa, Kristiina; Johnson, Mark S; Palosuo, Timo; Kulomaa, Markku S; Alenius, Harri

    2004-02-15

    Recently we have established that IgE Abs bind to conformational epitopes in the N- and C-terminal regions of the major natural rubber latex allergen, hevein (Hev b 6.02). To identify the critical amino acid residues that interact with IgE, the hevein sequence was scanned by using site-specific mutations. Twenty-nine hevein mutants were designed and produced by a baculovirus expression system in insect cells and tested by IgE inhibition-ELISA using sera from 26 latex allergic patients. Six potential IgE-interacting residues of hevein (Arg(5), Lys(10), Glu(29), Tyr(30), His(35), and Gln(38)) were identified and characterized further in detail. Based on these six residues, two triple mutants (Hdelta3A, Hdelta3B) and hevein mutant where all six residues were mutated (Hdelta6), were designed, modeled, and produced. Structural and functional properties of these combinatory mutants were compared experimentally and in silico with those of recombinant hevein. The IgE-binding affinity of the mutants decreased by three to five orders of magnitude as compared with that of recombinant hevein. Skin prick test reactivity of the triple mutant HDelta3A was drastically reduced and that of the six-residue mutant Hdelta6 was completely abolished in all patients examined in this study. The approach presented in this paper offers tools for identification and modification of amino acid residues on conformational epitopes of allergens that interact with IgE. Hevein with a highly reduced ability to bind IgE should provide a valuable candidate molecule for immunotherapy of latex allergy and is anticipated to have a low risk of systemic side effects.

  4. Modulating Transmembrane α-Helix Interactions through pH-Sensitive Boundary Residues.

    Science.gov (United States)

    Ng, Derek P; Deber, Charles M

    2016-08-09

    Changes in pH can alter the structure and activity of proteins and may be used by the cell to control molecular function. This coupling can also be used in non-native applications through the design of pH-sensitive biomolecules. For example, the pH (low) insertion peptide (pHLIP) can spontaneously insert into a lipid bilayer when the pH decreases. We have previously shown that the α-helicity and helix-helix interactions of the TM2 α-helix of the proteolipid protein (PLP) are sensitive to the local hydrophobicity at its C-terminus. Given that there is an ionizable residue (Glu-88) at the C-terminus of this transmembrane (TM) segment, we hypothesized that changing the ionization state of this residue through pH may alter the local hydrophobicity of the peptide enough to affect both its secondary structure and helix-helix interactions. To examine this phenomenon, we synthesized peptide analogues of the PLP TM2 α-helix (wild-type sequence (66)AFQYVIYGTASFFFLYGALLLAEGF(90)). Using circular dichroism and Förster resonance energy transfer in the membrane-mimetic detergent sodium dodecyl sulfate, we found that a decrease in pH increases both peptide α-helicity and the extent of self-association. This pH-dependent effect is due specifically to the presence of Glu-88 at the C-terminus. Additional experiments in which Phe-90 was mutated to residues of varying hydrophobicities indicated that the strength of this effect is dependent on the local hydrophobicity near Glu-88. Our results have implications for the design of TM peptide switches and improve our understanding of how membrane protein structure and activity can be regulated through local molecular environmental changes.

  5. Comparison of Heart and Coronary Artery Doses Associated With Intensity-Modulated Radiotherapy Versus Three-Dimensional Conformal Radiotherapy for Distal Esophageal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kole, Thomas P.; Aghayere, Osarhieme; Kwah, Jason [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Yorke, Ellen D. [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Goodman, Karyn A., E-mail: goodmank@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY (United States)

    2012-08-01

    Purpose: To compare heart and coronary artery radiation exposure using intensity-modulated radiotherapy (IMRT) vs. four-field three-dimensional conformal radiotherapy (3D-CRT) treatment plans for patients with distal esophageal cancer undergoing chemoradiation. Methods and Materials: Nineteen patients with distal esophageal cancers treated with IMRT from March 2007 to May 2008 were identified. All patients were treated to 50.4 Gy with five-field IMRT plans. Theoretical 3D-CRT plans with four-field beam arrangements were generated. Dose-volume histograms of the planning target volume, heart, right coronary artery, left coronary artery, and other critical normal tissues were compared between the IMRT and 3D-CRT plans, and selected parameters were statistically evaluated using the Wilcoxon rank-sum test. Results: Intensity-modulated radiotherapy treatment planning showed significant reduction (p < 0.05) in heart dose over 3D-CRT as assessed by average mean dose (22.9 vs. 28.2 Gy) and V30 (24.8% vs. 61.0%). There was also significant sparing of the right coronary artery (average mean dose, 23.8 Gy vs. 35.5 Gy), whereas the left coronary artery showed no significant improvement (mean dose, 11.2 Gy vs. 9.2 Gy), p = 0.11. There was no significant difference in percentage of total lung volume receiving at least 10, 15, or 20 Gy or in the mean lung dose between the planning methods. There were also no significant differences observed for the kidneys, liver, stomach, or spinal cord. Intensity-modulated radiotherapy achieved a significant improvement in target conformity as measured by the conformality index (ratio of total volume receiving 95% of prescription dose to planning target volume receiving 95% of prescription dose), with the mean conformality index reduced from 1.56 to 1.30 using IMRT. Conclusions: Treatment of patients with distal esophageal cancer using IMRT significantly decreases the exposure of the heart and right coronary artery when compared with 3D

  6. Nasopharynx carcinoma treatment: from the conventional radiotherapy to the conformal radiotherapy with intensity modulation; Traitement du carcinome du nasopharynx: de la radiotherapie conventionnelle a la radiotherapie conformationnelle avec modulation d'intensite

    Energy Technology Data Exchange (ETDEWEB)

    Mokaouim, K.; Grehange, G.; Truc, G.; Peingnaux, K.; Martin, E.; Zanetta, S.; Bruchon, Y.; Bonnetain, F.; Maingon, P. [Centre Georges-Francois Leclerc, 21 - Dijon (France)

    2009-10-15

    The objective of this study was to evaluate retrospectively the impact of factors linked to the radiotherapy realisation on the local and locoregional control, the global survival, the survival without disease of patients suffering of naso-pharynx carcinoma. Conclusion: the patients suffering of a nasopharynx carcinoma treated by irradiation associated to chemotherapy have an improved global survival and an improved survival without disease. The conformal radiotherapy with or without modulated intensity reduce the risk of serous otitis, trismus and xerostomia at long term. It seems necessary to realize multi centric studies with a longer period of follow up before asserting the advantages of the I.M.R.T. in comparison to the classical and conformal technique in the treatment of naso-pharynx carcinomas. (N.C.)

  7. External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor

    Science.gov (United States)

    Kazmierczak, Marcin; Zhang, Xiaofei; Chen, Bihan; Mulkey, Daniel K.; Shi, Yingtang; Wagner, Paul G.; Pivaroff-Ward, Kendra; Sassic, Jessica K.; Bayliss, Douglas A.

    2013-01-01

    The Ether-a-go-go (EAG) superfamily of voltage-gated K+ channels consists of three functionally distinct gene families (Eag, Elk, and Erg) encoding a diverse set of low-threshold K+ currents that regulate excitability in neurons and muscle. Previous studies indicate that external acidification inhibits activation of three EAG superfamily K+ channels, Kv10.1 (Eag1), Kv11.1 (Erg1), and Kv12.1 (Elk1). We show here that Kv10.2, Kv12.2, and Kv12.3 are similarly inhibited by external protons, suggesting that high sensitivity to physiological pH changes is a general property of EAG superfamily channels. External acidification depolarizes the conductance–voltage (GV) curves of these channels, reducing low threshold activation. We explored the mechanism of this high pH sensitivity in Kv12.1, Kv10.2, and Kv11.1. We first examined the role of acidic voltage sensor residues that mediate divalent cation block of voltage activation in EAG superfamily channels because protons reduce the sensitivity of Kv12.1 to Zn2+. Low pH similarly reduces Mg2+ sensitivity of Kv10.1, and we found that the pH sensitivity of Kv11.1 was greatly attenuated at 1 mM Ca2+. Individual neutralizations of a pair of EAG-specific acidic residues that have previously been implicated in divalent block of diverse EAG superfamily channels greatly reduced the pH response in Kv12.1, Kv10.2, and Kv11.1. Our results therefore suggest a common mechanism for pH-sensitive voltage activation in EAG superfamily channels. The EAG-specific acidic residues may form the proton-binding site or alternatively are required to hold the voltage sensor in a pH-sensitive conformation. The high pH sensitivity of EAG superfamily channels suggests that they could contribute to pH-sensitive K+ currents observed in vivo. PMID:23712551

  8. External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor.

    Science.gov (United States)

    Kazmierczak, Marcin; Zhang, Xiaofei; Chen, Bihan; Mulkey, Daniel K; Shi, Yingtang; Wagner, Paul G; Pivaroff-Ward, Kendra; Sassic, Jessica K; Bayliss, Douglas A; Jegla, Timothy

    2013-06-01

    The Ether-a-go-go (EAG) superfamily of voltage-gated K(+) channels consists of three functionally distinct gene families (Eag, Elk, and Erg) encoding a diverse set of low-threshold K(+) currents that regulate excitability in neurons and muscle. Previous studies indicate that external acidification inhibits activation of three EAG superfamily K(+) channels, Kv10.1 (Eag1), Kv11.1 (Erg1), and Kv12.1 (Elk1). We show here that Kv10.2, Kv12.2, and Kv12.3 are similarly inhibited by external protons, suggesting that high sensitivity to physiological pH changes is a general property of EAG superfamily channels. External acidification depolarizes the conductance-voltage (GV) curves of these channels, reducing low threshold activation. We explored the mechanism of this high pH sensitivity in Kv12.1, Kv10.2, and Kv11.1. We first examined the role of acidic voltage sensor residues that mediate divalent cation block of voltage activation in EAG superfamily channels because protons reduce the sensitivity of Kv12.1 to Zn(2+). Low pH similarly reduces Mg(2+) sensitivity of Kv10.1, and we found that the pH sensitivity of Kv11.1 was greatly attenuated at 1 mM Ca(2+). Individual neutralizations of a pair of EAG-specific acidic residues that have previously been implicated in divalent block of diverse EAG superfamily channels greatly reduced the pH response in Kv12.1, Kv10.2, and Kv11.1. Our results therefore suggest a common mechanism for pH-sensitive voltage activation in EAG superfamily channels. The EAG-specific acidic residues may form the proton-binding site or alternatively are required to hold the voltage sensor in a pH-sensitive conformation. The high pH sensitivity of EAG superfamily channels suggests that they could contribute to pH-sensitive K(+) currents observed in vivo.

  9. A comprehensive dosimetric study of pancreatic cancer treatment using three-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), volumetric-modulated radiation therapy (VMAT), and passive-scattering and modulated-scanning proton therapy (PT)

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Xuanfeng; Dionisi, Francesco; Tang, Shikui; Ingram, Mark; Hung, Chun-Yu; Prionas, Evangelos; Lichtenwalner, Phil; Butterwick, Ian; Zhai, Huifang; Yin, Lingshu; Lin, Haibo; Kassaee, Alireza; Avery, Stephen, E-mail: stephen.avery@uphs.upenn.edu

    2014-07-01

    With traditional photon therapy to treat large postoperative pancreatic target volume, it often leads to poor tolerance of the therapy delivered and may contribute to interrupted treatment course. This study was performed to evaluate the potential advantage of using passive-scattering (PS) and modulated-scanning (MS) proton therapy (PT) to reduce normal tissue exposure in postoperative pancreatic cancer treatment. A total of 11 patients with postoperative pancreatic cancer who had been previously treated with PS PT in University of Pennsylvania Roberts Proton Therapy Center from 2010 to 2013 were identified. The clinical target volume (CTV) includes the pancreatic tumor bed as well as the adjacent high-risk nodal areas. Internal (iCTV) was generated from 4-dimensional (4D) computed tomography (CT), taking into account target motion from breathing cycle. Three-field and 4-field 3D conformal radiation therapy (3DCRT), 5-field intensity-modulated radiation therapy, 2-arc volumetric-modulated radiation therapy, and 2-field PS and MS PT were created on the patients’ average CT. All the plans delivered 50.4 Gy to the planning target volume (PTV). Overall, 98% of PTV was covered by 95% of the prescription dose and 99% of iCTV received 98% prescription dose. The results show that all the proton plans offer significant lower doses to the left kidney (mean and V{sub 18} {sub Gy}), stomach (mean and V{sub 20} {sub Gy}), and cord (maximum dose) compared with all the photon plans, except 3-field 3DCRT in cord maximum dose. In addition, MS PT also provides lower doses to the right kidney (mean and V{sub 18} {sub Gy}), liver (mean dose), total bowel (V{sub 20} {sub Gy} and mean dose), and small bowel (V{sub 15} {sub Gy} absolute volume ratio) compared with all the photon plans and PS PT. The dosimetric advantage of PT points to the possibility of treating tumor bed and comprehensive nodal areas while providing a more tolerable treatment course that could be used for dose

  10. A comprehensive dosimetric study of pancreatic cancer treatment using three-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), volumetric-modulated radiation therapy (VMAT), and passive-scattering and modulated-scanning proton therapy (PT)

    International Nuclear Information System (INIS)

    Ding, Xuanfeng; Dionisi, Francesco; Tang, Shikui; Ingram, Mark; Hung, Chun-Yu; Prionas, Evangelos; Lichtenwalner, Phil; Butterwick, Ian; Zhai, Huifang; Yin, Lingshu; Lin, Haibo; Kassaee, Alireza; Avery, Stephen

    2014-01-01

    With traditional photon therapy to treat large postoperative pancreatic target volume, it often leads to poor tolerance of the therapy delivered and may contribute to interrupted treatment course. This study was performed to evaluate the potential advantage of using passive-scattering (PS) and modulated-scanning (MS) proton therapy (PT) to reduce normal tissue exposure in postoperative pancreatic cancer treatment. A total of 11 patients with postoperative pancreatic cancer who had been previously treated with PS PT in University of Pennsylvania Roberts Proton Therapy Center from 2010 to 2013 were identified. The clinical target volume (CTV) includes the pancreatic tumor bed as well as the adjacent high-risk nodal areas. Internal (iCTV) was generated from 4-dimensional (4D) computed tomography (CT), taking into account target motion from breathing cycle. Three-field and 4-field 3D conformal radiation therapy (3DCRT), 5-field intensity-modulated radiation therapy, 2-arc volumetric-modulated radiation therapy, and 2-field PS and MS PT were created on the patients’ average CT. All the plans delivered 50.4 Gy to the planning target volume (PTV). Overall, 98% of PTV was covered by 95% of the prescription dose and 99% of iCTV received 98% prescription dose. The results show that all the proton plans offer significant lower doses to the left kidney (mean and V 18 Gy ), stomach (mean and V 20 Gy ), and cord (maximum dose) compared with all the photon plans, except 3-field 3DCRT in cord maximum dose. In addition, MS PT also provides lower doses to the right kidney (mean and V 18 Gy ), liver (mean dose), total bowel (V 20 Gy and mean dose), and small bowel (V 15 Gy absolute volume ratio) compared with all the photon plans and PS PT. The dosimetric advantage of PT points to the possibility of treating tumor bed and comprehensive nodal areas while providing a more tolerable treatment course that could be used for dose escalation and combining with radiosensitizing

  11. Native Alanine Substitution in the Glycine Hinge Modulates Conformational Flexibility of Heme Nitric Oxide/Oxygen (H-NOX) Sensing Proteins.

    Science.gov (United States)

    Hespen, Charles W; Bruegger, Joel J; Guo, Yirui; Marletta, Michael A

    2018-06-15

    Heme nitric oxide/oxygen sensing (H-NOX) domains are direct NO sensors that regulate a variety of biological functions in both bacteria and eukaryotes. Previous work on H-NOX proteins has shown that upon NO binding, a conformational change occurs along two glycine residues on adjacent helices (termed the glycine hinge). Despite the apparent importance of the glycine hinge, it is not fully conserved in all H-NOX domains. Several H-NOX sensors from the family Flavobacteriaceae contain a native alanine substitution in one of the hinge residues. In this work, the effect of the increased steric bulk within the Ala-Gly hinge on H-NOX function was investigated. The hinge in Kordia algicida OT-1 ( Ka H-NOX) is composed of A71 and G145. Ligand-binding properties and signaling function for this H-NOX were characterized. The variant A71G was designed to convert the hinge region of Ka H-NOX to the typical Gly-Gly motif. In activity assays with its cognate histidine kinase (HnoK), the wild type displayed increased signal specificity compared to A71G. Increasing titrations of unliganded A71G gradually inhibits HnoK autophosphorylation, while increasing titrations of unliganded wild type H-NOX does not inhibit HnoK. Crystal structures of both wild type and A71G Ka H-NOX were solved to 1.9 and 1.6 Å, respectively. Regions of H-NOX domains previously identified as involved in protein-protein interactions with HnoK display significantly higher b-factors in A71G compared to wild-type H-NOX. Both biochemical and structural data indicate that the hinge region controls overall conformational flexibility of the H-NOX, affecting NO complex formation and regulation of its HnoK.

  12. Implementation of intensity-modulated conformational radiotherapy (IMRT) for the treatment of cervical cancers at the Alexis-Vautrin Centre; Implementation de la radiotherapie conformationnelle avec modulation d'intensite (RCMI) pour le traitement des cancers du col uterin au centre Alexis-Vautrin

    Energy Technology Data Exchange (ETDEWEB)

    Renard-Oldrini, S.; Brunaud, C.; Marchesi, V.; Tournier-Rangeard, L.; Peiffert, D. [Centre Alexis-Vautrin, 54 - Nancy (France)

    2010-10-15

    The authors discuss the comparison of the treatment plans of eleven patients treated either by conformational irradiation for seven of them, or by intensity-modulated conformational irradiation (IMRT) for four of them. The IMRT results in a good target volume coverage, can better protect the intestine than the conventional irradiation, and therefore is very promising, notably in terms of digestive toxicity. Short communication

  13. Pelvic nodal dose escalation with prostate hypofractionation using conformal avoidance defined (H-CAD) intensity modulated radiation therapy

    International Nuclear Information System (INIS)

    Hong, Theodore S.; Tome, Wolfgang A.; Jaradat, Hazim; Raisbeck, Bridget M.; Ritter, Mark A.

    2006-01-01

    The management of prostate cancer patients with a significant risk of pelvic lymph node involvement is controversial. Both whole pelvis radiotherapy and dose escalation to the prostate have been linked to improved outcome in such patients, but it is unclear whether conventional whole pelvis doses of only 45-50 Gy are optimal for ultimate nodal control. The purpose of this study is to examine the dosimetric and clinical feasibility of combining prostate dose escalation via hypofractionation with conformal avoidance-based IMRT (H-CAD) dose escalation to the pelvic lymph nodes. One conformal avoidance and one conventional plan were generated for each of eight patients. Conformal avoidance-based IMRT plans were generated that specifically excluded bowel, rectum, and bladder. The prostate and lower seminal vesicles (PTV 70) were planned to receive 70 Gy in 2.5 Gy/fraction while the pelvic lymph nodes (PTV 56) were to concurrently receive 56 Gy in 2 Gy/fraction. The volume of small bowel receiving >45 Gy was restricted to 300 ml or less. These conformal avoidance plans were delivered using helical tomotherapy or LINAC-based IMRT with daily imaging localization. All patients received neoadjuvant and concurrent androgen deprivation with a planned total of two years. The conventional, sequential plans created for comparison purposes for all patients consisted of a conventional 4-field pelvic box prescribed to 50.4 Gy (1.8 Gy/fraction) followed by an IMRT boost to the prostate of 25.2 Gy (1.8 Gy/fraction) yielding a final prostate dose of 75.6 Gy. For all plans, the prescription dose was to cover the target structure. Equivalent uniform dose (EUD) analyses were performed on all targets and dose-volume histograms (DVH) were displayed in terms of both physical and normalized total dose (NTD), i.e. dose in 2 Gy fraction equivalents. H-CAD IMRT plans were created for and delivered to all eight patients. Analysis of the H-CAD plans demonstrates prescription dose coverage of >95

  14. The role of Cobalt-60 source in Intensity Modulated Radiation Therapy: From modeling finite sources to treatment planning and conformal dose delivery

    Science.gov (United States)

    Dhanesar, Sandeep Kaur

    Cobalt-60 (Co-60) units played an integral role in radiation therapy from the mid-1950s to the 1970s. Although they continue to be used to treat cancer in some parts of the world, their role has been significantly reduced due to the invention of medical linear accelerators. A number of groups have indicated a strong potential for Co-60 units in modern radiation therapy. The Medical Physics group at the Cancer Center of the Southeastern Ontario and Queen's University has shown the feasibility of Intensity Modulated Radiation Therapy (IMRT) via simple conformal treatment planning and dose delivery using a Co-60 unit. In this thesis, initial Co-60 tomotherapy planning investigations on simple uniform phantoms are extended to actual clinical cases based on patient CT data. The planning is based on radiation dose data from a clinical Co-60 unit fitted with a multileaf collimator (MLC) and modeled in the EGSnrc Monte Carlo system. An in house treatment planning program is used to calculate IMRT dose distributions. Conformal delivery in a single slice on a uniform phantom based on sequentially delivered pencil beams is verified by Gafchromic film. Volumetric dose distributions for Co-60 serial tomotherapy are then generated for typical clinical sites that had been treated at our clinic by conventional 6MV IMRT using Varian Eclipse treatment plans. The Co-60 treatment plans are compared with the clinical IMRT plans using conventional matrices such as dose volume histograms (DVH). Dose delivery based on simultaneously opened MLC leaves is also explored and a novel MLC segmentation method is proposed. In order to increase efficiency of dose calculations, a novel convolution based fluence model for treatment planning is also proposed. The ion chamber measurements showed that the Monte Carlo modeling of the beam data under the MIMiC MLC is accurate. The film measurements from the uniform phantom irradiations confirm that IMRT plans from our in-house treatment planning system

  15. Potential for Improved Intelligence Quotient Using Volumetric Modulated Arc Therapy Compared With Conventional 3-Dimensional Conformal Radiation for Whole-Ventricular Radiation in Children

    International Nuclear Information System (INIS)

    Qi, X. Sharon; Stinauer, Michelle; Rogers, Brion; Madden, Jennifer R.; Wilkening, Greta N.; Liu, Arthur K.

    2012-01-01

    Purpose: To compare volumetric modulated arc therapy (VMAT) with 3-dimensional conformal radiation therapy (3D-CRT) in the treatment of localized intracranial germinoma. We modeled the effect of the dosimetric differences on intelligence quotient (IQ). Method and Materials: Ten children with intracranial germinomas were used for planning. The prescription doses were 23.4 Gy to the ventricles followed by 21.6 Gy to the tumor located in the pineal region. For each child, a 3D-CRT and full arc VMAT was generated. Coverage of the target was assessed by computing a conformity index and heterogeneity index. We also generated VMAT plans with explicit temporal lobe sparing and with smaller ventricular margin expansions. Mean dose to the temporal lobe was used to estimate IQ 5 years after completion of radiation, using a patient age of 10 years. Results: Compared with the 3D-CRT plan, VMAT improved conformality (conformity index 1.10 vs 1.85), with slightly higher heterogeneity (heterogeneity index 1.09 vs 1.06). The averaged mean doses for left and right temporal lobes were 31.3 and 31.7 Gy, respectively, for VMAT plans and 37.7 and 37.6 Gy for 3D-CRT plans. This difference in mean temporal lobe dose resulted in an estimated IQ difference of 3.1 points at 5 years after radiation therapy. When the temporal lobes were explicitly included in the VMAT optimization, the mean temporal lobe dose was reduced 5.6-5.7 Gy, resulting in an estimated IQ difference of an additional 3 points. Reducing the ventricular margin from 1.5 cm to 0.5 cm decreased mean temporal lobe dose 11.4-13.1 Gy, corresponding to an estimated increase in IQ of 7 points. Conclusion: For treatment of children with intracranial pure germinomas, VMAT compared with 3D-CRT provides increased conformality and reduces doses to normal tissue. This may result in improvements in IQ in these children.

  16. Dosimetric comparison of intensity-modulated, conformal, and four-field pelvic radiotherapy boost plans for gynecologic cancer: a retrospective planning study

    International Nuclear Information System (INIS)

    Chan, Philip; Yeo, Inhwan; Perkins, Gregory; Fyles, Anthony; Milosevic, Michael

    2006-01-01

    To evaluate intensity-modulated radiation therapy (IMRT) as an alternative to conformal radiotherapy (CRT) or 4-field box boost (4FB) in women with gynecologic malignancies who are unsuitable for brachytherapy for technical or medical reasons. Dosimetric and toxicity information was analyzed for 12 patients with cervical (8), endometrial (2) or vaginal (2) cancer previously treated with external beam pelvic radiotherapy and a CRT boost. Optimized IMRT boost treatment plans were then developed for each of the 12 patients and compared to CRT and 4FB plans. The plans were compared in terms of dose conformality and critical normal tissue avoidance. The median planning target volume (PTV) was 151 cm 3 (range 58–512 cm 3 ). The median overlap of the contoured rectum with the PTV was 15 (1–56) %, and 11 (4–35) % for the bladder. Two of the 12 patients, both with large PTVs and large overlap of the contoured rectum and PTV, developed grade 3 rectal bleeding. The dose conformity was significantly improved with IMRT over CRT and 4FB (p ≤ 0.001 for both). IMRT also yielded an overall improvement in the rectal and bladder dose-volume distributions relative to CRT and 4FB. The volume of rectum that received the highest doses (>66% of the prescription) was reduced by 22% (p < 0.001) with IMRT relative to 4FB, and the bladder volume was reduced by 19% (p < 0.001). This was at the expense of an increase in the volume of these organs receiving doses in the lowest range (<33%). These results indicate that IMRT can improve target coverage and reduce dose to critical structures in gynecologic patients receiving an external beam radiotherapy boost. This dosimetric advantage will be integrated with other patient and treatment-specific factors, particularly internal tumor movement during fractionated radiotherapy, in the context of a future image-guided radiation therapy study

  17. Investigation of conformal and intensity-modulated radiation therapy techniques to determine the absorbed fetal dose in pregnant patients with breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Öğretici, Akın, E-mail: akinogretici@gmail.com; Akbaş, Uğur; Köksal, Canan; Bilge, Hatice

    2016-07-01

    The aim of this research was to investigate the fetal doses of pregnant patients undergoing conformal radiotherapy or intensity-modulated radiation therapy (IMRT) for breast cancers. An Alderson Rando phantom was chosen to simulate a pregnant patient with breast cancer who is receiving radiation therapy. This phantom was irradiated using the Varian Clinac DBX 600 system (Varian Medical System, Palo Alto, CA) linear accelerator, according to the standard treatment plans of both three-dimensional conformal radiation therapy (3-D CRT) and IMRT techniques. Thermoluminescent dosimeters were used to measure the irradiated phantom's virtually designated uterus area. Thermoluminescent dosimeter measurements (in the phantom) revealed that the mean cumulative fetal dose for 3-D CRT is 1.39 cGy and for IMRT it is 8.48 cGy, for a pregnant breast cancer woman who received radiation treatment of 50 Gy. The fetal dose was confirmed to increase by 70% for 3-D CRT and 40% for IMRT, if it is closer to the irradiated field by 5 cm. The mean fetal dose from 3-D CRT is 1.39 cGy and IMRT is 8.48 cGy, consistent with theoretic calculations. The IMRT technique causes the fetal dose to be 5 times more than that of 3-D CRT. Theoretic knowledge concerning the increase in the peripheral doses as the measurements approached the beam was also practically proven.

  18. Clinical results of conformal versus intensity-modulated radiotherapy using a focal simultaneous boost for muscle-invasive bladder cancer in elderly or medically unfit patients.

    Science.gov (United States)

    Lutkenhaus, Lotte J; van Os, Rob M; Bel, Arjan; Hulshof, Maarten C C M

    2016-03-18

    For elderly or medically unfit patients with muscle-invasive bladder cancer, cystectomy or chemotherapy are contraindicated. This leaves radical radiotherapy as the only treatment option. It was the aim of this study to retrospectively analyze the treatment outcome and associated toxicity of conformal versus intensity-modulated radiotherapy (IMRT) using a focal simultaneous tumor boost for muscle-invasive bladder cancer in patients not suitable for cystectomy. One hundred eighteen patients with T2-4 N0-1 M0 bladder cancer were analyzed retrospectively. Median age was 80 years. Treatment consisted of either a conformal box technique or IMRT and included a simultaneous boost to the tumor. To enable an accurate boost delivery, fiducial markers were placed around the tumor. Patients were treated with 40 Gy in 20 fractions to the elective treatment volumes, and a daily tumor boost up to 55-60 Gy. Clinical complete response was seen in 87 % of patients. Three-year overall survival was 44 %, with a locoregional control rate of 73 % at 3 years. Toxicity was low, with late urinary and intestinal toxicity rates grade ≥ 2 of 14 and 5 %, respectively. The use of IMRT reduced late intestinal toxicity, whereas fiducial markers reduced acute urinary toxicity. Radical radiotherapy using a focal boost is feasible and effective for elderly or unfit patients, with a 3-year locoregional control of 73 %. Toxicity rates were low, and were reduced by the use of IMRT and fiducial markers.

  19. Health-related quality of life after intensity modulated radiation therapy for localized prostate cancer. Comparison with conventional and conformal radiotherapy

    International Nuclear Information System (INIS)

    Namiki, Shunichi; Ishidoya, Shigeto; Tochigi, Tatsuo

    2006-01-01

    No previous studies have reported the longitudinal health-related quality of life (HRQOL) for intensity modulated radiation therapy (IMRT). We compared HRQOL after IMRT with that after conventional and after conformal radiation therapy (XRT). A total of 110 patients underwent XRT (34 patients underwent conventional radiation therapy and 76 underwent conformal radiation therapy) and 30 underwent IMRT for clinically localized prostate cancer between 2000 and 2002. We measured the general and disease-specific HRQOL using the Medical Outcomes Study 36-Item Health Survey and University of California, Los Angeles, Prostate Cancer Index, respectively. There were no significant differences in the preoperative characteristics and HRQOL scores of the two groups. Repeated measure analyses of variance revealed significantly different patterns of alteration in several general HRQOL domains between XRT and the IMRT groups. In the urinary domain, there was no difference in the alteration patterns between the two groups. The XRT group suffered worse bowel function at 3 and 6 months than the IMRT group (P<0.05). In the XRT group, sexual function decreased at 3 months and remained substantially lower than the baseline level. However, the IMRT group showed no significant difference from the baseline level at any of the observation periods. At 18 months the XRT group showed worse sexual function than the IMRT group. The two approaches showed different longitudinal profiles regarding general and disease-specific HRQOL during the first 2 years after treatment. The IMRT approach produced little impairment in bowel and sexual function. (author)

  20. Modulation of Higher Order Chromatin Conformation in Mammalian Cell Nuclei Can Be Mediated by Polyamines and Divalent Cations.

    Directory of Open Access Journals (Sweden)

    Ashwat Visvanathan

    Full Text Available The organisation of the large volume of mammalian genomic DNA within cell nuclei requires mechanisms to regulate chromatin compaction involving the reversible formation of higher order structures. The compaction state of chromatin varies between interphase and mitosis and is also subject to rapid and reversible change upon ATP depletion/repletion. In this study we have investigated mechanisms that may be involved in promoting the hyper-condensation of chromatin when ATP levels are depleted by treating cells with sodium azide and 2-deoxyglucose. Chromatin conformation was analysed in both live and permeabilised HeLa cells using FLIM-FRET, high resolution fluorescence microscopy and by electron spectroscopic imaging microscopy. We show that chromatin compaction following ATP depletion is not caused by loss of transcription activity and that it can occur at a similar level in both interphase and mitotic cells. Analysis of both live and permeabilised HeLa cells shows that chromatin conformation within nuclei is strongly influenced by the levels of divalent cations, including calcium and magnesium. While ATP depletion results in an increase in the level of unbound calcium, chromatin condensation still occurs even in the presence of a calcium chelator. Chromatin compaction is shown to be strongly affected by small changes in the levels of polyamines, including spermine and spermidine. The data are consistent with a model in which the increased intracellular pool of polyamines and divalent cations, resulting from depletion of ATP, bind to DNA and contribute to the large scale hyper-compaction of chromatin by a charge neutralisation mechanism.

  1. Evaluation of a mixed beam therapy for post-mastectomy breast cancer patients: bolus electron conformal therapy combined with intensity modulated photon radiotherapy and volumetric modulated photon arc therapy.

    Science.gov (United States)

    Zhang, Rui; Heins, David; Sanders, Mary; Guo, Beibei; Hogstrom, Kenneth

    2018-05-10

    The purpose of this study was to assess the potential benefits and limitations of a mixed beam therapy, which combined bolus electron conformal therapy (BECT) with intensity modulated photon radiotherapy (IMRT) and volumetric modulated photon arc therapy (VMAT), for left-sided post-mastectomy breast cancer patients. Mixed beam treatment plans were produced for nine post-mastectomy radiotherapy (PMRT) patients previously treated at our clinic with VMAT alone. The mixed beam plans consisted of 40 Gy to the chest wall area using BECT, 40 Gy to the supraclavicular area using parallel opposed IMRT, and 10 Gy to the total planning target volume (PTV) by optimizing VMAT on top of the BECT+IMRT dose distribution. The treatment plans were created in a commercial treatment planning system (TPS), and all plans were evaluated based on PTV coverage, dose homogeneity index (DHI), conformity index (CI), dose to organs at risk (OARs), normal tissue complication probability (NTCP), and secondary cancer complication probability (SCCP). The standard VMAT alone planning technique was used as the reference for comparison. Both techniques produced clinically acceptable PMRT plans but with a few significant differences: VMAT showed significantly better CI (0.70 vs. 0.53, p 0.5 cm and volume of tissue between the distal PTV surface and heart or lung approximately > 250 cm 3 ) between distal PTV surface and lung may benefit the most from mixed beam therapy. This work has demonstrated that mixed beam therapy (BECT+IMRT : VMAT = 4 : 1) produces clinically acceptable plans having reduced OAR doses and risks of side effects compared with VMAT. Even though VMAT alone produces more homogenous and conformal dose distributions, mixed beam therapy remains as a viable option for treating post-mastectomy patients, possibly leading to reduced normal tissue complications. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  2. Conformal Nets II: Conformal Blocks

    Science.gov (United States)

    Bartels, Arthur; Douglas, Christopher L.; Henriques, André

    2017-08-01

    Conformal nets provide a mathematical formalism for conformal field theory. Associated to a conformal net with finite index, we give a construction of the `bundle of conformal blocks', a representation of the mapping class groupoid of closed topological surfaces into the category of finite-dimensional projective Hilbert spaces. We also construct infinite-dimensional spaces of conformal blocks for topological surfaces with smooth boundary. We prove that the conformal blocks satisfy a factorization formula for gluing surfaces along circles, and an analogous formula for gluing surfaces along intervals. We use this interval factorization property to give a new proof of the modularity of the category of representations of a conformal net.

  3. Dosimetric implications of residual seminal vesicle motion in fiducial-guided intensity-modulated radiotherapy for prostate cancer

    International Nuclear Information System (INIS)

    Stenmark, Matthew H.; Vineberg, Karen; Ten Haken, Randall K.; Hamstra, Daniel A.; Feng, Mary

    2012-01-01

    To determine whether residual interfraction seminal vesicle (SV) displacement necessitates specific planning target volume (PTV) margins during fiducial-guided intensity modulated radiation therapy (IMRT) of the prostate. A planning computed tomography (CT) scan and 2 subsequent CT scans were prospectively obtained for 20 prostate cancer patients with intraprostatic fiducial markers. After CT registration, SV displacement relative to the prostate was quantified as a function of margin size for both the proximal (1 cm) SV (PSV) and the full SV (FSV). Two IMRT plans were simulated for each patient (prostate + PSV and prostate + FSV) both with a uniform 5-mm PTV margin. Minimum clinical target volume (CTV) dose (D min ) and the volume of SV receiving 95% of the prescription dose (V 95% ) were assessed during treatment and compared with the initial plan. In all cases, SV displacement with respect to the prostate was greater for the FSV compared with the PSV. To ensure at least 95% geometrical coverage of the CTV for 90% of patients, margins of 5 and 8 mm were required for the PSV and FSV, respectively. Dosimetrically, residual SV displacement had minimal impact on PSV coverage compared with FSV coverage. For the PSV D min was ≥95% of the prescribed dose in 90% of patients with an overall mean V 95% of 99.6 ± 0.8%; for the FSV D min was ≥95% of the prescribed dose in only 45% of patients with a mean V 95% of 97.9 ± 2.4%. The SVs move differentially from the prostate and exhibit greater variation with increasing distance from the prostate. For plans targeting just the prostate and PSVs, 5-mm PTV expansions are adequate. However, despite daily localization of the prostate, larger PTV margins are required for cases where the intent is to completely cover the FSV.

  4. Substitutions of PrP N-terminal histidine residues modulate scrapie disease pathogenesis and incubation time in transgenic mice.

    Science.gov (United States)

    Eigenbrod, Sabina; Frick, Petra; Bertsch, Uwe; Mitteregger-Kretzschmar, Gerda; Mielke, Janina; Maringer, Marko; Piening, Niklas; Hepp, Alexander; Daude, Nathalie; Windl, Otto; Levin, Johannes; Giese, Armin; Sakthivelu, Vignesh; Tatzelt, Jörg; Kretzschmar, Hans; Westaway, David

    2017-01-01

    Prion diseases have been linked to impaired copper homeostasis and copper induced-oxidative damage to the brain. Divalent metal ions, such as Cu2+ and Zn2+, bind to cellular prion protein (PrPC) at octapeptide repeat (OR) and non-OR sites within the N-terminal half of the protein but information on the impact of such binding on conversion to the misfolded isoform often derives from studies using either OR and non-OR peptides or bacterially-expressed recombinant PrP. Here we created new transgenic mouse lines expressing PrP with disrupted copper binding sites within all four histidine-containing OR's (sites 1-4, H60G, H68G, H76G, H84G, "TetraH>G" allele) or at site 5 (composed of residues His-95 and His-110; "H95G" allele) and monitored the formation of misfolded PrP in vivo. Novel transgenic mice expressing PrP(TetraH>G) at levels comparable to wild-type (wt) controls were susceptible to mouse-adapted scrapie strain RML but showed significantly prolonged incubation times. In contrast, amino acid replacement at residue 95 accelerated disease progression in corresponding PrP(H95G) mice. Neuropathological lesions in terminally ill transgenic mice were similar to scrapie-infected wt controls, but less severe. The pattern of PrPSc deposition, however, was not synaptic as seen in wt animals, but instead dense globular plaque-like accumulations of PrPSc in TgPrP(TetraH>G) mice and diffuse PrPSc deposition in (TgPrP(H95G) mice), were observed throughout all brain sections. We conclude that OR and site 5 histidine substitutions have divergent phenotypic impacts and that cis interactions between the OR region and the site 5 region modulate pathogenic outcomes by affecting the PrP globular domain.

  5. Conformity index: A review

    International Nuclear Information System (INIS)

    Feuvret, Loic; Noel, Georges; Mazeron, Jean-Jacques; Bey, Pierre

    2006-01-01

    We present a critical analysis of the conformity indices described in the literature and an evaluation of their field of application. Three-dimensional conformal radiotherapy, with or without intensity modulation, is based on medical imaging techniques, three-dimensional dosimetry software, compression accessories, and verification procedures. It consists of delineating target volumes and critical healthy tissues to select the best combination of beams. This approach allows better adaptation of the isodose to the tumor volume, while limiting irradiation of healthy tissues. Tools must be developed to evaluate the quality of proposed treatment plans. Dosimetry software provides the dose distribution in each CT section and dose-volume histograms without really indicating the degree of conformity. The conformity index is a complementary tool that attributes a score to a treatment plan or that can compare several treatment plans for the same patient. The future of conformal index in everyday practice therefore remains unclear

  6. Dosimetric study of volumetric arc modulation with RapidArc and intensity-modulated radiotherapy in patients with cervical cancer and comparison with 3-dimensional conformal technique for definitive radiotherapy in patients with cervical cancer

    Energy Technology Data Exchange (ETDEWEB)

    Guy, Jean-Baptiste [Department of Radiation Oncology, Institut de Cancérologie de la Loire Lucien Neuwirth, Saint-Priest en Jarez (France); Falk, Alexander T. [Department of Radiation Oncology, Centre Antoine Lacassagne, Nice (France); Auberdiac, Pierre [Department of Radiation Oncology, Clinique Claude Bernard, Albi (France); Cartier, Lysian; Vallard, Alexis [Department of Radiation Oncology, Institut de Cancérologie de la Loire Lucien Neuwirth, Saint-Priest en Jarez (France); Ollier, Edouard [Department of Pharmacology-Toxicology, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Priest en Jarez (France); Trone, Jane-Chloé; Khodri, Moustapha [Department of Radiation Oncology, Institut de Cancérologie de la Loire Lucien Neuwirth, Saint-Priest en Jarez (France); Chargari, Cyrus [Department of Radiation Oncology, Hôpital d’instruction de Armées du Val-de-Grâce, Paris (France); Magné, Nicolas, E-mail: nicolas.magne@icloire.fr [Department of Radiation Oncology, Institut de Cancérologie de la Loire Lucien Neuwirth, Saint-Priest en Jarez (France)

    2016-04-01

    Introduction: For patients with cervical cancer, intensity-modulated radiation therapy (IMRT) improves target coverage and allows dose escalation while reducing the radiation dose to organs at risk (OARs). In this study, we compared dosimetric parameters among 3-dimensional conformal radiotherapy (3D-CRT), “step-and-shoot” IMRT, and volumetric intensity-modulated arc radiotherapy (VMAT) in a series of patients with cervical cancer receiving definitive radiotherapy. Computed tomography (CT) scans of 10 patients with histologically proven cervical cancer treated with definitive radiation therapy (RT) from December 2008 to March 2010 at our department were selected for this study. The gross tumor volume (GTV) and clinical target volume (CTV) were delineated following the guidelines of the Gyn IMRT consortium that included cervix, uterus, parametrial tissues, and the pelvic nodes including presacral. The median age was 57 years (range: 30 to 85 years). All 10 patients had squamous cell carcinoma with Federation of Gynecology and Obstetrics (FIGO) stage IB-IIIB. All patients were treated by VMAT. OAR doses were significantly reduced for plans with intensity-modulated technique compared with 3D-CRT except for the dose to the vagina. Between the 2 intensity-modulated techniques, significant difference was observed for the mean dose to the small intestine, to the benefit of VMAT (p < 0.001). There was no improvement in terms of OARs sparing for VMAT although there was a tendency for a slightly decreased average dose to the rectum: − 0.65 Gy but not significant (p = 0.07). The intensity modulation techniques have many advantages in terms of quality indexes, and particularly OAR sparing, compared with 3D-CRT. Following the ongoing technologic developments in modern radiotherapy, it is essential to evaluate the intensity-modulated techniques on prospective studies of a larger scale.

  7. Chemotherapy and intensity modulated conformational radiotherapy for locally advanced pancreas cancers; Chimiotherapie et radiotherapie conformationnelle avec modulation d'intensite pour les cancers du pancreas localement evolues

    Energy Technology Data Exchange (ETDEWEB)

    Huguet, F. [Hopital Tenon, Paris (France); Wu, A.; Zhang, Z.; Winston, C.; Reidy, D.; Ho, A.; Allen, P.; Karyn, G. [Memorial Sloan-Kettering Cancer Center, New York (United States)

    2011-10-15

    The authors report a retrospective study of the tolerance and survival of 48 patients who have been treated by a chemotherapy followed by a chemotherapy concomitant with an intensity-modulated radiotherapy for a locally advanced pancreas cancer. Results are discussed in terms of toxicity, cancer response, operability, survival rate. Tolerance is good. Local control rates, global survival rates and secondary resection rates are promising. Short communication

  8. In Vivo Characterization of a Wireless Telemetry Module for a Capsule Endoscopy System Utilizing a Conformal Antenna.

    Science.gov (United States)

    Faerber, Julia; Cummins, Gerard; Pavuluri, Sumanth Kumar; Record, Paul; Rodriguez, Adrian R Ayastuy; Lay, Holly S; McPhillips, Rachael; Cox, Benjamin F; Connor, Ciaran; Gregson, Rachael; Clutton, Richard Eddie; Khan, Sadeque Reza; Cochran, Sandy; Desmulliez, Marc P Y

    2018-02-01

    This paper describes the design, fabrication, packaging, and performance characterization of a conformal helix antenna created on the outside of a capsule endoscope designed to operate at a carrier frequency of 433 MHz within human tissue. Wireless data transfer was established between the integrated capsule system and an external receiver. The telemetry system was tested within a tissue phantom and in vivo porcine models. Two different types of transmission modes were tested. The first mode, replicating normal operating conditions, used data packets at a steady power level of 0 dBm, while the capsule was being withdrawn at a steady rate from the small intestine. The second mode, replicating the worst-case clinical scenario of capsule retention within the small bowel, sent data with stepwise increasing power levels of -10, 0, 6, and 10 dBm, with the capsule fixed in position. The temperature of the tissue surrounding the external antenna was monitored at all times using thermistors embedded within the capsule shell to observe potential safety issues. The recorded data showed, for both modes of operation, a low error transmission of 10 -3 packet error rate and 10 -5 bit error rate and no temperature increase of the tissue according to IEEE standards.

  9. Conformal radiotherapy with intensity modulation and integrated boost in the head and neck cancers: experience of the Curie Institute

    International Nuclear Information System (INIS)

    Toledano, I.; Serre, A.; Bensadoun, R.J.; Ortholan, C.; Racadot, S.; Calais, G.; Alfonsi, M.; Giraud, P.; Graff, P.; Serre, A.; Bensadoun, R.J.; Ortholan, C.; Racadot, S.; Calais, G.; Alfonsi, M.; Giraud, P.

    2009-01-01

    The modulated intensity radiotherapy (I.M.R.T.) is used in the treatment of cancers in superior aero digestive tracts to reduce the irradiation of parotids and to reduce the delayed xerostomia. This retrospective study presents the results got on the fourteen first patients according an original technique of I.M.R.T. with integrated boost. It appears that this technique is feasible and allows to reduce the xerostomia rate without modifying the local control rate. To limit the average dose to the parotids under 30 Gy seems reduce the incidence of severe xerostomia. (N.C.)

  10. Conformal house

    DEFF Research Database (Denmark)

    Ryttov, Thomas Aaby; Sannino, Francesco

    2010-01-01

    fixed point. As a consistency check we recover the previously investigated bounds of the conformal windows when restricting to a single matter representation. The earlier conformal windows can be imagined to be part now of the new conformal house. We predict the nonperturbative anomalous dimensions...... at the infrared fixed points. We further investigate the effects of adding mass terms to the condensates on the conformal house chiral dynamics and construct the simplest instanton induced effective Lagrangian terms...

  11. Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1

    Directory of Open Access Journals (Sweden)

    Frank Raven

    2017-10-01

    Full Text Available A central pathogenic event of Alzheimer's disease (AD is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced Aβ42 levels without affecting either α- and β-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the γ-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD.

  12. A 4 MV flattening filter-free beam: commissioning and application to conformal therapy and volumetric modulated arc therapy

    International Nuclear Information System (INIS)

    Stevens, S W; Rosser, K E; Bedford, J L

    2011-01-01

    Recent studies have indicated that radiotherapy treatments undertaken on a flattening filter-free (FFF) linear accelerator have a number of advantages over treatments undertaken on a conventional linear accelerator. In addition, 4 MV photon beams may give improved isodose coverage for some treatment volumes at air/tissue interfaces, compared to when utilizing the clinical standard of 6 MV photons. In order to investigate these benefits, FFF beams were established on an Elekta Beam Modulator linear accelerator for 4 MV photons. Commissioning beam data were obtained for open and wedged fields. The measured data were then imported into a treatment planning system and a beam model was commissioned. The beam model was optimized to improve dose calculations at shallow, clinically relevant depths. Following verification, the beam model was utilized in a treatment planning study, including volumetric modulated arc therapy, for a selection of lung, breast/chest wall and larynx patients. Increased dose rates of around 800 MU min -1 were recorded for open fields (relative to 320 MU min -1 for filtered open fields) and reduced head scatter was inferred from output factor measurements. Good agreement between planned and delivered dose was observed in verification of treatment plans. The planning study indicated that with a FFF beam, equivalent (and in some cases improved) isodose profiles could be achieved for small lung and larynx treatment volumes relative to 4 MV filtered treatments. Furthermore, FFF treatments with wedges could be replicated using open fields together with an 'effective wedge' technique and isocentre shift. Clinical feasibility of a FFF beam was therefore demonstrated, with beam modelling, treatment planning and verification being successfully accomplished.

  13. Residues in the extracellular loop 4 are critical for maintaining the conformational equilibrium of the gamma-aminobutyric acid transporter-1

    DEFF Research Database (Denmark)

    MacAulay, Nanna; Meinild, Anne-Kristine; Zeuthen, Thomas

    2003-01-01

    . Oocytes expressing M345H showed a decrease in apparent GABA affinity, an increase in apparent affinity for Na+, a shift in the charge/voltage (Q/Vm) relationship to more positive membrane potentials, and an increased Li+-induced leak current. Oocytes expressing T349H showed an increase in apparent GABA...... affinity, a decrease in apparent Na+ affinity, a profound shift in the Q/Vm relationship to more negative potentials, and a decreased Li+-induced leak current. The data are consistent with a shift in the conformational equilibrium of the mutant transporters, with M345H stabilized in an outward...

  14. The sigma-1 receptor modulates dopamine transporter conformation and cocaine binding and may thereby potentiate cocaine self-administration in rats.

    Science.gov (United States)

    Hong, Weimin Conrad; Yano, Hideaki; Hiranita, Takato; Chin, Frederick T; McCurdy, Christopher R; Su, Tsung-Ping; Amara, Susan G; Katz, Jonathan L

    2017-07-07

    The dopamine transporter (DAT) regulates dopamine (DA) neurotransmission by recapturing DA into the presynaptic terminals and is a principal target of the psychostimulant cocaine. The sigma-1 receptor (σ 1 R) is a molecular chaperone, and its ligands have been shown to modulate DA neuronal signaling, although their effects on DAT activity are unclear. Here, we report that the prototypical σ 1 R agonist (+)-pentazocine potentiated the dose response of cocaine self-administration in rats, consistent with the effects of the σR agonists PRE-084 and DTG (1,3-di- o -tolylguanidine) reported previously. These behavioral effects appeared to be correlated with functional changes of DAT. Preincubation with (+)-pentazocine or PRE-084 increased the B max values of [ 3 H]WIN35428 binding to DAT in rat striatal synaptosomes and transfected cells. A specific interaction between σ 1 R and DAT was detected by co-immunoprecipitation and bioluminescence resonance energy transfer assays. Mutational analyses indicated that the transmembrane domain of σ 1 R likely mediated this interaction. Furthermore, cysteine accessibility assays showed that σ 1 R agonist preincubation potentiated cocaine-induced changes in DAT conformation, which were blocked by the specific σ 1 R antagonist CM304. Moreover, σ 1 R ligands had distinct effects on σ 1 R multimerization. CM304 increased the proportion of multimeric σ 1 Rs, whereas (+)-pentazocine increased monomeric σ 1 Rs. Together these results support the hypothesis that σ 1 R agonists promote dissociation of σ 1 R multimers into monomers, which then interact with DAT to stabilize an outward-facing DAT conformation and enhance cocaine binding. We propose that this novel molecular mechanism underlies the behavioral potentiation of cocaine self-administration by σ 1 R agonists in animal models. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Intensity-modulated radiotherapy vs. parotid-sparing 3D conformal radiotherapy. Effect on outcome and toxicity in locally advanced head and neck cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lambrecht, M.; Nevens, D.; Nuyts, S. [University Hospitals Leuven (Belgium). Dept. of Radiation Oncology

    2013-03-15

    Background and purpose: Intensity-modulated radiotherapy (IMRT) has rapidly become standard of care in the management of locally advanced head and neck squamous cell carcinoma (HNSCC). In this study, our aim was to retrospectively investigate the effect of the introducing IMRT on outcome and treatment-related toxicity compared to parotid-sparing 3D conformal radiotherapy (3DCRT). Material and methods: A total of 245 patients with stage III and IV HNSCC treated with primary radiotherapy between January 2003 and December 2010 were included in this analysis: 135 patients were treated with 3DCRT, 110 patients with IMRT. Groups were compared for acute and late toxicity, locoregional control (LRC), and overall survival (OS). Oncologic outcomes were estimated using Kaplan-Meier analysis and compared using a log-rank test. Acute toxicity was analyzed according to the Common Terminology Criteria for Adverse Events v3.0 and late toxicity was scored using the RTOG/EORTC late toxicity scoring system. Results: Median follow-up was 35 months in the IMRT group and 68 months in the 3DCRT group. No significant differences were found in 3-year LRC and OS rates between the IMRT group and 3DCRT group. Significantly less acute mucositis {>=} grade 3 was observed in the IMRT group (32% vs. 44%, p = 0.03). There was significantly less late xerostomia {>=} grade 2 in the IMRT group than in the 3DCRT group (23% vs. 68%, p < 0.001). After 24 months, there was less dysphagia {>=} grade 2 in the IMRT group although differences failed to reach statistical significance. Conclusion: The introduction of IMRT in the radiotherapeutic management of locally advanced head and neck cancer significantly improved late toxicity without compromising tumor control compared to a parotid-sparing 3D conformal radiotherapy technique. (orig.)

  16. Clinical results of conformal versus intensity-modulated radiotherapy using a focal simultaneous boost for muscle-invasive bladder cancer in elderly or medically unfit patients

    International Nuclear Information System (INIS)

    Lutkenhaus, Lotte J.; Os, Rob M. van; Bel, Arjan; Hulshof, Maarten C. C. M.

    2016-01-01

    For elderly or medically unfit patients with muscle-invasive bladder cancer, cystectomy or chemotherapy are contraindicated. This leaves radical radiotherapy as the only treatment option. It was the aim of this study to retrospectively analyze the treatment outcome and associated toxicity of conformal versus intensity-modulated radiotherapy (IMRT) using a focal simultaneous tumor boost for muscle-invasive bladder cancer in patients not suitable for cystectomy. One hundred eighteen patients with T2-4 N0-1 M0 bladder cancer were analyzed retrospectively. Median age was 80 years. Treatment consisted of either a conformal box technique or IMRT and included a simultaneous boost to the tumor. To enable an accurate boost delivery, fiducial markers were placed around the tumor. Patients were treated with 40 Gy in 20 fractions to the elective treatment volumes, and a daily tumor boost up to 55–60 Gy. Clinical complete response was seen in 87 % of patients. Three-year overall survival was 44 %, with a locoregional control rate of 73 % at 3 years. Toxicity was low, with late urinary and intestinal toxicity rates grade ≥ 2 of 14 and 5 %, respectively. The use of IMRT reduced late intestinal toxicity, whereas fiducial markers reduced acute urinary toxicity. Radical radiotherapy using a focal boost is feasible and effective for elderly or unfit patients, with a 3-year locoregional control of 73 %. Toxicity rates were low, and were reduced by the use of IMRT and fiducial markers. The online version of this article (doi:10.1186/s13014-016-0618-6) contains supplementary material, which is available to authorized users

  17. Dosimetric comparison between intensity-modulated with coplanar field and 3D conformal radiotherapy with noncoplanar field for postocular invasion tumor.

    Science.gov (United States)

    Wenyong, Tu; Lu, Liu; Jun, Zeng; Weidong, Yin; Yun, Li

    2010-01-01

    This study presents a dosimetric optimization effort aiming to compare noncoplanar field (NCF) on 3 dimensions conformal radiotherapy (3D-CRT) and coplanar field (CF) on intensity-modulated radiotherapy (IMRT) planning for postocular invasion tumor. We performed a planning study on the computed tomography data of 8 consecutive patients with localized postocular invasion tumor. Four fields NCF 3D-CRT in the transverse plane with gantry angles of 0-10 degrees , 30-45 degrees , 240-270 degrees , and 310-335 degrees degrees were isocentered at the center of gravity of the target volume. The geometry of the beams was determined by beam's eye view. The same constraints were prepared with between CF IMRT optimization and NCF 3D-CRT treatment. The maximum point doses (D max) for the different optic pathway structures (OPS) with NCF 3D-CRT treatment should differ in no more than 3% from those with the NCF IMRT plan. Dose-volume histograms (DVHs) were obtained for all targets and organ at risk (OAR) with both treatment techniques. Plans with NCF 3D-CRT and CF IMRT constraints on target dose in homogeneity were computed, as well as the conformity index (CI) and homogeneity index (HI) in the target volume. The PTV coverage was optimal with both NCF 3D-CRT and CF IMRT plans in the 8 tumor sites. No difference was noted between the two techniques for the average D(max) and D(min) dose. NCF 3D-CRT and CF IMRT will yield similar results on CI. However, HI was a significant difference between NCF 3D-CRT and CF IMRT plan (p 3D-CRT versus CF IMRT set-up is very slight. NCF3D-CRT is one of the treatment options for postocular invasion tumor. However, constraints for OARs are needed. 2010 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

  18. 3D-conformal-intensity modulated radiotherapy with compensators for head and neck cancer: clinical results of normal tissue sparing

    Directory of Open Access Journals (Sweden)

    Koscielny Sven

    2006-06-01

    Full Text Available Abstract Background To investigate the potential of parotic gland sparing of intensity modulated radiotherapy (3D-c-IMRT performed with metallic compensators for head and neck cancer in a clinical series by analysis of dose distributions and clinical measures. Materials and methods 39 patients with squamous cell cancer of the head and neck irradiated using 3D-c-IMRT were evaluable for dose distribution within PTVs and at one parotid gland and 38 patients for toxicity analysis. 10 patients were treated primarily, 29 postoperatively, 19 received concomittant cis-platin based chemotherapy, 20 3D-c-IMRT alone. Initially the dose distribution was calculated with Helax ® and photon fluence was modulated using metallic compensators made of tin-granulate (n = 22. Later the dose distribution was calculated with KonRad ® and fluence was modified by MCP 96 alloy compensators (n = 17. Gross tumor/tumor bed (PTV 1 was irradiated up to 60–70 Gy, [5 fractions/week, single fraction dose: 2.0–2.2 (simultaneously integrated boost], adjuvantly irradiated bilateral cervical lymph nodes (PTV 2 with 48–54 Gy [single dose: 1.5–1.8]. Toxicity was scored according the RTOG scale and patient-reported xerostomia questionnaire (XQ. Results Mean of the median doses at the parotid glands to be spared was 25.9 (16.3–46.8 Gy, for tin graulate 26 Gy, for MCP alloy 24.2 Gy. Tin-granulate compensators resulted in a median parotid dose above 26 Gy in 10/22, MCP 96 alloy in 0/17 patients. Following acute toxicities were seen (°0–2/3: xerostomia: 87%/13%, dysphagia: 84%/16%, mucositis: 89%/11%, dermatitis: 100%/0%. No grade 4 reaction was encountered. During therapy the XQ forms showed °0–2/3: 88%/12%. 6 months postRT chronic xerostomia °0–2/3 was observed in 85%/15% of patients, none with °4 xerostomia. Conclusion 3D-c-IMRT using metallic compensators along with inverse calculation algorithm achieves sufficient parotid gland sparing in virtually all advanced

  19. Single-arc volumetric-modulated arc therapy (sVMAT) as adjuvant treatment for gastric cancer: Dosimetric comparisons with three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT)

    International Nuclear Information System (INIS)

    Wang, Xin; Li, Guangjun; Zhang, Yingjie; Bai, Sen; Xu, Feng; Wei, Yuquan; Gong, Youling

    2013-01-01

    To compare the dosimetric differences between the single-arc volumetric-modulated arc therapy (sVMAT), 3-dimensional conformal radiotherapy (3D-CRT), and intensity-modulated radiotherapy (IMRT) techniques in treatment planning for gastric cancer as adjuvant radiotherapy. Twelve patients were retrospectively analyzed. In each patient's case, the parameters were compared based on the dose-volume histogram (DVH) of the sVMAT, 3D-CRT, and IMRT plans, respectively. Three techniques showed similar target dose coverage. The maximum and mean doses of the target were significantly higher in the sVMAT plans than that in 3D-CRT plans and in the 3D-CRT/IMRT plans, respectively, but these differences were clinically acceptable. The IMRT and sVMAT plans successfully achieved better target dose conformity, reduced the V 20/30 , and mean dose of the left kidney, as well as the V 20/30 of the liver, compared with the 3D-CRT plans. And the sVMAT technique reduced the V 20 of the liver much significantly. Although the maximum dose of the spinal cord were much higher in the IMRT and sVMAT plans, respectively (mean 36.4 vs 39.5 and 40.6 Gy), these data were still under the constraints. Not much difference was found in the analysis of the parameters of the right kidney, intestine, and heart. The IMRT and sVMAT plans achieved similar dose distribution to the target, but superior to the 3D-CRT plans, in adjuvant radiotherapy for gastric cancer. The sVMAT technique improved the dose sparings of the left kidney and liver, compared with the 3D-CRT technique, but showed few dosimetric advantages over the IMRT technique. Studies are warranted to evaluate the clinical benefits of the VMAT treatment for patients with gastric cancer after surgery in the future

  20. Rapid Arc, helical tomotherapy, sliding window intensity modulated radiotherapy and three dimensional conformal radiation for localized prostate cancer: A dosimetric comparison

    Directory of Open Access Journals (Sweden)

    Rajesh A Kinhikar

    2014-01-01

    Full Text Available Objective: The objective of this study was to investigate the potential role of RapidArc (RA compared with helical tomotherapy (HT, sliding window intensity modulated radiotherapy (SW IMRT and three-dimensional conformal radiation therapy (3D CRT for localized prostate cancer. Materials and Methods: Prescription doses ranged from 60 Gy to planning target volume (PTV and 66.25 Gy for clinical target volume prostate (CTV-P over 25-30 fractions. PTV and CTV-P coverage were evaluated by conformity index (CI and homogeneity index (HI. Organ sparing comparison was done with mean doses to rectum and bladder. Results: CI 95 were 1.0 ± 0.01 (RA, 0.99 ± 0.01 (HT, 0.97 ± 0.02 (IMRT, 0.98 ± 0.02 (3D CRT for PTV and 1.0 ± 0.00 (RA, HT, SW IMRT and 3D CRT for CTV-P. HI was 0.11 ± 0.03 (RA, 0.16 ± 0.08 (HT, 0.12 ± 0.03 (IMRT, 0.06 ± 0.01 (3D CRT for PTV and 0.03 ± 0.00 (RA, 0.05 ± 0.01 (HT, 0.03 ± 0.01 (SW IMRT and 3D CRT for CTV-P. Mean dose to bladder were 23.68 ± 13.23 Gy (RA, 24.55 ± 12.51 Gy (HT, 19.82 ± 11.61 Gy (IMRT and 23.56 ± 12.81 Gy (3D CRT, whereas mean dose to rectum was 36.85 ± 12.92 Gy (RA, 33.18 ± 11.12 Gy (HT, IMRT and 38.67 ± 12.84 Gy (3D CRT. Conclusion: All studied intensity-modulated techniques yield treatment plans of significantly improved quality when compared with 3D CRT, with HT providing best organs at risk sparing and RA being the most efficient treatment option, reducing treatment time to 1.45-3.7 min and monitor unit to <400 for a 2 Gy fraction.

  1. Proton Arc Reduces Range Uncertainty Effects and Improves Conformality Compared With Photon Volumetric Modulated Arc Therapy in Stereotactic Body Radiation Therapy for Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Seco, Joao, E-mail: jseco@partners.org [Francis H. Burr Proton Therapy Center, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Gu, Guan; Marcelos, Tiago; Kooy, Hanne; Willers, Henning [Francis H. Burr Proton Therapy Center, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2013-09-01

    Purpose: To describe, in a setting of non-small cell lung cancer (NSCLC), the theoretical dosimetric advantages of proton arc stereotactic body radiation therapy (SBRT) in which the beam penumbra of a rotating beam is used to reduce the impact of range uncertainties. Methods and Materials: Thirteen patients with early-stage NSCLC treated with proton SBRT underwent repeat planning with photon volumetric modulated arc therapy (Photon-VMAT) and an in-house-developed arc planning approach for both proton passive scattering (Passive-Arc) and intensity modulated proton therapy (IMPT-Arc). An arc was mimicked with a series of beams placed at 10° increments. Tumor and organ at risk doses were compared in the context of high- and low-dose regions, represented by volumes receiving >50% and <50% of the prescription dose, respectively. Results: In the high-dose region, conformality index values are 2.56, 1.91, 1.31, and 1.74, and homogeneity index values are 1.29, 1.22, 1.52, and 1.18, respectively, for 3 proton passive scattered beams, Passive-Arc, IMPT-Arc, and Photon-VMAT. Therefore, proton arc leads to a 30% reduction in the 95% isodose line volume to 3-beam proton plan, sparing surrounding organs, such as lung and chest wall. For chest wall, V30 is reduced from 21 cm{sup 3} (3 proton beams) to 11.5 cm{sup 3}, 12.9 cm{sup 3}, and 8.63 cm{sup 3} (P=.005) for Passive-Arc, IMPT-Arc, and Photon-VMAT, respectively. In the low-dose region, the mean lung dose and V20 of the ipsilateral lung are 5.01 Gy(relative biological effectiveness [RBE]), 4.38 Gy(RBE), 4.91 Gy(RBE), and 5.99 Gy(RBE) and 9.5%, 7.5%, 9.0%, and 10.0%, respectively, for 3-beam, Passive-Arc, IMPT-Arc, and Photon-VMAT, respectively. Conclusions: Stereotactic body radiation therapy with proton arc and Photon-VMAT generate significantly more conformal high-dose volumes than standard proton SBRT, without loss of coverage of the tumor and with significant sparing of nearby organs, such as chest wall. In addition

  2. Residual nilpotence and residual solubility of groups

    International Nuclear Information System (INIS)

    Mikhailov, R V

    2005-01-01

    The properties of the residual nilpotence and the residual solubility of groups are studied. The main objects under investigation are the class of residually nilpotent groups such that each central extension of these groups is also residually nilpotent and the class of residually soluble groups such that each Abelian extension of these groups is residually soluble. Various examples of groups not belonging to these classes are constructed by homological methods and methods of the theory of modules over group rings. Several applications of the theory under consideration are presented and problems concerning the residual nilpotence of one-relator groups are considered.

  3. Changes in Pulmonary Function After Three-Dimensional Conformal Radiotherapy, Intensity-Modulated Radiotherapy, or Proton Beam Therapy for Non-Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Lopez Guerra, Jose L.; Gomez, Daniel R.; Zhuang Yan; Levy, Lawrence B.; Eapen, George; Liu, Hongmei; Mohan, Radhe; Komaki, Ritsuko; Cox, James D.; Liao Zhongxing

    2012-01-01

    Purpose: To investigate the extent of change in pulmonary function over time after definitive radiotherapy for non-small-cell lung cancer (NSCLC) with modern techniques and to identify predictors of changes in pulmonary function according to patient, tumor, and treatment characteristics. Patients and Methods: We analyzed 250 patients who had received ≥60 Gy radio(chemo)therapy for primary NSCLC in 1998–2010 and had undergone pulmonary function tests before and within 1 year after treatment. Ninety-three patients were treated with three-dimensional conformal radiotherapy, 97 with intensity-modulated radiotherapy, and 60 with proton beam therapy. Postradiation pulmonary function test values were evaluated among individual patients compared with the same patient’s preradiation value at the following time intervals: 0–4 (T1), 5–8 (T2), and 9–12 (T3) months. Results: Lung diffusing capacity for carbon monoxide (DLCO) was reduced in the majority of patients along the three time periods after radiation, whereas the forced expiratory volume in 1 s per unit of vital capacity (FEV1/VC) showed an increase and decrease after radiation in a similar percentage of patients. There were baseline differences (stage, radiotherapy dose, concurrent chemotherapy) among the radiation technology groups. On multivariate analysis, the following features were associated with larger posttreatment declines in DLCO: pretreatment DLCO, gross tumor volume, lung and heart dosimetric data, and total radiation dose. Only pretreatment DLCO was associated with larger posttreatment declines in FEV1/VC. Conclusions: Lung diffusing capacity for carbon monoxide is reduced in the majority of patients after radiotherapy with modern techniques. Multiple factors, including gross tumor volume, preradiation lung function, and dosimetric parameters, are associated with the DLCO decline. Prospective studies are needed to better understand whether new radiation technology, such as proton beam therapy

  4. Radiotherapy of intensity modulated VS conformational in the treatment of carcinoma of the prostate. A dosimetric comparison; Radioterapia de intensidad modulada VS conformacional en el tratamiento de carcinoma de prostata. Una camparacion dosimetrica

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez Martin, G.; Garcia Vicente, F.; Zapatero Laborda, A.; Bermudez Luna, R.; Roch Gonzalez, M.; Perez Gonzalez, L.; Torres Escobar, J. J.

    2013-07-01

    The intensity modulated (IMRT) radiation therapy is a technique of high conformation which, by its nature, has as one of its main directions prostate cancer radiotherapy treatment. The purpose of this work is presents results of the dosimetric indicators collected in our hospital a number of patients of carcinoma of the prostate with standard three-dimensional Conformal technique (3D-CRT) and IMRT. Aims to demonstrate and quantify with a statistical methodology that, establishing an adequate Protocol of IMRT, significant reductions in risk organ doses can be obtained by keeping the same prescription to the white volume. (Author)

  5. Mechanism of the pH-induced conformational change in the sensor domain of the DraK Histidine kinase via the E83, E105, and E107 residues.

    Science.gov (United States)

    Yeo, Kwon Joo; Hong, Young-Soo; Jee, Jun-Goo; Lee, Jae Kyoung; Kim, Hyo Jeong; Park, Jin-Wan; Kim, Eun-Hee; Hwang, Eunha; Kim, Sang-Yoon; Lee, Eun-Gyeong; Kwon, Ohsuk; Cheong, Hae-Kap

    2014-01-01

    The DraR/DraK two-component system was found to be involved in the differential regulation of antibiotic biosynthesis in a medium-dependent manner; however, its function and signaling and sensing mechanisms remain unclear. Here, we describe the solution structure of the extracellular sensor domain of DraK and suggest a mechanism for the pH-dependent conformational change of the protein. The structure contains a mixed alpha-beta fold, adopting a fold similar to the ubiquitous sensor domain of histidine kinase. A biophysical study demonstrates that the E83, E105, and E107 residues have abnormally high pKa values and that they drive the pH-dependent conformational change for the extracellular sensor domain of DraK. We found that a triple mutant (E83L/E105L/E107A) is pH independent and mimics the low pH structure. An in vivo study showed that DraK is essential for the recovery of the pH of Streptomyces coelicolor growth medium after acid shock. Our findings suggest that the DraR/DraK two-component system plays an important role in the pH regulation of S. coelicolor growth medium. This study provides a foundation for the regulation and the production of secondary metabolites in Streptomyces.

  6. Mechanism of the pH-induced conformational change in the sensor domain of the DraK Histidine kinase via the E83, E105, and E107 residues.

    Directory of Open Access Journals (Sweden)

    Kwon Joo Yeo

    Full Text Available The DraR/DraK two-component system was found to be involved in the differential regulation of antibiotic biosynthesis in a medium-dependent manner; however, its function and signaling and sensing mechanisms remain unclear. Here, we describe the solution structure of the extracellular sensor domain of DraK and suggest a mechanism for the pH-dependent conformational change of the protein. The structure contains a mixed alpha-beta fold, adopting a fold similar to the ubiquitous sensor domain of histidine kinase. A biophysical study demonstrates that the E83, E105, and E107 residues have abnormally high pKa values and that they drive the pH-dependent conformational change for the extracellular sensor domain of DraK. We found that a triple mutant (E83L/E105L/E107A is pH independent and mimics the low pH structure. An in vivo study showed that DraK is essential for the recovery of the pH of Streptomyces coelicolor growth medium after acid shock. Our findings suggest that the DraR/DraK two-component system plays an important role in the pH regulation of S. coelicolor growth medium. This study provides a foundation for the regulation and the production of secondary metabolites in Streptomyces.

  7. Conformal superalgebras via tractor calculus

    Science.gov (United States)

    Lischewski, Andree

    2015-01-01

    We use the manifestly conformally invariant description of a Lorentzian conformal structure in terms of a parabolic Cartan geometry in order to introduce a superalgebra structure on the space of twistor spinors and normal conformal vector fields formulated in purely algebraic terms on parallel sections in tractor bundles. Via a fixed metric in the conformal class, one reproduces a conformal superalgebra structure that has been considered in the literature before. The tractor approach, however, makes clear that the failure of this object to be a Lie superalgebra in certain cases is due to purely algebraic identities on the spinor module and to special properties of the conformal holonomy representation. Moreover, it naturally generalizes to higher signatures. This yields new formulas for constructing new twistor spinors and higher order normal conformal Killing forms out of existing ones, generalizing the well-known spinorial Lie derivative. Moreover, we derive restrictions on the possible dimension of the space of twistor spinors in any metric signature.

  8. Late toxicity after conformal and intensity-modulated radiation therapy for prostate cancer. Impact of previous surgery for benign prostatic hyperplasia

    International Nuclear Information System (INIS)

    Odrazka, K.; Dolezel, M.; Vanasek, J.

    2010-01-01

    The objective of this study was to retrospectively compare late toxicity of conventional-dose three-dimensional conformal radiation therapy (3D-CRT) and high-dose intensity-modulated radiation therapy (IMRT) for prostate cancer. A total of 340 patients with T1-3 prostate cancer were treated with 3D-CRT (n=228) and IMRT (n=112). The median follow-up time was 5.9 years and 3.0 years, respectively. The prescription dose was 70 Gy for 3D-CRT and 78 Gy for IMRT. Late gastrointestinal (GI) and genitourinary (GU) toxicities were graded according to the Fox Chase modification of the Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria. There was no difference between 3D-CRT and IMRT in the incidence of GI and GU toxicity at 3 years. On multivariate analysis, transurethral resection of prostate/open transvesical prostatectomy (TURP/TVPE) for benign prostatic hyperplasia, carried out before radiotherapy, significantly increased the risk of Grade ≥2 GU toxicity (risk ratio 1.88). Among patients who experienced TURP/TVPE, the 5-year actuarial likelihood of Grade 2-3 urinary incontinence was 23%, compared with 9% for those without prostate surgery (P=0.01). Tolerance of 3D-CRT and IMRT was similar, despite the use of high radiation dose with IMRT. Previous TURP/TVPE increased the risk of GU toxicity. (author)

  9. Simultaneous integrated boost intensity-modulated radiotherapy versus 3-dimensional conformal radiotherapy in preoperative concurrent chemoradiotherapy for locally advanced rectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Bong Kyung; Kang, Min Kyul; Kim, Jae Chul [Dept. of Radiation Oncology, Kyungpook National University School of Medicine, Daegu (Korea, Republic of); Kim, Min Young; Choi, Gyu Seog; Kim, Jong Gwang; Kang, Byung Woog; Kim, Hye Jin; Park, Soo Yeun [Kyungpook National University Chilgok Hospital, Kyungpook National University School of Medicine, Daegu (Korea, Republic of)

    2017-09-15

    To evaluate the feasibility of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for preoperative concurrent chemoradiotherapy (PCRT) in locally advanced rectal cancer (LARC), by comparing with 3-dimensional conformal radiotherapy (3D-CRT). Patients who were treated with PCRT for LARC from 2015 January to 2016 December were retrospectively enrolled. Total doses of 45 Gy to 50.4 Gy with 3D-CRT or SIB-IMRT were administered concomitantly with 5-fluorouracil plus leucovorin or capecitabine. Surgery was performed 8 weeks after PCRT. Between PCRT and surgery, one cycle of additional chemotherapy was administered. Pathologic tumor responses were compared between SIB-IMRT and 3D-CRT groups. Acute gastrointestinal, genitourinary, hematologic, and skin toxicities were compared between the two groups based on the RTOG toxicity criteria. SIB-IMRT was used in 53 patients, and 3D-CRT in 41 patients. After PCRT, no significant differences were noted in tumor responses, pathologic complete response (9% vs. 7%; p = 1.000), pathologic tumor regression Grade 3 or higher (85% vs. 71%; p = 0.096), and R0 resection (87% vs. 85%; p = 0.843). Grade 2 genitourinary toxicities were significantly lesser in the SIB-IMRT group (8% vs. 24%; p = 0.023), but gastrointestinal toxicities were not different across the two groups. SIB-IMRT showed lower GU toxicity and similar tumor responses when compared with 3D-CRT in PCRT for LARC.

  10. A comparison of swallowing dysfunction after three-dimensional conformal and intensity-modulated radiotherapy. A systematic review by the Italian Head and Neck Radiotherapy Study Group

    International Nuclear Information System (INIS)

    Ursino, Stefano; Morganti, Riccardo; Cristaudo, Agostino; Paiar, Fabiola; D'Angelo, Elisa; Lohr, Frank; Mazzola, Rosario; Merlotti, Anna; Russi, Elvio Grazioso; Musio, Daniela; Alterio, Daniela; Bacigalupo, Almalina

    2017-01-01

    Dysphagia is one of the most important treatment-related side effects in head and neck cancer (HNC), as it can lead to severe life-threating complications such as aspiration pneumonia and malnutrition. Intensity-modulated radiotherapy (IMRT) could reduce swallowing dysfunction by producing a concave dose distribution and reducing doses to the swallowing-related organs at risk (SWOARs). The aim of this study was to review the current literature in order to compare swallowing outcomes between IMRT and three-dimensional conformal radiotherapy (3DCRT). A search was conducted in the PubMed and Embase databases to identify studies on swallowing outcomes, both clinically and/or instrumentally assessed, after 3DCRT and IMRT. Dysphagia-specific quality of life and objective instrumental data are summarized and discussed. A total of 262 papers were retrieved from the searched databases. An additional 23 papers were retrieved by hand-searching the reference lists. Ultimately, 22 papers were identified which discussed swallowing outcomes after 3DCRT and IMRT for HNC. No outcomes from randomized trials were identified. Despite several methodological limitations, reports from the current literature seem to suggest better swallowing outcomes with IMRT compared to 3DCRT. Further improvements are likely to result from the increased use of IMRT plans optimized for SWOAR sparing. (orig.) [de

  11. Predictive factors of local-regional recurrences following parotid sparing intensity modulated or 3D conformal radiotherapy for head and neck cancer

    International Nuclear Information System (INIS)

    Feng, Mary; Jabbari, Siavash; Lin, Alexander; Bradford, Carol R.; Chepeha, Douglas B.; Teknos, Theodoros N.; Worden, Francis P.; Tsien, Christina; Schipper, Matthew J.; Wolf, Gregory T.; Dawson, Laura A.; Eisbruch, Avraham

    2005-01-01

    Background and purpose: Predictive factors for local-regional (LR) failures after parotid-sparing, Intensity modulated (IMRT) or 3D conformal radiotherapy for head and neck (HN) cancers were assessed. Patients and methods: One hundred and fifty-eight patients with mostly stages III-IV HN squamous cell carcinoma underwent curative bilateral neck irradiation aimed at sparing the parotid glands. Patient, tumor, and treatment factors were analyzed as predictive factors for LR failure. Results: Twenty-three patients had LR recurrence (19 in-field and four marginal). No differences were found in the doses delivered to the PTVs of patients with or without in-field recurrences. In univariate analysis, tumor site was highly predictive for LR failure in both postoperative and definitive RT patients. In postoperative RT patients, pathologic tumor size, margin status, extracapsular extension (ECE) and number of lymph node metastases, were also significantly predictive. Multivariate analysis showed tumor site (oropharynx vs. other sites) to be a significant predictor in all patients, and involved margins and number of involved lymph nodes in postoperative patients. Conclusions: Clinical rather than dosimetric factors predicted for LR failures in this series, and were similar to those reported following standard RT. These factors may aid in the selection of patients for studies of treatment intensification using IMRT

  12. Dosimetric comparison of helical tomotherapy, intensity-modulated radiation therapy, volumetric-modulated arc therapy, and 3-dimensional conformal therapy for the treatment of T1N0 glottic cancer

    International Nuclear Information System (INIS)

    Ekici, Kemal; Pepele, Eda K.; Yaprak, Bahaddin; Temelli, Oztun; Eraslan, Aysun F.; Kucuk, Nadir; Altınok, Ayse Y.; Sut, Pelin A.; Alpak, Ozlem D.; Colak, Cemil; Mayadagli, Alpaslan

    2016-01-01

    Various radiotherapy planning methods for T1N0 laryngeal cancer have been proposed to decrease normal tissue toxicity. We compare helical tomotherapy (HT), linac-based intensity-modulated radiation therapy (IMRT), volumetric-modulated arc therapy (VMAT), and 3-D conformal radiotherapy (3D-CRT) techniques for T1N0 laryngeal cancer. Overall, 10 patients with T1N0 laryngeal cancer were selected and evaluated. Furthermore, 10 radiotherapy treatment plans have been created for all 10 patients, including HT, IMRT, VMAT, and 3D-CRT. IMRT, VMAT, and HT plans vs 3D-CRT plans consistently provided superior planning target volume (PTV) coverage. Similar target coverage was observed between the 3 IMRT modalities. Compared with 3D-CRT, IMRT, HT, and VMAT significantly reduced the mean dose to the carotid arteries. VMAT resulted in the lowest mean dose to the submandibular and thyroid glands. Compared with 3D-CRT, IMRT, HT, and VMAT significantly increased the maximum dose to the spinal cord It was observed that the 3 IMRT modalities studied showed superior target coverage with less variation between each plan in comparison with 3D-CRT. The 3D-CRT plans performed better at the D max of the spinal cord. Clinical investigation is warranted to determine if these treatment approaches would translate into a reduction in radiation therapy–induced toxicities.

  13. Transportation Conformity

    Science.gov (United States)

    This section provides information on: current laws, regulations and guidance, policy and technical guidance, project-level conformity, general information, contacts and training, adequacy review of SIP submissions

  14. Transmembrane potential polarization, calcium influx, and receptor conformational state modulate the sensitivity of the imidacloprid-insensitive neuronal insect nicotinic acetylcholine receptor to neonicotinoid insecticides.

    Science.gov (United States)

    Bodereau-Dubois, Béatrice; List, Olivier; Calas-List, Delphine; Marques, Olivier; Communal, Pierre-Yves; Thany, Steeve H; Lapied, Bruno

    2012-05-01

    Neonicotinoid insecticides act selectively on insect nicotinic acetylcholine receptors (nAChRs). Recent studies revealed that their efficiency was altered by the phosphorylation/dephosphorylation process and the intracellular signaling pathway involved in the regulation of nAChRs. Using whole-cell patch-clamp electrophysiology adapted for dissociated cockroach dorsal unpaired median (DUM) neurons, we demonstrated that intracellular factors involved in the regulation of nAChR function modulated neonicotinoid sensitivity. DUM neurons were known to express two α-bungarotoxin-insensitive nAChR subtypes: nAChR1 and nAChR2. Whereas nAChR1 was sensitive to imidacloprid, nAChR2 was insensitive to this insecticide. Here, we demonstrated that, like nicotine, acetamiprid and clothianidin, other types of neonicotinoid insecticides, acted as agonists on the nAChR2 subtype. Using acetamiprid, we revealed that both steady-state depolarization and hyperpolarization affected nAChR2 sensitivity. The measurement of the input membrane resistance indicated that change in the acetamiprid-induced agonist activity was related to the receptor conformational state. Using cadmium chloride, ω-conotoxin GVIA, and (R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-acetamide (LOE 908), we found that inhibition of calcium influx through high voltage-activated calcium channels and transient receptor potential γ (TRPγ) activated by both depolarization and hyperpolarization increased nAChR2 sensitivity to acetamiprid. Finally, using N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W7), forskolin, and cAMP, we demonstrated that adenylyl cyclase sensitive to the calcium/calmodulin complex regulated internal cAMP concentration, which in turn modulated TRPγ function and nAChR2 sensitivity to acetamiprid. Similar TRPγ-induced modulatory effects were also obtained when clothianidin was tested. These findings bring insights into the signaling pathway modulating

  15. Temporal characterization and in vitro comparison of cell survival following the delivery of 3D-conformal, intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT)

    Energy Technology Data Exchange (ETDEWEB)

    McGarry, Conor K; Hounsell, Alan R [Radiotherapy Physics, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast (United Kingdom); Butterworth, Karl T; Trainor, Colman; O' Sullivan, Joe M; Prise, Kevin M, E-mail: conor.mcgarry@belfasttrust.hscni.net [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast (United Kingdom)

    2011-04-21

    A phantom was designed and implemented for the delivery of treatment plans to cells in vitro. Single beam, 3D-conformal radiotherapy (3D-CRT) plans, inverse planned five-field intensity-modulated radiation therapy (IMRT), nine-field IMRT, single-arc volumetric modulated arc therapy (VMAT) and dual-arc VMAT plans were created on a CT scan of the phantom to deliver 3 Gy to the cell layer and verified using a Farmer chamber, 2D ionization chamber array and gafchromic film. Each plan was delivered to a 2D ionization chamber array to assess the temporal characteristics of the plan including delivery time and 'cell's eye view' for the central ionization chamber. The effective fraction time, defined as the percentage of the fraction time where any dose is delivered to each point examined, was also assessed across 120 ionization chambers. Each plan was delivered to human prostate cancer DU-145 cells and normal primary AGO-1522b fibroblast cells. Uniform beams were delivered to each cell line with the delivery time varying from 0.5 to 20.54 min. Effective fraction time was found to increase with a decreasing number of beams or arcs. For a uniform beam delivery, AGO-1552b cells exhibited a statistically significant trend towards increased survival with increased delivery time. This trend was not repeated when the different modulated clinical delivery methods were used. Less sensitive DU-145 cells did not exhibit a significant trend towards increased survival with increased delivery time for either the uniform or clinical deliveries. These results confirm that dose rate effects are most prevalent in more radiosensitive cells. Cell survival data generated from uniform beam deliveries over a range of dose rates and delivery times may not always be accurate in predicting response to more complex delivery techniques, such as IMRT and VMAT.

  16. Temporal characterization and in vitro comparison of cell survival following the delivery of 3D-conformal, intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT)

    International Nuclear Information System (INIS)

    McGarry, Conor K; Hounsell, Alan R; Butterworth, Karl T; Trainor, Colman; O'Sullivan, Joe M; Prise, Kevin M

    2011-01-01

    A phantom was designed and implemented for the delivery of treatment plans to cells in vitro. Single beam, 3D-conformal radiotherapy (3D-CRT) plans, inverse planned five-field intensity-modulated radiation therapy (IMRT), nine-field IMRT, single-arc volumetric modulated arc therapy (VMAT) and dual-arc VMAT plans were created on a CT scan of the phantom to deliver 3 Gy to the cell layer and verified using a Farmer chamber, 2D ionization chamber array and gafchromic film. Each plan was delivered to a 2D ionization chamber array to assess the temporal characteristics of the plan including delivery time and 'cell's eye view' for the central ionization chamber. The effective fraction time, defined as the percentage of the fraction time where any dose is delivered to each point examined, was also assessed across 120 ionization chambers. Each plan was delivered to human prostate cancer DU-145 cells and normal primary AGO-1522b fibroblast cells. Uniform beams were delivered to each cell line with the delivery time varying from 0.5 to 20.54 min. Effective fraction time was found to increase with a decreasing number of beams or arcs. For a uniform beam delivery, AGO-1552b cells exhibited a statistically significant trend towards increased survival with increased delivery time. This trend was not repeated when the different modulated clinical delivery methods were used. Less sensitive DU-145 cells did not exhibit a significant trend towards increased survival with increased delivery time for either the uniform or clinical deliveries. These results confirm that dose rate effects are most prevalent in more radiosensitive cells. Cell survival data generated from uniform beam deliveries over a range of dose rates and delivery times may not always be accurate in predicting response to more complex delivery techniques, such as IMRT and VMAT.

  17. Workers’ Conformism

    Directory of Open Access Journals (Sweden)

    Nikolay Ivantchev

    2013-10-01

    Full Text Available Conformism was studied among 46 workers with different kinds of occupations by means of two modified scales measuring conformity by Santor, Messervey, and Kusumakar (2000 – scale for perceived peer pressure and scale for conformism in antisocial situations. The hypothesis of the study that workers’ conformism is expressed in a medium degree was confirmed partly. More than a half of the workers conform in a medium degree for taking risk, and for the use of alcohol and drugs, and for sexual relationships. More than a half of the respondents conform in a small degree for anti-social activities (like a theft. The workers were more inclined to conform for risk taking (10.9%, then – for the use of alcohol, drugs and for sexual relationships (8.7%, and in the lowest degree – for anti-social activities (6.5%. The workers who were inclined for the use of alcohol and drugs tended also to conform for anti-social activities.

  18. Late Side Effects After Image Guided Intensity Modulated Radiation Therapy Compared to 3D-Conformal Radiation Therapy for Prostate Cancer: Results From 2 Prospective Cohorts

    Energy Technology Data Exchange (ETDEWEB)

    Wortel, Ruud C.; Incrocci, Luca [Department of Radiation Oncology, Erasmus Medical Center Cancer Institute, Rotterdam (Netherlands); Pos, Floris J.; Heide, Uulke A. van der; Lebesque, Joos V. [Department of Radiation Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); Aluwini, Shafak [Department of Radiation Oncology, Erasmus Medical Center Cancer Institute, Rotterdam (Netherlands); Witte, Marnix G. [Department of Radiation Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); Heemsbergen, Wilma D., E-mail: w.heemsbergen@nki.nl [Department of Radiation Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands)

    2016-06-01

    Purpose: Technical developments in the field of external beam radiation therapy (RT) enabled the clinical introduction of image guided intensity modulated radiation therapy (IG-IMRT), which improved target conformity and allowed reduction of safety margins. Whether this had an impact on late toxicity levels compared to previously applied three-dimensional conformal radiation therapy (3D-CRT) is currently unknown. We analyzed late side effects after treatment with IG-IMRT or 3D-CRT, evaluating 2 prospective cohorts of men treated for localized prostate cancer to investigate the hypothesized reductions in toxicity. Methods and Materials: Patients treated with 3D-CRT (n=189) or IG-IMRT (n=242) to 78 Gy in 39 fractions were recruited from 2 Dutch randomized trials with identical toxicity scoring protocols. Late toxicity (>90 days after treatment) was derived from self-assessment questionnaires and case report forms, according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG-EORTC) scoring criteria. Grade ≥2 endpoints included gastrointestinal (GI) rectal bleeding, increased stool frequency, discomfort, rectal incontinence, proctitis, and genitourinary (GU) obstruction, increased urinary frequency, nocturia, urinary incontinence, and dysuria. The Cox proportional hazards regression model was used to compare grade ≥2 toxicities between both techniques, adjusting for other modifying factors. Results: The 5-year cumulative incidence of grade ≥2 GI toxicity was 24.9% for IG-IMRT and 37.6% following 3D-CRT (adjusted hazard ratio [HR]: 0.59, P=.005), with significant reductions in proctitis (HR: 0.37, P=.047) and increased stool frequency (HR: 0.23, P<.001). GU grade ≥2 toxicity levels at 5 years were comparable with 46.2% and 36.4% following IG-IMRT and 3D-CRT, respectively (adjusted HR: 1.19, P=.33). Other strong predictors (P<.01) of grade ≥2 late toxicity were baseline complaints, acute toxicity, and age

  19. Late Side Effects After Image Guided Intensity Modulated Radiation Therapy Compared to 3D-Conformal Radiation Therapy for Prostate Cancer: Results From 2 Prospective Cohorts

    International Nuclear Information System (INIS)

    Wortel, Ruud C.; Incrocci, Luca; Pos, Floris J.; Heide, Uulke A. van der; Lebesque, Joos V.; Aluwini, Shafak; Witte, Marnix G.; Heemsbergen, Wilma D.

    2016-01-01

    Purpose: Technical developments in the field of external beam radiation therapy (RT) enabled the clinical introduction of image guided intensity modulated radiation therapy (IG-IMRT), which improved target conformity and allowed reduction of safety margins. Whether this had an impact on late toxicity levels compared to previously applied three-dimensional conformal radiation therapy (3D-CRT) is currently unknown. We analyzed late side effects after treatment with IG-IMRT or 3D-CRT, evaluating 2 prospective cohorts of men treated for localized prostate cancer to investigate the hypothesized reductions in toxicity. Methods and Materials: Patients treated with 3D-CRT (n=189) or IG-IMRT (n=242) to 78 Gy in 39 fractions were recruited from 2 Dutch randomized trials with identical toxicity scoring protocols. Late toxicity (>90 days after treatment) was derived from self-assessment questionnaires and case report forms, according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG-EORTC) scoring criteria. Grade ≥2 endpoints included gastrointestinal (GI) rectal bleeding, increased stool frequency, discomfort, rectal incontinence, proctitis, and genitourinary (GU) obstruction, increased urinary frequency, nocturia, urinary incontinence, and dysuria. The Cox proportional hazards regression model was used to compare grade ≥2 toxicities between both techniques, adjusting for other modifying factors. Results: The 5-year cumulative incidence of grade ≥2 GI toxicity was 24.9% for IG-IMRT and 37.6% following 3D-CRT (adjusted hazard ratio [HR]: 0.59, P=.005), with significant reductions in proctitis (HR: 0.37, P=.047) and increased stool frequency (HR: 0.23, P<.001). GU grade ≥2 toxicity levels at 5 years were comparable with 46.2% and 36.4% following IG-IMRT and 3D-CRT, respectively (adjusted HR: 1.19, P=.33). Other strong predictors (P<.01) of grade ≥2 late toxicity were baseline complaints, acute toxicity, and age

  20. Dosimetric Comparison Between Intensity-Modulated with Coplanar Field and 3D Conformal Radiotherapy with Noncoplanar Field for Postocular Invasion Tumor

    International Nuclear Information System (INIS)

    Tu Wenyong; Liu Lu; Zeng Jun; Yin Weidong; Li Yun

    2010-01-01

    This study presents a dosimetric optimization effort aiming to compare noncoplanar field (NCF) on 3 dimensions conformal radiotherapy (3D-CRT) and coplanar field (CF) on intensity-modulated radiotherapy (IMRT) planning for postocular invasion tumor. We performed a planning study on the computed tomography data of 8 consecutive patients with localized postocular invasion tumor. Four fields NCF 3D-CRT in the transverse plane with gantry angles of 0-10 deg., 30-45 deg., 240-270 deg., and 310-335 deg. degrees were isocentered at the center of gravity of the target volume. The geometry of the beams was determined by beam's eye view. The same constraints were prepared with between CF IMRT optimization and NCF 3D-CRT treatment. The maximum point doses (D max) for the different optic pathway structures (OPS) with NCF 3D-CRT treatment should differ in no more than 3% from those with the NCF IMRT plan. Dose-volume histograms (DVHs) were obtained for all targets and organ at risk (OAR) with both treatment techniques. Plans with NCF 3D-CRT and CF IMRT constraints on target dose in homogeneity were computed, as well as the conformity index (CI) and homogeneity index (HI) in the target volume. The PTV coverage was optimal with both NCF 3D-CRT and CF IMRT plans in the 8 tumor sites. No difference was noted between the two techniques for the average D max and D min dose. NCF 3D-CRT and CF IMRT will yield similar results on CI. However, HI was a significant difference between NCF 3D-CRT and CF IMRT plan (p < 0.001). Physical endpoints for target showed the mean target dose to be low in the CF IMRT plan, caused by a large target dose in homogeneity (p < 0.001). The impact of NCF 3D-CRT versus CF IMRT set-up is very slight. NCF3D-CRT is one of the treatment options for postocular invasion tumor. However, constraints for OARs are needed.

  1. Propensity Score-based Comparison of Long-term Outcomes With 3-Dimensional Conformal Radiotherapy vs Intensity-Modulated Radiotherapy for Esophageal Cancer

    International Nuclear Information System (INIS)

    Lin, Steven H.; Wang Lu; Myles, Bevan; Thall, Peter F.; Hofstetter, Wayne L.; Swisher, Stephen G.; Ajani, Jaffer A.; Cox, James D.; Komaki, Ritsuko; Liao Zhongxing

    2012-01-01

    Purpose: Although 3-dimensional conformal radiotherapy (3D-CRT) is the worldwide standard for the treatment of esophageal cancer, intensity modulated radiotherapy (IMRT) improves dose conformality and reduces the radiation exposure to normal tissues. We hypothesized that the dosimetric advantages of IMRT should translate to substantive benefits in clinical outcomes compared with 3D-CRT. Methods and Materials: An analysis was performed of 676 nonrandomized patients (3D-CRT, n=413; IMRT, n=263) with stage Ib-IVa (American Joint Committee on Cancer 2002) esophageal cancers treated with chemoradiotherapy at a single institution from 1998-2008. An inverse probability of treatment weighting and inclusion of propensity score (treatment probability) as a covariate were used to compare overall survival time, interval to local failure, and interval to distant metastasis, while accounting for the effects of other clinically relevant covariates. The propensity scores were estimated using logistic regression analysis. Results: A fitted multivariate inverse probability weighted-adjusted Cox model showed that the overall survival time was significantly associated with several well-known prognostic factors, along with the treatment modality (IMRT vs 3D-CRT, hazard ratio 0.72, P<.001). Compared with IMRT, 3D-CRT patients had a significantly greater risk of dying (72.6% vs 52.9%, inverse probability of treatment weighting, log-rank test, P<.0001) and of locoregional recurrence (P=.0038). No difference was seen in cancer-specific mortality (Gray's test, P=.86) or distant metastasis (P=.99) between the 2 groups. An increased cumulative incidence of cardiac death was seen in the 3D-CRT group (P=.049), but most deaths were undocumented (5-year estimate, 11.7% in 3D-CRT vs 5.4% in IMRT group, Gray's test, P=.0029). Conclusions: Overall survival, locoregional control, and noncancer-related death were significantly better after IMRT than after 3D-CRT. Although these results need

  2. In-vitro investigation of out-of-field cell survival following the delivery of conformal, intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans

    International Nuclear Information System (INIS)

    McGarry, Conor K; Hounsell, Alan R; Butterworth, Karl T; Trainor, Colman; McMahon, Stephen J; O'Sullivan, Joe M; Prise, Kevin M

    2012-01-01

    The aim of this work is to determine the out-of-field survival of cells irradiated with either the primary field or scattered radiation in the presence and absence of intercellular communication following delivery of conformal, IMRT and VMAT treatment plans. Single beam, conformal, IMRT and VMAT plans were created to deliver 3 Gy to half the area of a T80 flask containing either DU-145 or AGO-1522 cells allowing intercellular communication between the in- and out-of-field cell populations. The same plans were delivered to a similar custom made phantom used to hold two T25 culture flasks, one flask in-field and one out-of-field to allow comparison of cell survival responses when intercellular communication is physically inhibited. Plans were created for the delivery of 8 Gy to the more radio-resistant DU-145 cells only in the presence and absence of intercellular communication. Cell survival was determined by clonogenic assay. In both cell lines, the out-of-field survival was not statistically different between delivery techniques for either cell line or dose. There was however, a statistically significant difference between survival out-of-field when intercellular communication was intact (single T80 culture flask) or inhibited (multiple T25 culture flasks) to in-field for all plans. No statistically significant difference was observed in-field with or without cellular communication to out-of-field for all plans. These data demonstrate out-of-field effects as important determinants of cell survival following exposure to modulated irradiation fields when cellular communication between differentially irradiated cell populations is present. This data is further evidence that refinement of existing radiobiological models to include indirect cell killing effects is required. (paper)

  3. Accurate Determination of Leucine and Valine Side-chain Conformations using U-[{sup 15}N/{sup 13}C/{sup 2}H]/[{sup 1}H-(methine/methyl)-Leu/Val] Isotope Labeling, NOE Pattern Recognition, and Methine C{gamma}-H{gamma}/C{beta}-H{beta} Residual Dipolar Couplings

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Chun; Iwahara, Junji; Clore, G. Marius [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Laboratory of Chemical Physics (United States)], E-mail: mariusc@intra.niddk.nih.gov

    2005-10-15

    An isotope labeling scheme is described in which specific protonation of methine and methyl protons of leucine and valine is obtained on a {sup 15}N/{sup 13}C labeled background with uniform deuteration of all other non-exchangeable protons. The presence of a protonated methine group has little effect on the favorable relaxation properties of the methyl protons of Leu and Val. This labeling scheme permits the rotameric state of leucine side-chains to be readily determined by simple inspection of the pattern of H{gamma}(i)-H{sub N}(i) and H{gamma}(i)-H{sub N}(i+1) NOEs in a 3D {sup 15}N-separated NOE spectrum free of complications arising from spectral overlap and spin-diffusion. In addition, one-bond residual dipolar couplings for the methine {sup 13}C-{sup 1}H bond vectors of Leu and Val can be accurately determined from an intensity J-modulated constant-time HCCH-COSY experiment and used to accurately orient the side-chains of Leu and Val. Incorporation of these data into structure refinement improves the accuracy with which the conformations of Leu and Val side-chains can be established. This is important to ensure optimal packing both within the protein core and at intermolecular interfaces. The impact of the method on protein structure determination is illustrated by application to enzyme IIA{sup Chitobiose}, a 34 kDa homotrimeric phosphotransferase protein.

  4. AQP4 plasma membrane trafficking or channel gating is not significantly modulated by phosphorylation at C-terminal serine residues

    DEFF Research Database (Denmark)

    Assentoft, Mette; Larsen, Brian R; Olesen, Emma T B

    2014-01-01

    heterologous expression in Xenopus laevis oocytes (along with serine-to-aspartate mutants of the same residues to mimic a phosphorylation). None of the mutant AQP4 constructs displayed alterations in the unit water permeability. Thus phosphorylation of six different serine residues in the COOH terminus of AQP4....... Phosphorylation of aquaporins can regulate plasma membrane localization and, possibly, the unit water permeability via gating of the AQP channel itself. In vivo phosphorylation of six serine residues in the COOH terminus of AQP4 has been detected by mass spectrometry: Ser(276), Ser(285), Ser(315), Ser(316), Ser...

  5. Patterns of local-regional recurrence following parotid-sparing conformal and segmental intensity-modulated radiotherapy for head and neck cancer

    International Nuclear Information System (INIS)

    Dawson, Laura A.; Anzai, Yoshimi; Marsh, Lon; Martel, Mary K.; Paulino, Augusto; Ship, Jonathan A.; Eisbruch, Avraham

    2000-01-01

    Purpose: To analyze the patterns of local-regional recurrence in patients with head and neck cancer treated with parotid-sparing conformal and segmental intensity-modulated radiotherapy (IMRT). Methods and Materials: Fifty-eight patients with head and neck cancer were treated with bilateral neck radiation (RT) using conformal or segmental IMRT techniques, while sparing a substantial portion of one parotid gland. The targets for CT-based RT planning included the gross tumor volume (GTV) (primary tumor and lymph node metastases) and the clinical target volume (CTV) (postoperative tumor bed, expansions of the GTVs and lymph node groups at risk of subclinical disease). Lymph node targets at risk of subclinical disease included the bilateral jugulodigastric and lower jugular lymph nodes, bilateral retropharyngeal lymph nodes at risk, and high jugular nodes at the base of skull in the side of the neck at highest risk (containing clinical neck metastases and/or ipsilateral to the primary tumor). The CTVs were expanded by 5 mm to yield planning target volumes (PTVs). Planning goals included coverage of all PTVs (with a minimum of 95% of the prescribed dose) and sparing of a substantial portion of the parotid gland in the side of the neck at less risk. The median RT doses to the gross tumor, the operative bed, and the subclinical disease PTVs were 70.4 Gy, 61.2 Gy, and 50.4 Gy respectively. All recurrences were defined on CT scans obtained at the time of recurrence, transferred to the pretreatment CT dataset used for RT planning, and analyzed using dose-volume histograms. The recurrences were classified as 1) 'in-field', in which 95% or more of the recurrence volume (V recur ) was within the 95% isodose; 2) 'marginal', in which 20% to 95% of V recur was within the 95% isodose; or 3) 'outside', in which less than 20% of V recur was within the 95% isodose. Results: With a median follow-up of 27 months (range 6 to 60 months), 10 regional recurrences, 5 local recurrences

  6. Patterns of local-regional recurrence following parotid-sparing conformal and segmental intensity-modulated radiotherapy for head and neck cancer.

    Science.gov (United States)

    Dawson, L A; Anzai, Y; Marsh, L; Martel, M K; Paulino, A; Ship, J A; Eisbruch, A

    2000-03-15

    To analyze the patterns of local-regional recurrence in patients with head and neck cancer treated with parotid-sparing conformal and segmental intensity-modulated radiotherapy (IMRT). Fifty-eight patients with head and neck cancer were treated with bilateral neck radiation (RT) using conformal or segmental IMRT techniques, while sparing a substantial portion of one parotid gland. The targets for CT-based RT planning included the gross tumor volume (GTV) (primary tumor and lymph node metastases) and the clinical target volume (CTV) (postoperative tumor bed, expansions of the GTVs and lymph node groups at risk of subclinical disease). Lymph node targets at risk of subclinical disease included the bilateral jugulodigastric and lower jugular lymph nodes, bilateral retropharyngeal lymph nodes at risk, and high jugular nodes at the base of skull in the side of the neck at highest risk (containing clinical neck metastases and/or ipsilateral to the primary tumor). The CTVs were expanded by 5 mm to yield planning target volumes (PTVs). Planning goals included coverage of all PTVs (with a minimum of 95% of the prescribed dose) and sparing of a substantial portion of the parotid gland in the side of the neck at less risk. The median RT doses to the gross tumor, the operative bed, and the subclinical disease PTVs were 70.4 Gy, 61.2 Gy, and 50.4 Gy respectively. All recurrences were defined on CT scans obtained at the time of recurrence, transferred to the pretreatment CT dataset used for RT planning, and analyzed using dose-volume histograms. The recurrences were classified as 1) "in-field," in which 95% or more of the recurrence volume (V(recur)) was within the 95% isodose; 2) "marginal," in which 20% to 95% of V(recur) was within the 95% isodose; or 3) "outside," in which less than 20% of V(recur) was within the 95% isodose. With a median follow-up of 27 months (range 6 to 60 months), 10 regional recurrences, 5 local recurrences (including one noninvasive recurrence) and 1

  7. Comparing two strategies of dynamic intensity modulated radiation therapy (dIMRT with 3-dimensional conformal radiation therapy (3DCRT in the hypofractionated treatment of high-risk prostate cancer

    Directory of Open Access Journals (Sweden)

    Yartsev Slav

    2008-01-01

    Full Text Available Abstract Background To compare two strategies of dynamic intensity modulated radiation therapy (dIMRT with 3-dimensional conformal radiation therapy (3DCRT in the setting of hypofractionated high-risk prostate cancer treatment. Methods 3DCRT and dIMRT/Helical Tomotherapy(HT planning with 10 CT datasets was undertaken to deliver 68 Gy in 25 fractions (prostate and simultaneously delivering 45 Gy in 25 fractions (pelvic lymph node targets in a single phase. The paradigms of pelvic vessel targeting (iliac vessels with margin are used to target pelvic nodes and conformal normal tissue avoidance (treated soft tissues of the pelvis while limiting dose to identified pelvic critical structures were assessed compared to 3DCRT controls. Both dIMRT/HT and 3DCRT solutions were compared to each other using repeated measures ANOVA and post-hoc paired t-tests. Results When compared to conformal pelvic vessel targeting, conformal normal tissue avoidance delivered more homogenous PTV delivery (2/2 t-test comparisons; p dose, 1–3 Gy over 5/10 dose points; p Conclusion dIMRT/HT nodal and pelvic targeting is superior to 3DCRT in dose delivery and critical structure sparing in the setting of hypofractionation for high-risk prostate cancer. The pelvic targeting paradigm is a potential solution to deliver highly conformal pelvic radiation treatment in the setting of nodal location uncertainty in prostate cancer and other pelvic malignancies.

  8. Study on the photoneutrons produced in 15 MV medical linear accelerators : Comparison of three dimensional conformal radiotherapy and intensity modulated radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Oh Nam [Gangneung Asan Hospital, Gangneung (Korea, Republic of); Yang, Oh Nam; Lim, Cheong Hwan [Hanseo Univ., Seosan (Korea, Republic of)

    2012-12-15

    Intensity-modulated radiotherapy(IMRT) have the ability to provide better dose conformity and sparing of critical normal tissues than three-dimensional radiotherapy(3DCRT). Especially, with the benefit of health insurance in 2011, its use now increasingly in many modern radiotherapy departments. Also the use of linear accelerator with high-energy photon beams over 10 MV is increasing. As is well known, these linacs have the capacity to produce photoneutrons due to photonuclear reactions in materials with a large atomic number such as the target, flattening filters, collimators, and multi-leaf collimators(MLC). MLC-based IMRT treatments increase the monitor units and the probability of production of photoneutrons from photon-induced nuclear reactions. The purpose of this study is to quantitatively evaluate the dose of photoneutrons produced from 3DCRT and IMRT technique for Rando phantom in cervical cancer. We performed the treatment plans with 3DCRT and IMRT technique using Rando phantom for treatment of cervical cancer. An Rando phantom placed on the couch in the supine position was irradiated using 15 MV photon beams. Optically stimulated luminescence dosimeters(OSLD) were attached to 4 different locations (abdomen, chest, head and neck, eyes) and from center of field size and measured 5 times each of locations. Measured neutron dose from IMRT technique increased by 9.0, 8.6, 8.8, and 14 times than 3DCRT technique for abdomen, chest, head and neck, and eyes, respectively. When using IMRT with 15 MV photon beams, the photoneutrons contributed a significant portion on out-of-field. It is difficult to prevent high energy photon beams to produce the photoneutrons due to physical properties, if necessary, It is difficult to prevent high energy photon beams to produce the photoneutrons due to physical properties, if necessary, it is need to provide the additional safe shielding on a linear accelerator and should therefore reduce the out-of-field dose.

  9. Study on the photoneutrons produced in 15 MV medical linear accelerators : Comparison of three dimensional conformal radiotherapy and intensity modulated radiotherapy

    International Nuclear Information System (INIS)

    Yang, Oh Nam; Yang, Oh Nam; Lim, Cheong Hwan

    2012-01-01

    Intensity-modulated radiotherapy(IMRT) have the ability to provide better dose conformity and sparing of critical normal tissues than three-dimensional radiotherapy(3DCRT). Especially, with the benefit of health insurance in 2011, its use now increasingly in many modern radiotherapy departments. Also the use of linear accelerator with high-energy photon beams over 10 MV is increasing. As is well known, these linacs have the capacity to produce photoneutrons due to photonuclear reactions in materials with a large atomic number such as the target, flattening filters, collimators, and multi-leaf collimators(MLC). MLC-based IMRT treatments increase the monitor units and the probability of production of photoneutrons from photon-induced nuclear reactions. The purpose of this study is to quantitatively evaluate the dose of photoneutrons produced from 3DCRT and IMRT technique for Rando phantom in cervical cancer. We performed the treatment plans with 3DCRT and IMRT technique using Rando phantom for treatment of cervical cancer. An Rando phantom placed on the couch in the supine position was irradiated using 15 MV photon beams. Optically stimulated luminescence dosimeters(OSLD) were attached to 4 different locations (abdomen, chest, head and neck, eyes) and from center of field size and measured 5 times each of locations. Measured neutron dose from IMRT technique increased by 9.0, 8.6, 8.8, and 14 times than 3DCRT technique for abdomen, chest, head and neck, and eyes, respectively. When using IMRT with 15 MV photon beams, the photoneutrons contributed a significant portion on out-of-field. It is difficult to prevent high energy photon beams to produce the photoneutrons due to physical properties, if necessary, It is difficult to prevent high energy photon beams to produce the photoneutrons due to physical properties, if necessary, it is need to provide the additional safe shielding on a linear accelerator and should therefore reduce the out-of-field dose

  10. Comparison of Toxicity Between Intensity-Modulated Radiotherapy and 3-Dimensional Conformal Radiotherapy for Locally Advanced Non-small-cell Lung Cancer.

    Science.gov (United States)

    Ling, Diane C; Hess, Clayton B; Chen, Allen M; Daly, Megan E

    2016-01-01

    The role of intensity-modulated radiotherapy (IMRT) in reducing treatment-related toxicity for locally advanced non-small-cell lung cancer (NSCLC) remains incompletely defined. We compared acute toxicity and oncologic outcomes in a large cohort of patients treated with IMRT or 3-dimensional conformal radiotherapy (3-DCRT), with or without elective nodal irradiation (ENI). A single-institution retrospective review was performed evaluating 145 consecutive patients with histologically confirmed stage III NSCLC treated with definitive chemoradiotherapy. Sixty-five (44.8%) were treated with 3-DCRT using ENI, 43 (30.0%) with 3-DCRT using involved-field radiotherapy (IFRT), and 37 (25.5%) with IMRT using IFRT. All patients received concurrent chemotherapy. Comparison of acute toxicities by treatment technique (IMRT vs. 3-DCRT) and extent of nodal irradiation (3-DCRT-IFRT vs. 3-DCRT-ENI) was performed for grade 2 or higher esophagitis or pneumonitis, number of acute hospitalizations, incidence of opioid requirement, percutaneous endoscopic gastrostomy utilization, and percentage weight loss during treatment. Local control and overall survival were analyzed by the Kaplan-Meier method. We identified no significant differences in any measures of acute toxicity by treatment technique or extent of nodal irradiation. There was a trend toward lower rates of grade 2 or higher pneumonitis among IMRT patients compared to 3-DCRT patients (5.4% vs. 23.0%; P = .065). Local control and overall survival were similar between cohorts. Acute and subacute toxicities were similar for patients treated with IMRT and with 3-DCRT with or without ENI, with a nonsignificant trend toward a reduction in pneumonitis with IMRT. Larger studies are needed to better define which patients will benefit from IMRT. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Improvement in toxicity in high risk prostate cancer patients treated with image-guided intensity-modulated radiotherapy compared to 3D conformal radiotherapy without daily image guidance.

    Science.gov (United States)

    Sveistrup, Joen; af Rosenschöld, Per Munck; Deasy, Joseph O; Oh, Jung Hun; Pommer, Tobias; Petersen, Peter Meidahl; Engelholm, Svend Aage

    2014-02-04

    Image-guided radiotherapy (IGRT) facilitates the delivery of a very precise radiation dose. In this study we compare the toxicity and biochemical progression-free survival between patients treated with daily image-guided intensity-modulated radiotherapy (IG-IMRT) and 3D conformal radiotherapy (3DCRT) without daily image guidance for high risk prostate cancer (PCa). A total of 503 high risk PCa patients treated with radiotherapy (RT) and endocrine treatment between 2000 and 2010 were retrospectively reviewed. 115 patients were treated with 3DCRT, and 388 patients were treated with IG-IMRT. 3DCRT patients were treated to 76 Gy and without daily image guidance and with 1-2 cm PTV margins. IG-IMRT patients were treated to 78 Gy based on daily image guidance of fiducial markers, and the PTV margins were 5-7 mm. Furthermore, the dose-volume constraints to both the rectum and bladder were changed with the introduction of IG-IMRT. The 2-year actuarial likelihood of developing grade > = 2 GI toxicity following RT was 57.3% in 3DCRT patients and 5.8% in IG-IMRT patients (p analysis, 3DCRT was associated with a significantly increased risk of developing grade > = 2 GI toxicity compared to IG-IMRT (p analysis there was no difference in biochemical progression-free survival between 3DCRT and IG-IMRT. The difference in toxicity can be attributed to the combination of the IMRT technique with reduced dose to organs-at-risk, daily image guidance and margin reduction.

  12. Does gap-free intensity modulated chemoradiation therapy provide a greater clinical benefit than 3D conformal chemoradiation in patients with anal cancer?

    International Nuclear Information System (INIS)

    Dewas, Claire Vautravers; Créhange, Gilles; Maingon, Philippe; Dalban, Cécile; Petitfils, Aurélie; Peignaux, Karine; Truc, Gilles; Martin, Etienne; Khoury, Cédric; Dewas, Sylvain

    2012-01-01

    Chemoradiation is the standard treatment for anal cancer. 3D conformal radiotherapy (3D-CRT) is usually split in 2 sequences with a therapeutic break (gap) in between. Intensity-modulated radiation therapy (IMRT) makes it possible to reduce treatment time by abandoning this gap. The purpose of this study was to compare outcomes and toxicities in patients treated with either IMRT or 3D-CRT. Between 2004 and 2011, the data of 51 patients treated with exclusive radiotherapy with or without concomitant chemotherapy for non-metastatic anal carcinoma were retrospectively analyzed. Twenty-seven patients were treated with 3D-CRT and 24 patients with IMRT, with a median dose delivered to the tumor of 59.4Gy [30.6-66.6], whatever the radiotherapy technique (p= 0.99). The median follow-up was 40 months [26.4-51.6]. There was no difference between the two groups for response to treatment (p= 0.46). Two-year overall survival, locoregional relapse-free survival and colostomy-free survival rates were 88.5%, 63% and 60.3%, respectively for the IMRT group and 81%, 76.5% and 81.1% for the 3D-CRT group (all NS). Ten patients (37%) in 3D-CRT and 11 patients (45.8%) in IMRT (p= 0.524) had grade 3 acute toxicity. No grade 4 toxicity occurred. Our study suggests that further investigations concerning the use of IMRT to treat cancer of the anus are warranted. IMRT makes it possible to remove the gap, but with no impact on the prognosis. Nonetheless, a longer follow-up is essential to determine whether or not IMRT has an impact on late toxicity, local control and survival compared with conventional 3D-CRT

  13. Two-Year and Lifetime Cost-Effectiveness of Intensity Modulated Radiation Therapy Versus 3-Dimensional Conformal Radiation Therapy for Head-and-Neck Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kohler, Racquel E. [Department of Health Policy and Management, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Sheets, Nathan C. [Department of Radiation Oncology, University of North Carolina Hospitals, Chapel Hill, North Carolina (United States); Wheeler, Stephanie B. [Department of Health Policy and Management, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Nutting, Chris [Royal Marsden Hospital, London, United Kindom (United Kingdom); Hall, Emma [Clinical Trials and Statistics Unit, Division of Clinical Studies, Institute of Cancer Research, London (United Kingdom); Chera, Bhishamjit S., E-mail: bchera@med.unc.edu [Department of Radiation Oncology, University of North Carolina Hospitals, Chapel Hill, North Carolina (United States)

    2013-11-15

    Purpose: To assess the cost-effectiveness of intensity modulated radiation therapy (IMRT) versus 3-dimensional conformal radiation therapy (3D-CRT) in the treatment of head-and neck-cancer (HNC). Methods and Materials: We used a Markov model to simulate radiation therapy-induced xerostomia and dysphagia in a hypothetical cohort of 65-year-old HNC patients. Model input parameters were derived from PARSPORT (CRUK/03/005) patient-level trial data and quality-of-life and Medicare cost data from published literature. We calculated average incremental cost-effectiveness ratios (ICERs) from the US health care perspective as cost per quality-adjusted life-year (QALY) gained and compared our ICERs with current cost-effectiveness standards whereby treatment comparators less than $50,000 per QALY gained are considered cost-effective. Results: In the first 2 years after initial treatment, IMRT is not cost-effective compared with 3D-CRT, given an average ICER of $101,100 per QALY gained. However, over 15 years (remaining lifetime on the basis of average life expectancy of a 65-year-old), IMRT is more cost-effective at $34,523 per QALY gained. Conclusion: Although HNC patients receiving IMRT will likely experience reduced xerostomia and dysphagia symptoms, the small quality-of-life benefit associated with IMRT is not cost-effective in the short term but may be cost-effective over a patient's lifetime, assuming benefits persist over time and patients are healthy and likely to live for a sustained period. Additional data quantifying the long-term benefits of IMRT, however, are needed.

  14. Quality of Life and Survival Outcome for Patients With Nasopharyngeal Carcinoma Receiving Three-Dimensional Conformal Radiotherapy vs. Intensity-Modulated Radiotherapy-A Longitudinal Study

    International Nuclear Information System (INIS)

    Fang, F.-M.; Chien, C.-Y.; Tsai, W.-L.; Chen, H.-C.; Hsu, H.-C.; Lui, C.-C.; Huang, T.-L.

    2008-01-01

    Purpose: To investigate the changes of quality of life (QoL) and survival outcomes for patients with nasopharyngeal carcinoma (NPC) treated by three-dimensional conformal radiotherapy (3D-CRT) vs. intensity-modulated radiotherapy (IMRT). Methods and Materials: Two hundred and three newly diagnosed NPC patients, who were curatively treated by 3D-CRT (n = 93) or IMRT (n = 110) between March 2002 and July 2004, were analyzed. The distributions of clinical stage according to American Joint Committee on Cancer 1997 were I: 15 (7.4%), II: 78 (38.4%), III: 74 (36.5%), and IV: 36 (17.7%). QoL was longitudinally assessed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EORTC QLQ-H and N35 questionnaires at the five time points: before RT, during RT (36 Gy), and 3 months, 12 months, and 24 months after RT. Results: The 3-year locoregional control, metastasis-free survival, and overall survival rates were 84.8%, 76.7%, and 81.7% for the 3D-CRT group, respectively, compared with 84.2%, 82.6%, and 85.4% for the IMRT group (p value > 0.05). A general trend of maximal deterioration in most QoL scales was observed during RT, followed by a gradual recovery thereafter. There was no significant difference in most scales between the two groups at each time point. The exception was that patients treated by IMRT had a both statistically and clinically significant improvement in global QoL, fatigue, taste/smell, dry mouth, and feeling ill at the time point of 3 months after RT. Conclusions: The potential advantage of IMRT over 3D-CRT in treating NPC patients might occur in QoL outcome during the recovery phase of acute toxicity

  15. Comparison of dose-volume histograms for Tomo therapy, linear accelerator-based 3D conformal radiation therapy, and intensity-modulated radiation therapy

    International Nuclear Information System (INIS)

    Ji, Youn-Sang; Dong, Kyung-Rae; Kim, Chang-Bok; Choi, Seong-Kwan; Chung, Woon-Kwan; Lee, Jong-Woong

    2011-01-01

    Highlights: → Evaluation of DVH from 3D CRT, IMRT and Tomo therapy was conducted for tumor therapy. → The doses of GTV and CTV were compared using DVHs from 3D CRT, IMRT and Tomo therapy. → The GTV was higher when Tomo therapy was used, while the doses of critical organ were low. → They said that Tomo therapy satisfied the goal of radiation therapy more than the others. - Abstract: Evaluation of dose-volume histograms from three-dimensional conformal radiation therapy (3D CRT), intensity-modulated radiation therapy (IMRT), and Tomo therapy was conducted. These three modalities are among the diverse treatment systems available for tumor therapy. Three patients who received tumor therapy for a malignant oligodendroglioma in the cranium, nasopharyngeal carcinoma in the cervical neck, and prostate cancer in the pelvis were selected as study subjects. Therapy plans were made for the three patients before dose-volume histograms were obtained. The doses of the gross tumor volume (GTV) and the clinical target volume (CTV) were compared using the dose-volume histograms obtained from the LINAC-based 3D CRT, IMRT planning station (Varian Eclipse-Varian, version 8.1), and Tomo therapy planning station. In addition, the doses of critical organs in the cranium, cervix, and pelvis that should be protected were compared. The GTV was higher when Tomo therapy was used compared to 3D CRT and the LINAC-based IMRT, while the doses of critical organ tissues that required protection were low. These results demonstrated that Tomo therapy satisfied the ultimate goal of radiation therapy more than the other therapies.

  16. Cost-Effectiveness Analysis of Intensity Modulated Radiation Therapy Versus 3-Dimensional Conformal Radiation Therapy for Preoperative Treatment of Extremity Soft Tissue Sarcomas

    Energy Technology Data Exchange (ETDEWEB)

    Richard, Patrick, E-mail: patrjr@uw.edu [Department of Radiation Oncology, University of Washington, Seattle, Washington (United States); Phillips, Mark; Smith, Wade [Department of Radiation Oncology, University of Washington, Seattle, Washington (United States); Davidson, Darin [Department of Orthopedic Surgery, University of Washington, Seattle, Washington (United States); Kim, Edward; Kane, Gabrielle [Department of Radiation Oncology, University of Washington, Seattle, Washington (United States)

    2016-07-01

    Purpose: Create a cost-effectiveness model comparing preoperative intensity modulated radiation therapy (IMRT) versus 3-dimensional conformal radiation therapy (3DCRT) for extremity soft tissue sarcomas. Methods and Materials: Input parameters included 5-year local recurrence rates, rates of acute wound adverse events, and chronic toxicities (edema, fracture, joint stiffness, and fibrosis). Health-state utilities were used to calculate quality-adjusted life years (QALYs). Overall treatment costs per QALY or incremental cost-effectiveness ratio (ICER) were calculated. Roll-back analysis was performed using average costs and utilities to determine the baseline preferred radiation technique. One-way, 2-way, and probabilistic sensitivity analyses (PSA) were performed for input parameters with the largest impact on the ICER. Results: Overall treatment costs were $17,515.58 for 3DCRT compared with $22,920.51 for IMRT. The effectiveness was higher for IMRT (3.68 QALYs) than for 3DCRT (3.35 QALYs). The baseline ICER for IMRT was $16,842.75/QALY, making it the preferable treatment. The ICER was most sensitive to the probability of local recurrence, upfront radiation costs, local recurrence costs, certain utilities (no toxicity/no recurrence, grade 1 toxicity/no local recurrence, grade 4 toxicity/no local recurrence), and life expectancy. Dominance patterns emerged when the cost of 3DCRT exceeded $15,532.05 (IMRT dominates) or the life expectancy was under 1.68 years (3DCRT dominates). Furthermore, preference patterns changed based on the rate of local recurrence (threshold: 13%). The PSA results demonstrated that IMRT was the preferred cost-effective technique for 64% of trials compared with 36% for 3DCRT. Conclusions: Based on our model, IMRT is the preferred technique by lowering rates of local recurrence, severe toxicities, and improving QALYs. From a third-party payer perspective, IMRT should be a supported approach for extremity soft tissue sarcomas.

  17. Cost-Effectiveness Analysis of Intensity Modulated Radiation Therapy Versus 3-Dimensional Conformal Radiation Therapy for Preoperative Treatment of Extremity Soft Tissue Sarcomas

    International Nuclear Information System (INIS)

    Richard, Patrick; Phillips, Mark; Smith, Wade; Davidson, Darin; Kim, Edward; Kane, Gabrielle

    2016-01-01

    Purpose: Create a cost-effectiveness model comparing preoperative intensity modulated radiation therapy (IMRT) versus 3-dimensional conformal radiation therapy (3DCRT) for extremity soft tissue sarcomas. Methods and Materials: Input parameters included 5-year local recurrence rates, rates of acute wound adverse events, and chronic toxicities (edema, fracture, joint stiffness, and fibrosis). Health-state utilities were used to calculate quality-adjusted life years (QALYs). Overall treatment costs per QALY or incremental cost-effectiveness ratio (ICER) were calculated. Roll-back analysis was performed using average costs and utilities to determine the baseline preferred radiation technique. One-way, 2-way, and probabilistic sensitivity analyses (PSA) were performed for input parameters with the largest impact on the ICER. Results: Overall treatment costs were $17,515.58 for 3DCRT compared with $22,920.51 for IMRT. The effectiveness was higher for IMRT (3.68 QALYs) than for 3DCRT (3.35 QALYs). The baseline ICER for IMRT was $16,842.75/QALY, making it the preferable treatment. The ICER was most sensitive to the probability of local recurrence, upfront radiation costs, local recurrence costs, certain utilities (no toxicity/no recurrence, grade 1 toxicity/no local recurrence, grade 4 toxicity/no local recurrence), and life expectancy. Dominance patterns emerged when the cost of 3DCRT exceeded $15,532.05 (IMRT dominates) or the life expectancy was under 1.68 years (3DCRT dominates). Furthermore, preference patterns changed based on the rate of local recurrence (threshold: 13%). The PSA results demonstrated that IMRT was the preferred cost-effective technique for 64% of trials compared with 36% for 3DCRT. Conclusions: Based on our model, IMRT is the preferred technique by lowering rates of local recurrence, severe toxicities, and improving QALYs. From a third-party payer perspective, IMRT should be a supported approach for extremity soft tissue sarcomas.

  18. Three-Dimensional Conformal Radiation Therapy and Intensity-Modulated Radiation Therapy Combined With Transcatheter Arterial Chemoembolization for Locally Advanced Hepatocellular Carcinoma: An Irradiation Dose Escalation Study

    International Nuclear Information System (INIS)

    Ren Zhigang; Zhao Jiandong; Gu Ke; Chen Zhen; Lin Junhua; Xu Zhiyong; Hu Weigang; Zhou Zhenhua; Liu Luming; Jiang Guoliang

    2011-01-01

    Purpose: To determine the maximum tolerated dose (MTD) of three-dimensional conformal radiation therapy (3DCRT)/intensity-modulated radiation therapy (IMRT) combined with transcatheter arterial chemoembolization for locally advanced hepatocellular carcinoma. Methods and Materials: Patients were assigned to two subgroups based on tumor diameter: Group 1 had tumors <10 cm; Group II had tumors ≥10 cm. Escalation was achieved by increments of 4.0 Gy for each cohort in both groups. Dose-limiting toxicity (DLT) was defined as a grade of ≥3 acute liver or gastrointestinal toxicity or any grade 5 acute toxicity in other organs at risk or radiation-induced liver disease. The dose escalation would be terminated when ≥2 of 8 patients in a cohort experienced DLT. Results: From April 2005 to May 2008, 40 patients were enrolled. In Group I, 11 patients had grade ≤2 acute treatment-related toxicities, and no patient experienced DLT; and in Group II, 10 patients had grade ≤2 acute toxicity, and 1 patient in the group receiving 52 Gy developed radiation-induced liver disease. MTD was 62 Gy for Group I and 52 Gy for Group II. In-field progression-free and local progression-free rates were 100% and 69% at 1 year, and 93% and 44% at 2 years, respectively. Distant metastasis rates were 6% at 1 year and 15% at 2 years. Overall survival rates for 1-year and 2-years were 72% and 62%, respectively. Conclusions: The irradiation dose was safely escalated in hepatocellular carcinoma patients by using 3DCRT/IMRT with an active breathing coordinator. MTD was 62 Gy and 52 Gy for patients with tumor diameters of <10 cm and ≥10 cm, respectively.

  19. SCit: web tools for protein side chain conformation analysis

    OpenAIRE

    Gautier, R.; Camproux, A.-C.; Tufféry, P.

    2004-01-01

    SCit is a web server providing services for protein side chain conformation analysis and side chain positioning. Specific services use the dependence of the side chain conformations on the local backbone conformation, which is described using a structural alphabet that describes the conformation of fragments of four-residue length in a limited library of structural prototypes. Based on this concept, SCit uses sets of rotameric conformations dependent on the local backbone conformation of each...

  20. Optimisation of radiotherapy for carcinoma of the parotid gland: a comparison of conventional, three-dimensional conformal, and intensity-modulated techniques

    International Nuclear Information System (INIS)

    Nutting, Christopher M.; Rowbottom, Carl G.; Cosgrove, Vivian P.; Henk, J. Michael; Dearnaley, David P.; Robinson, Martin H.; Conway, John; Webb, Steve

    2001-01-01

    Background and purpose: To compare external beam radiotherapy techniques for parotid gland tumours using conventional radiotherapy (RT), three-dimensional conformal radiotherapy (3DCRT), and intensity-modulated radiotherapy (IMRT). To optimise the IMRT techniques, and to produce an IMRT class solution. Materials and methods: The planning target volume (PTV), contra-lateral parotid gland, oral cavity, brain-stem, brain and cochlea were outlined on CT planning scans of six patients with parotid gland tumours. Optimised conventional RT and 3DCRT plans were created and compared with inverse-planned IMRT dose distributions using dose-volume histograms. The aim was to reduce the radiation dose to organs at risk and improve the PTV dose distribution. A beam-direction optimisation algorithm was used to improve the dose distribution of the IMRT plans, and a class solution for parotid gland IMRT was investigated. Results: 3DCRT plans produced an equivalent PTV irradiation and reduced the dose to the cochlea, oral cavity, brain, and other normal tissues compared with conventional RT. IMRT further reduced the radiation dose to the cochlea and oral cavity compared with 3DCRT. For nine- and seven-field IMRT techniques, there was an increase in low-dose radiation to non-target tissue and the contra-lateral parotid gland. IMRT plans produced using three to five optimised intensity-modulated beam directions maintained the advantages of the more complex IMRT plans, and reduced the contra-lateral parotid gland dose to acceptable levels. Three- and four-field non-coplanar beam arrangements increased the volume of brain irradiated, and increased PTV dose inhomogeneity. A four-field class solution consisting of paired ipsilateral coplanar anterior and posterior oblique beams (15, 45, 145 and 170 degree sign from the anterior plane) was developed which maintained the benefits without the complexity of individual patient optimisation. Conclusions: For patients with parotid gland tumours

  1. Dosimetric impact of inter-observer variability for 3D conformal radiotherapy and volumetric modulated arc therapy: the rectal tumor target definition case

    International Nuclear Information System (INIS)

    Lobefalo, Francesca; Cozzi, Luca; Scorsetti, Marta; Mancosu, Pietro; Bignardi, Mario; Reggiori, Giacomo; Tozzi, Angelo; Tomatis, Stefano; Alongi, Filippo; Fogliata, Antonella; Gaudino, Anna; Navarria, Piera

    2013-01-01

    To assess the dosimetric effect induced by inter-observer variability in target definition for 3D-conformal RT (3DCRT) and volumetric modulated arc therapy by RapidArc (RA) techniques for rectal cancer treatment. Ten patients with rectal cancer subjected to neo-adjuvant RT were randomly selected from the internal database. Four radiation oncologists independently contoured the clinical target volume (CTV) in blind mode. Planning target volume (PTV) was defined as CTV + 7 mm in the three directions. Afterwards, shared guidelines between radiation oncologists were introduced to give general criteria for the contouring of rectal target and the four radiation oncologists defined new CTV following the guidelines. For each patient, six intersections (I) and unions (U) volumes were calculated coupling the contours of the various oncologists. This was repeated for the contours drawn after the guidelines. Agreement Index (AI = I/U) was calculated pre and post guidelines. Two RT plans (one with 3DCRT technique using 3–4 fields and one with RA using a single modulated arc) were optimized on each radiation oncologist’s PTV. For each plan the PTV volume receiving at least 95% of the prescribed dose (PTV V95%) was calculated for both target and non-target PTVs. The inter-operator AI pre-guidelines was 0.57 and was increased up to 0.69 post-guidelines. The maximum volume difference between the various CTV couples, drawn for each patient, passed from 380 ± 147 cm 3 to 137 ± 83 cm 3 after the introduction of guidelines. The mean percentage for the non-target PTV V95% was 93.7 ± 9.2% before and 96.6 ± 4.9%after the introduction of guidelines for the 3DCRT, for RA the increase was more relevant, passing from 86.5 ± 13.8% (pre) to 94.5 ± 7.5% (post). The OARs were maximally spared with VMAT technique while the variability between pre and post guidelines was not relevant in both techniques. The contouring inter-observer variability has dosimetric effects in the PTV coverage

  2. Conformal Infinity

    Directory of Open Access Journals (Sweden)

    Frauendiener Jörg

    2000-08-01

    Full Text Available The notion of conformal infinity has a long history within the research in Einstein's theory of gravity. Today, ``conformal infinity'' is related with almost all other branches of research in general relativity, from quantisation procedures to abstract mathematical issues to numerical applications. This review article attempts to show how this concept gradually and inevitably evolved out of physical issues, namely the need to understand gravitational radiation and isolated systems within the theory of gravitation and how it lends itself very naturally to solve radiation problems in numerical relativity. The fundamental concept of null-infinity is introduced. Friedrich's regular conformal field equations are presented and various initial value problems for them are discussed. Finally, it is shown that the conformal field equations provide a very powerful method within numerical relativity to study global problems such as gravitational wave propagation and detection.

  3. Conformal Infinity.

    Science.gov (United States)

    Frauendiener, Jörg

    2004-01-01

    The notion of conformal infinity has a long history within the research in Einstein's theory of gravity. Today, "conformal infinity" is related to almost all other branches of research in general relativity, from quantisation procedures to abstract mathematical issues to numerical applications. This review article attempts to show how this concept gradually and inevitably evolved from physical issues, namely the need to understand gravitational radiation and isolated systems within the theory of gravitation, and how it lends itself very naturally to the solution of radiation problems in numerical relativity. The fundamental concept of null-infinity is introduced. Friedrich's regular conformal field equations are presented and various initial value problems for them are discussed. Finally, it is shown that the conformal field equations provide a very powerful method within numerical relativity to study global problems such as gravitational wave propagation and detection.

  4. Conformal Infinity

    Directory of Open Access Journals (Sweden)

    Frauendiener Jörg

    2004-01-01

    Full Text Available The notion of conformal infinity has a long history within the research in Einstein's theory of gravity. Today, 'conformal infinity' is related to almost all other branches of research in general relativity, from quantisation procedures to abstract mathematical issues to numerical applications. This review article attempts to show how this concept gradually and inevitably evolved from physical issues, namely the need to understand gravitational radiation and isolated systems within the theory of gravitation, and how it lends itself very naturally to the solution of radiation problems in numerical relativity. The fundamental concept of null-infinity is introduced. Friedrich's regular conformal field equations are presented and various initial value problems for them are discussed. Finally, it is shown that the conformal field equations provide a very powerful method within numerical relativity to study global problems such as gravitational wave propagation and detection.

  5. General Conformity

    Science.gov (United States)

    The General Conformity requirements ensure that the actions taken by federal agencies in nonattainment and maintenance areas do not interfere with a state’s plans to meet national standards for air quality.

  6. Conformal Infinity

    OpenAIRE

    Frauendiener, J?rg

    2000-01-01

    The notion of conformal infinity has a long history within the research in Einstein's theory of gravity. Today, 'conformal infinity' is related to almost all other branches of research in general relativity, from quantisation procedures to abstract mathematical issues to numerical applications. This review article attempts to show how this concept gradually and inevitably evolved from physical issues, namely the need to understand gravitational radiation and isolated systems within the theory...

  7. Notice of Violation of IEEE Publication PrinciplesJoint Redundant Residue Number Systems and Module Isolation for Mitigating Single Event Multiple Bit Upsets in Datapath

    Science.gov (United States)

    Li, Lei; Hu, Jianhao

    2010-12-01

    Notice of Violation of IEEE Publication Principles"Joint Redundant Residue Number Systems and Module Isolation for Mitigating Single Event Multiple Bit Upsets in Datapath"by Lei Li and Jianhao Hu,in the IEEE Transactions on Nuclear Science, vol.57, no.6, Dec. 2010, pp. 3779-3786After careful and considered review of the content and authorship of this paper by a duly constituted expert committee, this paper has been found to be in violation of IEEE's Publication Principles.This paper contains substantial duplication of original text from the paper cited below. The original text was copied without attribution (including appropriate references to the original author(s) and/or paper title) and without permission.Due to the nature of this violation, reasonable effort should be made to remove all past references to this paper, and future references should be made to the following articles:"Multiple Error Detection and Correction Based on Redundant Residue Number Systems"by Vik Tor Goh and M.U. Siddiqi,in the IEEE Transactions on Communications, vol.56, no.3, March 2008, pp.325-330"A Coding Theory Approach to Error Control in Redundant Residue Number Systems. I: Theory and Single Error Correction"by H. Krishna, K-Y. Lin, and J-D. Sun, in the IEEE Transactions on Circuits and Systems II: Analog and Digital Signal Processing, vol.39, no.1, Jan 1992, pp.8-17In this paper, we propose a joint scheme which combines redundant residue number systems (RRNS) with module isolation (MI) for mitigating single event multiple bit upsets (SEMBUs) in datapath. The proposed hardening scheme employs redundant residues to improve the fault tolerance for datapath and module spacings to guarantee that SEMBUs caused by charge sharing do not propagate among the operation channels of different moduli. The features of RRNS, such as independence, parallel and error correction, are exploited to establish the radiation hardening architecture for the datapath in radiation environments. In the proposed

  8. The recovery of the salivary function in the course of time among patients damaged by a cancer of the O.R.L. sphere treated by conformal irradiation with intensity modulation; La recuperation de la fonction salivaire au cours du temps chez les patients atteints de cancer de la sphere ORL traite par irradiation conformationnelle avec modulation d'intensite

    Energy Technology Data Exchange (ETDEWEB)

    Gardner, M.; Valinta, D.; Banal, P.; Roch, P.; Bensaoula, O.; Labib, A. [Centre Rene-Huguenin, 92 - Saint-Cloud (France); Halimi, P.; Hans, S. [Hopital Europeen Georges-Pompidou, 75 - Paris (France)

    2006-11-15

    The conformal radiotherapy with intensity modulation (R.C.M.I.) has allowed for 8 patients a partial preservation of the salivary production. The salivary production was insufficient to allow a correct quality of life for patients because the decrease of salivary production had a limited clinical translation. (N.C.)

  9. Analysis of calcium-induced effects on the conformation of fengycin.

    Science.gov (United States)

    Nasir, Mehmet Nail; Laurent, Pascal; Flore, Christelle; Lins, Laurence; Ongena, Marc; Deleu, Magali

    2013-06-01

    Fengycin is a natural lipopeptide with antifungal and eliciting properties and able to inhibit the activity of phospholipase A2. A combination of CD, FT-IR, NMR and fluorescence spectroscopic techniques was applied to elucidate its conformation in a membrane-mimicking environment and to investigate the effect of calcium ions on it. We mainly observed that fengycin adopts a turn conformation. Our results showed that calcium ions are bound by the two charged glutamates. The calcium binding has an influence on the fengycin conformation and more particularly, on the environment of the tyrosine residues. The modulation of the fengycin conformation by the environmental conditions may influence its biological properties. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Irradiation of head-and-neck tumors with intensity modulated radiotherapy (IMRT). Comparison between two IMRT techniques with 3D conformal irradiation

    International Nuclear Information System (INIS)

    Heeger, Jonas

    2013-01-01

    For 12 patients with inoperable head-neck carcinoma that were treated with 3D conformal irradiation techniques additional irradiation plans using IMRT were developed. It was shown that the IMRT techniques are superior to the 3D conformal technique. The new rapid arc technique is unclear with respect to the critical organs (parotid glands, spinal canal and mandibles) but is significantly advantageous for the other normal tissue with respect to conformity (steeper dose gradients) and thus radiation dose reduction. The resulting lower irradiation time and the reduced radiation exposure being important for the treatment economy and patients' comfort should favor the more planning intensive rapid arc technique.

  11. Frustration-guided motion planning reveals conformational transitions in proteins.

    Science.gov (United States)

    Budday, Dominik; Fonseca, Rasmus; Leyendecker, Sigrid; van den Bedem, Henry

    2017-10-01

    Proteins exist as conformational ensembles, exchanging between substates to perform their function. Advances in experimental techniques yield unprecedented access to structural snapshots of their conformational landscape. However, computationally modeling how proteins use collective motions to transition between substates is challenging owing to a rugged landscape and large energy barriers. Here, we present a new, robotics-inspired motion planning procedure called dCC-RRT that navigates the rugged landscape between substates by introducing dynamic, interatomic constraints to modulate frustration. The constraints balance non-native contacts and flexibility, and instantaneously redirect the motion towards sterically favorable conformations. On a test set of eight proteins determined in two conformations separated by, on average, 7.5 Å root mean square deviation (RMSD), our pathways reduced the Cα atom RMSD to the goal conformation by 78%, outperforming peer methods. We then applied dCC-RRT to examine how collective, small-scale motions of four side-chains in the active site of cyclophilin A propagate through the protein. dCC-RRT uncovered a spatially contiguous network of residues linked by steric interactions and collective motion connecting the active site to a recently proposed, non-canonical capsid binding site 25 Å away, rationalizing NMR and multi-temperature crystallography experiments. In all, dCC-RRT can reveal detailed, all-atom molecular mechanisms for small and large amplitude motions. Source code and binaries are freely available at https://github.com/ExcitedStates/KGS/. © 2017 Wiley Periodicals, Inc.

  12. Conformal Gravity

    International Nuclear Information System (INIS)

    Hooft, G.

    2012-01-01

    The dynamical degree of freedom for the gravitational force is the metric tensor, having 10 locally independent degrees of freedom (of which 4 can be used to fix the coordinate choice). In conformal gravity, we split this field into an overall scalar factor and a nine-component remainder. All unrenormalizable infinities are in this remainder, while the scalar component can be handled like any other scalar field such as the Higgs field. In this formalism, conformal symmetry is spontaneously broken. An imperative demand on any healthy quantum gravity theory is that black holes should be described as quantum systems with micro-states as dictated by the Hawking-Bekenstein theory. This requires conformal symmetry that may be broken spontaneously but not explicitly, and this means that all conformal anomalies must cancel out. Cancellation of conformal anomalies yields constraints on the matter sector as described by some universal field theory. Thus black hole physics may eventually be of help in the construction of unified field theories. (author)

  13. Dynamics of Linker Residues Modulate the Nucleic Acid Binding Properties of the HIV-1 Nucleocapsid Protein Zinc Fingers

    Science.gov (United States)

    Zargarian, Loussiné; Tisné, Carine; Barraud, Pierre; Xu, Xiaoqian; Morellet, Nelly; René, Brigitte; Mély, Yves; Fossé, Philippe; Mauffret, Olivier

    2014-01-01

    The HIV-1 nucleocapsid protein (NC) is a small basic protein containing two zinc fingers (ZF) separated by a short linker. It is involved in several steps of the replication cycle and acts as a nucleic acid chaperone protein in facilitating nucleic acid strand transfers occurring during reverse transcription. Recent analysis of three-dimensional structures of NC-nucleic acids complexes established a new property: the unpaired guanines targeted by NC are more often inserted in the C-terminal zinc finger (ZF2) than in the N-terminal zinc finger (ZF1). Although previous NMR dynamic studies were performed with NC, the dynamic behavior of the linker residues connecting the two ZF domains remains unclear. This prompted us to investigate the dynamic behavior of the linker residues. Here, we collected 15N NMR relaxation data and used for the first time data at several fields to probe the protein dynamics. The analysis at two fields allows us to detect a slow motion occurring between the two domains around a hinge located in the linker at the G35 position. However, the amplitude of motion appears limited in our conditions. In addition, we showed that the neighboring linker residues R29, A30, P31, R32, K33 displayed restricted motion and numerous contacts with residues of ZF1. Our results are fully consistent with a model in which the ZF1-linker contacts prevent the ZF1 domain to interact with unpaired guanines, whereas the ZF2 domain is more accessible and competent to interact with unpaired guanines. In contrast, ZF1 with its large hydrophobic plateau is able to destabilize the double-stranded regions adjacent to the guanines bound by ZF2. The linker residues and the internal dynamics of NC regulate therefore the different functions of the two zinc fingers that are required for an optimal chaperone activity. PMID:25029439

  14. Assessment of renal function after conformal radiotherapy and intensity-modulated radiotherapy by functional {sup 1}H-MRI and {sup 23}Na-MRI

    Energy Technology Data Exchange (ETDEWEB)

    Haneder, S.; Michaely, H.J.; Schoenberg, S.O. [Universitaetsmedizin Mannheim, Heidelberg Univ., Mannheim (Germany). Inst. of Clinical Radiology and Nuclear Medicine; Konstandin, S.; Schad, L.R. [Universitaetsmedizin Mannheim, Heidelberg Univ., Mannheim (Germany). Computer-Assisted Clinical Medicine; Siebenlist, K.; Wertz, H.; Wenz, F.; Lohr, F.; Boda-Heggemann, J. [Universitaetsmedizin Mannheim, Heidelberg Univ., Mannheim (Germany). Dept. of Radiation Oncology

    2012-12-15

    Purpose: Adjuvant radiochemotherapy (RCHT) improves survival of patients with locally advanced gastric cancer. Conventional three-dimensional conformal radiotherapy (3D-CRT) results in ablative doses to a significant amount of the left kidney, while image-guided intensity-modulated radiotherapy (IG-IMRT) provides excellent target coverage with improved kidney sparing. Few long-term results on IMRT for gastric cancer, however, have been published. Functional magnetic resonance imaging (fMRI) at 3.0 T including blood oxygenation-level dependent (BOLD) imaging, diffusion-weighted imaging (DWI) and, for the first time, {sup 23}Na imaging was used to evaluate renal status after radiotherapy with 3D-CRT or IG-IMRT. Patients and methods Four disease-free patients (2 after 3D-CRT and 2 after IMRT; FU for all patients > 5 years) were included in this feasibility study. Morphological sequences, axial DWI images, 2D-gradient echo (GRE)-BOLD images, and {sup 23}Na images were acquired. Mean values/standard deviations for ({sup 23}Na), the apparent diffusion coefficient (ADC), and R2{sup *} values were calculated for the upper/middle/lower parts of both kidneys. Corticomedullary {sup 23}Na-concentration gradients were determined. Results: Surprisingly, IG-IMRT patients showed no morphological alterations and no statistically significant differences of ADC and R2{sup *} values in all renal parts. Values for mean corticomedullary {sup 23}Na-concentration matched those for healthy volunteers. Results were similar in 3D-CRT patients, except for the cranial part of the left kidney. This was atrophic and presented significantly reduced functional parameters (p = 0.001 - p = 0.033). Reduced ADC values indicated reduced cell density and reduced extracellular space. Cortical and medullary R2{sup *} values of the left cranial kidney in the 3D-CRT group were higher, indicating more deoxygenated hemoglobin due to reduced blood flow/oxygenation. ({sup 23}Na) of the renal cranial parts in

  15. A comparison of swallowing dysfunction after three-dimensional conformal and intensity-modulated radiotherapy. A systematic review by the Italian Head and Neck Radiotherapy Study Group

    Energy Technology Data Exchange (ETDEWEB)

    Ursino, Stefano; Morganti, Riccardo; Cristaudo, Agostino; Paiar, Fabiola [University Hospital S. Chiara, Radiation Oncology, Pisa (Italy); D' Angelo, Elisa; Lohr, Frank [University Hospital, Radiation Oncology, Modena (Italy); Mazzola, Rosario [Sacro Cuore-Don Calabria Cancer Care Center, Radiation Oncology, Negrar-Verona (Italy); Merlotti, Anna; Russi, Elvio Grazioso [S. Croce e Carle Hospital, Radiation Oncology, Cuneo (Italy); Musio, Daniela [University Hospital La Sapienza, Radiation Oncology, Roma (Italy); Alterio, Daniela [European Institute of Oncology, Radiation Oncology, Advanced Radiotherapy Center, Milan (Italy); Bacigalupo, Almalina [AOU IRCCS San Martino - IST National Cancer Research Institute and University, Radiation Oncology, Genoa (Italy)

    2017-11-15

    Dysphagia is one of the most important treatment-related side effects in head and neck cancer (HNC), as it can lead to severe life-threating complications such as aspiration pneumonia and malnutrition. Intensity-modulated radiotherapy (IMRT) could reduce swallowing dysfunction by producing a concave dose distribution and reducing doses to the swallowing-related organs at risk (SWOARs). The aim of this study was to review the current literature in order to compare swallowing outcomes between IMRT and three-dimensional conformal radiotherapy (3DCRT). A search was conducted in the PubMed and Embase databases to identify studies on swallowing outcomes, both clinically and/or instrumentally assessed, after 3DCRT and IMRT. Dysphagia-specific quality of life and objective instrumental data are summarized and discussed. A total of 262 papers were retrieved from the searched databases. An additional 23 papers were retrieved by hand-searching the reference lists. Ultimately, 22 papers were identified which discussed swallowing outcomes after 3DCRT and IMRT for HNC. No outcomes from randomized trials were identified. Despite several methodological limitations, reports from the current literature seem to suggest better swallowing outcomes with IMRT compared to 3DCRT. Further improvements are likely to result from the increased use of IMRT plans optimized for SWOAR sparing. (orig.) [German] Dysphagie ist eine der wichtigsten Nebenwirkungen bei der Behandlung von Kopf-Hals-Tumoren (HNC), da sie zu lebensbedrohlichen Komplikationen wie Aspirationspneumonien und Mangelernaehrung fuehren kann. Durch Erzeugung konkaver Dosisverteilungen und durch die Reduzierung der Dosis an schluckrelevanten Strukturen (SWOAR) kann die IMRT Schluckstoerungen moeglicherweise vermindern. Ziel dieser Studie war es, die gegenwaertige Literaturlage hinsichtlich der Schluckfunktion nach IMRT und konformaler dreidimensionaler Strahlentherapie (3DCRT) systematisch zu ueberpruefen. Studien, die die

  16. External validation of three dimensional conformal radiotherapy based NTCP models for patient-rated xerostomia and sticky saliva among patients treated with intensity modulated radiotherapy

    International Nuclear Information System (INIS)

    Beetz, Ivo; Schilstra, Cornelis; Luijk, Peter van; Christianen, Miranda E.M.C.; Doornaert, Patricia; Bijl, Henk P.; Chouvalova, Olga; Heuvel, Edwin R. van den; Steenbakkers, Roel J.H.M.; Langendijk, Johannes A.

    2012-01-01

    Purpose: The purpose of this study was to investigate the ability of predictive models for patient-rated xerostomia (XER 6M ) and sticky saliva (STIC 6M ) at 6 months after completion of primary (chemo)radiation developed in head and neck cancer patients treated with 3D-conformal radiotherapy (3D-CRT) to predict outcome in patients treated with intensity modulated radiotherapy (IMRT). Methods and materials: Recently, we published the results of a prospective study on predictive models for patient-rated xerostomia and sticky saliva in head and neck cancer patients treated with 3D-CRT (3D-CRT based NTCP models). The 3D-CRT based model for XER 6M consisted of three factors, including the mean parotid dose, age, and baseline xerostomia (none versus a bit). The 3D-CRT based model for STIC 6M consisted of the mean submandibular dose, age, the mean sublingual dose, and baseline sticky saliva (none versus a bit). In the current study, a population consisting of 162 patients treated with IMRT was used to test the external validity of these 3D-CRT based models. External validity was described by the explained variation (R 2 Nagelkerke) and the Brier score. The discriminative abilities of the models were calculated using the area under the receiver operating curve (AUC) and calibration (i.e. the agreement between predicted and observed outcome) was assessed with the Hosmer–Lemeshow “goodness-of-fit” test. Results: Overall model performance of the 3D-CRT based predictive models for XER 6M and STIC 6M was significantly worse in terms of the Brier score and R 2 Nagelkerke among patients treated with IMRT. Moreover the AUC for both 3D-CRT based models in the IMRT treated patients were markedly lower. The Hosmer–Lemeshow test showed a significant disagreement for both models between predicted risk and observed outcome. Conclusion: 3D-CRT based models for patient-rated xerostomia and sticky saliva among head and neck cancer patients treated with primary radiotherapy or

  17. Comparing morbidity and cancer control after 3D-conformal (70/74 Gy) and intensity modulated radiotherapy (78/82 Gy) for prostate cancer

    International Nuclear Information System (INIS)

    Dolezel, Martin; Odrazka, Karel; Zouhar, Milan; Jansa, Jan; Paluska, Petr; Vaculikova, Miloslava; Sefrova, Jana; Kohlova, Tereza; Vanasek, Jaroslav; Kovarik, Josef

    2015-01-01

    The purpose of this work was to compare toxicity and cancer control between patients with prostate cancer treated using three-dimensional conformal radiotherapy (3D-CRT) and those treated using intensity-modulated radiation therapy (IMRT). A total of 553 patients with prostate cancer were treated with 3D-CRT 70-74 Gy (3D-CRT 70, 3D-CRT 74) or IMRT 78-82 Gy (IMRT 78, IMRT/SIB 82). Late toxicity was scored according to FC-RTOG/LENT criteria. Biochemical failure was defined using the Phoenix and ASTRO definitions. The 5-year risk of grade 2-4 genitourinary toxicity was 26.3 % (3D-CRT 70), 27.2 % (3D-CRT 74), 17.3 % (IMRT 78), and 25.1 % (IMRT/SIB 82) without statistical differences. The 5-year risk of grade 2-4 gastrointestinal toxicity was 19.4 % (3D-CRT 70), 42.1 % (3D-CRT 74), 20.5 % (IMRT 78), and 26.6 % (IMRT/SIB 82). The differences between 3D-CRT 74 and 3D-CRT 70 and between 3D-CRT 74 and IMRT 78 were statistically significant (log rank p = 0.03). The 5-year Phoenix PSA relapse-free survival (PSA-RFS) in low-risk, intermediate-risk, and high-risk patients treated using 3D-CRT were 89.4, 65.5, and 57.8 %, respectively. Patients treated with IMRT achieved the following results: 90.9, 89.4, and 83.9 %. Clinical relapse-free survival (C-RFS) in patients treated using 3D-CRT vs. IMRT for the aforementioned groups were 94.7 vs. 100 %, 86.8 vs. 98.6 %, and 84.4 vs. 94.5 %. Disease-free survival (DFS) for patients treated using 3D-CRT were 83.1, 70.9, and 71.5 %. The IMRT group reached 95.8, 89.1, and 87.6 %. The PSA-RFS for intermediate- and high-risk patients were statistically significant, while C-RFS and DFS were marginally better. Dose escalation with IMRT was associated with improved cancer control in intermediate- and high-risk patients in comparison with 3D-CRT, without compromising toxicity. (orig.) [de

  18. Comparison of dosimetry distribution between three-dimension conformal and intensity modulated plan integrated with breath motion in postoperative radiation of gastric cancer

    International Nuclear Information System (INIS)

    Sun Wenjie; Zhang Zhen; Hu Weigang; Gu Weilie; Zhu Ji; Li Guichao; Cai Gang; Ma Xuejun

    2010-01-01

    Objective: To compare the dose distribution of the target and normal tissues in gastric cancers between three-dimension conformal radiation therapy (3DCRT) and intensity modulated radiation therapy (IMRT) plan when respiratory motion factors integrated in the plan. Methods: From January 2005 to November 2006, 10 patients with post-operatively radiation of gastric cancer were enrolled in this study. Planning CT were acquired conventionally with free-breath mode and the static treatment plans of the 3DCRT and IMRT were designed respectively. Probability distribution functions (PDF) were generated and convoluted with the static dose distributions from 3DCRT and IMRT plans to obtain the integrated plans. The dose distributions of the target and normal tissues were compared between 3DCRT and IMRT integration treatment plans, such as V 45 of clinical target volume, V 40 of liver and V 15 , V 18 of left and right kidney. Results: In the respiratory integrated treatment planning, the target volume coverage and homogeneity with IMRT are superior to those with 3DCRT ((V 45 98% : 87% (t = -3.35, P =0.010), mean dose 46.81 Gy ±0.75 Gy : 45.99 Gy ± 1.12 Gy (t = -0.31, P=0.020)). The V 40 of the liver in IMRT are smaller than those in 3DCRT ( 12% : 16%; t=3.75, P=0.010). For the left kidney, the V 15 and V 18 in IMRT are smaller than those in 3DCRT ((34% : 50% (t = 2.17, P = 0.050) and 27% : 46% (t = 3.11, P = 0.020) ),but for the right kidney, V 15 and V 18 in 3DCRT are smaller than those in IMRT ((15% : 21% (t = - 2.42, P=0.040) and 11% : 15% (t= -2.71, P=0.030)). Conclusions: When respiratory motion factor integrated in the treatment plan, IMRT showed advantage both in target coverage and normal tissue sparing in the high dose region of liver and left kidney. (authors)

  19. Prostate and seminal vesicle volume based consideration of prostate cancer patients for treatment with 3D-conformal or intensity-modulated radiation therapy

    International Nuclear Information System (INIS)

    Reddy, Nandanuri M. S.; Nori, Dattatreyudu; Chang, Hyesook; Lange, Christopher S.; Ravi, Akkamma

    2010-01-01

    Purpose: The purpose of this article was to determine the suitability of the prostate and seminal vesicle volumes as factors to consider patients for treatment with image-guided 3D-conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT), using common dosimetry parameters as comparison tools. Methods: Dosimetry of 3D and IMRT plans for 48 patients was compared. Volumes of prostate, SV, rectum, and bladder, and prescriptions were the same for both plans. For both 3D and IMRT plans, expansion margins to prostate+SV (CTV) and prostate were 0.5 cm posterior and superior and 1 cm in other dimensions to create PTV and CDPTV, respectively. Six-field 3D plans were prepared retrospectively. For 3D plans, an additional 0.5 cm margin was added to PTV and CDPTV. Prescription for both 3D and IMRT plans was the same: 45 Gy to CTV followed by a 36 Gy boost to prostate. Dosimetry parameters common to 3D and IMRT plans were used for comparison: Mean doses to prostate, CDPTV, SV, rectum, bladder, and femurs; percent volume of rectum and bladder receiving 30 (V30), 50 (V50), and 70 Gy (V70), dose to 30% of rectum and bladder, minimum and maximum point dose to CDPTV, and prescription dose covering 95% of CDPTV (D95). Results: When the data for all patients were combined, mean dose to prostate and CDPTV was higher with 3D than IMRT plans (P 0.2). On average, among all cases, the minimum point dose was less for 3D-CRT plans and the maximum point dose was greater for 3D-CRT than for IMRT (P 0.1). V30 was less (P 0.2), and V70 was more (P 0.2). Mean dose to femurs was more with 3D than IMRT plans (P 3 (39/48), respectively (P 3 , respectively, would be suitable for 3D-CRT. Patients with prostate and prostate+SV volumes >65 and 85 cm 3 , respectively, might get benefit from IMRT.

  20. Improvement in toxicity in high risk prostate cancer patients treated with image-guided intensity-modulated radiotherapy compared to 3D conformal radiotherapy without daily image guidance

    International Nuclear Information System (INIS)

    Sveistrup, Joen; Rosenschöld, Per Munck af; Deasy, Joseph O; Oh, Jung Hun; Pommer, Tobias; Petersen, Peter Meidahl; Engelholm, Svend Aage

    2014-01-01

    Image-guided radiotherapy (IGRT) facilitates the delivery of a very precise radiation dose. In this study we compare the toxicity and biochemical progression-free survival between patients treated with daily image-guided intensity-modulated radiotherapy (IG-IMRT) and 3D conformal radiotherapy (3DCRT) without daily image guidance for high risk prostate cancer (PCa). A total of 503 high risk PCa patients treated with radiotherapy (RT) and endocrine treatment between 2000 and 2010 were retrospectively reviewed. 115 patients were treated with 3DCRT, and 388 patients were treated with IG-IMRT. 3DCRT patients were treated to 76 Gy and without daily image guidance and with 1–2 cm PTV margins. IG-IMRT patients were treated to 78 Gy based on daily image guidance of fiducial markers, and the PTV margins were 5–7 mm. Furthermore, the dose-volume constraints to both the rectum and bladder were changed with the introduction of IG-IMRT. The 2-year actuarial likelihood of developing grade > = 2 GI toxicity following RT was 57.3% in 3DCRT patients and 5.8% in IG-IMRT patients (p < 0.001). For GU toxicity the numbers were 41.8% and 29.7%, respectively (p = 0.011). On multivariate analysis, 3DCRT was associated with a significantly increased risk of developing grade > = 2 GI toxicity compared to IG-IMRT (p < 0.001, HR = 11.59 [CI: 6.67-20.14]). 3DCRT was also associated with an increased risk of developing GU toxicity compared to IG-IMRT. The 3-year actuarial biochemical progression-free survival probability was 86.0% for 3DCRT and 90.3% for IG-IMRT (p = 0.386). On multivariate analysis there was no difference in biochemical progression-free survival between 3DCRT and IG-IMRT. The difference in toxicity can be attributed to the combination of the IMRT technique with reduced dose to organs-at-risk, daily image guidance and margin reduction

  1. Assessment of renal function after conformal radiotherapy and intensity-modulated radiotherapy by functional 1H-MRI and 23Na-MRI

    International Nuclear Information System (INIS)

    Haneder, S.; Michaely, H.J.; Schoenberg, S.O.; Konstandin, S.; Schad, L.R.; Siebenlist, K.; Wertz, H.; Wenz, F.; Lohr, F.; Boda-Heggemann, J.

    2012-01-01

    Purpose: Adjuvant radiochemotherapy (RCHT) improves survival of patients with locally advanced gastric cancer. Conventional three-dimensional conformal radiotherapy (3D-CRT) results in ablative doses to a significant amount of the left kidney, while image-guided intensity-modulated radiotherapy (IG-IMRT) provides excellent target coverage with improved kidney sparing. Few long-term results on IMRT for gastric cancer, however, have been published. Functional magnetic resonance imaging (fMRI) at 3.0 T including blood oxygenation-level dependent (BOLD) imaging, diffusion-weighted imaging (DWI) and, for the first time, 23 Na imaging was used to evaluate renal status after radiotherapy with 3D-CRT or IG-IMRT. Patients and methods Four disease-free patients (2 after 3D-CRT and 2 after IMRT; FU for all patients > 5 years) were included in this feasibility study. Morphological sequences, axial DWI images, 2D-gradient echo (GRE)-BOLD images, and 23 Na images were acquired. Mean values/standard deviations for ( 23 Na), the apparent diffusion coefficient (ADC), and R2 * values were calculated for the upper/middle/lower parts of both kidneys. Corticomedullary 23 Na-concentration gradients were determined. Results: Surprisingly, IG-IMRT patients showed no morphological alterations and no statistically significant differences of ADC and R2 * values in all renal parts. Values for mean corticomedullary 23 Na-concentration matched those for healthy volunteers. Results were similar in 3D-CRT patients, except for the cranial part of the left kidney. This was atrophic and presented significantly reduced functional parameters (p = 0.001 - p = 0.033). Reduced ADC values indicated reduced cell density and reduced extracellular space. Cortical and medullary R2 * values of the left cranial kidney in the 3D-CRT group were higher, indicating more deoxygenated hemoglobin due to reduced blood flow/oxygenation. ( 23 Na) of the renal cranial parts in the 3D-CRT group was significantly reduced

  2. Intensity-Modulated Radiotherapy Causes Fewer Side Effects than Three-Dimensional Conformal Radiotherapy When Used in Combination With Brachytherapy for the Treatment of Prostate Cancer

    International Nuclear Information System (INIS)

    Forsythe, Kevin; Blacksburg, Seth; Stone, Nelson; Stock, Richard G.

    2012-01-01

    Purpose: To measure the benefits of intensity-modulated radiotherapy (IMRT) compared with three-dimensional conformal radiotherapy (3D-CRT) when used in combination with brachytherapy for the treatment of prostate cancer. Methods and Materials: We conducted a retrospective review of all patients with localized prostate cancer who received external-beam radiotherapy (EBRT) in combination with brachytherapy with at least 1 year follow-up (n = 812). Combination therapy consisted of 103 Pd or 125 I implant, followed by a course of EBRT. From 1993 to March 2003 521 patients were treated with 3D-CRT, and from April 2003 to March 2009 291 patients were treated with IMRT. Urinary symptoms were prospectively measured with the International Prostate Symptom Score questionnaire with a single quality of life (QOL) question; rectal bleeding was assessed per the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Schema. The Pearson χ 2 test was used to compare toxicities experienced by patients who were treated with either IMRT or 3D-CRT. Logistic regression analyses were also performed to rule out possible confounding factors. Results: Within the first 3 months after treatment, patients treated with 3D-CRT scored their urinary symptoms as follows: 19% mild, 44% moderate, and 37% severe; patients treated with IMRT scored their urinary symptoms as follows: 36% mild, 47% moderate, and 17% severe (p < 0.001). The 3D-CRT patients rated their QOL as follows: 35% positive, 20% neutral, and 45% negative; IMRT patients rated their QOL as follows: 51% positive, 18% neutral, and 31% negative (p < 0.001). After 1 year of follow-up there was no longer any difference in urinary morbidity between the two groups. Logistic regression confirmed the differences in International Prostate Symptom Score and QOL in the acute setting (p < 0.001 for both). Grade ≥2 rectal bleeding was reported by 11% of 3D-CRT patients and 7

  3. Volumetric intensity-modulated arc therapy vs. 3-dimensional conformal radiotherapy for primary chemoradiotherapy of anal carcinoma. Effects on treatment-related side effects and survival

    Energy Technology Data Exchange (ETDEWEB)

    Weber, Hanne Elisabeth; Droege, Leif Hendrik; Hennies, Steffen; Herrmann, Markus Karl; Wolff, Hendrik Andreas [University Medical Center Goettingen, Dept. of Radiotherapy and Radiooncology, Goettingen (Germany); Gaedcke, Jochen [University Medical Center Goettingen, Dept. of General Surgery, Goettingen (Germany)

    2015-11-15

    Primary chemoradiotherapy (CRT) is the standard treatment for locally advanced anal carcinoma. This study compared volumetric intensity-modulated arc therapy (VMAT) to 3-dimensional conformal radiotherapy (3DCRT) in terms of treatment-related side effects and survival. From 1992-2014, 103 consecutive patients with anal carcinoma UICC stage I-III were treated. Concomitant CRT consisted of whole pelvic irradiation, including the iliac and inguinal lymph nodes, with 50.4 Gy (1.8 Gy per fractions) by VMAT (n = 17) or 3DCRT (n = 86) as well as two cycles of 5-fluorouracil and mitomycin C. Acute organ and hematological toxicity were assessed according to the Common Terminology Criteria (CTC) for Adverse Events version 3.0. Side effects ≥ grade 3 were scored as high-grade toxicity. High-grade acute organ toxicity CTC ≥ 3 (P < 0.05), especially proctitis (P = 0.03), was significantly reduced in VMAT patients. The 2-year locoregional control (LRC) and disease-free survival (DFS) were both 100 % for VMAT patients compared with 80 and 73 % for 3DCRT patients. VMAT was shown to be a feasible technique, achieving significantly lower rates of acute organ toxicity and promising results for LRC and DFS. Future investigations will aim at assessing the advantages of VMAT with respect to late toxicity and survival after a prolonged follow-up time. (orig.) [German] Die primaere Radiochemotherapie (RCT) gilt als Standardtherapie fuer lokal fortgeschrittene Analkarzinome. In dieser Studie wurde die volumetrisch modulierte Rotationstherapie (''volumetric intensity-modulated arc therapy'', VMAT) mit der klassischen dreidimensionalen konformalen Radiotherapie (3DCRT) hinsichtlich therapieassoziierter Nebenwirkungen und Ueberleben verglichen. Von 1992-2014 wurden 103 aufeinanderfolgende Patienten mit einem Analkarzinom im UICC-Stadium I-III behandelt. Die kombinierte RCT bestand aus der Bestrahlung des gesamten Beckens inklusive der iliakalen und der inguinalen

  4. Cys-X scanning for expansion of active-site residues and modulation of catalytic functions in a glutathione transferase.

    Science.gov (United States)

    Norrgård, Malena A; Hellman, Ulf; Mannervik, Bengt

    2011-05-13

    We propose Cys-X scanning as a semisynthetic approach to engineer the functional properties of recombinant proteins. As in the case of Ala scanning, key residues in the primary structure are identified, and one of them is replaced by Cys via site-directed mutagenesis. The thiol of the residue introduced is subsequently modified by alternative chemical reagents to yield diverse Cys-X mutants of the protein. This chemical approach is orthogonal to Ala or Cys scanning and allows the expansion of the repertoire of amino acid side chains far beyond those present in natural proteins. In its present application, we have introduced Cys-X residues in human glutathione transferase (GST) M2-2, replacing Met-212 in the substrate-binding site. To achieve selectivity of the modifications, the Cys residues in the wild-type enzyme were replaced by Ala. A suite of simple substitutions resulted in a set of homologous Met derivatives ranging from normethionine to S-heptyl-cysteine. The chemical modifications were validated by HPLC and mass spectrometry. The derivatized mutant enzymes were assayed with alternative GST substrates representing diverse chemical reactions: aromatic substitution, epoxide opening, transnitrosylation, and addition to an ortho-quinone. The Cys substitutions had different effects on the alternative substrates and differentially enhanced or suppressed catalytic activities depending on both the Cys-X substitution and the substrate assayed. As a consequence, the enzyme specificity profile could be changed among the alternative substrates. The procedure lends itself to large-scale production of Cys-X modified protein variants.

  5. Recursion Relations for Conformal Blocks

    CERN Document Server

    Penedones, João; Yamazaki, Masahito

    2016-09-12

    In the context of conformal field theories in general space-time dimension, we find all the possible singularities of the conformal blocks as functions of the scaling dimension $\\Delta$ of the exchanged operator. In particular, we argue, using representation theory of parabolic Verma modules, that in odd spacetime dimension the singularities are only simple poles. We discuss how to use this information to write recursion relations that determine the conformal blocks. We first recover the recursion relation introduced in 1307.6856 for conformal blocks of external scalar operators. We then generalize this recursion relation for the conformal blocks associated to the four point function of three scalar and one vector operator. Finally we specialize to the case in which the vector operator is a conserved current.

  6. Comparing two strategies of dynamic intensity modulated radiation therapy (dIMRT) with 3-dimensional conformal radiation therapy (3DCRT) in the hypofractionated treatment of high-risk prostate cancer

    International Nuclear Information System (INIS)

    Yuen, Jasper; Rodrigues, George; Trenka, Kristina; Coad, Terry; Yartsev, Slav; D'Souza, David; Lock, Michael; Bauman, Glenn

    2008-01-01

    To compare two strategies of dynamic intensity modulated radiation therapy (dIMRT) with 3-dimensional conformal radiation therapy (3DCRT) in the setting of hypofractionated high-risk prostate cancer treatment. 3DCRT and dIMRT/Helical Tomotherapy(HT) planning with 10 CT datasets was undertaken to deliver 68 Gy in 25 fractions (prostate) and simultaneously delivering 45 Gy in 25 fractions (pelvic lymph node targets) in a single phase. The paradigms of pelvic vessel targeting (iliac vessels with margin are used to target pelvic nodes) and conformal normal tissue avoidance (treated soft tissues of the pelvis while limiting dose to identified pelvic critical structures) were assessed compared to 3DCRT controls. Both dIMRT/HT and 3DCRT solutions were compared to each other using repeated measures ANOVA and post-hoc paired t-tests. When compared to conformal pelvic vessel targeting, conformal normal tissue avoidance delivered more homogenous PTV delivery (2/2 t-test comparisons; p < 0.001), similar nodal coverage (8/8 t-test comparisons; p = ns), higher and more homogenous pelvic tissue dose (6/6 t-test comparisons; p < 0.03), at the cost of slightly higher critical structure dose (D dose , 1–3 Gy over 5/10 dose points; p < 0.03). The dIMRT/HT approaches were superior to 3DCRT in sparing organs at risk (22/24 t-test comparisons; p < 0.05). dIMRT/HT nodal and pelvic targeting is superior to 3DCRT in dose delivery and critical structure sparing in the setting of hypofractionation for high-risk prostate cancer. The pelvic targeting paradigm is a potential solution to deliver highly conformal pelvic radiation treatment in the setting of nodal location uncertainty in prostate cancer and other pelvic malignancies

  7. Encouraging Early Clinical Outcomes With Helical Tomotherapy–Based Image-Guided Intensity-Modulated Radiation Therapy for Residual, Recurrent, and/or Progressive Benign/Low-Grade Intracranial Tumors: A Comprehensive Evaluation

    International Nuclear Information System (INIS)

    Gupta, Tejpal; Wadasadawala, Tabassum; Master, Zubin; Phurailatpam, Reena; Pai-Shetty, Rajershi; Jalali, Rakesh

    2012-01-01

    Purpose: To report early clinical outcomes of helical tomotherapy (HT)-based image-guided intensity-modulated radiation therapy (IMRT) in brain tumors of varying shape, size, and location. Materials and Methods: Patients with residual, recurrent, and/or progressive low-grade intracranial and skull-base tumors were treated on a prospective protocol of HT-based IMRT and followed clinicoradiologically. Standardized metrics were used for plan evaluation and outcome analysis. Results: Twenty-seven patients with 30 lesions were treated to a median radiotherapy dose of 54 Gy in 30 fractions. All HT plans resulted in excellent target volume coverage with steep dose-gradients. The mean (standard deviation) dose homogeneity index and conformity index was 0.07 (0.05) and 0.71 (0.08) respectively. At first response assessment, 20 of 30 lesions were stable, whereas 9 showed partial regression. One patient with a recurrent clival chordoma though neurologically stable showed imaging-defined progression, whereas another patient with stable disease on serial imaging had sustained neurologic worsening. With a median follow-up of 19 months (interquartile range, 11–26 months), the 2-year clinicoradiological progression-free survival and overall survival was 93.3% and 100% respectively. Conclusions: Careful selection of radiotherapy technique is warranted for benign/low-grade brain tumors to achieve durable local control with minimum long-term morbidity. Large or complex-shaped tumors benefit most from IMRT. Our early clinical experience of HT-based IMRT for brain tumors has been encouraging.

  8. Encouraging Early Clinical Outcomes With Helical Tomotherapy-Based Image-Guided Intensity-Modulated Radiation Therapy for Residual, Recurrent, and/or Progressive Benign/Low-Grade Intracranial Tumors: A Comprehensive Evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Gupta, Tejpal [Department of Radiation Oncology, ACTREC/TMH, Tata Memorial Centre, Kharghar, Navi Mumbai (India); Wadasadawala, Tabassum; Master, Zubin; Phurailatpam, Reena; Pai-Shetty, Rajershi; Jalali, Rakesh [Department of Radiation Oncology, ACTREC/TMH, Tata Memorial Centre, Kharghar, Navi Mumbai (India)

    2012-02-01

    Purpose: To report early clinical outcomes of helical tomotherapy (HT)-based image-guided intensity-modulated radiation therapy (IMRT) in brain tumors of varying shape, size, and location. Materials and Methods: Patients with residual, recurrent, and/or progressive low-grade intracranial and skull-base tumors were treated on a prospective protocol of HT-based IMRT and followed clinicoradiologically. Standardized metrics were used for plan evaluation and outcome analysis. Results: Twenty-seven patients with 30 lesions were treated to a median radiotherapy dose of 54 Gy in 30 fractions. All HT plans resulted in excellent target volume coverage with steep dose-gradients. The mean (standard deviation) dose homogeneity index and conformity index was 0.07 (0.05) and 0.71 (0.08) respectively. At first response assessment, 20 of 30 lesions were stable, whereas 9 showed partial regression. One patient with a recurrent clival chordoma though neurologically stable showed imaging-defined progression, whereas another patient with stable disease on serial imaging had sustained neurologic worsening. With a median follow-up of 19 months (interquartile range, 11-26 months), the 2-year clinicoradiological progression-free survival and overall survival was 93.3% and 100% respectively. Conclusions: Careful selection of radiotherapy technique is warranted for benign/low-grade brain tumors to achieve durable local control with minimum long-term morbidity. Large or complex-shaped tumors benefit most from IMRT. Our early clinical experience of HT-based IMRT for brain tumors has been encouraging.

  9. Residues in the 5th module of the low-density lipoprotein receptor that bind apoE and apoB-100

    International Nuclear Information System (INIS)

    Kroon, P.A.; Zhang, H.-Y.; Smith, R.

    2000-01-01

    Full text: The low-density lipoprotein receptor (LDLR) binds and removes cholesterol-rich lipoproteins from the circulation. Its ligand-binding (LB) domain consists of seven cysteine-rich LB modules that bind apoB-100 and apoE. These modules fold into well-defined structures with three disulfide bonds, in the presence of Ca 2+ . The 5th module (LB5) is unique in that it is required to bind both apoB-100 and apoE. The aim of the current study was to map residues in human LB5 that are required for ligand binding. This was done by alanine mutagenesis of a series of residues that are conserved in human, mouse, rat and rabbit LB5 (E9, S14, E16, H19, S21, K31, and K33), but not in the other six modules. E37 (R37 in the rabbit) was included, since it has been previously hypothesized to play a role in binding. The variant LB5 modules were first produced as recombinant peptides, and subjected to oxidative folding to determine whether the mutations interfered with Ca 2+ '-dependent folding. Only the S14A and E16A mutations interfered significantly with folding, suggesting that S14 and E16 are required for the structural framework of LB5 and that their substitution in the LDLR may interfere with its folding. The native LDLR and E9A, H19A, S21A, K31A, K33A and E37A LDLRs were expressed in LDLR negative IdlA-7 CHO cells. Labeling with 125 I-lgG-C7 showed that all receptors were expressed on the cell surface. Binding of Dil-labeled LDL (Dil-LDL) and Dil-labeled DMPC, complexed with the N-terminal receptor-binding domain of apoE3 (Dil-E3), at 4 deg C, was used to assess receptor binding. Binding of Dil-E3 (0.1 μ/ml) to the H19A, S21A, K31A, K33A and E37A LDLRs was 65-92% of binding to the native LDLR. In contrast, the E9A LDLR only bound 3% of that of the native LDLR. The binding of Dil-LDL (0.5 Ag/ml) to the E9A LDLR was 23% of that of the native LDLR, while binding to the remaining variant LDLRs ranged from 44-70% of what of the native LDLR. We conclude that (i) E9 of LB5

  10. Late xerostomia after intensity-modulated conformational radiotherapy of upper aero-digestive tract cancers: study 2004-03 by the head and neck oncology and radiotherapy Group (Gortec)

    International Nuclear Information System (INIS)

    Toledano, I.; Lapeyre, M.; Graff, P.; Serre, C.; Bensadoun, R.J.; Bensadoun, R.J.; Ortholan, C.; Calais, G.; Alfonsi, M.; Giraud, P.; Racadot, S.

    2010-01-01

    The authors report a retrospective assessment of late xerostomia according to the RTOG (Radiation Therapy Oncology Group) classification of the European Organization for Research and Treatment of Cancer (EORTC) among patients treated by intensity-modulated conformational radiotherapy (IMRT) and suffering from upper aero-digestive tract carcinomas of different stages. Some of these patients have bee operated, and some have been treated by chemotherapy. It appears that the IMRT results in a reduction of late xerostomia, and even in an absence of salivary toxicity. Short communication

  11. Prognosis comparison of three-dimensional conformal radiotherapy/intensity modulated radiation therapy for esophageal carcinoma with local regional lymph node metastasis

    International Nuclear Information System (INIS)

    Wang Yuxiang; Wang Jun; Wang Yi; Tian Dandan; Yang Jie; Zhu Shuchai

    2011-01-01

    Objective: To explore the prognosis and related factor of esophageal carcinoma with locoregional lymph node metastasis (N 1 ) treated with three-dimensional conformal radiotherapy (3DCRT) or intensity modulated radiation therapy (IMRT). Methods: From January 2001 to December 2008, 60 patients of esophageal carcinoma with local regional lymph node metastasis were treated with 3DCRT and 52 with IMRT. For all patients,dose of tumor was 56 - 70 Gy/28 - 35 fraction/5.6 - 7.0 weeks. Among them, 58 cases was treated with chemotherapy including cisplatin and 5-fluorouracil; 40 with concurrent chemoradiotherapy and 18 with sequential radiotherapy and chemotherapy. Results: After radiotherapy,the total efficiency rate was 98.2%, 96.7% in 3DCRT and 100% in IMRT (χ 2 =1.77, P =0.184). The follow-up rate was 99.1%. The number of patients completed follow-up were 68 and 53, respectively at 2-year and 3-year. The 1 and 3-year overall survival rates were 62.5%, 23.7%, respectively; the median survival time was 17 months. The 1 and 3-year survival rates and median were 52%, 19% and 12.4 months in 3DCRT and 75%, 40% and 17 months in IMRT, respectively (χ 2 =4.74, P =0.030). The 1 and 3-year free-recurrence survival rates were 64%, 45% in 3DCRT and 72%, 59% in IMRT (χ 2 =2.27, P =0.132), respectively. With univariate analysis, for female, ages ≤ 65, tumor located in cervical and upper-thoracic, >5 cm lesion length in barium esophagogram, ≤4 cm the largest diameter of lesion in CT scanning image, T 4 stage, or semiliquid or liquid diet before radiotherapy, survival rate were higher in IMRT than in 3DCRT group (χ 2 =4.63, 5.56, 7.19, 5.08, 4.43, 4.48, 8.25; P=0.031, 0.018, 0.007, 0.025, 0.035, 0.034, 0.004, respectively); but for male, ages > 65, tumor located in middle and lower-thoracic, ≤5 cm lesion length in barium esophagogram, >4 cm the largest diameter of lesion in CT scanning image, T 1-3 stage, or normal diet before radiotherapy, chemotherapy and dose of radiotherapy

  12. The study of treatment value of concurrent chemotherapy for patients with esophageal carcinoma received three-dimensional conformal radiotherapy or intensity modulated radiotherapy

    International Nuclear Information System (INIS)

    Wang Lan; Wang Jun; Han Chun; Zhang Jing; Li Xiaoning; Gao Chao

    2011-01-01

    Objective: To observe the acute side effects, local control rate and survival rate of concurrent chemoradiotherapy (CC) and radiotherapy alone (R) for patients with esophageal carcinoma. Methods: From June 2006 to February 2009, 209 patients with esophageal carcinoma were observed, 105 of them were treated with CC. Of all the patients, 117 received three-dimensional conformal radiotherapy, 92 received intensity modulated radiotherapy, the median prescription dose was 60 Gy. The regimen of LFP (5-FU, cisplatin and calcium folinate) was selected for this study, side effects, local control rate and survival rate were observed and subsets analysis were performed. Results: The overall follow-up rate was 99.0%,there were 99 and 44 patients whose follow-up time was more than 2 and 3 years, respectively;for the CC group, the data were 45 and 14, respectively; and for the R group, 54 and 30, respectively. The 1-, 2-, 3-year local control rates of CC group and R group were 88.1%, 69.2%, 66.2% and 81.0%, 64.0%, 54.9% (χ 2 =2.31, P=0.128), respectively. The 1-, 2-, 3-year overall survival rates of CC group and R group were 84.4%, 52.9%, 45.6% and 75.2%, 50.7%, 37.0%(χ 2 =1.57, P=0.210), respectively. Subset analysis indicated that for the patients of N 0 group and whose length of GTV >7 cm, the local control rate of CC was significantly higher than that of radiotherapy alone (χ 2 =5.11, 7.66; P=0.024, 0.006). For N 0 group, the survival rate of CC was higher than that of R alone. (χ 2 =5.07, P=0.024). The incidence of WBC, PLT and HGB reduction for the two groups were 81.9% and 49.0% (χ 2 =36.45, P=0.000), 14.3% and 1.9% (χ 2 =10.54, P=0.006), and 24.8% and 2.9% (χ 2 =22.95, P=0.000), respectively. The incidence of nausea, vomiting and constipation for the two groups were 63.8% and 7.7% (χ 2 =71.52, P=0.000), respectively. The incidence of ≥2 grade esophagitis of CC group and R group were 48.57% and 38.46% (χ 2 =2.17, P=0.141), respectively. The incidence of ≥2

  13. Prostate and seminal vesicle volume based consideration of prostate cancer patients for treatment with 3D-conformal or intensity-modulated radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Reddy, Nandanuri M. S.; Nori, Dattatreyudu; Chang, Hyesook; Lange, Christopher S.; Ravi, Akkamma [Department of Radiation Oncology, New York Hospital Queens, Flushing, New York 11355 (United States); Department of Radiation Oncology, State University of New York Downstate Medical Center, Brooklyn, New York 11203 (United States); Department of Radiation Oncology, New York Hospital Queens, Flushing, New York 11355 (United States)

    2010-07-15

    Purpose: The purpose of this article was to determine the suitability of the prostate and seminal vesicle volumes as factors to consider patients for treatment with image-guided 3D-conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT), using common dosimetry parameters as comparison tools. Methods: Dosimetry of 3D and IMRT plans for 48 patients was compared. Volumes of prostate, SV, rectum, and bladder, and prescriptions were the same for both plans. For both 3D and IMRT plans, expansion margins to prostate+SV (CTV) and prostate were 0.5 cm posterior and superior and 1 cm in other dimensions to create PTV and CDPTV, respectively. Six-field 3D plans were prepared retrospectively. For 3D plans, an additional 0.5 cm margin was added to PTV and CDPTV. Prescription for both 3D and IMRT plans was the same: 45 Gy to CTV followed by a 36 Gy boost to prostate. Dosimetry parameters common to 3D and IMRT plans were used for comparison: Mean doses to prostate, CDPTV, SV, rectum, bladder, and femurs; percent volume of rectum and bladder receiving 30 (V30), 50 (V50), and 70 Gy (V70), dose to 30% of rectum and bladder, minimum and maximum point dose to CDPTV, and prescription dose covering 95% of CDPTV (D95). Results: When the data for all patients were combined, mean dose to prostate and CDPTV was higher with 3D than IMRT plans (P<0.01). Mean D95 to CDPTV was the same for 3D and IMRT plans (P>0.2). On average, among all cases, the minimum point dose was less for 3D-CRT plans and the maximum point dose was greater for 3D-CRT than for IMRT (P<0.01). Mean dose to 30% rectum with 3D and IMRT plans was comparable (P>0.1). V30 was less (P<0.01), V50 was the same (P>0.2), and V70 was more (P<0.01) for rectum with 3D than IMRT plans. Mean dose to bladder was less with 3D than IMRT plans (P<0.01). V30 for bladder with 3D plans was less than that of IMRT plans (P<0.01). V50 and V70 for 3D plans were the same for 3D and IMRT plans (P>0.2). Mean dose to femurs

  14. Conformality lost

    International Nuclear Information System (INIS)

    Kaplan, David B.; Lee, Jong-Wan; Son, Dam T.; Stephanov, Mikhail A.

    2009-01-01

    We consider zero-temperature transitions from conformal to nonconformal phases in quantum theories. We argue that there are three generic mechanisms for the loss of conformality in any number of dimensions: (i) fixed point goes to zero coupling, (ii) fixed point runs off to infinite coupling, or (iii) an IR fixed point annihilates with a UV fixed point and they both disappear into the complex plane. We give both relativistic and nonrelativistic examples of the last case in various dimensions and show that the critical behavior of the mass gap behaves similarly to the correlation length in the finite temperature Berezinskii-Kosterlitz-Thouless (BKT) phase transition in two dimensions, ξ∼exp(c/|T-T c | 1/2 ). We speculate that the chiral phase transition in QCD at large number of fermion flavors belongs to this universality class, and attempt to identify the UV fixed point that annihilates with the Banks-Zaks fixed point at the lower end of the conformal window.

  15. Identification and modulation of the key amino acid residue responsible for the pH sensitivity of neoculin, a taste-modifying protein.

    Directory of Open Access Journals (Sweden)

    Ken-ichiro Nakajima

    Full Text Available Neoculin occurring in the tropical fruit of Curculigo latifolia is currently the only protein that possesses both a sweet taste and a taste-modifying activity of converting sourness into sweetness. Structurally, this protein is a heterodimer consisting of a neoculin acidic subunit (NAS and a neoculin basic subunit (NBS. Recently, we found that a neoculin variant in which all five histidine residues are replaced with alanine elicits intense sweetness at both neutral and acidic pH but has no taste-modifying activity. To identify the critical histidine residue(s responsible for this activity, we produced a series of His-to-Ala neoculin variants and evaluated their sweetness levels using cell-based calcium imaging and a human sensory test. Our results suggest that NBS His11 functions as a primary pH sensor for neoculin to elicit taste modification. Neoculin variants with substitutions other than His-to-Ala were further analyzed to clarify the role of the NBS position 11 in the taste-modifying activity. We found that the aromatic character of the amino acid side chain is necessary to elicit the pH-dependent sweetness. Interestingly, since the His-to-Tyr variant is a novel taste-modifying protein with alternative pH sensitivity, the position 11 in NBS can be critical to modulate the pH-dependent activity of neoculin. These findings are important for understanding the pH-sensitive functional changes in proteinaceous ligands in general and the interaction of taste receptor-taste substance in particular.

  16. SCit: web tools for protein side chain conformation analysis.

    Science.gov (United States)

    Gautier, R; Camproux, A-C; Tufféry, P

    2004-07-01

    SCit is a web server providing services for protein side chain conformation analysis and side chain positioning. Specific services use the dependence of the side chain conformations on the local backbone conformation, which is described using a structural alphabet that describes the conformation of fragments of four-residue length in a limited library of structural prototypes. Based on this concept, SCit uses sets of rotameric conformations dependent on the local backbone conformation of each protein for side chain positioning and the identification of side chains with unlikely conformations. The SCit web server is accessible at http://bioserv.rpbs.jussieu.fr/SCit.

  17. Health-Related Quality of Life in Patients With Locally Advanced Prostate Cancer After 76 Gy Intensity-Modulated Radiotherapy vs. 70 Gy Conformal Radiotherapy in a Prospective and Longitudinal Study

    International Nuclear Information System (INIS)

    Lips, Irene; Dehnad, Human; Kruger, Arto Boeken; Moorselaar, Jeroen van; Heide, Uulke van; Battermann, Jan; Vulpen, Marco van

    2007-01-01

    Purpose: To compare quality of life (QoL) after 70 Gy conformal radiotherapy with QoL after 76 Gy intensity-modulated radiotherapy (IMRT) in patients with locally advanced prostate carcinoma. Methods and Materials: Seventy-eight patients with locally advanced prostate cancer were treated with 70 Gy three-field conformal radiotherapy, and 92 patients received 76 Gy IMRT with fiducial markers for position verification. Quality of life was measured by RAND-36, the European Organization for Research and Treatment of Cancer core questionnaire (EORTC QLQ-C30(+3)), and the prostate-specific EORTC QLQ-PR25, before radiotherapy (baseline) and 1 month and 6 months after treatment. Quality of life changes in time (baseline vs. 1 month and baseline vs. 6 months) of ≥10 points were considered clinically relevant. Results: Differences between the treatment groups for QoL changes over time occurred in several QoL domains. The 76-Gy group revealed no significant deterioration in QoL compared with the 70-Gy group. The IMRT 76-Gy group even demonstrated a significantly better change in QoL from baseline to 1 month in several domains. The conformal 70-Gy group revealed temporary deterioration in pain, role functioning, and urinary symptoms; for the IMRT 76-Gy group a better QoL in terms of change in health existed after 1 month, which persisted after 6 months. For both treatment groups temporary deterioration in physical role restriction occurred after 1 month, and an improvement in emotional role restriction occurred after 6 months. Sexual activity was reduced after treatment for both groups and remained decreased after 6 months. Conclusions: Intensity-modulated radiotherapy and accurate position verification seem to provide a possibility to increase the radiation dose for prostate cancer without deterioration in QoL

  18. Design of a compressed air modulator to be used in comprehensive multidimensional gas chromatography and its application in the determination of pesticide residues in grapes.

    Science.gov (United States)

    Pizzutti, Ionara R; Vreuls, René J J; de Kok, André; Roehrs, Rafael; Martel, Samile; Friggi, Caroline A; Zanella, Renato

    2009-04-10

    In this study, a new modulator that is simple, robust and presents low operation costs, was developed. This modulator uses compressed air to cool two small portions in the first centimeters of the second chromatographic column of a comprehensive multidimensional gas chromatography (GCxGC) system. The results show a variation in the peak area less than 3 and 5% to alkanes and pesticides, respectively. The standard deviations for the retention times in the first and second dimension are around 0.05 min and 0.05s for all the compounds. The system was optimized with n-alkanes. The GCxGC system proposed was applied in the determination of pyrethroid pesticides (bifenthrin, cypermethrin, deltamethrin, fenvalerate, esfenvalerate, cis- and trans-permethrin) in grape samples. Samples were extracted by the mini-Luke modified method and pesticides were quantified by comprehensive multidimensional gas chromatography with micro electron-capture detection (microECD). The values of method limit of quantification (LOQ) were 0.01-0.02 mg kg(-1) for all studied pyrethroid and the values of recovery were between 94.3 and 115.2%, with good precision (RSDcompressed air has the potential for application in the analysis of a wider range of pesticide residues in other commodities since it provides low values of LOQ with acceptable accuracy and precision.

  19. Conformational Clusters of Phosphorylated Tyrosine.

    Science.gov (United States)

    Abdelrasoul, Maha; Ponniah, Komala; Mao, Alice; Warden, Meghan S; Elhefnawy, Wessam; Li, Yaohang; Pascal, Steven M

    2017-12-06

    Tyrosine phosphorylation plays an important role in many cellular and intercellular processes including signal transduction, subcellular localization, and regulation of enzymatic activity. In 1999, Blom et al., using the limited number of protein data bank (PDB) structures available at that time, reported that the side chain structures of phosphorylated tyrosine (pY) are partitioned into two conserved conformational clusters ( Blom, N.; Gammeltoft, S.; Brunak, S. J. Mol. Biol. 1999 , 294 , 1351 - 1362 ). We have used the spectral clustering algorithm to cluster the increasingly growing number of protein structures with pY sites, and have found that the pY residues cluster into three distinct side chain conformations. Two of these pY conformational clusters associate strongly with a narrow range of tyrosine backbone conformation. The novel cluster also highly correlates with the identity of the n + 1 residue, and is strongly associated with a sequential pYpY conformation which places two adjacent pY side chains in a specific relative orientation. Further analysis shows that the three pY clusters are associated with distinct distributions of cognate protein kinases.

  20. A disulfide-stabilized conformer of methionine synthase reveals an unexpected role for the histidine ligand of the cobalamin cofactor

    Energy Technology Data Exchange (ETDEWEB)

    Datta, Supratim; Koutmos, Markos; Pattridge, Katherine A.; Ludwig, Martha L.; Matthews, Rowena G. (Michigan)

    2008-07-08

    B{sub 12}-dependent methionine synthase (MetH) from Escherichia coli is a large modular protein that is alternately methylated by methyltetrahydrofolate to form methylcobalamin and demethylated by homocysteine to form cob(I)alamin. Major domain rearrangements are required to allow cobalamin to react with three different substrates: homocysteine, methyltetrahydrofolate, and S-adenosyl-l-methionine (AdoMet). These same rearrangements appear to preclude crystallization of the wild-type enzyme. Disulfide cross-linking was used to lock a C-terminal fragment of the enzyme into a unique conformation. Cysteine point mutations were introduced at Ile-690 and Gly-743. These cysteine residues span the cap and the cobalamin-binding module and form a cross-link that reduces the conformational space accessed by the enzyme, facilitating protein crystallization. Here, we describe an x-ray structure of the mutant fragment in the reactivation conformation; this conformation enables the transfer of a methyl group from AdoMet to the cobalamin cofactor. In the structure, the axial ligand to the cobalamin, His-759, dissociates from the cobalamin and forms intermodular contacts with residues in the AdoMet-binding module. This unanticipated intermodular interaction is expected to play a major role in controlling the distribution of conformers required for the catalytic and the reactivation cycles of the enzyme.

  1. C-Terminal Tyrosine Residue Modifications Modulate the Protective Phosphorylation of Serine 129 of α-Synuclein in a Yeast Model of Parkinson's Disease.

    Science.gov (United States)

    Kleinknecht, Alexandra; Popova, Blagovesta; Lázaro, Diana F; Pinho, Raquel; Valerius, Oliver; Outeiro, Tiago F; Braus, Gerhard H

    2016-06-01

    Parkinson´s disease (PD) is characterized by the presence of proteinaceous inclusions called Lewy bodies that are mainly composed of α-synuclein (αSyn). Elevated levels of oxidative or nitrative stresses have been implicated in αSyn related toxicity. Phosphorylation of αSyn on serine 129 (S129) modulates autophagic clearance of inclusions and is prominently found in Lewy bodies. The neighboring tyrosine residues Y125, Y133 and Y136 are phosphorylation and nitration sites. Using a yeast model of PD, we found that Y133 is required for protective S129 phosphorylation and for S129-independent proteasome clearance. αSyn can be nitrated and form stable covalent dimers originating from covalent crosslinking of two tyrosine residues. Nitrated tyrosine residues, but not di-tyrosine-crosslinked dimers, contributed to αSyn cytotoxicity and aggregation. Analysis of tyrosine residues involved in nitration and crosslinking revealed that the C-terminus, rather than the N-terminus of αSyn, is modified by nitration and di-tyrosine formation. The nitration level of wild-type αSyn was higher compared to that of A30P mutant that is non-toxic in yeast. A30P formed more dimers than wild-type αSyn, suggesting that dimer formation represents a cellular detoxification pathway in yeast. Deletion of the yeast flavohemoglobin gene YHB1 resulted in an increase of cellular nitrative stress and cytotoxicity leading to enhanced aggregation of A30P αSyn. Yhb1 protected yeast from A30P-induced mitochondrial fragmentation and peroxynitrite-induced nitrative stress. Strikingly, overexpression of neuroglobin, the human homolog of YHB1, protected against αSyn inclusion formation in mammalian cells. In total, our data suggest that C-terminal Y133 plays a major role in αSyn aggregate clearance by supporting the protective S129 phosphorylation for autophagy and by promoting proteasome clearance. C-terminal tyrosine nitration increases pathogenicity and can only be partially detoxified by

  2. Energetically Unfavorable Amide Conformations for N6-Acetyllysine Side Chains in Refined Protein Structures

    Science.gov (United States)

    Genshaft, Alexander; Moser, Joe-Ann S.; D'Antonio, Edward L.; Bowman, Christine M.; Christianson, David W.

    2013-01-01

    The reversible acetylation of lysine to form N6-acetyllysine in the regulation of protein function is a hallmark of epigenetics. Acetylation of the positively charged amino group of the lysine side chain generates a neutral N-alkylacetamide moiety that serves as a molecular “switch” for the modulation of protein function and protein-protein interactions. We now report the analysis of 381 N6-acetyllysine side chain amide conformations as found in 79 protein crystal structures and 11 protein NMR structures deposited in the Protein Data Bank (PDB) of the Research Collaboratory for Structural Bioinformatics. We find that only 74.3% of N6-acetyllysine residues in protein crystal structures and 46.5% in protein NMR structures contain amide groups with energetically preferred trans or generously trans conformations. Surprisingly, 17.6% of N6-acetyllysine residues in protein crystal structures and 5.3% in protein NMR structures contain amide groups with energetically unfavorable cis or generously cis conformations. Even more surprisingly, 8.1% of N6-acetyllysine residues in protein crystal structures and 48.2% in NMR structures contain amide groups with energetically prohibitive twisted conformations that approach the transition state structure for cis-trans isomerization. In contrast, 109 unique N-alkylacetamide groups contained in 84 highly-accurate small molecule crystal structures retrieved from the Cambridge Structural Database exclusively adopt energetically preferred trans conformations. Therefore, we conclude that cis and twisted N6-acetyllysine amides in protein structures deposited in the PDB are erroneously modeled due to their energetically unfavorable or prohibitive conformations. PMID:23401043

  3. SU-F-P-52: A Meta-Analysis of Controlled Clinical Trials Comparing Elective Nodal Irradiation with Involved-Field Irradiation for Conformal Or Intensity-Modulated Radiotherapy in Patients with Esophageal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bai, W; Zhang, R; Zhou, Z; Qiao, X [The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei (China)

    2016-06-15

    Purpose: To compare elective nodal irradiation with involved-field irradiation for three-dimensional conformal radiotherapy or intensity-modulated radiotherapy in patients with esophageal cancer by a metaanalysis. Methods: Wanfang, CNKI, VIP, CBM databases, PubMed, Embase and Cochrane Library were searched to identify the controlled clinical trials of elective nodal irradiation with involved-field irradiation for three-dimensional conformal radiotherapy or intensity-modulated radiotherapy in patients with esophageal cancer. The obtained data were analyzed using Stata 11.0. The difference between two groups was estimated by calculating the odds ratio (OR) with 95% confidence interval (95% CI). Results: A total of 12 controlled clinical trials involving 1095 esophageal cancer patients, which were selected according to inclusion and exclusion criteria, were included in this meta-analysis. The meta-analysis showed that the elective nodal irradiation group reduced the rates of out-field failure comparing with involved-field irradiation group (OR=3.727, P=0.007). However, the rates of ≥grades 3 acute radiation pneumonitis and esophagitis were significantly higher in the elective nodal irradiation group than in the involved-field irradiation group (OR=0.348, P=0.001, OR=0.385, P=0.000). 1-, 2-, 3-year local control rates (OR=0.966, P=0.837, OR=0.946, P=0.781; OR=0.732P=0.098) and 1-, 3-, 5-year survival rates were similar in the two groups ( OR=0.966, P=0.837; OR=0.946, P=0.781; OR=0.732, P=0.098; OR=0.952, P=0.756; OR=1.149, P=0.422; OR=0.768, P=0.120). It is the same with the rates of distant metastasis (OR=0.986, P=0.937). Conclusion: Compared with involved-field irradiation, the elective nodal irradiation can reduce the rates of out-field failure for three-dimensional conformal radiotherapy or intensity-modulated radiotherapy in patients with esophageal cancer. However, its advantage of local control and survival rates is not obvious and it increases the incidence

  4. Impact of residual setup error on parotid gland dose in intensity-modulated radiation therapy with or without planning organ-at-risk margin

    International Nuclear Information System (INIS)

    Delana, Anna; Menegotti, Loris; Valentini, Aldo; Bolner, Andrea; Tomio, Luigi; Vanoni, Valentina; Lohr, Frank

    2009-01-01

    Purpose: To estimate the dosimetric impact of residual setup errors on parotid sparing in head-and-neck (H and N) intensity-modulated treatments and to evaluate the effect of employing an PRV (planning organ-at-risk volume) margin for the parotid gland. Patients and methods: Ten patients treated for H and N cancer were considered. A nine-beam intensity-modulated radiotherapy (IMRT) was planned for each patient. A second optimization was performed prescribing dose constraint to the PRV of the parotid gland. Systematic setup errors of 2 mm, 3 mm, and 5 mm were simulated. The dose-volume histograms of the shifted and reference plans were compared with regard to mean parotid gland dose (MPD), normal-tissue complication probability (NTCP), and coverage of the clinical target volume (V 95% and equivalent uniform dose [EUD]); the sensitivity of parotid sparing on setup error was evaluated with a probability-based approach. Results: MPD increased by 3.4%/mm and 3.0%/mm for displacements in the craniocaudal and lateral direction and by 0.7%/mm for displacements in the anterior-posterior direction. The probability to irradiate the parotid with a mean dose > 30 Gy was > 50%, for setup errors in cranial and lateral direction and 95% and EUD variations < 1% and < 1 Gy). Conclusion: The parotid gland is more sensitive to craniocaudal and lateral displacements. A setup error of 2 mm guarantees an MPD ≤ 30 Gy in most cases, without adding a PRV margin. If greater displacements are expected/accepted, an adequate PRV margin could be used to meet the clinical parotid gland constraint of 30 Gy, without affecting target volume coverage. (orig.)

  5. Acute Toxicity After Image-Guided Intensity Modulated Radiation Therapy Compared to 3D Conformal Radiation Therapy in Prostate Cancer Patients

    NARCIS (Netherlands)

    Wortel, Ruud C.; Incrocci, Luca; Pos, Floris J.; Lebesque, Joos V.; Witte, Marnix G.; van der Heide, Uulke A.; van Herk, Marcel; Heemsbergen, Wilma D.

    2015-01-01

    Purpose: Image-guided intensity modulated radiation therapy (IG-IMRT) allows significant dose reductions to organs at risk in prostate cancer patients. However, clinical data identifying the benefits of IG-IMRT in daily practice are scarce. The purpose of this study was to compare dose distributions

  6. Conformal Tachyons

    CERN Document Server

    Tomaschitz, R

    2000-01-01

    We study tachyons conformally coupled to the background geometry of a Milne universe. The causality of superluminal signal transfer is scrutinized in this context. The cosmic time of the comoving frame determines a distinguished time order for events connected by superluminal signals. An observer can relate his rest frame to the galaxy frame, and compare so the time order of events in his proper time to the cosmic time order. All observers can in this way arrive at identical conclusions on the causality of events connected by superluminal signals. An unambiguous energy concept for tachyonic rays is defined by means of the cosmic time of the comoving reference frame, without resorting to an antiparticle interpretation. On that basis we give an explicit proof that no signals can be sent into the past of observers. Causality violating signals are energetically forbidden, as they would have negative energy in the rest frame of the emitting observer. If an observer emits a superluminal signal, the tachyonic respon...

  7. Conformal field theory in conformal space

    International Nuclear Information System (INIS)

    Preitschopf, C.R.; Vasiliev, M.A.

    1999-01-01

    We present a new framework for a Lagrangian description of conformal field theories in various dimensions based on a local version of d + 2-dimensional conformal space. The results include a true gauge theory of conformal gravity in d = (1, 3) and any standard matter coupled to it. An important feature is the automatic derivation of the conformal gravity constraints, which are necessary for the analysis of the matter systems

  8. Use of hydrostatic pressure for modulation of protein chemical modification and enzymatic selectivity.

    Science.gov (United States)

    Makarov, Alexey A; Helmy, Roy; Joyce, Leo; Reibarkh, Mikhail; Maust, Mathew; Ren, Sumei; Mergelsberg, Ingrid; Welch, Christopher J

    2016-05-11

    Using hydrostatic pressure to induce protein conformational changes can be a powerful tool for altering the availability of protein reactive sites and for changing the selectivity of enzymatic reactions. Using a pressure apparatus, it has been demonstrated that hydrostatic pressure can be used to modulate the reactivity of lysine residues of the protein ubiquitin with a water-soluble amine-specific homobifunctional coupling agent. Fewer reactive lysine residues were observed when the reaction was carried out under elevated pressure of 3 kbar, consistent with a pressure-induced conformational change of ubiquitin that results in fewer exposed lysine residues. Additionally, modulation of the stereoselectivity of an enzymatic transamination reaction was observed at elevated hydrostatic pressure. In one case, the minor diasteromeric product formed at atmospheric pressure became the major product at elevated pressure. Such pressure-induced alterations of protein reactivity may provide an important new tool for enzymatic reactions and the chemical modification of proteins.

  9. Differential conformational modulations of MreB folding upon interactions with GroEL/ES and TRiC chaperonin components

    Science.gov (United States)

    Moparthi, Satish Babu; Carlsson, Uno; Vincentelli, Renaud; Jonsson, Bengt-Harald; Hammarström, Per; Wenger, Jérôme

    2016-01-01

    Here, we study and compare the mechanisms of action of the GroEL/GroES and the TRiC chaperonin systems on MreB client protein variants extracted from E. coli. MreB is a homologue to actin in prokaryotes. Single-molecule fluorescence correlation spectroscopy (FCS) and time-resolved fluorescence polarization anisotropy report the binding interaction of folding MreB with GroEL, GroES and TRiC. Fluorescence resonance energy transfer (FRET) measurements on MreB variants quantified molecular distance changes occurring during conformational rearrangements within folding MreB bound to chaperonins. We observed that the MreB structure is rearranged by a binding-induced expansion mechanism in TRiC, GroEL and GroES. These results are quantitatively comparable to the structural rearrangements found during the interaction of β-actin with GroEL and TRiC, indicating that the mechanism of chaperonins is conserved during evolution. The chaperonin-bound MreB is also significantly compacted after addition of AMP-PNP for both the GroEL/ES and TRiC systems. Most importantly, our results showed that GroES may act as an unfoldase by inducing a dramatic initial expansion of MreB (even more than for GroEL) implicating a role for MreB folding, allowing us to suggest a delivery mechanism for GroES to GroEL in prokaryotes. PMID:27328749

  10. The impact of computed tomography slice thickness on the assessment of stereotactic, 3D conformal and intensity-modulated radiotherapy of brain tumors.

    Science.gov (United States)

    Caivano, R; Fiorentino, A; Pedicini, P; Califano, G; Fusco, V

    2014-05-01

    To evaluate radiotherapy treatment planning accuracy by varying computed tomography (CT) slice thickness and tumor size. CT datasets from patients with primary brain disease and metastatic brain disease were selected. Tumor volumes ranging from about 2.5 to 100 cc and CT scan at different slice thicknesses (1, 2, 4, 6 and 10 mm) were used to perform treatment planning (1-, 2-, 4-, 6- and 10-CT, respectively). For any slice thickness, a conformity index (CI) referring to 100, 98, 95 and 90 % isodoses and tumor size was computed. All the CI and volumes obtained were compared to evaluate the impact of CT slice thickness on treatment plans. The smallest volumes reduce significantly if defined on 1-CT with respect to 4- and 6-CT, while the CT slice thickness does not affect target definition for the largest volumes. The mean CI for all the considered isodoses and CT slice thickness shows no statistical differences when 1-CT is compared to 2-CT. Comparing the mean CI of 1- with 4-CT and 1- with 6-CT, statistical differences appear only for the smallest volumes with respect to 100, 98 and 95 % isodoses-the CI for 90 % isodose being not statistically significant for all the considered PTVs. The accuracy of radiotherapy tumor volume definition depends on CT slice thickness. To achieve a better tumor definition and dose coverage, 1- and 2-CT would be suitable for small targets, while 4- and 6-CT are suitable for the other volumes.

  11. Conformational regulation of urokinase receptor function

    DEFF Research Database (Denmark)

    Gårdsvoll, Henrik; Jacobsen, Benedikte; Kriegbaum, Mette C

    2011-01-01

    PA per se into the hydrophobic ligand binding cavity of uPAR that modulates the function of this receptor. Based on these data, we now propose a model in which the inherent interdomain mobility in uPAR plays a major role in modulating its function. Particularly one uPAR conformation, which is stabilized...

  12. Comparison of anisotropic aperture based intensity modulated radiotherapy with 3D-conformal radiotherapy for the treatment of large lung tumors.

    Science.gov (United States)

    Simeonova, Anna; Abo-Madyan, Yasser; El-Haddad, Mostafa; Welzel, Grit; Polednik, Martin; Boggula, Ramesh; Wenz, Frederik; Lohr, Frank

    2012-02-01

    IMRT allows dose escalation for large lung tumors, but respiratory motion may compromise delivery. A treatment plan that modulates fluence predominantly in the transversal direction and leaves the fluence identical in the direction of the breathing motion may reduce this problem. Planning-CT-datasets of 20 patients with Stage I-IV non small cell lung cancer (NSCLC) formed the basis of this study. A total of two IMRT plans and one 3D plan were created for each patient. Prescription dose was 60 Gy to the CTV and 70 Gy to the GTV. For the 3D plans an energy of 18 MV photons was used. IMRT plans were calculated for 6 MV photons with 13 coplanar and with 17 noncoplanar beams. Robustness of the used method of anisotropic modulation toward breathing motion was tested in a 13-field IMRT plan. As a consequence of identical prescription doses, mean target doses were similar for 3D and IMRT. Differences between 3D and 13- and 17-field IMRT were significant for CTV Dmin (43 Gy vs. 49.1 Gy vs. 48.6 Gy; p3D: 12.5 Gy vs. 14.8 Gy vs. 15.8 Gy: p3D-plans. Heart D(max) was only marginally reduced with IMRT (3D vs. 13- vs. 17-field IMRT: 38.2 Gy vs. 36.8 Gy vs. 37.8 Gy). Simulated breathing motion caused only minor changes in the IMRT dose distribution (~0.5-1 Gy). Anisotropic modulation of IMRT improves dose delivery over 3D-RT and renders IMRT plans robust toward breathing induced organ motion, effectively preventing interplay effects. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  13. Conformational differences between the methoxy groups of QA and QB site ubisemiquinones in bacterial reaction centers: a key role for methoxy group orientation in modulating ubiquinone redox potential.

    Science.gov (United States)

    Taguchi, Alexander T; O'Malley, Patrick J; Wraight, Colin A; Dikanov, Sergei A

    2013-07-09

    Ubiquinone is an almost universal, membrane-associated redox mediator. Its ability to accept either one or two electrons allows it to function in critical roles in biological electron transport. The redox properties of ubiquinone in vivo are determined by its environment in the binding sites of proteins and by the dihedral angle of each methoxy group relative to the ring plane. This is an attribute unique to ubiquinone among natural quinones and could account for its widespread function with many different redox complexes. In this work, we use the photosynthetic reaction center as a model system for understanding the role of methoxy conformations in determining the redox potential of the ubiquinone/semiquinone couple. Despite the abundance of X-ray crystal structures for the reaction center, quinone site resolution has thus far been too low to provide a reliable measure of the methoxy dihedral angles of the primary and secondary quinones, QA and QB. We performed 2D ESEEM (HYSCORE) on isolated reaction centers with ubiquinones (13)C-labeled at the headgroup methyl and methoxy substituents, and have measured the (13)C isotropic and anisotropic components of the hyperfine tensors. Hyperfine couplings were compared to those derived by DFT calculations as a function of methoxy torsional angle allowing estimation of the methoxy dihedral angles for the semiquinones in the QA and QB sites. Based on this analysis, the orientation of the 2-methoxy groups are distinct in the two sites, with QB more out of plane by 20-25°. This corresponds to an ≈50 meV larger electron affinity for the QB quinone, indicating a substantial contribution to the experimental difference in redox potentials (60-75 mV) of the two quinones. The methods developed here can be readily extended to ubiquinone-binding sites in other protein complexes.

  14. Intensity modulated radiotherapy and 3D conformal radiotherapy for whole breast irradiation: a comparative dosimetric study and introduction of a novel qualitative index for plan evaluation, the normal tissue index

    Energy Technology Data Exchange (ETDEWEB)

    Yim, Jackie; Suttie, Clare; Bromley, Regina; Morgia, Marita; Lamoury, Gillian [Department of Radiation Oncology, Royal North Shore Hospital, St Leonards, New South Wales (Australia)

    2015-09-15

    We report on a retrospective dosimetric study, comparing 3D conformal radiotherapy (3DCRT) and hybrid intensity modulated radiotherapy (hIMRT). We evaluated plans based on their planning target volume coverage, dose homogeneity, dose to organs at risk (OARs) and exposure of normal tissue to radiation. The Homogeneity Index (HI) was used to assess the dose homogeneity in the target region, and we describe a new index, the normal tissue index (NTI), to assess the dose in the normal tissue inside the tangent treatment portal. Plans were generated for 25 early-stage breast cancer patients, using a hIMRT technique. These were compared with the 3DCRT plans of the treatment previously received by the patients. Plan quality was evaluated using the HI, NTI and dose to OARs. The hIMRT technique was significantly more homogenous than the 3DCRT technique, while maintaining target coverage. The hIMRT technique was also superior at minimising the amount of tissue receiving D{sub 105%} and above (P < 0.0001). The ipsilateral lung and contralateral breast maximum were significantly lower in the hIMRT plans (P < 0.05 and P < 0.005), but the 3DCRT technique achieved a lower mean heart dose in left-sided breast cancer patients (P < 0.05). Hybrid intensity modulated radiotherapy plans achieved improved dose homogeneity compared to the 3DCRT plans and superior outcome with regard to dose to normal tissues. We propose that the addition of both HI and NTI in evaluating the quality of intensity modulated radiotherapy (IMRT) breast plans provides clinically relevant comparators which more accurately reflect the new paradigm of treatment goals and outcomes in the era of breast IMRT.

  15. Intensity modulated radiotherapy and 3D conformal radiotherapy for whole breast irradiation: a comparative dosimetric study and introduction of a novel qualitative index for plan evaluation, the normal tissue index

    International Nuclear Information System (INIS)

    Yim, Jackie; Suttie, Clare; Bromley, Regina; Morgia, Marita; Lamoury, Gillian

    2015-01-01

    We report on a retrospective dosimetric study, comparing 3D conformal radiotherapy (3DCRT) and hybrid intensity modulated radiotherapy (hIMRT). We evaluated plans based on their planning target volume coverage, dose homogeneity, dose to organs at risk (OARs) and exposure of normal tissue to radiation. The Homogeneity Index (HI) was used to assess the dose homogeneity in the target region, and we describe a new index, the normal tissue index (NTI), to assess the dose in the normal tissue inside the tangent treatment portal. Plans were generated for 25 early-stage breast cancer patients, using a hIMRT technique. These were compared with the 3DCRT plans of the treatment previously received by the patients. Plan quality was evaluated using the HI, NTI and dose to OARs. The hIMRT technique was significantly more homogenous than the 3DCRT technique, while maintaining target coverage. The hIMRT technique was also superior at minimising the amount of tissue receiving D 105% and above (P < 0.0001). The ipsilateral lung and contralateral breast maximum were significantly lower in the hIMRT plans (P < 0.05 and P < 0.005), but the 3DCRT technique achieved a lower mean heart dose in left-sided breast cancer patients (P < 0.05). Hybrid intensity modulated radiotherapy plans achieved improved dose homogeneity compared to the 3DCRT plans and superior outcome with regard to dose to normal tissues. We propose that the addition of both HI and NTI in evaluating the quality of intensity modulated radiotherapy (IMRT) breast plans provides clinically relevant comparators which more accurately reflect the new paradigm of treatment goals and outcomes in the era of breast IMRT

  16. Acute toxicity in comprehensive head and neck radiation for nasopharynx and paranasal sinus cancers: cohort comparison of 3D conformal proton therapy and intensity modulated radiation therapy

    International Nuclear Information System (INIS)

    McDonald, Mark W.; Liu, Yuan; Moore, Michael G.; Johnstone, Peter A. S.

    2016-01-01

    To evaluate acute toxicity endpoints in a cohort of patients receiving head and neck radiation with proton therapy or intensity modulated radiation therapy (IMRT). Forty patients received comprehensive head and neck radiation including bilateral cervical nodal radiation, given with or without chemotherapy, for tumors of the nasopharynx, nasal cavity or paranasal sinuses, any T stage, N0-2. Fourteen received comprehensive treatment with proton therapy, and 26 were treated with IMRT, either comprehensively or matched to proton therapy delivered to the primary tumor site. Toxicity endpoints assessed included g-tube dependence at the completion of radiation and at 3 months after radiation, opioid pain medication requirement compared to pretreatment normalized as equivalent morphine dose (EMD) at completion of treatment, and at 1 and 3 months after radiation. In a multivariable model including confounding variables of concurrent chemotherapy and involved nodal disease, comprehensive head and neck radiation therapy using proton therapy was associated with a lower opioid pain requirement at the completion of radiation and a lower rate of gastrostomy tube dependence by the completion of radiation therapy and at 3 months after radiation compared to IMRT. Proton therapy was associated with statistically significant lower mean doses to the oral cavity, esophagus, larynx, and parotid glands. In subgroup analysis of 32 patients receiving concurrent chemotherapy, there was a statistically significant correlation with a greater opioid pain medication requirement at the completion of radiation and both increasing mean dose to the oral cavity and to the esophagus. Proton therapy was associated with significantly reduced radiation dose to assessed non-target normal tissues and a reduced rate of gastrostomy tube dependence and opioid pain medication requirements. This warrants further evaluation in larger studies, ideally with patient-reported toxicity outcomes and quality of life

  17. Can All Centers Plan Intensity-Modulated Radiotherapy (IMRT) Effectively? An External Audit of Dosimetric Comparisons Between Three-Dimensional Conformal Radiotherapy and IMRT for Adjuvant Chemoradiation for Gastric Cancer

    International Nuclear Information System (INIS)

    Chung, Hans T.; Lee, Brian; Park, Eileen; Lu, Jiade J.; Xia Ping

    2008-01-01

    Purpose: To compare dosimetric endpoints between three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) at our center with limited IMRT experience, and to perform an external audit of the IMRT plans. Methods and Materials: Ten patients, who received adjuvant chemoradiation for gastric cancer, formed the study cohort. For standardization, the planning target volume (PTV) and organs at risk were recontoured with the assistance of a study protocol radiologic atlas. The cohort was replanned with CMS Xio to generate coplanar 3D-CRT and IMRT plans. All 10 datasets, including volumes but without the plans (i.e., blinded), were transmitted to an experienced center where IMRT plans were designed using Nomos Corvus (IMRT-C) and ADAC Pinnacle (IMRT-P). All IMRT plans were normalized to D95% receiving 45 Gy. Results: Intensity-modulated radiotherapy yielded higher PTV V45 (volume that receives ≥45 Gy) (p < 0.001) than 3D-CRT. No difference in V20 was seen in the right (p = 0.9) and left (p 0.3) kidneys, but the liver mean dose (p < 0.001) was superior with IMRT. For the external audit, IMRT-C (p = 0.002) and IMRT-P (p < 0.001) achieved significantly lower left kidney V20 than IMRT, and IMRT-P (p < 0.001) achieved lower right kidney V20 than IMRT. The IMRT-C (p = 0.003) but not IMRT-P (p = 0.6) had lower liver mean doses than IMRT. Conclusions: At our institution with early IMRT experience, IMRT improved PTV dose coverage and liver doses but not kidney doses. An external audit of IMRT plans showed that an experienced center can yield superior IMRT plans

  18. Analysis of Biochemical Control and Prognostic Factors in Patients Treated With Either Low-Dose Three-Dimensional Conformal Radiation Therapy or High-Dose Intensity-Modulated Radiotherapy for Localized Prostate Cancer

    International Nuclear Information System (INIS)

    Vora, Sujay A.; Wong, William W.; Schild, Steven E.; Ezzell, Gary A.; Halyard, Michele Y.

    2007-01-01

    Purpose: To identify prognostic factors and evaluate biochemical control rates for patients with localized prostate cancer treated with either high-dose intensity-modulated radiotherapy (IMRT) or conventional-dose three-dimensional conformal radiotherapy 3D-CRT. Methods: Four hundred sixteen patients with a minimum follow-up of 3 years (median, 5 years) were included. Two hundred seventy-one patients received 3D-CRT with a median dose of 68.4 Gy (range, 66-71 Gy). The next 145 patients received IMRT with a median dose of 75.6 Gy (range, 70.2-77.4 Gy). Biochemical control rates were calculated according to both American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definitions. Prognostic factors were identified using both univariate and multivariate analyses. Results: The 5-year biochemical control rate was 60.4% for 3D-CRT and 74.1% for IMRT (p < 0.0001, first ASTRO Consensus definition). Using the ASTRO Phoenix definition, the 5-year biochemical control rate was 74.4% and 84.6% with 3D-RT and IMRT, respectively (p = 0.0326). Univariate analyses determined that PSA level, T stage, Gleason score, perineural invasion, and radiation dose were predictive of biochemical control. On multivariate analysis, dose, Gleason score, and perineural invasion remained significant. Conclusion: On the basis of both ASTRO definitions, dose, Gleason score, and perineural invasion were predictive of biochemical control. Intensity-modulated radiotherapy allowed delivery of higher doses of radiation with very low toxicity, resulting in improved biochemical control

  19. Acute Toxicity After Image-Guided Intensity Modulated Radiation Therapy Compared to 3D Conformal Radiation Therapy in Prostate Cancer Patients

    Energy Technology Data Exchange (ETDEWEB)

    Wortel, Ruud C.; Incrocci, Luca [Department of Radiation Oncology, Erasmus Medical Center Cancer Institute, Rotterdam (Netherlands); Pos, Floris J.; Lebesque, Joos V.; Witte, Marnix G.; Heide, Uulke A. van der; Herk, Marcel van [Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam (Netherlands); Heemsbergen, Wilma D., E-mail: w.heemsbergen@nki.nl [Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam (Netherlands)

    2015-03-15

    Purpose: Image-guided intensity modulated radiation therapy (IG-IMRT) allows significant dose reductions to organs at risk in prostate cancer patients. However, clinical data identifying the benefits of IG-IMRT in daily practice are scarce. The purpose of this study was to compare dose distributions to organs at risk and acute gastrointestinal (GI) and genitourinary (GU) toxicity levels of patients treated to 78 Gy with either IG-IMRT or 3D-CRT. Methods and Materials: Patients treated with 3D-CRT (n=215) and IG-IMRT (n=260) receiving 78 Gy in 39 fractions within 2 randomized trials were selected. Dose surface histograms of anorectum, anal canal, and bladder were calculated. Identical toxicity questionnaires were distributed at baseline, prior to fraction 20 and 30 and at 90 days after treatment. Radiation Therapy Oncology Group (RTOG) grade ≥1, ≥2, and ≥3 endpoints were derived directly from questionnaires. Univariate and multivariate binary logistic regression analyses were applied. Results: The median volumes receiving 5 to 75 Gy were significantly lower (all P<.001) with IG-IMRT for anorectum, anal canal, and bladder. The mean dose to the anorectum was 34.4 Gy versus 47.3 Gy (P<.001), 23.6 Gy versus 44.6 Gy for the anal canal (P<.001), and 33.1 Gy versus 43.2 Gy for the bladder (P<.001). Significantly lower grade ≥2 toxicity was observed for proctitis, stool frequency ≥6/day, and urinary frequency ≥12/day. IG-IMRT resulted in significantly lower overall RTOG grade ≥2 GI toxicity (29% vs 49%, respectively, P=.002) and overall GU grade ≥2 toxicity (38% vs 48%, respectively, P=.009). Conclusions: A clinically meaningful reduction in dose to organs at risk and acute toxicity levels was observed in IG-IMRT patients, as a result of improved technique and tighter margins. Therefore reduced late toxicity levels can be expected as well; additional research is needed to quantify such reductions.

  20. Epigenetic dominance of prion conformers.

    Directory of Open Access Journals (Sweden)

    Eri Saijo

    2013-10-01

    Full Text Available Although they share certain biological properties with nucleic acid based infectious agents, prions, the causative agents of invariably fatal, transmissible neurodegenerative disorders such as bovine spongiform encephalopathy, sheep scrapie, and human Creutzfeldt Jakob disease, propagate by conformational templating of host encoded proteins. Once thought to be unique to these diseases, this mechanism is now recognized as a ubiquitous means of information transfer in biological systems, including other protein misfolding disorders such as those causing Alzheimer's and Parkinson's diseases. To address the poorly understood mechanism by which host prion protein (PrP primary structures interact with distinct prion conformations to influence pathogenesis, we produced transgenic (Tg mice expressing different sheep scrapie susceptibility alleles, varying only at a single amino acid at PrP residue 136. Tg mice expressing ovine PrP with alanine (A at (OvPrP-A136 infected with SSBP/1 scrapie prions propagated a relatively stable (S prion conformation, which accumulated as punctate aggregates in the brain, and produced prolonged incubation times. In contrast, Tg mice expressing OvPrP with valine (V at 136 (OvPrP-V136 infected with the same prions developed disease rapidly, and the converted prion was comprised of an unstable (U, diffusely distributed conformer. Infected Tg mice co-expressing both alleles manifested properties consistent with the U conformer, suggesting a dominant effect resulting from exclusive conversion of OvPrP-V136 but not OvPrP-A136. Surprisingly, however, studies with monoclonal antibody (mAb PRC5, which discriminates OvPrP-A136 from OvPrP-V136, revealed substantial conversion of OvPrP-A136. Moreover, the resulting OvPrP-A136 prion acquired the characteristics of the U conformer. These results, substantiated by in vitro analyses, indicated that co-expression of OvPrP-V136 altered the conversion potential of OvPrP-A136 from the S to

  1. A decision model to estimate the cost-effectiveness of intensity modulated radiation therapy (IMRT) compared to three dimensional conformal radiation therapy (3DCRT) in patients receiving radiotherapy to the prostate bed

    International Nuclear Information System (INIS)

    Carter, Hannah E.; Martin, Andrew; Schofield, Deborah; Duchesne, Gillian; Haworth, Annette; Hornby, Colin; Sidhom, Mark; Jackson, Michael

    2014-01-01

    Background: Intensity modulated radiation therapy (IMRT) is a radiation therapy technology that facilitates the delivery of an improved dose distribution with less dose to surrounding critical structures. This study estimates the longer term effectiveness and cost-effectiveness of IMRT in patients post radical prostatectomy. Methods: A Markov decision model was developed to calculate the incremental quality adjusted life years (QALYs) and costs of IMRT compared with three dimensional conformal radiation therapy (3DCRT). Costs were estimated from the perspective of the Australian health care system. Results: IMRT was both more effective and less costly than 3DCRT over 20 years, with an additional 20 QALYs gained and over $1.1 million saved per 1000 patients treated. This result was robust to plausible levels of uncertainty. Conclusions: IMRT was estimated to have a modest long term advantage over 3DCRT in terms of both improved effectiveness and reduced cost. This result was reliant on clinical judgement and interpretation of the existing literature, but provides quantitative guidance on the cost effectiveness of IMRT whilst long term trial evidence is awaited

  2. Viscous conformal gauge theories

    DEFF Research Database (Denmark)

    Toniato, Arianna; Sannino, Francesco; Rischke, Dirk H.

    2017-01-01

    We present the conformal behavior of the shear viscosity-to-entropy density ratio and the fermion-number diffusion coefficient within the perturbative regime of the conformal window for gauge-fermion theories.......We present the conformal behavior of the shear viscosity-to-entropy density ratio and the fermion-number diffusion coefficient within the perturbative regime of the conformal window for gauge-fermion theories....

  3. Conformal Einstein spaces

    International Nuclear Information System (INIS)

    Kozameh, C.N.; Newman, E.T.; Tod, K.P.

    1985-01-01

    Conformal transformations in four-dimensional. In particular, a new set of two necessary and sufficient conditions for a space to be conformal to an Einstein space is presented. The first condition defines the class of spaces conformal to C spaces, whereas the last one (the vanishing of the Bach tensor) gives the particular subclass of C spaces which are conformally related to Einstein spaces. (author)

  4. Superspace conformal field theory

    Energy Technology Data Exchange (ETDEWEB)

    Quella, Thomas [Koeln Univ. (Germany). Inst. fuer Theoretische Physik; Schomerus, Volker [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)

    2013-07-15

    Conformal sigma models and WZW models on coset superspaces provide important examples of logarithmic conformal field theories. They possess many applications to problems in string and condensed matter theory. We review recent results and developments, including the general construction of WZW models on type I supergroups, the classification of conformal sigma models and their embedding into string theory.

  5. Superspace conformal field theory

    International Nuclear Information System (INIS)

    Quella, Thomas

    2013-07-01

    Conformal sigma models and WZW models on coset superspaces provide important examples of logarithmic conformal field theories. They possess many applications to problems in string and condensed matter theory. We review recent results and developments, including the general construction of WZW models on type I supergroups, the classification of conformal sigma models and their embedding into string theory.

  6. Non-coplanar volumetric-modulated arc therapy (VMAT) for craniopharyngiomas reduces radiation doses to the bilateral hippocampus: a planning study comparing dynamic conformal arc therapy, coplanar VMAT, and non-coplanar VMAT

    International Nuclear Information System (INIS)

    Uto, Megumi; Mizowaki, Takashi; Ogura, Kengo; Hiraoka, Masahiro

    2016-01-01

    Recent studies suggest that radiation-induced injuries to the hippocampus play important roles in compromising neurocognitive functioning for patients with brain tumors and it could be important to spare the hippocampus using modern planning methods for patients with craniopharyngiomas. As bilateral hippocampus are located on the same level as the planning target volume (PTV) in patients with craniopharyngioma, it seems possible to reduce doses to hippocampus using non-coplanar beams. While the use of non-coplanar beams in volumetric-modulated arc therapy (VMAT) of malignant intracranial tumors has recently been reported, no dosimetric comparison has yet been made between VMAT using non-coplanar arcs (ncVMAT) and VMAT employing only coplanar arcs (coVMAT) among patients with craniopharyngiomas. We performed a planning study comparing dose distributions to the PTV, hippocampus, and other organs at risk (OAR) of dynamic conformal arc therapy (DCAT), coVMAT, and ncVMAT. DCAT, coVMAT, and ncVMAT plans were created for 10 patients with craniopharyngiomas. The prescription dose was 52.2 Gy in 29 fractions, and 99 % of each PTV was covered by 90 % of the prescribed dose. The maximum dose was held below 107 % of the prescribed dose. CoVMAT and ncVMAT plans were formulated to satisfy the following criteria: the doses to the hippocampus were minimized, and the doses to the OAR were similar to or lower than those of DCAT. The mean equivalent doses in 2-Gy fractions to 40 % of the volumes of the bilateral hippocampus [EQD 2 (40% hippos )] were 15.4/10.8/6.5 Gy for DCAT/coVMAT/ncVMAT, respectively. The EQD 2 (40% hippos ) for ncVMAT were <7.3 Gy, which is the threshold predicting cognitive impairment, as defined by Gondi et al.. The mean doses to normal brain tissue and the conformity indices were similar for the three plans, and the homogeneity indices were significantly better for coVMAT and ncVMAT compared with DCAT. NcVMAT is more appropriate than DCAT and coVMAT for

  7. Constituent Components of Out-of-Field Scatter Dose for 18-MV Intensity Modulated Radiation Therapy Versus 3-Dimensional Conformal Radiation Therapy: A Comparison With 6-MV and Implications for Carcinogenesis

    International Nuclear Information System (INIS)

    Ruben, Jeremy D.; Smith, Ryan; Lancaster, Craig M.; Haynes, Matthew; Jones, Phillip; Panettieri, Vanessa

    2014-01-01

    Purpose: To characterize and compare the components of out-of-field dose for 18-MV intensity modulated radiation therapy (IMRT) versus 3-dimensional conformal radiation therapy (3D-CRT) and their 6-MV counterparts and consider implications for second cancer induction. Methods and Materials: Comparable plans for each technique/energy were delivered to a water phantom with a sloping wall; under full scatter conditions; with field edge abutting but outside the bath to prevent internal/phantom scatter; and with shielding below the linear accelerator head to attenuate head leakage. Neutron measurements were obtained from published studies. Results: Eighteen-megavolt IMRT produces 1.7 times more out-of-field scatter than 18-MV 3D-CRT. In absolute terms, however, differences are just approximately 0.1% of central axis dose. Eighteen-megavolt IMRT reduces internal/patient scatter by 13%, but collimator scatter (C) is 2.6 times greater than 18-MV 3D-CRT. Head leakage (L) is minimal. Increased out-of-field photon scatter from 18-MV IMRT carries out-of-field second cancer risks of approximately 0.2% over and above the 0.4% from 18-MV 3D-CRT. Greater photoneutron dose from 18-MV IMRT may result in further maximal, absolute increased risk to peripheral tissue of approximately 1.2% over 18-MV 3D-CRT. Out-of-field photon scatter remains comparable for the same modality irrespective of beam energy. Machine scatter (C+L) from 18 versus 6 MV is 1.2 times higher for IMRT and 1.8 times for 3D-CRT. It is 4 times higher for 6-MV IMRT versus 3D-CRT. Reduction in internal scatter with 18 MV versus 6 MV is 27% for 3D-CRT and 29% for IMRT. Compared with 6-MV 3D-CRT, 18-MV IMRT increases out-of-field second cancer risk by 0.2% from photons and adds 0.28-2.2% from neutrons. Conclusions: Out-of-field photon dose seems to be independent of beam energy for both techniques. Eighteen-megavolt IMRT increases out-of-field scatter 1.7-fold over 3D-CRT because of greater collimator scatter despite

  8. Design of a compressed air modulator to be used in comprehensive multidimensional gas chromatography and its application in the determination of pesticide residues in grapes

    NARCIS (Netherlands)

    Pizzutti, I.R.; Vreuls, J.J.; Kok, A; Roehrs, R.; Martel, S.; Friggi, C.A.; Zanella, R.

    2009-01-01

    In this study, a new modulator that is simple, robust and presents low operation costs, was developed. This modulator uses compressed air to cool two small portions in the first centimeters of the second chromatographic column of a comprehensive multidimensional gas chromatography (GC × GC) system.

  9. Non-conformable, partial and conformable transposition

    DEFF Research Database (Denmark)

    König, Thomas; Mäder, Lars Kai

    2013-01-01

    and the Commission regarding a directive’s outcome, play a much more strategic role than has to date acknowledged in the transposition literature. Whereas disagreement of a member state delays conformable transposition, it speeds up non-conformable transposition. Disagreement of the Commission only prolongs...... the transposition process. We therefore conclude that a stronger focus on an effective sanctioning mechanism is warranted for safeguarding compliance with directives....

  10. Use of benchmark dose-volume histograms for selection of the optimal technique between three-dimensional conformal radiation therapy and intensity-modulated radiation therapy in prostate cancer

    International Nuclear Information System (INIS)

    Luo Chunhui; Yang, Claus Chunli; Narayan, Samir; Stern, Robin L.; Perks, Julian; Goldberg, Zelanna; Ryu, Janice; Purdy, James A.; Vijayakumar, Srinivasan

    2006-01-01

    Purpose: The aim of this study was to develop and validate our own benchmark dose-volume histograms (DVHs) of bladder and rectum for both conventional three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT), and to evaluate quantitatively the benefits of using IMRT vs. 3D-CRT in treating localized prostate cancer. Methods and Materials: During the implementation of IMRT for prostate cancer, our policy was to plan each patient with both 3D-CRT and IMRT. This study included 31 patients with T1b to T2c localized prostate cancer, for whom we completed double-planning using both 3D-CRT and IMRT techniques. The target volumes included prostate, either with or without proximal seminal vesicles. Bladder and rectum DVH data were summarized to obtain an average DVH for each technique and then compared using two-tailed paired t test analysis. Results: For 3D-CRT our bladder doses were as follows: mean 28.8 Gy, v60 16.4%, v70 10.9%; rectal doses were: mean 39.3 Gy, v60 21.8%, v70 13.6%. IMRT plans resulted in similar mean dose values: bladder 26.4 Gy, rectum 34.9 Gy, but lower values of v70 for the bladder (7.8%) and rectum (9.3%). These benchmark DVHs have resulted in a critical evaluation of our 3D-CRT techniques over time. Conclusion: Our institution has developed benchmark DVHs for bladder and rectum based on our clinical experience with 3D-CRT and IMRT. We use these standards as well as differences in individual cases to make decisions on whether patients may benefit from IMRT treatment rather than 3D-CRT

  11. Intensity-modulated radiation therapy versus three-dimensional conformal radiation therapy with concurrent nedaplatin-based chemotherapy after radical hysterectomy for uterine cervical cancer: comparison of outcomes, complications, and dose-volume histogram parameters

    International Nuclear Information System (INIS)

    Isohashi, Fumiaki; Mabuchi, Seiji; Yoshioka, Yasuo; Seo, Yuji; Suzuki, Osamu; Tamari, Keisuke; Yamashita, Michiko; Unno, Hikari; Kinose, Yasuto; Kozasa, Katsumi; Sumida, Iori; Otani, Yuki; Kimura, Tadashi; Ogawa, Kazuhiko

    2015-01-01

    The purpose of this study is to report our clinical outcomes using intensity-modulated radiation therapy (IMRT) for adjuvant treatment of cervical cancer, compared with three-dimensional conformal radiation therapy (3DCRT), in terms of tumor control, complications and dose-volume histogram (DVH) parameters. Between March 2008 and February 2014, 62 patients were treated with concurrent nedaplatin-based chemotherapy and whole-pelvic external beam radiation therapy (RT). Of these patients, 32 (52 %) received 3DCRT and 30 (48 %) received IMRT. The median follow-up periods were 40 months (range 2–74 months). The 3-year overall survival rate (OS), locoregional control rate (LRC) and progression-free survival rate (PFS) were 92, 95 and 92 % in the IMRT group, and 85, 82 and 70 % in the 3DCRT group, respectively. A comparison of OS, LRC and PFS showed no significant differences between IMRT and 3DCRT. The 3-year cumulative incidences of grade 2 or higher chronic gastrointestinal (GI) complications were significantly lower with IMRT compared to 3DCRT (3 % vs. 45 %, p < .02) and in patients with V40 of the small bowel loops of ≤340 mL compared to those with >340 mL (3 % vs. 45 %, p < .001). Patients treated with IMRT had a higher incidence of grade 3 acute hematologic complications (p < .05). V40 and V45 of the small bowel loops or bowel bag were predictive for development of both acute and chronic GI complications. Our results suggest that IMRT for adjuvant treatment of cervical cancer is useful for decreasing GI complications without worsening outcomes

  12. Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in Stage I or Stage III non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Chang, Joe Y.; Zhang Xiaodong; Wang Xiaochun; Kang Yixiu; Riley, Beverly C.; Bilton, Stephen C.; Mohan, Radhe; Komaki, Ritsuko; Cox, James D.

    2006-01-01

    Purpose: To compare dose-volume histograms (DVH) in patients with non-small-cell lung cancer (NSCLC) treated by photon or proton radiotherapy. Methods and Materials: Dose-volume histograms were compared between photon, including three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and proton plans at doses of 66 Gy, 87.5 Gy in Stage I (n = 10) and 60-63 Gy, and 74 Gy in Stage III (n 15). Results: For Stage I, the mean total lung V5, V10, and V20 were 31.8%, 24.6%, and 15.8%, respectively, for photon 3D-CRT with 66 Gy, whereas they were 13.4%, 12.3%, and 10.9%, respectively, with proton with dose escalation to 87.5 cobalt Gray equivalents (CGE) (p = 0.002). For Stage III, the mean total lung V5, V10, and V20 were 54.1%, 46.9%, and 34.8%, respectively, for photon 3D-CRT with 63 Gy, whereas they were 39.7%, 36.6%, and 31.6%, respectively, for proton with dose escalation to 74 CGE (p = 0.002). In all cases, the doses to lung, spinal cord, heart, esophagus, and integral dose were lower with proton therapy even compared with IMRT. Conclusions: Proton treatment appears to reduce dose to normal tissues significantly, even with dose escalation, compared with standard-dose photon therapy, either 3D-CRT or IMRT

  13. Preliminary Toxicity Analysis of 3-Dimensional Conformal Radiation Therapy Versus Intensity Modulated Radiation Therapy on the High-Dose Arm of the Radiation Therapy Oncology Group 0126 Prostate Cancer Trial

    Energy Technology Data Exchange (ETDEWEB)

    Michalski, Jeff M., E-mail: jmichalski@radonc.wustl.edu [Department of Radiation Oncology Washington University Medical Center, St. Louis, Missouri (United States); Yan, Yan [Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (United States); Watkins-Bruner, Deborah [Emory University School of Nursing, Atlanta, Georgia (United States); Bosch, Walter R. [Department of Radiation Oncology Washington University Medical Center, St. Louis, Missouri (United States); Winter, Kathryn [Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (United States); Galvin, James M. [Department of Radiation Oncology Thomas Jefferson University Hospital, Philadelphia, Pennsylvania (United States); Bahary, Jean-Paul [Department of Radiation Oncology Centre Hospitalier de l' Université de Montréal-Notre Dame, Montreal, QC (Canada); Morton, Gerard C. [Department of Radiation Oncology Toronto-Sunnybrook Regional Cancer Centre, Toronto, ON (Canada); Parliament, Matthew B. [Department of Oncology Cross Cancer Institute, Edmonton, AB (Canada); Sandler, Howard M. [Department of Radiation Oncology Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California (United States)

    2013-12-01

    Purpose: To give a preliminary report of clinical and treatment factors associated with toxicity in men receiving high-dose radiation therapy (RT) on a phase 3 dose-escalation trial. Methods and Materials: The trial was initiated with 3-dimensional conformal RT (3D-CRT) and amended after 1 year to allow intensity modulated RT (IMRT). Patients treated with 3D-CRT received 55.8 Gy to a planning target volume that included the prostate and seminal vesicles, then 23.4 Gy to prostate only. The IMRT patients were treated to the prostate and proximal seminal vesicles to 79.2 Gy. Common Toxicity Criteria, version 2.0, and Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late morbidity scores were used for acute and late effects. Results: Of 763 patients randomized to the 79.2-Gy arm of Radiation Therapy Oncology Group 0126 protocol, 748 were eligible and evaluable: 491 and 257 were treated with 3D-CRT and IMRT, respectively. For both bladder and rectum, the volumes receiving 65, 70, and 75 Gy were significantly lower with IMRT (all P<.0001). For grade (G) 2+ acute gastrointestinal/genitourinary (GI/GU) toxicity, both univariate and multivariate analyses showed a statistically significant decrease in G2+ acute collective GI/GU toxicity for IMRT. There were no significant differences with 3D-CRT or IMRT for acute or late G2+ or 3+ GU toxicities. Univariate analysis showed a statistically significant decrease in late G2+ GI toxicity for IMRT (P=.039). On multivariate analysis, IMRT showed a 26% reduction in G2+ late GI toxicity (P=.099). Acute G2+ toxicity was associated with late G3+ toxicity (P=.005). With dose–volume histogram data in the multivariate analysis, RT modality was not significant, whereas white race (P=.001) and rectal V70 ≥15% were associated with G2+ rectal toxicity (P=.034). Conclusions: Intensity modulated RT is associated with a significant reduction in acute G2+ GI/GU toxicity. There is a trend for a

  14. Modulation of procaspase-7 self-activation by PEST amino acid residues of the N-terminal prodomain and intersubunit linker.

    Science.gov (United States)

    Alves, Juliano; Garay-Malpartida, Miguel; Occhiucci, João M; Belizário, José E

    2017-12-01

    Procaspase-7 zymogen polypeptide is composed of a short prodomain, a large subunit (p20), and a small subunit (p10) connected to an intersubunit linker. Caspase-7 is activated by an initiator caspase-8 and -9, or by autocatalysis after specific cleavage at IQAD 198 ↓S located at the intersubunit linker. Previously, we identified that PEST regions made of amino acid residues Pro (P), Glu (E), Asp (D), Ser (S), Thr (T), Asn (N), and Gln (Q) are conserved flanking amino acid residues in the cleavage sites within a prodomain and intersubunit linker of all caspase family members. Here we tested the impact of alanine substitution of PEST amino acid residues on procaspase-7 proteolytic self-activation directly in Escherichia coli. The p20 and p10 subunit cleavage were significantly delayed in double caspase-7 mutants in the prodomain (N18A/P26A) and intersubunit linker (S199A/P201A), compared with the wild-type caspase-7. The S199A/P201A mutants effectively inhibited the p10 small subunit cleavage. However, the mutations did not change the kinetic parameters (k cat /K M ) and optimal tetrapeptide specificity (DEVD) of the purified mutant enzymes. The results suggest a role of PEST-amino acid residues in the molecular mechanism for prodomain and intersubunit cleavage and caspase-7 self-activation.

  15. Bioactive focus in conformational ensembles: a pluralistic approach

    Science.gov (United States)

    Habgood, Matthew

    2017-12-01

    Computational generation of conformational ensembles is key to contemporary drug design. Selecting the members of the ensemble that will approximate the conformation most likely to bind to a desired target (the bioactive conformation) is difficult, given that the potential energy usually used to generate and rank the ensemble is a notoriously poor discriminator between bioactive and non-bioactive conformations. In this study an approach to generating a focused ensemble is proposed in which each conformation is assigned multiple rankings based not just on potential energy but also on solvation energy, hydrophobic or hydrophilic interaction energy, radius of gyration, and on a statistical potential derived from Cambridge Structural Database data. The best ranked structures derived from each system are then assembled into a new ensemble that is shown to be better focused on bioactive conformations. This pluralistic approach is tested on ensembles generated by the Molecular Operating Environment's Low Mode Molecular Dynamics module, and by the Cambridge Crystallographic Data Centre's conformation generator software.

  16. Residual stresses

    International Nuclear Information System (INIS)

    Sahotra, I.M.

    2006-01-01

    The principal effect of unloading a material strained into the plastic range is to create a permanent set (plastic deformation), which if restricted somehow, gives rise to a system of self-balancing within the same member or reaction balanced by other members of the structure., known as residual stresses. These stresses stay there as locked-in stresses, in the body or a part of it in the absence of any external loading. Residual stresses are induced during hot-rolling and welding differential cooling, cold-forming and extruding: cold straightening and spot heating, fabrication and forced fitting of components constraining the structure to a particular geometry. The areas which cool more quickly develop residual compressive stresses, while the slower cooling areas develop residual tensile stresses, and a self-balancing or reaction balanced system of residual stresses is formed. The phenomenon of residual stresses is the most challenging in its application in surface modification techniques determining endurance mechanism against fracture and fatigue failures. This paper discusses the mechanism of residual stresses, that how the residual stresses are fanned and what their behavior is under the action of external forces. Such as in the case of a circular bar under limit torque, rectangular beam under limt moment, reclaiming of shafts welds and peening etc. (author)

  17. Induced quantum conformal gravity

    International Nuclear Information System (INIS)

    Novozhilov, Y.V.; Vassilevich, D.V.

    1988-11-01

    Quantum gravity is considered as induced by matter degrees of freedom and related to the symmetry breakdown in the low energy region of a non-Abelian gauge theory of fundamental fields. An effective action for quantum conformal gravity is derived where both the gravitational constant and conformal kinetic term are positive. Relation with induced classical gravity is established. (author). 15 refs

  18. Thickenings and conformal gravity

    Science.gov (United States)

    Lebrun, Claude

    1991-07-01

    A twistor correspondence is given for complex conformal space-times with vanishing Bach and Eastwood-Dighton tensors; when the Weyl curvature is algebraically general, these equations are precisely the conformal version of Einstein's vacuum equations with cosmological constant. This gives a fully curved version of the linearized correspondence of Baston and Mason [B-M].

  19. Thickenings and conformal gravity

    Energy Technology Data Exchange (ETDEWEB)

    LeBrun, C. (State Univ. of New York, Stony Brook, NY (USA). Dept. of Mathematics)

    1991-07-01

    A twistor correspondence is given for complex conformal space-times with vanishing Bach and Eastwood-Dighton tensors; when the Weyl curvature is algebraically general, these equations are precisely the conformal version of Einstein's vacuum equations with cosmological constant. This gives a fully curved version of the linearized correspondence of Baston and Mason (B-M). (orig.).

  20. Thickenings and conformal gravity

    International Nuclear Information System (INIS)

    LeBrun, C.

    1991-01-01

    A twistor correspondence is given for complex conformal space-times with vanishing Bach and Eastwood-Dighton tensors; when the Weyl curvature is algebraically general, these equations are precisely the conformal version of Einstein's vacuum equations with cosmological constant. This gives a fully curved version of the linearized correspondence of Baston and Mason [B-M]. (orig.)

  1. Conformal transformations in superspace

    International Nuclear Information System (INIS)

    Dao Vong Duc

    1977-01-01

    The spinor extension of the conformal algebra is investigated. The transformation law of superfields under the conformal coordinate inversion R defined in the superspace is derived. Using R-technique, the superconformally covariant two-point and three-point correlation functions are found

  2. Conformational stability of calreticulin

    DEFF Research Database (Denmark)

    Jørgensen, C.S.; Trandum, C.; Larsen, N.

    2005-01-01

    The conformational stability of calreticulin was investigated. Apparent unfolding temperatures (T-m) increased from 31 degrees C at pH 5 to 51 degrees C at pH 9, but electrophoretic analysis revealed that calreticulin oligomerized instead of unfolding. Structural analyses showed that the single C......-terminal a-helix was of major importance to the conformational stability of calreticulin....

  3. Residual stresses

    International Nuclear Information System (INIS)

    Macherauch, E.

    1978-01-01

    Residual stresses are stresses which exist in a material without the influence of external powers and moments. They come into existence when the volume of a material constantly changes its form as a consequence of mechanical, thermal, and/or chemical processes and is hindered by neighbouring volumes. Bodies with residual stress are in mechanical balance. These residual stresses can be manifested by means of all mechanical interventions disturbing this balance. Acoustical, optical, radiological, and magnetical methods involving material changes caused by residual stress can also serve for determining residual stress. Residual stresses have an ambivalent character. In technical practice, they are feared and liked at the same time. They cause trouble because they can be the cause for unexpected behaviour of construction elements. They are feared since they can cause failure, in the worst case with catastrophical consequences. They are appreciated, on the other hand, because, in many cases, they can contribute to improvements of the material behaviour under certain circumstances. But they are especially liked for their giving convenient and (this is most important) mostly uncontrollable explanations. For only in very few cases we have enough knowledge and possibilities for the objective evaluation of residual stresses. (orig.) [de

  4. Dosimetric comparison of standard three-dimensional conformal radiotherapy followed by intensity-modulated radiotherapy boost schedule (sequential IMRT plan) with simultaneous integrated boost-IMRT (SIB IMRT) treatment plan in patients with localized carcinoma prostate.

    Science.gov (United States)

    Bansal, A; Kapoor, R; Singh, S K; Kumar, N; Oinam, A S; Sharma, S C

    2012-07-01

    DOSIMETERIC AND RADIOBIOLOGICAL COMPARISON OF TWO RADIATION SCHEDULES IN LOCALIZED CARCINOMA PROSTATE: Standard Three-Dimensional Conformal Radiotherapy (3DCRT) followed by Intensity Modulated Radiotherapy (IMRT) boost (sequential-IMRT) with Simultaneous Integrated Boost IMRT (SIB-IMRT). Thirty patients were enrolled. In all, the target consisted of PTV P + SV (Prostate and seminal vesicles) and PTV LN (lymph nodes) where PTV refers to planning target volume and the critical structures included: bladder, rectum and small bowel. All patients were treated with sequential-IMRT plan, but for dosimetric comparison, SIB-IMRT plan was also created. The prescription dose to PTV P + SV was 74 Gy in both strategies but with different dose per fraction, however, the dose to PTV LN was 50 Gy delivered in 25 fractions over 5 weeks for sequential-IMRT and 54 Gy delivered in 27 fractions over 5.5 weeks for SIB-IMRT. The treatment plans were compared in terms of dose-volume histograms. Also, Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) obtained with the two plans were compared. The volume of rectum receiving 70 Gy or more (V > 70 Gy) was reduced to 18.23% with SIB-IMRT from 22.81% with sequential-IMRT. SIB-IMRT reduced the mean doses to both bladder and rectum by 13% and 17%, respectively, as compared to sequential-IMRT. NTCP of 0.86 ± 0.75% and 0.01 ± 0.02% for the bladder, 5.87 ± 2.58% and 4.31 ± 2.61% for the rectum and 8.83 ± 7.08% and 8.25 ± 7.98% for the bowel was seen with sequential-IMRT and SIB-IMRT plans respectively. For equal PTV coverage, SIB-IMRT markedly reduced doses to critical structures, therefore should be considered as the strategy for dose escalation. SIB-IMRT achieves lesser NTCP than sequential-IMRT.

  5. A critical evaluation of secondary cancer risk models applied to Monte Carlo dose distributions of 2-dimensional, 3-dimensional conformal and hybrid intensity-modulated radiation therapy for breast cancer

    International Nuclear Information System (INIS)

    Joosten, A; Bochud, F; Moeckli, R

    2014-01-01

    The comparison of radiotherapy techniques regarding secondary cancer risk has yielded contradictory results possibly stemming from the many different approaches used to estimate risk. The purpose of this study was to make a comprehensive evaluation of different available risk models applied to detailed whole-body dose distributions computed by Monte Carlo for various breast radiotherapy techniques including conventional open tangents, 3D conformal wedged tangents and hybrid intensity modulated radiation therapy (IMRT). First, organ-specific linear risk models developed by the International Commission on Radiological Protection (ICRP) and the Biological Effects of Ionizing Radiation (BEIR) VII committee were applied to mean doses for remote organs only and all solid organs. Then, different general non-linear risk models were applied to the whole body dose distribution. Finally, organ-specific non-linear risk models for the lung and breast were used to assess the secondary cancer risk for these two specific organs. A total of 32 different calculated absolute risks resulted in a broad range of values (between 0.1% and 48.5%) underlying the large uncertainties in absolute risk calculation. The ratio of risk between two techniques has often been proposed as a more robust assessment of risk than the absolute risk. We found that the ratio of risk between two techniques could also vary substantially considering the different approaches to risk estimation. Sometimes the ratio of risk between two techniques would range between values smaller and larger than one, which then translates into inconsistent results on the potential higher risk of one technique compared to another. We found however that the hybrid IMRT technique resulted in a systematic reduction of risk compared to the other techniques investigated even though the magnitude of this reduction varied substantially with the different approaches investigated. Based on the epidemiological data available, a reasonable

  6. Persistently better treatment planning results of intensity-modulated (IMRT) over conformal radiotherapy (3D-CRT) in prostate cancer patients with significant variation of clinical target volume and/or organs-at-risk

    International Nuclear Information System (INIS)

    Fenoglietto, Pascal; Laliberte, Benoit; Allaw, Ali; Ailleres, Norbert; Idri, Katia; Hay, Meng Huor; Moscardo, Carmen Llacer; Gourgou, Sophie; Dubois, Jean-Bernard; Azria, David

    2008-01-01

    Purpose: To compare the dose coverage of planning and clinical target volume (PTV, CTV), and organs-at-risk (OAR) between intensity-modulated (3D-IMRT) and conventional conformal radiotherapy (3D-CRT) before and after internal organ variation in prostate cancer. Methods and materials: We selected 10 patients with clinically significant interfraction volume changes. Patients were treated with 3D-IMRT to 80 Gy (minimum PTV dose of 76 Gy, excluding rectum). Fictitious, equivalent 3D-CRT plans (80 Gy at isocenter, with 95% isodose (76 Gy) coverage of PTV, with rectal blocking above 76 Gy) were generated using the same planning CT data set ('CT planning'). The plans were then also applied to a verification CT scan ('CT verify') obtained at a different moment. PTV, CTV, and OAR dose coverage were compared using non-parametric tests statistics for V95, V90 (% of the volume receiving ≥95 or 90% of the dose) and D50 (dose to 50% of the volume). Results: Mean V95 of the PTV for 'CT planning' was 94.3% (range, 88-99) vs 89.1% (range, 84-94.5) for 3D-IMRT and 3D-CRT (p = 0.005), respectively. Mean V95 of the CTV for 'CT verify' was 97% for both 3D-IMRT and 3D-CRT. Mean D50 of the rectum for 'CT planning' was 26.8 Gy (range, 22-35) vs 43.5 Gy (range, 33.5-50.5) for 3D-IMRT and 3D-CRT (p = 0.0002), respectively. For 'CT verify', this D50 was 31.1 Gy (range, 16.5-44) vs 44.2 Gy (range, 34-55) for 3D-IMRT and 3D-CRT (p = 0.006), respectively. V95 of the rectum was 0% for both plans for 'CT planning', and 2.3% (3D-IMRT) vs 2.1% (3D-CRT) for 'CT verify' (p = non-sig.). Conclusion: Dose coverage of the PTV and OAR was better with 3D-IMRT for each patient and remained so after internal volume changes

  7. Conformal invariance in supergravity

    International Nuclear Information System (INIS)

    Bergshoeff, E.A.

    1983-01-01

    In this thesis the author explains the role of conformal invariance in supergravity. He presents the complete structure of extended conformal supergravity for N <= 4. The outline of this work is as follows. In chapter 2 he briefly summarizes the essential properties of supersymmetry and supergravity and indicates the use of conformal invariance in supergravity. The idea that the introduction of additional symmetry transformations can make clear the structure of a field theory is not reserved to supergravity only. By means of some simple examples it is shown in chapter 3 how one can always introduce additional gauge transformations in a theory of massive vector fields. Moreover it is shown how the gauge invariant formulation sometimes explains the quantum mechanical properties of the theory. In chapter 4 the author defines the conformal transformations and summarizes their main properties. He explains how these conformal transformations can be used to analyse the structure of gravity. The supersymmetric extension of these results is discussed in chapter 5. Here he describes as an example how N=1 supergravity can be reformulated in a conformally-invariant way. He also shows that beyond N=1 the gauge fields of the superconformal symmetries do not constitute an off-shell field representation of extended conformal supergravity. Therefore, in chapter 6, a systematic method to construct the off-shell formulation of all extended conformal supergravity theories with N <= 4 is developed. As an example he uses this method to construct N=1 conformal supergravity. Finally, in chapter 7 N=4 conformal supergravity is discussed. (Auth.)

  8. Rapid roll inflation with conformal coupling

    International Nuclear Information System (INIS)

    Kofman, Lev; Mukohyama, Shinji

    2008-01-01

    Usual inflation is realized with a slow rolling scalar field minimally coupled to gravity. In contrast, we consider dynamics of a scalar with a flat effective potential, conformally coupled to gravity. Surprisingly, it contains an attractor inflationary solution with the rapidly rolling inflaton field. We discuss models with the conformal inflaton with a flat potential (including hybrid inflation). There is no generation of cosmological fluctuations from the conformally coupled inflaton. We consider realizations of modulated (inhomogeneous reheating) or curvaton cosmological fluctuations in these models. We also implement these unusual features for the popular string-theoretic warped inflationary scenario, based on the interacting D3-D3 branes. The original warped brane inflation suffers a large inflaton mass due to conformal coupling to 4-dimensional gravity. Instead of considering this as a problem and trying to cure it with extra engineering, we show that warped inflation with the conformally coupled, rapidly rolling inflaton is yet possible with N=37 efoldings, which requires low-energy scales 1-100 TeV of inflation. Coincidentally, the same warping numerology can be responsible for the hierarchy. It is shown that the scalars associated with angular isometries of the warped geometry of compact manifold (e.g. S 3 of Klebanov-Strassler (KS) geometry) have solutions identical to conformally coupled modes and also cannot be responsible for cosmological fluctuations. We discuss other possibilities

  9. Rapid roll inflation with conformal coupling

    Science.gov (United States)

    Kofman, Lev; Mukohyama, Shinji

    2008-02-01

    Usual inflation is realized with a slow rolling scalar field minimally coupled to gravity. In contrast, we consider dynamics of a scalar with a flat effective potential, conformally coupled to gravity. Surprisingly, it contains an attractor inflationary solution with the rapidly rolling inflaton field. We discuss models with the conformal inflaton with a flat potential (including hybrid inflation). There is no generation of cosmological fluctuations from the conformally coupled inflaton. We consider realizations of modulated (inhomogeneous reheating) or curvaton cosmological fluctuations in these models. We also implement these unusual features for the popular string-theoretic warped inflationary scenario, based on the interacting D3-D¯3 branes. The original warped brane inflation suffers a large inflaton mass due to conformal coupling to 4-dimensional gravity. Instead of considering this as a problem and trying to cure it with extra engineering, we show that warped inflation with the conformally coupled, rapidly rolling inflaton is yet possible with N=37 efoldings, which requires low-energy scales 1 100 TeV of inflation. Coincidentally, the same warping numerology can be responsible for the hierarchy. It is shown that the scalars associated with angular isometries of the warped geometry of compact manifold (e.g. S3 of Klebanov-Strassler (KS) geometry) have solutions identical to conformally coupled modes and also cannot be responsible for cosmological fluctuations. We discuss other possibilities.

  10. The Conformational Dynamics of Cas9 Governing DNA Cleavage Are Revealed by Single-Molecule FRET

    Directory of Open Access Journals (Sweden)

    Mengyi Yang

    2018-01-01

    Full Text Available Summary: Off-target binding and cleavage by Cas9 pose major challenges in its application. How the conformational dynamics of Cas9 govern its nuclease activity under on- and off-target conditions remains largely unknown. Here, using intra-molecular single-molecule fluorescence resonance energy transfer measurements, we revealed that Cas9 in apo, sgRNA-bound, and dsDNA/sgRNA-bound forms spontaneously transits among three major conformational states, mainly reflecting significant conformational mobility of the catalytic HNH domain. We also uncovered surprising long-range allosteric communication between the HNH domain and the RNA/DNA heteroduplex at the PAM-distal end to ensure correct positioning of the catalytic site, which demonstrated that a unique proofreading mechanism served as the last checkpoint before DNA cleavage. Several Cas9 residues were likely to mediate the allosteric communication and proofreading step. Modulating interactions between Cas9 and heteroduplex at the PAM-distal end by introducing mutations on these sites provides an alternative route to improve and optimize the CRISPR/Cas9 toolbox. : Yang et al. revealed significant conformational dynamics of Cas9 at global and local scales using single-molecule FRET. They uncovered surprising long-range allosteric communication between the HNH nuclease domain and the RNA/DNA heteroduplex at the PAM-distal end that serves as a proofreading checkpoint to govern the nuclease activity and specificity of Cas9. Keywords: CRISPR, Cas9, single-molecule, FRET, conformational dynamics, proofreading, off-target, allosteric communication, genome editing

  11. Conformal expansions and renormalons

    Energy Technology Data Exchange (ETDEWEB)

    Rathsman, J.

    2000-02-07

    The coefficients in perturbative expansions in gauge theories are factorially increasing, predominantly due to renormalons. This type of factorial increase is not expected in conformal theories. In QCD conformal relations between observables can be defined in the presence of a perturbative infrared fixed-point. Using the Banks-Zaks expansion the authors study the effect of the large-order behavior of the perturbative series on the conformal coefficients. The authors find that in general these coefficients become factorially increasing. However, when the factorial behavior genuinely originates in a renormalon integral, as implied by a postulated skeleton expansion, it does not affect the conformal coefficients. As a consequence, the conformal coefficients will indeed be free of renormalon divergence, in accordance with previous observations concerning the smallness of these coefficients for specific observables. The authors further show that the correspondence of the BLM method with the skeleton expansion implies a unique scale-setting procedure. The BLM coefficients can be interpreted as the conformal coefficients in the series relating the fixed-point value of the observable with that of the skeleton effective charge. Through the skeleton expansion the relevance of renormalon-free conformal coefficients extends to real-world QCD.

  12. Conformal sequestering simplified

    International Nuclear Information System (INIS)

    Schmaltz, Martin; Sundrum, Raman

    2006-01-01

    Sequestering is important for obtaining flavor-universal soft masses in models where supersymmetry breaking is mediated at high scales. We construct a simple and robust class of hidden sector models which sequester themselves from the visible sector due to strong and conformally invariant hidden dynamics. Masses for hidden matter eventually break the conformal symmetry and lead to supersymmetry breaking by the mechanism recently discovered by Intriligator, Seiberg and Shih. We give a unified treatment of subtleties due to global symmetries of the CFT. There is enough review for the paper to constitute a self-contained account of conformal sequestering

  13. Conformally connected universes

    International Nuclear Information System (INIS)

    Cantor, M.; Piran, T.

    1983-01-01

    A well-known difficulty associated with the conformal method for the solution of the general relativistic Hamiltonian constraint is the appearance of an aphysical ''bag of gold'' singularity at the nodal surface of the conformal factor. This happens whenever the background Ricci scalar is too large. Using a simple model, it is demonstrated that some of these singular solutions do have a physical meaning, and that these can be considered as initial data for Universe containing black holes, which are connected, in a conformally nonsingular way with each other. The relation between the ADM mass and the horizon area in this solution supports the cosmic censorship conjecture. (author)

  14. The Conformational Dynamics of Cas9 Governing DNA Cleavage Are Revealed by Single-Molecule FRET.

    Science.gov (United States)

    Yang, Mengyi; Peng, Sijia; Sun, Ruirui; Lin, Jingdi; Wang, Nan; Chen, Chunlai

    2018-01-09

    Off-target binding and cleavage by Cas9 pose major challenges in its application. How the conformational dynamics of Cas9 govern its nuclease activity under on- and off-target conditions remains largely unknown. Here, using intra-molecular single-molecule fluorescence resonance energy transfer measurements, we revealed that Cas9 in apo, sgRNA-bound, and dsDNA/sgRNA-bound forms spontaneously transits among three major conformational states, mainly reflecting significant conformational mobility of the catalytic HNH domain. We also uncovered surprising long-range allosteric communication between the HNH domain and the RNA/DNA heteroduplex at the PAM-distal end to ensure correct positioning of the catalytic site, which demonstrated that a unique proofreading mechanism served as the last checkpoint before DNA cleavage. Several Cas9 residues were likely to mediate the allosteric communication and proofreading step. Modulating interactions between Cas9 and heteroduplex at the PAM-distal end by introducing mutations on these sites provides an alternative route to improve and optimize the CRISPR/Cas9 toolbox. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  15. Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics.

    Directory of Open Access Journals (Sweden)

    Barry J Grant

    2009-03-01

    Full Text Available Ras mediates signaling pathways controlling cell proliferation and development by cycling between GTP- and GDP-bound active and inactive conformational states. Understanding the complete reaction path of this conformational change and its intermediary structures is critical to understanding Ras signaling. We characterize nucleotide-dependent conformational transition using multiple-barrier-crossing accelerated molecular dynamics (aMD simulations. These transitions, achieved for the first time for wild-type Ras, are impossible to observe with classical molecular dynamics (cMD simulations due to the large energetic barrier between end states. Mapping the reaction path onto a conformer plot describing the distribution of the crystallographic structures enabled identification of highly populated intermediate structures. These structures have unique switch orientations (residues 25-40 and 57-75 intermediate between GTP and GDP states, or distinct loop3 (46-49, loop7 (105-110, and alpha5 C-terminus (159-166 conformations distal from the nucleotide-binding site. In addition, these barrier-crossing trajectories predict novel nucleotide-dependent correlated motions, including correlations of alpha2 (residues 66-74 with alpha3-loop7 (93-110, loop2 (26-37 with loop10 (145-151, and loop3 (46-49 with alpha5 (152-167. The interconversion between newly identified Ras conformations revealed by this study advances our mechanistic understanding of Ras function. In addition, the pattern of correlated motions provides new evidence for a dynamic linkage between the nucleotide-binding site and the membrane interacting C-terminus critical for the signaling function of Ras. Furthermore, normal mode analysis indicates that the dominant collective motion that occurs during nucleotide-dependent conformational exchange, and captured in aMD (but absent in cMD simulations, is a low-frequency motion intrinsic to the structure.

  16. Conformable variational iteration method

    Directory of Open Access Journals (Sweden)

    Omer Acan

    2017-02-01

    Full Text Available In this study, we introduce the conformable variational iteration method based on new defined fractional derivative called conformable fractional derivative. This new method is applied two fractional order ordinary differential equations. To see how the solutions of this method, linear homogeneous and non-linear non-homogeneous fractional ordinary differential equations are selected. Obtained results are compared the exact solutions and their graphics are plotted to demonstrate efficiency and accuracy of the method.

  17. Delineating the conformal window

    DEFF Research Database (Denmark)

    Frandsen, Mads Toudal; Pickup, Thomas; Teper, Michael

    2011-01-01

    We identify and characterise the conformal window in gauge theories relevant for beyond the standard model building, e.g. Technicolour, using the criteria of metric confinement and causal analytic couplings, which are known to be consistent with the phase diagram of supersymmetric QCD from Seiberg...... duality. Using these criteria we find perturbation theory to be consistent throughout the predicted conformal window for several of these gauge theories and we discuss recent lattice results in the light of our findings....

  18. Coadjoint orbits and conformal field theory

    International Nuclear Information System (INIS)

    Taylor, W. IV.

    1993-08-01

    This thesis is primarily a study of certain aspects of the geometric and algebraic structure of coadjoint orbit representations of infinite-dimensional Lie groups. The goal of this work is to use coadjoint orbit representations to construct conformal field theories, in a fashion analogous to the free-field constructions of conformal field theories. The new results which are presented in this thesis are as follows: First, an explicit set of formulae are derived giving an algebraic realization of coadjoint orbit representations in terms of differential operators acting on a polynomial Fock space. These representations are equivalent to dual Verma module representations. Next, intertwiners are explicitly constructed which allow the construction of resolutions for irreducible representations using these Fock space realizations. Finally, vertex operators between these irreducible representations are explicitly constructed as chain maps between the resolutions; these vertex operators allow the construction of rational conformal field theories according to an algebraic prescription

  19. Solid residues

    International Nuclear Information System (INIS)

    Mulder, E.; Duin, P.J. van; Grootenboer, G.J.

    1995-01-01

    A summary is presented of the many investigations that have been done on solid residues of atmospheric fluid bed combustion (AFBC). These residues are bed ash, cyclone ash and bag filter ash. Physical and chemical properties are discussed and then the various uses of residues (in fillers, bricks, gravel, and for recovery of aluminium) are summarised. Toxicological properties of fly ash and stack ash are discussed as are risks of pneumoconiosis for workers handling fly ash, and contamination of water by ashes. On the basis of present information it is concluded that risks to public health from exposure to emissions of coal fly ash from AFBC appear small or negligible as are health risk to workers in the coal fly ash processing industry. 35 refs., 5 figs., 12 tabs

  20. Logarithmic conformal field theory

    Science.gov (United States)

    Gainutdinov, Azat; Ridout, David; Runkel, Ingo

    2013-12-01

    theories including those with boundaries, supersymmetry and galilean relativity. Gurarie has written an historical overview of his seminal contributions to this field, putting his results (and those of his collaborators) in the context of understanding applications to condensed matter physics. This includes the link between the non-diagonalisability of L0 and logarithmic singularities, a study of the c → 0 catastrophe, and a proposed resolution involving supersymmetric partners for the stress-energy tensor and its logarithmic partner field. Henkel and Rouhani describe a direction in which logarithmic singularities are observed in correlators of non-relativistic field theories. Their review covers the appropriate modifications of conformal invariance that are appropriate to non-equilibrium statistical mechanics, strongly anisotropic critical points and certain variants of TMG. The main variation away from the standard relativistic idea of conformal invariance is that time is explicitly distinguished from space when considering dilations and this leads to a variety of algebraic structures to explore. In this review, the link between non-diagonalisable representations and logarithmic singularities in correlators is generalised to these algebras, before two applications of the theory are discussed. Huang and Lepowsky give a non-technical overview of their work on braided tensor structures on suitable categories of representations of vertex operator algebras. They also place their work in historic context and compare it to related approaches. The authors sketch their construction of the so-called P(z)-tensor product of modules of a vertex operator algebra, and the construction of the associativity isomorphisms for this tensor product. They proceed to give a guide to their works leading to the first authorrsquo;s proof of modularity for a class of vertex operator algebras, and to their works, joint with Zhang, on logarithmic intertwining operators and the resulting tensor

  1. [Conformation analysis of the N-glycosylation site Asn-X-Thr/Ser in glycoproteins].

    Science.gov (United States)

    Avanov, A Ia; Lipkind, G M

    1990-03-01

    Theoretical conformational analysis of oligopeptides CH3CO-Asn-X-Thr-NHCH3 (X = Gly, Ala, Pro), modelling N-glycosylation site, and their glycosylated derivatives CH3CO-(GlcNAc beta 1-4GlcNAc beta 1) Asn-X-Thr-NHCH3 has been carried out. Active conformations of the site are found, corresponding to structural prerequisities of N-glycosylation: Asn residue's position in beta-turn and hydrogen bond formation between side chains of Asn and Thr/Ser residues. In this case the L conformation of the central residue X is most probable. Since Pro residue does not possess this conformation, sequences with X = Pro are not glycosylated. It is shown that glycosylation of the above-mentioned sites is accompanied by reorientation of the Asn residue's side chains.

  2. Focused conformational sampling in proteins

    Science.gov (United States)

    Bacci, Marco; Langini, Cassiano; Vymětal, Jiří; Caflisch, Amedeo; Vitalis, Andreas

    2017-11-01

    A detailed understanding of the conformational dynamics of biological molecules is difficult to obtain by experimental techniques due to resolution limitations in both time and space. Computer simulations avoid these in theory but are often too short to sample rare events reliably. Here we show that the progress index-guided sampling (PIGS) protocol can be used to enhance the sampling of rare events in selected parts of biomolecules without perturbing the remainder of the system. The method is very easy to use as it only requires as essential input a set of several features representing the parts of interest sufficiently. In this feature space, new states are discovered by spontaneous fluctuations alone and in unsupervised fashion. Because there are no energetic biases acting on phase space variables or projections thereof, the trajectories PIGS generates can be analyzed directly in the framework of transition networks. We demonstrate the possibility and usefulness of such focused explorations of biomolecules with two loops that are part of the binding sites of bromodomains, a family of epigenetic "reader" modules. This real-life application uncovers states that are structurally and kinetically far away from the initial crystallographic structures and are also metastable. Representative conformations are intended to be used in future high-throughput virtual screening campaigns.

  3. Residual deficits in quality of life one year after intensity-modulated radiotherapy for patients with locally advanced head and neck cancer. Results of a prospective study

    International Nuclear Information System (INIS)

    Tribius, Silke; Raguse, Marieclaire; Voigt, Christian; Petersen, Cordula; Kruell, Andreas; Muenscher, Adrian; Groebe, Alexander; Bergelt, Corinna; Singer, Susanne

    2015-01-01

    Patients with locally advanced head and neck cancer (LAHNC) undergo life-changing treatments that can seriously affect quality of life (QoL). This prospective study examined the key QoL domains during the first year after intensity-modulated radiotherapy (IMRT) and identified predictors of these changes in order to improve patient outcomes. A consecutive series of patients with LAHNC completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core module (QLQ-C30) and the HNC-specific QLQ-HN35 before (t0) and at the end (t1) of definitive or adjuvant IMRT, then at 6-8 weeks (t2), 6 months (t3), and 1 year (t4) after IMRT. Patients (n = 111) completing questionnaires at all five time points were included (baseline response rate: 99 %; dropout rate between t0 and t4: 5 %). QoL deteriorated in all domains during IMRT and improved slowly during the first year thereafter. Many domains recovered to baseline values after 1 year but problems with smelling and tasting, dry mouth, and sticky saliva remained issues at this time. Increases in problems with sticky saliva were greater after 1 year in patients with definitive versus adjuvant IMRT (F = 3.5, P = 0.05). QoL in patients with LAHNC receiving IMRT takes approximately 1 year to return to baseline; some domains remain compromised after 1 year. Although IMRT aims to maintain function and QoL, patients experience long-term dry mouth and sticky saliva, particularly following definitive IMRT. Patients should be counseled at the start of therapy to reduce disappointment with the pace of recovery. (orig.) [de

  4. Dosimetric Effect of Intrafraction Motion and Residual Setup Error for Hypofractionated Prostate Intensity-Modulated Radiotherapy With Online Cone Beam Computed Tomography Image Guidance

    International Nuclear Information System (INIS)

    Adamson, Justus; Wu Qiuwen; Yan Di

    2011-01-01

    Purpose: To quantify the dosimetric effect and margins required to account for prostate intrafractional translation and residual setup error in a cone beam computed tomography (CBCT)-guided hypofractionated radiotherapy protocol. Methods and Materials: Prostate position after online correction was measured during dose delivery using simultaneous kV fluoroscopy and posttreatment CBCT in 572 fractions to 30 patients. We reconstructed the dose distribution to the clinical tumor volume (CTV) using a convolution of the static dose with a probability density function (PDF) based on the kV fluoroscopy, and we calculated the minimum dose received by 99% of the CTV (D 99 ). We compared reconstructed doses when the convolution was performed per beam, per patient, and when the PDF was created using posttreatment CBCT. We determined the minimum axis-specific margins to limit CTV D 99 reduction to 1%. Results: For 3-mm margins, D 99 reduction was ≤5% for 29/30 patients. Using post-CBCT rather than localizations at treatment delivery exaggerated dosimetric effects by ∼47%, while there was no such bias between the dose convolved with a beam-specific and patient-specific PDF. After eight fractions, final cumulative D 99 could be predicted with a root mean square error of <1%. For 90% of patients, the required margins were ≤2, 4, and 3 mm, with 70%, 40%, and 33% of patients requiring no right-left (RL), anteroposterior (AP), and superoinferior margins, respectively. Conclusions: For protocols with CBCT guidance, RL, AP, and SI margins of 2, 4, and 3 mm are sufficient to account for translational errors; however, the large variation in patient-specific margins suggests that adaptive management may be beneficial.

  5. Dosimetric effect of intrafraction motion and residual setup error for hypofractionated prostate intensity-modulated radiotherapy with online cone beam computed tomography image guidance.

    LENUS (Irish Health Repository)

    Adamson, Justus

    2012-02-01

    PURPOSE: To quantify the dosimetric effect and margins required to account for prostate intrafractional translation and residual setup error in a cone beam computed tomography (CBCT)-guided hypofractionated radiotherapy protocol. METHODS AND MATERIALS: Prostate position after online correction was measured during dose delivery using simultaneous kV fluoroscopy and posttreatment CBCT in 572 fractions to 30 patients. We reconstructed the dose distribution to the clinical tumor volume (CTV) using a convolution of the static dose with a probability density function (PDF) based on the kV fluoroscopy, and we calculated the minimum dose received by 99% of the CTV (D(99)). We compared reconstructed doses when the convolution was performed per beam, per patient, and when the PDF was created using posttreatment CBCT. We determined the minimum axis-specific margins to limit CTV D(99) reduction to 1%. RESULTS: For 3-mm margins, D(99) reduction was <\\/=5% for 29\\/30 patients. Using post-CBCT rather than localizations at treatment delivery exaggerated dosimetric effects by ~47%, while there was no such bias between the dose convolved with a beam-specific and patient-specific PDF. After eight fractions, final cumulative D(99) could be predicted with a root mean square error of <1%. For 90% of patients, the required margins were <\\/=2, 4, and 3 mm, with 70%, 40%, and 33% of patients requiring no right-left (RL), anteroposterior (AP), and superoinferior margins, respectively. CONCLUSIONS: For protocols with CBCT guidance, RL, AP, and SI margins of 2, 4, and 3 mm are sufficient to account for translational errors; however, the large variation in patient-specific margins suggests that adaptive management may be beneficial.

  6. Conformity and statistical tolerancing

    Science.gov (United States)

    Leblond, Laurent; Pillet, Maurice

    2018-02-01

    Statistical tolerancing was first proposed by Shewhart (Economic Control of Quality of Manufactured Product, (1931) reprinted 1980 by ASQC), in spite of this long history, its use remains moderate. One of the probable reasons for this low utilization is undoubtedly the difficulty for designers to anticipate the risks of this approach. The arithmetic tolerance (worst case) allows a simple interpretation: conformity is defined by the presence of the characteristic in an interval. Statistical tolerancing is more complex in its definition. An interval is not sufficient to define the conformance. To justify the statistical tolerancing formula used by designers, a tolerance interval should be interpreted as the interval where most of the parts produced should probably be located. This tolerance is justified by considering a conformity criterion of the parts guaranteeing low offsets on the latter characteristics. Unlike traditional arithmetic tolerancing, statistical tolerancing requires a sustained exchange of information between design and manufacture to be used safely. This paper proposes a formal definition of the conformity, which we apply successively to the quadratic and arithmetic tolerancing. We introduce a concept of concavity, which helps us to demonstrate the link between tolerancing approach and conformity. We use this concept to demonstrate the various acceptable propositions of statistical tolerancing (in the space decentring, dispersion).

  7. Axiomatic conformal field theory

    International Nuclear Information System (INIS)

    Gaberdiel, M.R.; Goddard, P.

    2000-01-01

    A new rigourous approach to conformal field theory is presented. The basic objects are families of complex-valued amplitudes, which define a meromorphic conformal field theory (or chiral algebra) and which lead naturally to the definition of topological vector spaces, between which vertex operators act as continuous operators. In fact, in order to develop the theory, Moebius invariance rather than full conformal invariance is required but it is shown that every Moebius theory can be extended to a conformal theory by the construction of a Virasoro field. In this approach, a representation of a conformal field theory is naturally defined in terms of a family of amplitudes with appropriate analytic properties. It is shown that these amplitudes can also be derived from a suitable collection of states in the meromorphic theory. Zhu's algebra then appears naturally as the algebra of conditions which states defining highest weight representations must satisfy. The relationship of the representations of Zhu's algebra to the classification of highest weight representations is explained. (orig.)

  8. Extended conformal algebras

    International Nuclear Information System (INIS)

    Goddard, Peter

    1990-01-01

    The algebra of the group of conformal transformations in two dimensions consists of two commuting copies of the Virasoro algebra. In many mathematical and physical contexts, the representations of ν which are relevant satisfy two conditions: they are unitary and they have the ''positive energy'' property that L o is bounded below. In an irreducible unitary representation the central element c takes a fixed real value. In physical contexts, the value of c is a characteristic of a theory. If c < 1, it turns out that the conformal algebra is sufficient to ''solve'' the theory, in the sense of relating the calculation of the infinite set of physically interesting quantities to a finite subset which can be handled in principle. For c ≥ 1, this is no longer the case for the algebra alone and one needs some sort of extended conformal algebra, such as the superconformal algebra. It is these algebras that this paper aims at addressing. (author)

  9. Algebraic conformal field theory

    International Nuclear Information System (INIS)

    Fuchs, J.; Nationaal Inst. voor Kernfysica en Hoge-Energiefysica

    1991-11-01

    Many conformal field theory features are special versions of structures which are present in arbitrary 2-dimensional quantum field theories. So it makes sense to describe 2-dimensional conformal field theories in context of algebraic theory of superselection sectors. While most of the results of the algebraic theory are rather abstract, conformal field theories offer the possibility to work out many formulae explicitly. In particular, one can construct the full algebra A-bar of global observables and the endomorphisms of A-bar which represent the superselection sectors. Some explicit results are presented for the level 1 so(N) WZW theories; the algebra A-bar is found to be the enveloping algebra of a Lie algebra L-bar which is an extension of the chiral symmetry algebra of the WZW theory. (author). 21 refs., 6 figs

  10. Residual deficits in quality of life one year after intensity-modulated radiotherapy for patients with locally advanced head and neck cancer. Results of a prospective study

    Energy Technology Data Exchange (ETDEWEB)

    Tribius, Silke; Raguse, Marieclaire; Voigt, Christian; Petersen, Cordula; Kruell, Andreas [University Medical Center Hamburg-Eppendorf, Department of Radiation Oncology, Hamburg (Germany); Muenscher, Adrian [University Medical Center Hamburg-Eppendorf, Department of Otorhinolaryngology and Head and Neck Surgery, Hamburg (Germany); Groebe, Alexander [University Medical Center Hamburg-Eppendorf, Department of Maxillofacial Surgery, Hamburg (Germany); Bergelt, Corinna [University Medical Center Hamburg-Eppendorf, Department of Medical Psychology, Hamburg (Germany); Singer, Susanne [University Medical Center Mainz, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), Mainz (Germany)

    2015-03-08

    Patients with locally advanced head and neck cancer (LAHNC) undergo life-changing treatments that can seriously affect quality of life (QoL). This prospective study examined the key QoL domains during the first year after intensity-modulated radiotherapy (IMRT) and identified predictors of these changes in order to improve patient outcomes. A consecutive series of patients with LAHNC completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core module (QLQ-C30) and the HNC-specific QLQ-HN35 before (t0) and at the end (t1) of definitive or adjuvant IMRT, then at 6-8 weeks (t2), 6 months (t3), and 1 year (t4) after IMRT. Patients (n = 111) completing questionnaires at all five time points were included (baseline response rate: 99 %; dropout rate between t0 and t4: 5 %). QoL deteriorated in all domains during IMRT and improved slowly during the first year thereafter. Many domains recovered to baseline values after 1 year but problems with smelling and tasting, dry mouth, and sticky saliva remained issues at this time. Increases in problems with sticky saliva were greater after 1 year in patients with definitive versus adjuvant IMRT (F = 3.5, P = 0.05). QoL in patients with LAHNC receiving IMRT takes approximately 1 year to return to baseline; some domains remain compromised after 1 year. Although IMRT aims to maintain function and QoL, patients experience long-term dry mouth and sticky saliva, particularly following definitive IMRT. Patients should be counseled at the start of therapy to reduce disappointment with the pace of recovery. (orig.) [German] Die Therapie von Patienten mit lokal fortgeschrittenen Kopf-Hals-Tumoren (LFKHT) geht mit einschneidenden Veraenderungen einher und beeinflusst die Lebensqualitaet (LQ) erheblich. Diese prospektive Studie untersucht die LQ waehrend des ersten Jahres nach intensitaetsmodulierter Strahlentherapie (IMRT) und hat Praediktoren dieser Veraenderungen herausgearbeitet, um

  11. Killing tensors and conformal Killing tensors from conformal Killing vectors

    International Nuclear Information System (INIS)

    Rani, Raffaele; Edgar, S Brian; Barnes, Alan

    2003-01-01

    Koutras has proposed some methods to construct reducible proper conformal Killing tensors and Killing tensors (which are, in general, irreducible) when a pair of orthogonal conformal Killing vectors exist in a given space. We give the completely general result demonstrating that this severe restriction of orthogonality is unnecessary. In addition, we correct and extend some results concerning Killing tensors constructed from a single conformal Killing vector. A number of examples demonstrate that it is possible to construct a much larger class of reducible proper conformal Killing tensors and Killing tensors than permitted by the Koutras algorithms. In particular, by showing that all conformal Killing tensors are reducible in conformally flat spaces, we have a method of constructing all conformal Killing tensors, and hence all the Killing tensors (which will in general be irreducible) of conformally flat spaces using their conformal Killing vectors

  12. Residual basins

    International Nuclear Information System (INIS)

    D'Elboux, C.V.; Paiva, I.B.

    1980-01-01

    Exploration for uranium carried out over a major portion of the Rio Grande do Sul Shield has revealed a number of small residual basins developed along glacially eroded channels of pre-Permian age. Mineralization of uranium occurs in two distinct sedimentary units. The lower unit consists of rhythmites overlain by a sequence of black shales, siltstones and coal seams, while the upper one is dominated by sandstones of probable fluvial origin. (Author) [pt

  13. New conformations of linear polyubiquitin chains from crystallographic and solution-scattering studies expand the conformational space of polyubiquitin.

    Science.gov (United States)

    Thach, Trung Thanh; Shin, Donghyuk; Han, Seungsu; Lee, Sangho

    2016-04-01

    The conformational flexibility of linkage-specific polyubiquitin chains enables ubiquitylated proteins and their receptors to be involved in a variety of cellular processes. Linear or Met1-linked polyubiquitin chains, associated with nondegradational cellular signalling pathways, have been known to adopt multiple conformations from compact to extended conformations. However, the extent of such conformational flexibility remains open. Here, the crystal structure of linear Ub2 was determined in a more compact conformation than that of the previously known structure (PDB entry 3axc). The two structures differ significantly from each other, as shown by an r.m.s.d. between C(α) atoms of 3.1 Å. The compactness of the linear Ub2 structure in comparison with PDB entry 3axc is supported by smaller values of the radius of gyration (Rg; 18 versus 18.9 Å) and the maximum interatomic distance (Dmax; 55.5 versus 57.8 Å). Extra intramolecular hydrogen bonds formed among polar residues between the distal and proximal ubiquitin moieties seem to contribute to stabilization of the compact conformation of linear Ub2. An ensemble of three semi-extended and extended conformations of linear Ub2 was also observed by small-angle X-ray scattering (SAXS) analysis in solution. In addition, the conformational heterogeneity in linear polyubiquitin chains is clearly manifested by SAXS analyses of linear Ub3 and Ub4: at least three distinct solution conformations are observed in each chain, with the linear Ub3 conformations being compact. The results expand the extent of conformational space of linear polyubiquitin chains and suggest that changes in the conformational ensemble may be pivotal in mediating multiple signalling pathways.

  14. The Role of Conserved Waters in Conformational Transitions of Q61H K-ras

    Science.gov (United States)

    Prakash, Priyanka; Sayyed-Ahmad, Abdallah; Gorfe, Alemayehu A.

    2012-01-01

    To investigate the stability and functional role of long-residence water molecules in the Q61H variant of the signaling protein K-ras, we analyzed all available Ras crystal structures and conformers derived from a series of independent explicit solvent molecular dynamics (MD) simulations totaling 1.76 µs. We show that the protein samples a different region of phase space in the presence and absence of several crystallographically conserved and buried water molecules. The dynamics of these waters is coupled with the local as well as the global motions of the protein, in contrast to less buried waters whose exchange with bulk is only loosely coupled with the motion of loops in their vicinity. Aided by two novel reaction coordinates involving the distance (d) between the Cα atoms of G60 at switch 2 and G10 at the P-loop and the N-Cα-C-O dihedral (ξ) of G60, we further show that three water molecules located in lobe1, at the interface between the lobes and at lobe2, are involved in the relative motion of residues at the two lobes of Q61H K-ras. Moreover, a d/ξ plot classifies the available Ras x-ray structures and MD-derived K-ras conformers into active GTP-, intermediate GTP-, inactive GDP-bound, and nucleotide-free conformational states. The population of these states and the transition between them is modulated by water-mediated correlated motions involving the functionally critical switch 2, P-loop and helix 3. These results suggest that water molecules act as allosteric ligands to induce a population shift among distinct switch 2 conformations that differ in effector recognition. PMID:22359497

  15. Massive Conformal Gravity

    International Nuclear Information System (INIS)

    Faria, F. F.

    2014-01-01

    We construct a massive theory of gravity that is invariant under conformal transformations. The massive action of the theory depends on the metric tensor and a scalar field, which are considered the only field variables. We find the vacuum field equations of the theory and analyze its weak-field approximation and Newtonian limit.

  16. Taming the conformal zoo

    International Nuclear Information System (INIS)

    Moore, G.; Seiberg, N.

    1989-01-01

    All known rational conformal field theories may be obtained from (2+1)-dimensional Chern-Simons gauge theories by appropriate choice of gauge group. We conjecture that all rational field theories are classified by groups via (2+1)-dimensional Chern-Simons gauge theories. (orig.)

  17. Conformal special relativity

    International Nuclear Information System (INIS)

    Maia, M.D.

    2006-01-01

    It is shown that the information loss/recovery theorem based on the ADS/CFT correspondence is not consistent with the stability of the Schwarzschild or Reissner-Nordstrom black holes. Nonetheless, the conformal invariance of Yang-Mills theory points to new relativity principle compatible with quantum unitarity near those black holes

  18. Animal culture: chimpanzee conformity?

    Science.gov (United States)

    van Schaik, Carel P

    2012-05-22

    Culture-like phenomena in wild animals have received much attention, but how good is the evidence and how similar are they to human culture? New data on chimpanzees suggest their culture may even have an element of conformity. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Parafermionic conformal field theory

    International Nuclear Information System (INIS)

    Kurak, V.

    1989-09-01

    Conformal parafermionic field theories are reviewed with emphasis on the computation of their OPE estructure constants. It is presented a simple computational of these for the Z(N) parafermions, unveilling their Lie algebra content. (A.C.A.S.) [pt

  20. Quantifying polypeptide conformational space: sensitivity to conformation and ensemble definition.

    Science.gov (United States)

    Sullivan, David C; Lim, Carmay

    2006-08-24

    Quantifying the density of conformations over phase space (the conformational distribution) is needed to model important macromolecular processes such as protein folding. In this work, we quantify the conformational distribution for a simple polypeptide (N-mer polyalanine) using the cumulative distribution function (CDF), which gives the probability that two randomly selected conformations are separated by less than a "conformational" distance and whose inverse gives conformation counts as a function of conformational radius. An important finding is that the conformation counts obtained by the CDF inverse depend critically on the assignment of a conformation's distance span and the ensemble (e.g., unfolded state model): varying ensemble and conformation definition (1 --> 2 A) varies the CDF-based conformation counts for Ala(50) from 10(11) to 10(69). In particular, relatively short molecular dynamics (MD) relaxation of Ala(50)'s random-walk ensemble reduces the number of conformers from 10(55) to 10(14) (using a 1 A root-mean-square-deviation radius conformation definition) pointing to potential disconnections in comparing the results from simplified models of unfolded proteins with those from all-atom MD simulations. Explicit waters are found to roughen the landscape considerably. Under some common conformation definitions, the results herein provide (i) an upper limit to the number of accessible conformations that compose unfolded states of proteins, (ii) the optimal clustering radius/conformation radius for counting conformations for a given energy and solvent model, (iii) a means of comparing various studies, and (iv) an assessment of the applicability of random search in protein folding.

  1. Molecular Determinants Underlying Binding Specificities of the ABL Kinase Inhibitors: Combining Alanine Scanning of Binding Hot Spots with Network Analysis of Residue Interactions and Coevolution.

    Directory of Open Access Journals (Sweden)

    Amanda Tse

    Full Text Available Quantifying binding specificity and drug resistance of protein kinase inhibitors is of fundamental importance and remains highly challenging due to complex interplay of structural and thermodynamic factors. In this work, molecular simulations and computational alanine scanning are combined with the network-based approaches to characterize molecular determinants underlying binding specificities of the ABL kinase inhibitors. The proposed theoretical framework unveiled a relationship between ligand binding and inhibitor-mediated changes in the residue interaction networks. By using topological parameters, we have described the organization of the residue interaction networks and networks of coevolving residues in the ABL kinase structures. This analysis has shown that functionally critical regulatory residues can simultaneously embody strong coevolutionary signal and high network centrality with a propensity to be energetic hot spots for drug binding. We have found that selective (Nilotinib and promiscuous (Bosutinib, Dasatinib kinase inhibitors can use their energetic hot spots to differentially modulate stability of the residue interaction networks, thus inhibiting or promoting conformational equilibrium between inactive and active states. According to our results, Nilotinib binding may induce a significant network-bridging effect and enhance centrality of the hot spot residues that stabilize structural environment favored by the specific kinase form. In contrast, Bosutinib and Dasatinib can incur modest changes in the residue interaction network in which ligand binding is primarily coupled only with the identity of the gate-keeper residue. These factors may promote structural adaptability of the active kinase states in binding with these promiscuous inhibitors. Our results have related ligand-induced changes in the residue interaction networks with drug resistance effects, showing that network robustness may be compromised by targeted mutations

  2. Molecular Determinants Underlying Binding Specificities of the ABL Kinase Inhibitors: Combining Alanine Scanning of Binding Hot Spots with Network Analysis of Residue Interactions and Coevolution

    Science.gov (United States)

    Tse, Amanda; Verkhivker, Gennady M.

    2015-01-01

    Quantifying binding specificity and drug resistance of protein kinase inhibitors is of fundamental importance and remains highly challenging due to complex interplay of structural and thermodynamic factors. In this work, molecular simulations and computational alanine scanning are combined with the network-based approaches to characterize molecular determinants underlying binding specificities of the ABL kinase inhibitors. The proposed theoretical framework unveiled a relationship between ligand binding and inhibitor-mediated changes in the residue interaction networks. By using topological parameters, we have described the organization of the residue interaction networks and networks of coevolving residues in the ABL kinase structures. This analysis has shown that functionally critical regulatory residues can simultaneously embody strong coevolutionary signal and high network centrality with a propensity to be energetic hot spots for drug binding. We have found that selective (Nilotinib) and promiscuous (Bosutinib, Dasatinib) kinase inhibitors can use their energetic hot spots to differentially modulate stability of the residue interaction networks, thus inhibiting or promoting conformational equilibrium between inactive and active states. According to our results, Nilotinib binding may induce a significant network-bridging effect and enhance centrality of the hot spot residues that stabilize structural environment favored by the specific kinase form. In contrast, Bosutinib and Dasatinib can incur modest changes in the residue interaction network in which ligand binding is primarily coupled only with the identity of the gate-keeper residue. These factors may promote structural adaptability of the active kinase states in binding with these promiscuous inhibitors. Our results have related ligand-induced changes in the residue interaction networks with drug resistance effects, showing that network robustness may be compromised by targeted mutations of key mediating

  3. Structural Basis for Prereceptor Modulation of Plant Hormones by GH3 Proteins

    Energy Technology Data Exchange (ETDEWEB)

    Westfall, Corey S.; Zubieta, Chloe; Herrmann, Jonathan; Kapp, Ulrike; Nanao, Max H.; Jez, Joseph M. (WU); (EMBL); (ESRF)

    2013-04-08

    Acyl acid amido synthetases of the GH3 family act as critical prereceptor modulators of plant hormone action; however, the molecular basis for their hormone selectivity is unclear. Here, we report the crystal structures of benzoate-specific Arabidopsis thaliana AtGH3.12/PBS3 and jasmonic acid-specific AtGH3.11/JAR1. These structures, combined with biochemical analysis, define features for the conjugation of amino acids to diverse acyl acid substrates and highlight the importance of conformational changes in the carboxyl-terminal domain for catalysis. We also identify residues forming the acyl acid binding site across the GH3 family and residues critical for amino acid recognition. Our results demonstrate how a highly adaptable three-dimensional scaffold is used for the evolution of promiscuous activity across an enzyme family for modulation of plant signaling molecules.

  4. Transportation Conformity Training and Presentations

    Science.gov (United States)

    EPA's OTAQ has provided multiple conformity training sessions in the past to assist state and local governments in implementing conformity requirements. As training information is prepared for other venues, it will be posted on this page.

  5. Conformation of antifreeze glycoproteins as determined from conformational energy calculations and fully assigned proton NMR spectra

    International Nuclear Information System (INIS)

    Bush, C.A.; Rao, B.N.N.

    1986-01-01

    The 1 H NMR spectra of AFGP's ranging in molecular weight from 2600 to 30,000 Daltons isolated from several different species of polar fish have been measured. The spectrum of AFGP 1-4 from Pagothenia borchgrevinki with an average of 30 repeating subunits has a single resonance for each proton of the glycotripeptide repeating unit, (ala-[gal-(β-1→3) galNAc-(α--O-]thr-ala)/sub n/. Its 1 H NMR spectrum including resonances of the amide protons has been completely assigned. Coupling constants and nuclear Overhauser enhancements (n.O.e.) between protons on distant residues imply conformational order. The 2600 dalton molecular weight glycopeptides (AFGP-8) have pro in place of ala at certain specific points in the sequence and AFGP-8R of Eleginus gracilis has arg in place of one thr. The resonances of pro and arg were assigned by decoupling. The resonances of the carboxy and amino terminals have distinct chemical shifts and were assigned in AFGP-8 of Boreogadus saida by titration. n.O.e. between α--protons and amide protons of the adjacent residue (sequential n.O.e.) were used in assignments of additional resonances and to assign the distinctive resonances of thr followed by pro. Conformational energy calculations on the repeating glycotripeptide subunit of AFGP show that the α--glucosidic linkage has a fixed conformation while the β--linkage is less rigid. A conformational model for AFGP 1-4, which is based on the calculations has the peptide in an extended left-handed helix with three residues per turn similar to polyproline II. The model is consistent with CD data, amide proton coupling constants, temperature dependence of amide proton chemical shifts

  6. Hot Conformal Gauge Theories

    DEFF Research Database (Denmark)

    Mojaza, Matin; Pica, Claudio; Sannino, Francesco

    2010-01-01

    of flavors. Surprisingly this number, if computed to the order g^2, agrees with previous predictions for the lower boundary of the conformal window for nonsupersymmetric gauge theories. The higher order results tend to predict a higher number of critical flavors. These are universal properties, i......We compute the nonzero temperature free energy up to the order g^6 \\ln(1/g) in the coupling constant for vector like SU(N) gauge theories featuring matter transforming according to different representations of the underlying gauge group. The number of matter fields, i.e. flavors, is arranged...... in such a way that the theory develops a perturbative stable infrared fixed point at zero temperature. Due to large distance conformality we trade the coupling constant with its fixed point value and define a reduced free energy which depends only on the number of flavors, colors and matter representation. We...

  7. Conformational flexibility of aspartame.

    Science.gov (United States)

    Toniolo, Claudio; Temussi, Pierandrea

    2016-05-01

    L-Aspartyl-L-phenylalanine methyl ester, better known as aspartame, is not only one of the most used artificial sweeteners, but also a very interesting molecule with respect to the correlation between molecular structure and taste. The extreme conformational flexibility of this dipeptide posed a huge difficulty when researchers tried to use it as a lead compound to design new sweeteners. In particular, it was difficult to take advantage of its molecular model as a mold to infer the shape of the, then unknown, active site of the sweet taste receptor. Here, we follow the story of the 3D structural aspects of aspartame from early conformational studies to recent docking into homology models of the receptor. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 376-384, 2016. © 2016 Wiley Periodicals, Inc.

  8. Conformal description of spinning particles

    International Nuclear Information System (INIS)

    Todorov, I.T.

    1986-01-01

    This book is an introduction to the application of the conformal group to quantum field theory of particles with spin. After an introduction to the twistor representations of the conformal group of a conformally flat space-time and twistor flag manifolds with Su(2,2) orbits the classical phase space of conformal spinning particles is described. Thereafter the twistor description of classical zero mass fields is considered together with the quantization. (HSI)

  9. Conformal boundaries of warped products

    DEFF Research Database (Denmark)

    Kokkendorff, Simon Lyngby

    2006-01-01

    In this note we prove a result on how to determine the conformal boundary of a type of warped product of two length spaces in terms of the individual conformal boundaries. In the situation, that we treat, the warping and conformal distortion functions are functions of distance to a base point....... The result is applied to produce examples of CAT(0)-spaces, where the conformal and ideal boundaries differ in interesting ways....

  10. Conformal radiotherapy: a glossary

    International Nuclear Information System (INIS)

    Dubray, B.; Giraud, P.; Beaudre, A.

    1999-01-01

    Most of the concepts and terms related to conformal radiotherapy were produced by English-speaking authors and eventually validated by international groups of experts, whose working language was also English. Therefore, a significant part of this literature is poorly accessible to the French-speaking radiation oncology community. The present paper gathers the 'official' definitions already published in French, along with propositions for the remaining terms which should be submitted to a more formal and representative validation process. (author)

  11. Investigating ion channel conformational changes using voltage clamp fluorometry.

    Science.gov (United States)

    Talwar, Sahil; Lynch, Joseph W

    2015-11-01

    Ion channels are membrane proteins whose functions are governed by conformational changes. The widespread distribution of ion channels, coupled with their involvement in most physiological and pathological processes and their importance as therapeutic targets, renders the elucidation of these conformational mechanisms highly compelling from a drug discovery perspective. Thanks to recent advances in structural biology techniques, we now have high-resolution static molecular structures for members of the major ion channel families. However, major questions remain to be resolved about the conformational states that ion channels adopt during activation, drug modulation and desensitization. Patch-clamp electrophysiology has long been used to define ion channel conformational states based on functional criteria. It achieves this by monitoring conformational changes at the channel gate and cannot detect conformational changes occurring in regions distant from the gate. Voltage clamp fluorometry involves labelling cysteines introduced into domains of interest with environmentally sensitive fluorophores and inferring structural rearrangements from voltage or ligand-induced fluorescence changes. Ion channel currents are monitored simultaneously to verify the conformational status. By defining real time conformational changes in domains distant from the gate, this technique provides unexpected new insights into ion channel structure and function. This review aims to summarise the methodology and highlight recent innovative applications of this powerful technique. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Characterizing protein conformations by correlation analysis of coarse-grained contact matrices

    Science.gov (United States)

    Lindsay, Richard J.; Siess, Jan; Lohry, David P.; McGee, Trevor S.; Ritchie, Jordan S.; Johnson, Quentin R.; Shen, Tongye

    2018-01-01

    We have developed a method to capture the essential conformational dynamics of folded biopolymers using statistical analysis of coarse-grained segment-segment contacts. Previously, the residue-residue contact analysis of simulation trajectories was successfully applied to the detection of conformational switching motions in biomolecular complexes. However, the application to large protein systems (larger than 1000 amino acid residues) is challenging using the description of residue contacts. Also, the residue-based method cannot be used to compare proteins with different sequences. To expand the scope of the method, we have tested several coarse-graining schemes that group a collection of consecutive residues into a segment. The definition of these segments may be derived from structural and sequence information, while the interaction strength of the coarse-grained segment-segment contacts is a function of the residue-residue contacts. We then perform covariance calculations on these coarse-grained contact matrices. We monitored how well the principal components of the contact matrices is preserved using various rendering functions. The new method was demonstrated to assist the reduction of the degrees of freedom for describing the conformation space, and it potentially allows for the analysis of a system that is approximately tenfold larger compared with the corresponding residue contact-based method. This method can also render a family of similar proteins into the same conformational space, and thus can be used to compare the structures of proteins with different sequences.

  13. Molecular insight into conformational transmission of human P-glycoprotein

    International Nuclear Information System (INIS)

    Chang, Shan-Yan; Liu, Fu-Feng; Dong, Xiao-Yan; Sun, Yan

    2013-01-01

    P-glycoprotein (P-gp), a kind of ATP-binding cassette transporter, can export candidates through a channel at the two transmembrane domains (TMDs) across the cell membranes using the energy released from ATP hydrolysis at the two nucleotide-binding domains (NBDs). Considerable evidence has indicated that human P-gp undergoes large-scale conformational changes to export a wide variety of anti-cancer drugs out of the cancer cells. However, molecular mechanism of the conformational transmission of human P-gp from the NBDs to the TMDs is still unclear. Herein, targeted molecular dynamics simulations were performed to explore the atomic detail of the conformational transmission of human P-gp. It is confirmed that the conformational transition from the inward- to outward-facing is initiated by the movement of the NBDs. It is found that the two NBDs move both on the two directions (x and y). The movement on the x direction leads to the closure of the NBDs, while the movement on the y direction adjusts the conformations of the NBDs to form the correct ATP binding pockets. Six key segments (KSs) protruding from the TMDs to interact with the NBDs are identified. The relative movement of the KSs along the y axis driven by the NBDs can be transmitted through α-helices to the rest of the TMDs, rendering the TMDs to open towards periplasm in the outward-facing conformation. Twenty eight key residue pairs are identified to participate in the interaction network that contributes to the conformational transmission from the NBDs to the TMDs of human P-gp. In addition, 9 key residues in each NBD are also identified. The studies have thus provided clear insight into the conformational transmission from the NBDs to the TMDs in human P-gp

  14. Logarithmic conformal field theory: beyond an introduction

    International Nuclear Information System (INIS)

    Creutzig, Thomas; Ridout, David

    2013-01-01

    This article aims to review a selection of central topics and examples in logarithmic conformal field theory. It begins with the remarkable observation of Cardy that the horizontal crossing probability of critical percolation may be computed analytically within the formalism of boundary conformal field theory. Cardy’s derivation relies on certain implicit assumptions which are shown to lead inexorably to indecomposable modules and logarithmic singularities in correlators. For this, a short introduction to the fusion algorithm of Nahm, Gaberdiel and Kausch is provided. While the percolation logarithmic conformal field theory is still not completely understood, there are several examples for which the formalism familiar from rational conformal field theory, including bulk partition functions, correlation functions, modular transformations, fusion rules and the Verlinde formula, has been successfully generalized. This is illustrated for three examples: the singlet model M(1,2), related to the triplet model W(1,2), symplectic fermions and the fermionic bc ghost system; the fractional level Wess–Zumino–Witten model based on sl-hat (2) at k=−(1/2), related to the bosonic βγ ghost system; and the Wess–Zumino–Witten model for the Lie supergroup GL(1∣1), related to SL(2∣1) at k=−(1/2) and 1, the Bershadsky–Polyakov algebra W 3 (2) and the Feigin–Semikhatov algebras W n (2) . These examples have been chosen because they represent the most accessible, and most useful, members of the three best-understood families of logarithmic conformal field theories. The logarithmic minimal models W(q,p), the fractional level Wess–Zumino–Witten models, and the Wess–Zumino–Witten models on Lie supergroups (excluding OSP(1∣2n)). In this review, the emphasis lies on the representation theory of the underlying chiral algebra and the modular data pertaining to the characters of the representations. Each of the archetypal logarithmic conformal field theories is

  15. Conformational analysis by intersection: CONAN.

    Science.gov (United States)

    Smellie, Andrew; Stanton, Robert; Henne, Randy; Teig, Steve

    2003-01-15

    As high throughput techniques in chemical synthesis and screening improve, more demands are placed on computer assisted design and virtual screening. Many of these computational methods require one or more three-dimensional conformations for molecules, creating a demand for a conformational analysis tool that can rapidly and robustly cover the low-energy conformational spaces of small molecules. A new algorithm of intersection is presented here, which quickly generates (on average heuristics are applied after intersection to generate a small representative collection of conformations that span the conformational space. In a study of approximately 97,000 randomly selected molecules from the MDDR, results are presented that explore these conformations and their ability to cover low-energy conformational space. Copyright 2002 Wiley Periodicals, Inc. J Comput Chem 24: 10-20, 2003

  16. The pH Stability of Foot-and-Mouth Disease Virus Particles Is Modulated by Residues Located at the Pentameric Interface and in the N Terminus of VP1.

    Science.gov (United States)

    Caridi, Flavia; Vázquez-Calvo, Angela; Sobrino, Francisco; Martín-Acebes, Miguel A

    2015-05-01

    The picornavirus foot-and-mouth disease virus (FMDV) is the etiological agent of a highly contagious disease that affects important livestock species. The FMDV capsid is highly acid labile, and viral particles lose infectivity due to their disassembly at pH values slightly below neutrality. This acid sensitivity is related to the mechanism of viral uncoating and genome penetration from endosomes. In this study, we have analyzed the molecular basis of FMDV acid-induced disassembly by isolating and characterizing a panel of novel FMDV mutants differing in acid sensitivity. Amino acid replacements altering virion stability were preferentially distributed in two different regions of the capsid: the N terminus of VP1 and the pentameric interface. Even more, the acid labile phenotype induced by a mutation located at the pentameric interface in VP3 could be compensated by introduction of an amino acid substitution in the N terminus of VP1. These results indicate that the acid sensitivity of FMDV can be considered a multifactorial trait and that virion stability is the fine-tuned product of the interaction between residues from different capsid proteins, in particular those located within the N terminus of VP1 or close to the pentameric interface. The viral capsid protects the viral genome from environmental factors and contributes to virus dissemination and infection. Thus, understanding of the molecular mechanisms that modulate capsid stability is of interest for the basic knowledge of the biology of viruses and as a tool to improve the stability of conventional vaccines based on inactivated virions or empty capsids. Using foot-and-mouth disease virus (FMDV), which displays a capsid with extreme acid sensitivity, we have performed a genetic study to identify the molecular determinants involved in capsid stability. A panel of FMDV mutants with differential sensitivity to acidic pH was generated and characterized, and the results showed that two different regions of FMDV

  17. Classical extended conformal symmetries

    International Nuclear Information System (INIS)

    Viswanathan, R.

    1990-02-01

    Extensions of the Virasoro algebra are constructed as Poisson brackets of higher spin fields which appear as coefficient fields in certain covariant derivative operators of order N. These differential operators are constructed so as to be covariant under reparametrizations on fields of definite conformal dimension. Factorization of such an N-th order operator in terms of first order operators, together with the inclusion of a spin one U(1) current, is shown to lead to a two-parameter W-algebra. One of these parameters plays the role of interpolating between W-algebras based on different Lie algebras of the same rank. (author). 11 refs

  18. Remarks on the quantization of conformal fields

    International Nuclear Information System (INIS)

    Bakas, I.

    1988-01-01

    The quantization of a general (b,c) system in two dimensions is formulated in terms of an infinite hierarchy of modules for the Virasoro algebra that interpolate between the space of classical conformal fields of weight j and the Dirac sea of semi-infinite forms. This provides a natural framework in which to study the relation between algebraic geometry and representations of the Virasoro algebra with central charge c j = -2(6j 2 -6j+1). The importance of the construction is discussed in the context of string theory. (orig.)

  19. Conformally symmetric traversable wormholes

    International Nuclear Information System (INIS)

    Boehmer, Christian G.; Harko, Tiberiu; Lobo, Francisco S. N.

    2007-01-01

    Exact solutions of traversable wormholes are found under the assumption of spherical symmetry and the existence of a nonstatic conformal symmetry, which presents a more systematic approach in searching for exact wormhole solutions. In this work, a wide variety of solutions are deduced by considering choices for the form function, a specific linear equation of state relating the energy density and the pressure anisotropy, and various phantom wormhole geometries are explored. A large class of solutions impose that the spatial distribution of the exotic matter is restricted to the throat neighborhood, with a cutoff of the stress-energy tensor at a finite junction interface, although asymptotically flat exact solutions are also found. Using the 'volume integral quantifier', it is found that the conformally symmetric phantom wormhole geometries may, in principle, be constructed by infinitesimally small amounts of averaged null energy condition violating matter. Considering the tidal acceleration traversability conditions for the phantom wormhole geometry, specific wormhole dimensions and the traversal velocity are also deduced

  20. Supergravitational conformal Galileons

    Science.gov (United States)

    Deen, Rehan; Ovrut, Burt

    2017-08-01

    The worldvolume actions of 3+1 dimensional bosonic branes embedded in a five-dimensional bulk space can lead to important effective field theories, such as the DBI conformal Galileons, and may, when the Null Energy Condition is violated, play an essential role in cosmological theories of the early universe. These include Galileon Genesis and "bouncing" cosmology, where a pre-Big Bang contracting phase bounces smoothly to the presently observed expanding universe. Perhaps the most natural arena for such branes to arise is within the context of superstring and M -theory vacua. Here, not only are branes required for the consistency of the theory, but, in many cases, the exact spectrum of particle physics occurs at low energy. However, such theories have the additional constraint that they must be N = 1 supersymmetric. This motivates us to compute the worldvolume actions of N = 1 supersymmetric three-branes, first in flat superspace and then to generalize them to N = 1 supergravitation. In this paper, for simplicity, we begin the process, not within the context of a superstring vacuum but, rather, for the conformal Galileons arising on a co-dimension one brane embedded in a maximally symmetric AdS 5 bulk space. We proceed to N = 1 supersymmetrize the associated worldvolume theory and then generalize the results to N = 1 supergravity, opening the door to possible new cosmological scenarios

  1. Structure-based network analysis of activation mechanisms in the ErbB family of receptor tyrosine kinases: the regulatory spine residues are global mediators of structural stability and allosteric interactions.

    Directory of Open Access Journals (Sweden)

    Kevin A James

    Full Text Available The ErbB protein tyrosine kinases are among the most important cell signaling families and mutation-induced modulation of their activity is associated with diverse functions in biological networks and human disease. We have combined molecular dynamics simulations of the ErbB kinases with the protein structure network modeling to characterize the reorganization of the residue interaction networks during conformational equilibrium changes in the normal and oncogenic forms. Structural stability and network analyses have identified local communities integrated around high centrality sites that correspond to the regulatory spine residues. This analysis has provided a quantitative insight to the mechanism of mutation-induced "superacceptor" activity in oncogenic EGFR dimers. We have found that kinase activation may be determined by allosteric interactions between modules of structurally stable residues that synchronize the dynamics in the nucleotide binding site and the αC-helix with the collective motions of the integrating αF-helix and the substrate binding site. The results of this study have pointed to a central role of the conserved His-Arg-Asp (HRD motif in the catalytic loop and the Asp-Phe-Gly (DFG motif as key mediators of structural stability and allosteric communications in the ErbB kinases. We have determined that residues that are indispensable for kinase regulation and catalysis often corresponded to the high centrality nodes within the protein structure network and could be distinguished by their unique network signatures. The optimal communication pathways are also controlled by these nodes and may ensure efficient allosteric signaling in the functional kinase state. Structure-based network analysis has quantified subtle effects of ATP binding on conformational dynamics and stability of the EGFR structures. Consistent with the NMR studies, we have found that nucleotide-induced modulation of the residue interaction networks is not

  2. ANCA: Anharmonic Conformational Analysis of Biomolecular Simulations.

    Science.gov (United States)

    Parvatikar, Akash; Vacaliuc, Gabriel S; Ramanathan, Arvind; Chennubhotla, S Chakra

    2018-05-08

    Anharmonicity in time-dependent conformational fluctuations is noted to be a key feature of functional dynamics of biomolecules. Although anharmonic events are rare, long-timescale (μs-ms and beyond) simulations facilitate probing of such events. We have previously developed quasi-anharmonic analysis to resolve higher-order spatial correlations and characterize anharmonicity in biomolecular simulations. In this article, we have extended this toolbox to resolve higher-order temporal correlations and built a scalable Python package called anharmonic conformational analysis (ANCA). ANCA has modules to: 1) measure anharmonicity in the form of higher-order statistics and its variation as a function of time, 2) output a storyboard representation of the simulations to identify key anharmonic conformational events, and 3) identify putative anharmonic conformational substates and visualization of transitions between these substates. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  3. Conformational responses to changes in the state of ionization of titrable groups in proteins

    Science.gov (United States)

    Richman, Daniel Eric

    -bond) breaking on at least the mus timescale, and segmental unfolding were detected near titrating groups as pH decreased into the acidic range. The study identified local structural features and stabilities that modulate the magnitude of electrostatic effects. The data demonstrate that computational approaches to pK a calculations for surface groups must account for local fluctuations spanning a wide range of timescales. A comparative NMR spectroscopy study with the L25K and L125K variants of SNase, each with a Lys residue buried in the hydrophobic interior of the protein, determined locations, timescales, and amplitudes of backbone conformational reorganization coupled with ionization of the buried Lys residues. The L25K protein exhibited an ensemble of local fluctuations of the beta barrel in the hundreds of mus timescale and an ensemble of subglobally unfolded beta-barrel states in the hundreds of ms timescale with strong pH dependence. The L125K protein exhibited fluctuations of the helix around site 125 in the mus timescale, with negligible pH dependence. These data illustrate the diverse timescales and local structural properties of conformational reorganization coupled to ionization of buried groups, and the challenge to structure-based electrostatics calculations, which must capture these long-timescale processes.

  4. Ward identities for conformal models

    International Nuclear Information System (INIS)

    Lazzarini, S.; Stora, R.

    1988-01-01

    Ward identities which express the symmetry of conformal models are treated. Diffeomorphism invariance or locally holomorphic coordinate transformations are used. Diffeomorphism invariance is then understood in terms of Riemannian geometry. Two different sets of Ward identities expressing diffeomorphism invariance in a conformally invariant way are found for the free bosonic string. Using a geometrical argument, the correct invariance for a large class of conformal models is given

  5. Conformational analysis of lignin models

    International Nuclear Information System (INIS)

    Santos, Helio F. dos

    2001-01-01

    The conformational equilibrium for two 5,5' biphenyl lignin models have been analyzed using a quantum mechanical semiempirical method. The gas phase and solution structures are discussed based on the NMR and X-ray experimental data. The results obtained showed that the observed conformations are solvent-dependent, being the geometries and the thermodynamic properties correlated with the experimental information. This study shows how a systematic theoretical conformational analysis can help to understand chemical processes at a molecular level. (author)

  6. On the linear conformal gravitation

    International Nuclear Information System (INIS)

    Pal'chik, M.Ya.; Fradkin, E.S.

    1984-01-01

    Conformal gravitation is analyzed under the assumption that its solution possesses the property of conformal symmetry. This assumption has sense in the case of small distances and only for definite types of matter fields, namely: at special choice of matter fields and their interactions, providing a lack of conformal anomalies; or at definite magnitudes of binding constants, coinciding with the zeroes of the Gell-Mann-Low function. The field equations, of the group-theoretical natura are obtained

  7. Fermion-scalar conformal blocks

    Energy Technology Data Exchange (ETDEWEB)

    Iliesiu, Luca [Joseph Henry Laboratories, Princeton University,Washington Road, Princeton, NJ 08544 (United States); Kos, Filip [Department of Physics, Yale University,217 Prospect Street, New Haven, CT 06520 (United States); Poland, David [Department of Physics, Yale University,217 Prospect Street, New Haven, CT 06520 (United States); School of Natural Sciences, Institute for Advanced Study,1 Einstein Dr, Princeton, New Jersey 08540 (United States); Pufu, Silviu S. [Joseph Henry Laboratories, Princeton University,Washington Road, Princeton, NJ 08544 (United States); Simmons-Duffin, David [School of Natural Sciences, Institute for Advanced Study,1 Einstein Dr, Princeton, New Jersey 08540 (United States); Yacoby, Ran [Joseph Henry Laboratories, Princeton University,Washington Road, Princeton, NJ 08544 (United States)

    2016-04-13

    We compute the conformal blocks associated with scalar-scalar-fermion-fermion 4-point functions in 3D CFTs. Together with the known scalar conformal blocks, our result completes the task of determining the so-called ‘seed blocks’ in three dimensions. Conformal blocks associated with 4-point functions of operators with arbitrary spins can now be determined from these seed blocks by using known differential operators.

  8. Development of conformal respirator monitoring technology

    International Nuclear Information System (INIS)

    Shonka, J.J.; Weismann, J.J.; Logan, R.J.

    1997-04-01

    This report summarizes the results of a Small Business Innovative Research Phase II project to develop a modular, surface conforming respirator monitor to improve upon the manual survey techniques presently used by the nuclear industry. Research was performed with plastic scintillator and gas proportional modules in an effort to find the most conducive geometry for a surface conformal, position sensitive monitor. The respirator monitor prototype developed is a computer controlled, position-sensitive detection system employing 56 modular proportional counters mounted in molds conforming to the inner and outer surfaces of a commonly used respirator (Scott Model 801450-40). The molds are housed in separate enclosures and hinged to create a open-quotes waffle-ironclose quotes effect so that the closed monitor will simultaneously survey both surfaces of the respirator. The proportional counter prototype was also designed to incorporate Shonka Research Associates previously developed charge-division electronics. This research provided valuable experience into pixellated position sensitive detection systems. The technology developed can be adapted to other monitoring applications where there is a need for deployment of many traditional radiation detectors

  9. Increased Conformational Flexibility of a Macrocycle–Receptor Complex Contributes to Reduced Dissociation Rates

    NARCIS (Netherlands)

    Glas, Adrian; Wamhoff, Eike Christian; Krüger, Dennis M.; Rademacher, Christoph; Grossmann, Tom N.

    2017-01-01

    Constraining a peptide in its bioactive conformation by macrocyclization represents a powerful strategy to design modulators of challenging biomolecular targets. This holds particularly true for the development of inhibitors of protein-protein interactions which often involve interfaces lacking

  10. Instantons in conformal gravity

    International Nuclear Information System (INIS)

    Strominger, A.; Horowitz, G.T.; Perry, M.J.

    1984-01-01

    Fe study extrema of the general conformally invariant action: Ssub(c)=∫1/sub(α) 2 Csup(abcd)Csub(abcd)+γRsup(abcd*)Rsup(*)sub(abcd)+iTHETARsup(abcd)*Rsub(abcd). We find the first examples in four dimensions of asymptotically euclidean gravitational instantons. These have arbitrary Euler number and Hirzebruch signature. Some of these instantons represent tunneling between zero-curvature vacua that are not related by small gauge transformations. Others represent tunneling between flat space and topologically non-trivial zero-energy initial data. A general formula for the one-loop determinant is derived in terms of the renormalization group invariant masses, the volume of space-time, the Euler number and the Hirzebruch signature. (orig.)

  11. Conformance and Deviance

    DEFF Research Database (Denmark)

    Gjerdrum Pedersen, Esben Rahbek; Neergaard, Peter; Thusgaard Pedersen, Janni

    2013-01-01

    This paper analyses how large Danish companies are responding to new governmental regulation which requires them to report on corporate social responsibility (CSR). The paper is based on an analysis of 142 company annual reports required by the new Danish regulation regarding CSR reporting, plus 10...... interviews with first-time reporting companies and six interviews with companies that failed to comply with the new law. It is concluded that coercive pressures from government have an impact on CSR reporting practices. Further, the analysis finds traces of mimetic isomorphism which inspires a homogenisation...... in CSR reporting practices. Finally, it is argued that non-conformance with the new regulatory requirements is not solely about conscious resistance but may also be caused by, for example, lack of awareness, resource limitations, misinterpretations, and practical difficulties....

  12. Reflections on Conformal Spectra

    CERN Multimedia

    CERN. Geneva

    2015-01-01

    We use modular invariance and crossing symmetry of conformal field theory to reveal approximate reflection symmetries in the spectral decompositions of the partition function in two dimensions in the limit of large central charge and of the four-point function in any dimension in the limit of large scaling dimensions Δ0 of external operators. We use these symmetries to motivate universal upper bounds on the spectrum and the operator product expansion coefficients, which we then derive by independent techniques. Some of the bounds for four-point functions are valid for finite Δ0 as well as for large Δ0. We discuss a similar symmetry in a large spacetime dimension limit. Finally, we comment on the analogue of the Cardy formula and sparse light spectrum condition for the four-point function. (based on 1510.08772 with Kim & Ooguri). This seminar will be given via videolink

  13. Conformal boundary loop models

    International Nuclear Information System (INIS)

    Jacobsen, Jesper Lykke; Saleur, Hubert

    2008-01-01

    We study a model of densely packed self-avoiding loops on the annulus, related to the Temperley-Lieb algebra with an extra idempotent boundary generator. Four different weights are given to the loops, depending on their homotopy class and whether they touch the outer rim of the annulus. When the weight of a contractible bulk loop x≡q+q -1 element of (-2,2], this model is conformally invariant for any real weight of the remaining three parameters. We classify the conformal boundary conditions and give exact expressions for the corresponding boundary scaling dimensions. The amplitudes with which the sectors with any prescribed number and types of non-contractible loops appear in the full partition function Z are computed rigorously. Based on this, we write a number of identities involving Z which hold true for any finite size. When the weight of a contractible boundary loop y takes certain discrete values, y r ≡([r+1] q )/([r] q ) with r integer, other identities involving the standard characters K r,s of the Virasoro algebra are established. The connection with Dirichlet and Neumann boundary conditions in the O(n) model is discussed in detail, and new scaling dimensions are derived. When q is a root of unity and y=y r , exact connections with the A m type RSOS model are made. These involve precise relations between the spectra of the loop and RSOS model transfer matrices, valid in finite size. Finally, the results where y=y r are related to the theory of Temperley-Lieb cabling

  14. Conformal Aspects of QCD

    Energy Technology Data Exchange (ETDEWEB)

    Brodsky, S

    2003-11-19

    Theoretical and phenomenological evidence is now accumulating that the QCD coupling becomes constant at small virtuality; i.e., {alpha}{sub s}(Q{sup 2}) develops an infrared fixed point in contradiction to the usual assumption of singular growth in the infrared. For example, the hadronic decays of the {tau} lepton can be used to determine the effective charge {alpha}{sub {tau}}(m{sub {tau}{prime}}{sup 2}) for a hypothetical {tau}-lepton with mass in the range 0 < m{sub {tau}{prime}} < m{sub {tau}}. The {tau} decay data at low mass scales indicates that the effective charge freezes at a value of s = m{sub {tau}{prime}}{sup 2} of order 1 GeV{sup 2} with a magnitude {alpha}{sub {tau}} {approx} 0.9 {+-} 0.1. The near-constant behavior of effective couplings suggests that QCD can be approximated as a conformal theory even at relatively small momentum transfer and why there are no significant running coupling corrections to quark counting rules for exclusive processes. The AdS/CFT correspondence of large N{sub c} supergravity theory in higher-dimensional anti-de Sitter space with supersymmetric QCD in 4-dimensional space-time also has interesting implications for hadron phenomenology in the conformal limit, including an all-orders demonstration of counting rules for exclusive processes and light-front wavefunctions. The utility of light-front quantization and light-front Fock wavefunctions for analyzing nonperturbative QCD and representing the dynamics of QCD bound states is also discussed.

  15. Structural alphabets derived from attractors in conformational space

    Directory of Open Access Journals (Sweden)

    Kleinjung Jens

    2010-02-01

    Full Text Available Abstract Background The hierarchical and partially redundant nature of protein structures justifies the definition of frequently occurring conformations of short fragments as 'states'. Collections of selected representatives for these states define Structural Alphabets, describing the most typical local conformations within protein structures. These alphabets form a bridge between the string-oriented methods of sequence analysis and the coordinate-oriented methods of protein structure analysis. Results A Structural Alphabet has been derived by clustering all four-residue fragments of a high-resolution subset of the protein data bank and extracting the high-density states as representative conformational states. Each fragment is uniquely defined by a set of three independent angles corresponding to its degrees of freedom, capturing in simple and intuitive terms the properties of the conformational space. The fragments of the Structural Alphabet are equivalent to the conformational attractors and therefore yield a most informative encoding of proteins. Proteins can be reconstructed within the experimental uncertainty in structure determination and ensembles of structures can be encoded with accuracy and robustness. Conclusions The density-based Structural Alphabet provides a novel tool to describe local conformations and it is specifically suitable for application in studies of protein dynamics.

  16. Logarithmic conformal field theory through nilpotent conformal dimensions

    International Nuclear Information System (INIS)

    Moghimi-Araghi, S.; Rouhani, S.; Saadat, M.

    2001-01-01

    We study logarithmic conformal field theories (LCFTs) through the introduction of nilpotent conformal weights. Using this device, we derive the properties of LCFTs such as the transformation laws, singular vectors and the structure of correlation functions. We discuss the emergence of an extra energy momentum tensor, which is the logarithmic partner of the energy momentum tensor

  17. Gs protein peptidomimetics as allosteric modulators of the β2-adrenergic receptor

    DEFF Research Database (Denmark)

    Boyhus, Lotte Emilie; Danielsen, Mia; Bengtson, Nina Smidt

    2018-01-01

    A series of Gs protein peptidomimetics were designed and synthesised based on the published X-ray crystal structure of the active state β2-Adrenergic receptor (β2AR) in complex with the Gs protein (PDB 3SN6). We hypothesised that such peptidomimetics may function as allosteric modulators...... that target the intracellular Gs protein binding site of the β2AR. Peptidomimetics were designed to mimic the 15 residue C-Terminal α-helix of the Gs protein and were pre-organised in a helical conformation by (i, i + 4)-stapling using copper catalysed azide alkyne cycloaddition. Linear and stapled...... be able to compete with the native Gs protein for the intracellular binding site to block ISO-induced cAMP formation, but are unable to stabilise an active-like receptor conformation....

  18. Replacement between conformity and counter-conformity in consumption decisions.

    Science.gov (United States)

    Chou, Ting-Jui; Chang, En-Chung; Dai, Qi; Wong, Veronica

    2013-02-01

    This study assessed, in a Chinese context, how self-esteem interacts with perceived similarity and uniqueness to yield cognitive dissonance, and whether the dissonance leads to self-reported conformity or counter-conformity behavior. Participants were 408 respondents from 4 major Chinese cities (M age = 33.0 yr., SD = 4.3; 48% men). Self-perceptions of uniqueness, similarity, cognitive dissonance, self-esteem and need to behave in conformity or counter-conformity were measured. A theoretical model was assessed in four situations, relating the ratings of self-esteem and perceived similarity/uniqueness to the way other people at a wedding were dressed, and the resultant cognitive dissonance and conformity/ counter-conformity behavior. Regardless of high or low self-esteem, all participants reported cognitive dissonance when they were told that they were dressed extremely similarly to or extremely differently from the other people attending the wedding. However, the conforming/counter-conforming strategies used by participants to resolve the cognitive dissonance differed. When encountering dissonance induced by the perceived extreme uniqueness of dress, participants with low self-esteem tended to say they would dress next time so as to conform with the way others were dressed, while those with high self-esteem indicated they would continue their counter-conformity in attire. When encountering dissonance induced by the perceived extreme similarity to others, both those with high and low self-esteem tended to say they would dress in an unorthodox manner to surprise other people in the future.

  19. On Associative Conformal Algebras of Linear Growth

    OpenAIRE

    Retakh, Alexander

    2000-01-01

    Lie conformal algebras appear in the theory of vertex algebras. Their relation is similar to that of Lie algebras and their universal enveloping algebras. Associative conformal algebras play a role in conformal representation theory. We introduce the notions of conformal identity and unital associative conformal algebras and classify finitely generated simple unital associative conformal algebras of linear growth. These are precisely the complete algebras of conformal endomorphisms of finite ...

  20. Recent advancements in conformal gravity

    International Nuclear Information System (INIS)

    O’Brien, James G.; Chaykov, Spasen S.; Moss, Robert J.; Dentico, Jeremy; Stulge, Modestas; Stefanski, Brian

    2017-01-01

    In recent years, due to the lack of direct observed evidence of cold dark matter, coupled with the shrinking parameter space to search for new dark matter particles, there has been increased interest in Alternative Gravitational theories. This paper, addresses three recent advances in conformal gravity, a fourth order renormalizable metric theory of gravitation originally formulated by Weyl, and later advanced by Mannheim and Kazanas. The first section of the paper applies conformal gravity to the rotation curves of the LITTLE THINGS survey, extending the total number of rotation curves successfully fit by conformal gravity to well over 200 individual data sets without the need for additional dark matter. Further, in this rotation curve study, we show how MOND and conformal gravity compare for each galaxy in the sample. Second, we look at the original Zwicky problem of applying the virial theorem to the Coma cluster in order to get an estimate for the cluster mass. However, instead of using the standard Newtonian potential, here we use the weak field approximation of conformal gravity. We show that in the conformal case we can get a much smaller mass estimate and thus there is no apparent need to include dark matter. We then show that this calculation is in agreement with the observational data from other well studied clusters. Last, we explore the calculation of the deflection of starlight through conformal gravity, as a first step towards applying conformal gravity to gravitaitonal lensing. (paper)

  1. Conformal invariance in harmonic superspace

    International Nuclear Information System (INIS)

    Galperin, A.; Ivanov, E.; Ogievetsky, V.; Sokatchev, E.

    1985-01-01

    N=2 conformal supersymmetry is realized in harmonic superspace, its peculiarities are analyzed. The coordinate group and analytical prepotentials for N=2 conformal supergravity are found. A new version of the N=2 Einstein supergravity with infinite number of auxiliary fields is suggested. A hypermultiplet without central charges and constraints is used as a compensator

  2. Counselor Identity: Conformity or Distinction?

    Science.gov (United States)

    McLaughlin, Jerry E.; Boettcher, Kathryn

    2009-01-01

    The authors explore 3 debates in other disciplines similar to counseling's identity debate in order to learn about common themes and outcomes. Conformity, distinction, and cohesion emerged as common themes. They conclude that counselors should retain their distinctive, humanistic approach rather than conforming to the dominant, medical approach.

  3. Conformal algebra of Riemann surfaces

    International Nuclear Information System (INIS)

    Vafa, C.

    1988-01-01

    It has become clear over the last few years that 2-dimensional conformal field theories are a crucial ingredient of string theory. Conformal field theories correspond to vacuum solutions of strings; or more precisely we know how to compute string spectrum and scattering amplitudes by starting from a formal theory (with a proper value of central charge of the Virasoro algebra). Certain non-linear sigma models do give rise to conformal theories. A lot of progress has been made in the understanding of conformal theories. The author discusses a different view of conformal theories which was motivated by the development of operator formalism on Riemann surfaces. The author discusses an interesting recent work from this point of view

  4. The logarithmic conformal field theories

    International Nuclear Information System (INIS)

    Rahimi Tabar, M.R.; Aghamohammadi, A.; Khorrami, M.

    1997-01-01

    We study the correlation functions of logarithmic conformal field theories. First, assuming conformal invariance, we explicitly calculate two- and three-point functions. This calculation is done for the general case of more than one logarithmic field in a block, and more than one set of logarithmic fields. Then we show that one can regard the logarithmic field as a formal derivative of the ordinary field with respect to its conformal weight. This enables one to calculate any n-point function containing the logarithmic field in terms of ordinary n-point functions. Finally, we calculate the operator product expansion (OPE) coefficients of a logarithmic conformal field theory, and show that these can be obtained from the corresponding coefficients of ordinary conformal theory by a simple derivation. (orig.)

  5. Fast, clash-free RNA conformational morphing using molecular junctions.

    Science.gov (United States)

    Héliou, Amélie; Budday, Dominik; Fonseca, Rasmus; van den Bedem, Henry

    2017-07-15

    Non-coding ribonucleic acids (ncRNA) are functional RNA molecules that are not translated into protein. They are extremely dynamic, adopting diverse conformational substates, which enables them to modulate their interaction with a large number of other molecules. The flexibility of ncRNA provides a challenge for probing their complex 3D conformational landscape, both experimentally and computationally. Despite their conformational diversity, ncRNAs mostly preserve their secondary structure throughout the dynamic ensemble. Here we present a kinematics-based procedure to morph an RNA molecule between conformational substates, while avoiding inter-atomic clashes. We represent an RNA as a kinematic linkage, with fixed groups of atoms as rigid bodies and rotatable bonds as degrees of freedom. Our procedure maintains RNA secondary structure by treating hydrogen bonds between base pairs as constraints. The constraints define a lower-dimensional, secondary-structure constraint manifold in conformation space, where motions are largely governed by molecular junctions of unpaired nucleotides. On a large benchmark set, we show that our morphing procedure compares favorably to peer algorithms, and can approach goal conformations to within a low all-atom RMSD by directing fewer than 1% of its atoms. Our results suggest that molecular junctions can modulate 3D structural rearrangements, while secondary structure elements guide large parts of the molecule along the transition to the correct final conformation. The source code, binaries and data are available at https://simtk.org/home/kgs . amelie.heliou@polytechnique.edu or vdbedem@stanford.edu. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  6. Conformal solids and holography

    Science.gov (United States)

    Esposito, A.; Garcia-Saenz, S.; Nicolis, A.; Penco, R.

    2017-12-01

    We argue that a SO( d) magnetic monopole in an asymptotically AdS space-time is dual to a d-dimensional strongly coupled system in a solid state. In light of this, it would be remiss of us not to dub such a field configuration solidon. In the presence of mixed boundary conditions, a solidon spontaneously breaks translations (among many other symmetries) and gives rise to Goldstone excitations on the boundary — the phonons of the solid. We derive the quadratic action for the boundary phonons in the probe limit and show that, when the mixed boundary conditions preserve conformal symmetry, the longitudinal and transverse sound speeds are related to each other as expected from effective field theory arguments. We then include backreaction and calculate the free energy of the solidon for a particular choice of mixed boundary conditions, corresponding to a relevant multi-trace deformation of the boundary theory. We find such free energy to be lower than that of thermal AdS. This suggests that our solidon undergoes a solid-to-liquid first order phase transition by melting into a Schwarzschild-AdS black hole as the temperature is raised.

  7. 6d Conformal matter

    International Nuclear Information System (INIS)

    Zotto, Michele Del; Heckman, Jonathan J.; Tomasiello, Alessandro; Vafa, Cumrun

    2015-01-01

    A single M5-brane probing G, an ADE-type singularity, leads to a system which has G×G global symmetry and can be viewed as “bifundamental” (G,G) matter. For the A N series, this leads to the usual notion of bifundamental matter. For the other cases it corresponds to a strongly interacting (1,0) superconformal system in six dimensions. Similarly, an ADE singularity intersecting the Hořava-Witten wall leads to a superconformal matter system with E 8 ×G global symmetry. Using the F-theory realization of these theories, we elucidate the Coulomb/tensor branch of (G,G ′ ) conformal matter. This leads to the notion of fractionalization of an M5-brane on an ADE singularity as well as fractionalization of the intersection point of the ADE singularity with the Hořava-Witten wall. Partial Higgsing of these theories leads to new 6d SCFTs in the infrared, which we also characterize. This generalizes the class of (1,0) theories which can be perturbatively realized by suspended branes in IIA string theory. By reducing on a circle, we arrive at novel duals for 5d affine quiver theories. Introducing many M5-branes leads to large N gravity duals.

  8. Towards conformal loop quantum gravity

    International Nuclear Information System (INIS)

    Wang, Charles H-T

    2006-01-01

    A discussion is given of recent developments in canonical gravity that assimilates the conformal analysis of gravitational degrees of freedom. The work is motivated by the problem of time in quantum gravity and is carried out at the metric and the triad levels. At the metric level, it is shown that by extending the Arnowitt-Deser-Misner (ADM) phase space of general relativity (GR), a conformal form of geometrodynamics can be constructed. In addition to the Hamiltonian and Diffeomorphism constraints, an extra first class constraint is introduced to generate conformal transformations. This phase space consists of York's mean extrinsic curvature time, conformal three-metric and their momenta. At the triad level, the phase space of GR is further enlarged by incorporating spin-gauge as well as conformal symmetries. This leads to a canonical formulation of GR using a new set of real spin connection variables. The resulting gravitational constraints are first class, consisting of the Hamiltonian constraint and the canonical generators for spin-gauge and conformorphism transformations. The formulation has a remarkable feature of being parameter-free. Indeed, it is shown that a conformal parameter of the Barbero-Immirzi type can be absorbed by the conformal symmetry of the extended phase space. This gives rise to an alternative approach to loop quantum gravity that addresses both the conceptual problem of time and the technical problem of functional calculus in quantum gravity

  9. Benchmarking Commercial Conformer Ensemble Generators.

    Science.gov (United States)

    Friedrich, Nils-Ole; de Bruyn Kops, Christina; Flachsenberg, Florian; Sommer, Kai; Rarey, Matthias; Kirchmair, Johannes

    2017-11-27

    We assess and compare the performance of eight commercial conformer ensemble generators (ConfGen, ConfGenX, cxcalc, iCon, MOE LowModeMD, MOE Stochastic, MOE Conformation Import, and OMEGA) and one leading free algorithm, the distance geometry algorithm implemented in RDKit. The comparative study is based on a new version of the Platinum Diverse Dataset, a high-quality benchmarking dataset of 2859 protein-bound ligand conformations extracted from the PDB. Differences in the performance of commercial algorithms are much smaller than those observed for free algorithms in our previous study (J. Chem. Inf. 2017, 57, 529-539). For commercial algorithms, the median minimum root-mean-square deviations measured between protein-bound ligand conformations and ensembles of a maximum of 250 conformers are between 0.46 and 0.61 Å. Commercial conformer ensemble generators are characterized by their high robustness, with at least 99% of all input molecules successfully processed and few or even no substantial geometrical errors detectable in their output conformations. The RDKit distance geometry algorithm (with minimization enabled) appears to be a good free alternative since its performance is comparable to that of the midranked commercial algorithms. Based on a statistical analysis, we elaborate on which algorithms to use and how to parametrize them for best performance in different application scenarios.

  10. Evaluating conformational free energies: the colony energy and its application to the problem of loop prediction.

    Science.gov (United States)

    Xiang, Zhexin; Soto, Cinque S; Honig, Barry

    2002-05-28

    In this paper, we introduce a method to account for the shape of the potential energy curve in the evaluation of conformational free energies. The method is based on a procedure that generates a set of conformations, each with its own force-field energy, but adds a term to this energy that favors conformations that are close in structure (have a low rmsd) to other conformations. The sum of the force-field energy and rmsd-dependent term is defined here as the "colony energy" of a given conformation, because each conformation that is generated is viewed as representing a colony of points. The use of the colony energy tends to select conformations that are located in broad energy basins. The approach is applied to the ab initio prediction of the conformations of all of the loops in a dataset of 135 nonredundant proteins. By using an rmsd from a native criterion based on the superposition of loop stems, the average rmsd of 5-, 6-, 7-, and 8-residue long loops is 0.85, 0.92, 1.23, and 1.45 A, respectively. For 8-residue loops, 60 of 61 predictions have an rmsd of less than 3.0 A. The use of the colony energy is found to improve significantly the results obtained from the potential function alone. (The loop prediction program, "Loopy," can be downloaded at http://trantor.bioc.columbia.edu.)

  11. Conformal invariance in harmonic superspace

    International Nuclear Information System (INIS)

    Galperin, A.; Ivanov, E.; Ogievetsky, V.; Sokatchev, E.

    1987-01-01

    In the present paper we show how the N = 2 superconformal group is realised in harmonic superspace and examine conformal invariance of N = 2 off-shell theories. We believe that the example of N = O self-dual Yang-Mills equations can serve as an instructive introduction to the subject of harmonic superspace and this is examined. The rigid N = 2 conformal supersymmetry and its local version, i.e. N = 2 conformal supergravity is also discussed. The paper is a contribution to the book commemorating the sixtieth birthday of E.S. Fradkin. (author)

  12. Two dimensional infinite conformal symmetry

    International Nuclear Information System (INIS)

    Mohanta, N.N.; Tripathy, K.C.

    1993-01-01

    The invariant discontinuous (discrete) conformal transformation groups, namely the Kleinian and Fuchsian groups Gamma (with an arbitrary signature) of H (the Poincare upper half-plane l) and the unit disc Delta are explicitly constructed from the fundamental domain D. The Riemann surface with signatures of Gamma and conformally invariant automorphic forms (functions) with Peterson scalar product are discussed. The functor, where the category of complex Hilbert spaces spanned by the space of cusp forms constitutes the two dimensional conformal field theory. (Author) 7 refs

  13. Harmony of spinning conformal blocks

    Energy Technology Data Exchange (ETDEWEB)

    Schomerus, Volker [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Theory Group; Sobko, Evgeny [Stockholm Univ. (Sweden); Nordita, Stockholm (Sweden); Isachenkov, Mikhail [Weizmann Institute of Science, Rehovoth (Israel). Dept. of Particle Physics and Astrophysics

    2016-12-07

    Conformal blocks for correlation functions of tensor operators play an increasingly important role for the conformal bootstrap programme. We develop a universal approach to such spinning blocks through the harmonic analysis of certain bundles over a coset of the conformal group. The resulting Casimir equations are given by a matrix version of the Calogero-Sutherland Hamiltonian that describes the scattering of interacting spinning particles in a 1-dimensional external potential. The approach is illustrated in several examples including fermionic seed blocks in 3D CFT where they take a very simple form.

  14. Harmony of spinning conformal blocks

    Energy Technology Data Exchange (ETDEWEB)

    Schomerus, Volker [DESY Hamburg, Theory Group,Notkestraße 85, 22607 Hamburg (Germany); Sobko, Evgeny [Nordita and Stockholm University,Roslagstullsbacken 23, SE-106 91 Stockholm (Sweden); Isachenkov, Mikhail [Department of Particle Physics and Astrophysics, Weizmann Institute of Science,Rehovot 7610001 (Israel)

    2017-03-15

    Conformal blocks for correlation functions of tensor operators play an increasingly important role for the conformal bootstrap programme. We develop a universal approach to such spinning blocks through the harmonic analysis of certain bundles over a coset of the conformal group. The resulting Casimir equations are given by a matrix version of the Calogero-Sutherland Hamiltonian that describes the scattering of interacting spinning particles in a 1-dimensional external potential. The approach is illustrated in several examples including fermionic seed blocks in 3D CFT where they take a very simple form.

  15. Computational prediction of protein hot spot residues.

    Science.gov (United States)

    Morrow, John Kenneth; Zhang, Shuxing

    2012-01-01

    Most biological processes involve multiple proteins interacting with each other. It has been recently discovered that certain residues in these protein-protein interactions, which are called hot spots, contribute more significantly to binding affinity than others. Hot spot residues have unique and diverse energetic properties that make them challenging yet important targets in the modulation of protein-protein complexes. Design of therapeutic agents that interact with hot spot residues has proven to be a valid methodology in disrupting unwanted protein-protein interactions. Using biological methods to determine which residues are hot spots can be costly and time consuming. Recent advances in computational approaches to predict hot spots have incorporated a myriad of features, and have shown increasing predictive successes. Here we review the state of knowledge around protein-protein interactions, hot spots, and give an overview of multiple in silico prediction techniques of hot spot residues.

  16. Computational Prediction of Hot Spot Residues

    Science.gov (United States)

    Morrow, John Kenneth; Zhang, Shuxing

    2013-01-01

    Most biological processes involve multiple proteins interacting with each other. It has been recently discovered that certain residues in these protein-protein interactions, which are called hot spots, contribute more significantly to binding affinity than others. Hot spot residues have unique and diverse energetic properties that make them challenging yet important targets in the modulation of protein-protein complexes. Design of therapeutic agents that interact with hot spot residues has proven to be a valid methodology in disrupting unwanted protein-protein interactions. Using biological methods to determine which residues are hot spots can be costly and time consuming. Recent advances in computational approaches to predict hot spots have incorporated a myriad of features, and have shown increasing predictive successes. Here we review the state of knowledge around protein-protein interactions, hot spots, and give an overview of multiple in silico prediction techniques of hot spot residues. PMID:22316154

  17. Mass generation within conformal invariant theories

    International Nuclear Information System (INIS)

    Flato, M.; Guenin, M.

    1981-01-01

    The massless Yang-Mills theory is strongly conformally invariant and renormalizable; however, when masses are introduced the theory becomes nonrenormalizable and weakly conformally invariant. Conditions which recover strong conformal invariance are discussed in the letter. (author)

  18. Ranking multiple docking solutions based on the conservation of inter-residue contacts

    KAUST Repository

    Oliva, Romina M.; Vangone, Anna; Cavallo, Luigi

    2013-01-01

    ) conformations in the top positions is still an open problem. Herein we present CONSRANK, a simple and effective tool to rank multiple docking solutions, which relies on the conservation of inter-residue contacts in the analyzed decoys ensemble. First

  19. Improvements to robotics-inspired conformational sampling in rosetta.

    Directory of Open Access Journals (Sweden)

    Amelie Stein

    Full Text Available To accurately predict protein conformations in atomic detail, a computational method must be capable of sampling models sufficiently close to the native structure. All-atom sampling is difficult because of the vast number of possible conformations and extremely rugged energy landscapes. Here, we test three sampling strategies to address these difficulties: conformational diversification, intensification of torsion and omega-angle sampling and parameter annealing. We evaluate these strategies in the context of the robotics-based kinematic closure (KIC method for local conformational sampling in Rosetta on an established benchmark set of 45 12-residue protein segments without regular secondary structure. We quantify performance as the fraction of sub-Angstrom models generated. While improvements with individual strategies are only modest, the combination of intensification and annealing strategies into a new "next-generation KIC" method yields a four-fold increase over standard KIC in the median percentage of sub-Angstrom models across the dataset. Such improvements enable progress on more difficult problems, as demonstrated on longer segments, several of which could not be accurately remodeled with previous methods. Given its improved sampling capability, next-generation KIC should allow advances in other applications such as local conformational remodeling of multiple segments simultaneously, flexible backbone sequence design, and development of more accurate energy functions.

  20. Conformational elasticity can facilitate TALE-DNA recognition.

    Science.gov (United States)

    Lei, Hongxing; Sun, Jiya; Baldwin, Enoch P; Segal, David J; Duan, Yong

    2014-01-01

    Sequence-programmable transcription activator-like effector (TALE) proteins have emerged as a highly efficient tool for genome engineering. Recent crystal structures depict a transition between an open unbound solenoid and more compact DNA-bound solenoid formed by the 34 amino acid repeats. How TALEs switch conformation between these two forms without substantial energetic compensation, and how the repeat-variable di-residues (RVDs) discriminate between the cognate base and other bases still remain unclear. Computational analysis on these two aspects of TALE-DNA interaction mechanism has been conducted in order to achieve a better understanding of the energetics. High elasticity was observed in the molecular dynamics simulations of DNA-free TALE structure that started from the bound conformation where it sampled a wide range of conformations including the experimentally determined apo and bound conformations. This elastic feature was also observed in the simulations starting from the apo form which suggests low free energy barrier between the two conformations and small compensation required upon binding. To analyze binding specificity, we performed free energy calculations of various combinations of RVDs and bases using Poisson-Boltzmann surface area (PBSA) and other approaches. The PBSA calculations indicated that the native RVD-base structures had lower binding free energy than mismatched structures for most of the RVDs examined. Our theoretical analyses provided new insight on the dynamics and energetics of TALE-DNA binding mechanism. © 2014 Elsevier Inc. All rights reserved.

  1. Higher-derivative generalization of conformal mechanics

    Science.gov (United States)

    Baranovsky, Oleg

    2017-08-01

    Higher-derivative analogs of multidimensional conformal particle and many-body conformal mechanics are constructed. Their Newton-Hooke counterparts are derived by applying appropriate coordinate transformations.

  2. Naturality in conformal field theory

    International Nuclear Information System (INIS)

    Moore, G.; Seiberg, N.

    1989-01-01

    We discuss constraints on the operator product coefficients in diagonal and nondiagonal rational conformal field theories. Nondiagonal modular invariants always arise from automorphisms of the fusion rule algebra or from extensions of the chiral algebra. Moreover, when the chiral algebra has been maximally extended a strong form of the naturality principle of field theory can be proven for rational conformal field theory: operator product coefficients vanish if and only if the corresponding fusion rules vanish; that is, if and only if the vanishing can be understood in terms of a symmetry. We illustrate these ideas with several examples. We also generalize our ideas about rational conformal field theories to a larger class of theories: 'quasi-rational conformal field theories' and we explore some of their properties. (orig.)

  3. Steady states in conformal theories

    CERN Multimedia

    CERN. Geneva

    2015-01-01

    A novel conjecture regarding the steady state behavior of conformal field theories placed between two heat baths will be presented. Some verification of the conjecture will be provided in the context of fluid dynamics and holography.

  4. National Automated Conformity Inspection Process -

    Data.gov (United States)

    Department of Transportation — The National Automated Conformity Inspection Process (NACIP) Application is intended to expedite the workflow process as it pertains to the FAA Form 81 0-10 Request...

  5. Aspect of the conformal invariance

    International Nuclear Information System (INIS)

    Bauer, M.

    1990-11-01

    This thesis is about the study of several physical and mathematical aspects of critical phenomena at two dimensions. These phenomena have remarkable symmetry properties in the coordonnates changes keeping the angles. They are named conformal theories

  6. Some Progress in Conformal Geometry

    Directory of Open Access Journals (Sweden)

    Sun-Yung A. Chang

    2007-12-01

    Full Text Available This is a survey paper of our current research on the theory of partial differential equations in conformal geometry. Our intention is to describe some of our current works in a rather brief and expository fashion. We are not giving a comprehensive survey on the subject and references cited here are not intended to be complete. We introduce a bubble tree structure to study the degeneration of a class of Yamabe metrics on Bach flat manifolds satisfying some global conformal bounds on compact manifolds of dimension 4. As applications, we establish a gap theorem, a finiteness theorem for diffeomorphism type for this class, and diameter bound of the $sigma_2$-metrics in a class of conformal 4-manifolds. For conformally compact Einstein metrics we introduce an eigenfunction compactification. As a consequence we obtain some topological constraints in terms of renormalized volumes.

  7. Conformity Adequacy Review: Region 5

    Science.gov (United States)

    Resources are for air quality and transportation government and community leaders. Information on the conformity SIP adequacy/inadequacy of state implementation plans (SIPs) in EPA Region 5 (IL, IN, MI, OH, WI) is provided here.

  8. Inverse bootstrapping conformal field theories

    Science.gov (United States)

    Li, Wenliang

    2018-01-01

    We propose a novel approach to study conformal field theories (CFTs) in general dimensions. In the conformal bootstrap program, one usually searches for consistent CFT data that satisfy crossing symmetry. In the new method, we reverse the logic and interpret manifestly crossing-symmetric functions as generating functions of conformal data. Physical CFTs can be obtained by scanning the space of crossing-symmetric functions. By truncating the fusion rules, we are able to concentrate on the low-lying operators and derive some approximate relations for their conformal data. It turns out that the free scalar theory, the 2d minimal model CFTs, the ϕ 4 Wilson-Fisher CFT, the Lee-Yang CFTs and the Ising CFTs are consistent with the universal relations from the minimal fusion rule ϕ 1 × ϕ 1 = I + ϕ 2 + T , where ϕ 1 , ϕ 2 are scalar operators, I is the identity operator and T is the stress tensor.

  9. A single mutation in the envelope protein modulates flavivirus antigenicity, stability, and pathogenesis.

    Directory of Open Access Journals (Sweden)

    Leslie Goo

    2017-02-01

    Full Text Available The structural flexibility or 'breathing' of the envelope (E protein of flaviviruses allows virions to sample an ensemble of conformations at equilibrium. The molecular basis and functional consequences of virus conformational dynamics are poorly understood. Here, we identified a single mutation at residue 198 (T198F of the West Nile virus (WNV E protein domain I-II hinge that regulates virus breathing. The T198F mutation resulted in a ~70-fold increase in sensitivity to neutralization by a monoclonal antibody targeting a cryptic epitope in the fusion loop. Increased exposure of this otherwise poorly accessible fusion loop epitope was accompanied by reduced virus stability in solution at physiological temperatures. Introduction of a mutation at the analogous residue of dengue virus (DENV, but not Zika virus (ZIKV, E protein also increased accessibility of the cryptic fusion loop epitope and decreased virus stability in solution, suggesting that this residue modulates the structural ensembles sampled by distinct flaviviruses at equilibrium in a context dependent manner. Although the T198F mutation did not substantially impair WNV growth kinetics in vitro, studies in mice revealed attenuation of WNV T198F infection. Overall, our study provides insight into the molecular basis and the in vitro and in vivo consequences of flavivirus breathing.

  10. A single amino acid of human immunodeficiency virus type 2 capsid protein affects conformation of two external loops and viral sensitivity to TRIM5α.

    Directory of Open Access Journals (Sweden)

    Tadashi Miyamoto

    Full Text Available We previously reported that human immunodeficiency virus type 2 (HIV-2 carrying alanine or glutamine but not proline at position 120 of the capsid protein (CA could grow in the presence of anti-viral factor TRIM5α of cynomolgus monkey (CM. To elucidate details of the interaction between the CA and TRIM5α, we generated mutant HIV-2 viruses, each carrying one of the remaining 17 possible amino acid residues, and examined their sensitivity to CM TRIM5α-mediated restriction. Results showed that hydrophobic residues or those with ring structures were associated with sensitivity, while those with small side chains or amide groups conferred resistance. Molecular dynamics simulation study revealed a structural basis for the differential TRIM5α sensitivities. The mutations at position 120 in the loop between helices 6 and 7 (L6/7 affected conformation of the neighboring loop between helices 4 and 5 (L4/5, and sensitive viruses had a common L4/5 conformation. In addition, the common L4/5 structures of the sensitive viruses were associated with a decreased probability of hydrogen bond formation between the 97th aspartic acid in L4/5 and the 119th arginine in L6/7. When we introduced aspartic acid-to-alanine substitution at position 97 (D97A of the resistant virus carrying glutamine at position 120 to disrupt hydrogen bond formation, the resultant virus became moderately sensitive. Interestingly, the virus carrying glutamic acid at position 120 showed resistance, while its predicted L4/5 conformation was similar to those of sensitive viruses. The D97A substitution failed to alter the resistance of this particular virus, indicating that the 120th amino acid residue itself is also involved in sensitivity regardless of the L4/5 conformation. These results suggested that a hydrogen bond between the L4/5 and L6/7 modulates the overall structure of the exposed surface of the CA, but the amino acid residue at position 120 is also directly involved in CM TRIM5

  11. Conformal radiotherapy: principles and classification

    International Nuclear Information System (INIS)

    Rosenwald, J.C.; Gaboriaud, G.; Pontvert, D.

    1999-01-01

    'Conformal radiotherapy' is the name fixed by usage and given to a new form of radiotherapy resulting from the technological improvements observed during the last ten years. While this terminology is now widely used, no precise definition can be found in the literature. Conformal radiotherapy refers to an approach in which the dose distribution is more closely 'conformed' or adapted to the actual shape of the target volume. However, the achievement of a consensus on a more specific definition is hampered by various difficulties, namely in characterizing the degree of 'conformality'. We have therefore suggested a classification scheme be established on the basis of the tools and the procedures actually used for all steps of the process, i.e., from prescription to treatment completion. Our classification consists of four levels: schematically, at level 0, there is no conformation (rectangular fields); at level 1, a simple conformation takes place, on the basis of conventional 2D imaging; at level 2, a 3D reconstruction of the structures is used for a more accurate conformation; and level 3 includes research and advanced dynamic techniques. We have used our personal experience, contacts with colleagues and data from the literature to analyze all the steps of the planning process, and to define the tools and procedures relevant to a given level. The corresponding tables have been discussed and approved at the European level within the Dynarad concerted action. It is proposed that the term 'conformal radiotherapy' be restricted to procedures where all steps are at least at level 2. (author)

  12. Conformal Cosmology and Supernova Data

    OpenAIRE

    Behnke, Danilo; Blaschke, David; Pervushin, Victor; Proskurin, Denis

    2000-01-01

    We define the cosmological parameters $H_{c,0}$, $\\Omega_{m,c}$ and $\\Omega_{\\Lambda, c}$ within the Conformal Cosmology as obtained by the homogeneous approximation to the conformal-invariant generalization of Einstein's General Relativity theory. We present the definitions of the age of the universe and of the luminosity distance in the context of this approach. A possible explanation of the recent data from distant supernovae Ia without a cosmological constant is presented.

  13. Scalar perturbations and conformal transformation

    International Nuclear Information System (INIS)

    Fabris, J.C.; Tossa, J.

    1995-11-01

    The non-minimal coupling of gravity to a scalar field can be transformed into a minimal coupling through a conformal transformation. We show how to connect the results of a perturbation calculation, performed around a Friedman-Robertson-Walker background solution, before and after the conformal transformation. We work in the synchronous gauge, but we discuss the implications of employing other frames. (author). 16 refs

  14. Solid state detector module

    International Nuclear Information System (INIS)

    Hoffman, D. M.

    1985-01-01

    A solid state detector in which each scintillator is optimally configured and coupled with its associated sensing diode in a way which exploits light piping effects to enhance efficiency, and at the same time provide a detector which is modular in nature. To achieve light piping, the scintillator crystal is oriented such that its sides conform with the crystal cleavage plane, and the sides are highly polished. An array of tungsten collimator plates define the individual channels. Multi-channel scintillator/diode modules are mounted behind and in registry with the plurality of collimator plates. A plurality of scintillators are bonded together after coating the surfaces thereof to minimize optical crosstalk. After lapping the face of the scintillator module, it is then bonded to a diode module with individual scintillators in registration with individual diodes. The module is then positioned in the detector array with collimator plates at the junctions between the scintillators

  15. Takiff superalgebras and conformal field theory

    International Nuclear Information System (INIS)

    Babichenko, Andrei; Ridout, David

    2013-01-01

    A class of non-semisimple extensions of Lie superalgebras is studied. They are obtained by adjoining to the superalgebra its adjoint representation as an Abelian ideal. When the superalgebra is of affine Kac–Moody type, a generalization of Sugawara’s construction is shown to give rise to a copy of the Virasoro algebra and so, presumably, to a conformal field theory. Evidence for this is detailed for the extension of the affinization of the superalgebra gl( 1|1): its highest weight irreducible modules are classified using spectral flow, the irreducible supercharacters are computed and a continuum version of the Verlinde formula is verified to give non-negative integer structure coefficients. Interpreting these coefficients as those of the Grothendieck ring of fusion, partial results on the true fusion ring and its indecomposable structures are deduced. (paper)

  16. Quantum Conformal Algebras and Closed Conformal Field Theory

    CERN Document Server

    Anselmi, D

    1999-01-01

    We investigate the quantum conformal algebras of N=2 and N=1 supersymmetric gauge theories. Phenomena occurring at strong coupling are analysed using the Nachtmann theorem and very general, model-independent, arguments. The results lead us to introduce a novel class of conformal field theories, identified by a closed quantum conformal algebra. We conjecture that they are the exact solution to the strongly coupled large-N_c limit of the open conformal field theories. We study the basic properties of closed conformal field theory and work out the operator product expansion of the conserved current multiplet T. The OPE structure is uniquely determined by two central charges, c and a. The multiplet T does not contain just the stress-tensor, but also R-currents and finite mass operators. For this reason, the ratio c/a is different from 1. On the other hand, an open algebra contains an infinite tower of non-conserved currents, organized in pairs and singlets with respect to renormalization mixing. T mixes with a se...

  17. Generating intrinsically disordered protein conformational ensembles from a Markov chain

    Science.gov (United States)

    Cukier, Robert I.

    2018-03-01

    Intrinsically disordered proteins (IDPs) sample a diverse conformational space. They are important to signaling and regulatory pathways in cells. An entropy penalty must be payed when an IDP becomes ordered upon interaction with another protein or a ligand. Thus, the degree of conformational disorder of an IDP is of interest. We create a dichotomic Markov model that can explore entropic features of an IDP. The Markov condition introduces local (neighbor residues in a protein sequence) rotamer dependences that arise from van der Waals and other chemical constraints. A protein sequence of length N is characterized by its (information) entropy and mutual information, MIMC, the latter providing a measure of the dependence among the random variables describing the rotamer probabilities of the residues that comprise the sequence. For a Markov chain, the MIMC is proportional to the pair mutual information MI which depends on the singlet and pair probabilities of neighbor residue rotamer sampling. All 2N sequence states are generated, along with their probabilities, and contrasted with the probabilities under the assumption of independent residues. An efficient method to generate realizations of the chain is also provided. The chain entropy, MIMC, and state probabilities provide the ingredients to distinguish different scenarios using the terminologies: MoRF (molecular recognition feature), not-MoRF, and not-IDP. A MoRF corresponds to large entropy and large MIMC (strong dependence among the residues' rotamer sampling), a not-MoRF corresponds to large entropy but small MIMC, and not-IDP corresponds to low entropy irrespective of the MIMC. We show that MorFs are most appropriate as descriptors of IDPs. They provide a reasonable number of high-population states that reflect the dependences between neighbor residues, thus classifying them as IDPs, yet without very large entropy that might lead to a too high entropy penalty.

  18. Can advanced new radiation therapy technologies improve outcome of high grade glioma (HGG) patients? analysis of 3D-conformal radiotherapy (3DCRT) versus volumetric-modulated arc therapy (VMAT) in patients treated with surgery, concomitant and adjuvant chemo-radiotherapy

    International Nuclear Information System (INIS)

    Navarria, Pierina; Pessina, Federico; Cozzi, Luca; Ascolese, Anna Maria; Lobefalo, Francesca; Stravato, Antonella; D’Agostino, Giuseppe; Franzese, Ciro; Caroli, Manuela; Bello, Lorenzo; Scorsetti, Marta

    2016-01-01

    To assess the impact of volumetric-modulated arc therapy (VMAT) compared with 3D-conformal radiotherapy (3DCRT) in patients with newly diagnosed high grade glioma in terms of toxicity, progression free survival (PFS) and overall survival (OS). From March 2004 to October 2014, 341 patients underwent surgery followed by concomitant and adjuvant chemo-radiotherapy. From 2003 to 2010, 167 patients were treated using 3DCRT; starting from 2011, 174 patients underwent VMAT. The quantitative evaluation of the treatment plans was performed by means of standard dose volume histogram analysis. Response was recorded using the Response Assessment in Neuro-Oncology (RANO) criteria and toxicities graded according to Common Terminology Criteria for Adverse Event version 4.0. Both techniques achieved an adequate dose conformity to the target. The median follow up time was 1.3 years; at the last observation 76 patients (23.4 %) were alive and 249 (76.6 %) dead (16 patients were lot to follow-up). For patients who underwent 3DCRT, the median PFS was 0.99 ± 0.07 years (CI95: 0.9–1.1 years); the 1 and 3 years PFS were, 49.6 ± 4 and 19.1 ± 3.1 %. This shall be compared, respectively, to 1.29 ± 0.13 years (CI95: 1.01–1.5 years), 60.8 ± 3.8, and 29.7 ± 4.6 % for patients who underwent VMAT (p = 0.02). The median OS for 3DCRT patients was 1.21 ± 0.09 years (CI95:1.03–1.3 years); 1 and 5 year OS was, 63.3 ± 3.8 and 21.5 ± 3.3 %. The corresponding results for 3DRCT patients were 1.56 ± 0.09 years (CI95:1.37–1.74 years), 73.4 ± 3.5, 30 ± 4.6 % respectively (p < 0.01). In both groups, prognostic factors conditioning PFS and OS were age, gender, KPS, histology and extent of resection (EOR). VMAT resulted superior to 3DCRT in terms of dosimetric findings and clinical results

  19. Conformational Dynamics of apo-GlnBP Revealed by Experimental and Computational Analysis

    KAUST Repository

    Feng, Yitao

    2016-10-13

    The glutamine binding protein (GlnBP) binds l-glutamine and cooperates with its cognate transporters during glutamine uptake. Crystal structure analysis has revealed an open and a closed conformation for apo- and holo-GlnBP, respectively. However, the detailed conformational dynamics have remained unclear. Herein, we combined NMR spectroscopy, MD simulations, and single-molecule FRET techniques to decipher the conformational dynamics of apo-GlnBP. The NMR residual dipolar couplings of apo-GlnBP were in good agreement with a MD-derived structure ensemble consisting of four metastable states. The open and closed conformations are the two major states. This four-state model was further validated by smFRET experiments and suggests the conformational selection mechanism in ligand recognition of GlnBP. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

  20. Conformational Dynamics of apo-GlnBP Revealed by Experimental and Computational Analysis

    KAUST Repository

    Feng, Yitao; Zhang, Lu; Wu, Shaowen; Liu, Zhijun; Gao, Xin; Zhang, Xu; Liu, Maili; Liu, Jianwei; Huang, Xuhui; Wang, Wenning

    2016-01-01

    The glutamine binding protein (GlnBP) binds l-glutamine and cooperates with its cognate transporters during glutamine uptake. Crystal structure analysis has revealed an open and a closed conformation for apo- and holo-GlnBP, respectively. However, the detailed conformational dynamics have remained unclear. Herein, we combined NMR spectroscopy, MD simulations, and single-molecule FRET techniques to decipher the conformational dynamics of apo-GlnBP. The NMR residual dipolar couplings of apo-GlnBP were in good agreement with a MD-derived structure ensemble consisting of four metastable states. The open and closed conformations are the two major states. This four-state model was further validated by smFRET experiments and suggests the conformational selection mechanism in ligand recognition of GlnBP. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

  1. Information content of long-range NMR data for the characterization of conformational heterogeneity

    Energy Technology Data Exchange (ETDEWEB)

    Andrałojć, Witold [University of Florence, Center for Magnetic Resonance (CERM) (Italy); Berlin, Konstantin; Fushman, David, E-mail: fushman@umd.edu [University of Maryland, Department of Chemistry and Biochemistry, Center for Biomolecular Structure and Organization (United States); Luchinat, Claudio, E-mail: luchinat@cerm.unifi.it; Parigi, Giacomo; Ravera, Enrico [University of Florence, Center for Magnetic Resonance (CERM) (Italy); Sgheri, Luca [CNR, Istituto per le Applicazioni del Calcolo, Sezione di Firenze (Italy)

    2015-07-15

    Long-range NMR data, namely residual dipolar couplings (RDCs) from external alignment and paramagnetic data, are becoming increasingly popular for the characterization of conformational heterogeneity of multidomain biomacromolecules and protein complexes. The question addressed here is how much information is contained in these averaged data. We have analyzed and compared the information content of conformationally averaged RDCs caused by steric alignment and of both RDCs and pseudocontact shifts caused by paramagnetic alignment, and found that, despite the substantial differences, they contain a similar amount of information. Furthermore, using several synthetic tests we find that both sets of data are equally good towards recovering the major state(s) in conformational distributions.

  2. Gauge fixing problem in the conformal QED

    International Nuclear Information System (INIS)

    Ichinose, Shoichi

    1986-01-01

    The gauge fixing problem in the conformal (spinor and scalar) QED is examined. For the analysis, we generalize Dirac's manifestly conformal-covariant formalism. It is shown that the (vector and matter) fields must obey a certain mixed (conformal and gauge) type of transformation law in order to fix the local gauge symmetry preserving the conformal invariance in the Lagrangian. (orig.)

  3. 40 CFR 93.154 - Conformity analysis.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Conformity analysis. 93.154 Section 93...) DETERMINING CONFORMITY OF FEDERAL ACTIONS TO STATE OR FEDERAL IMPLEMENTATION PLANS Determining Conformity of General Federal Actions to State or Federal Implementation Plans § 93.154 Conformity analysis. Any Federal...

  4. A dualistic conformational response to substrate binding in the human serotonin transporter reveals a high affinity state for serotonin

    DEFF Research Database (Denmark)

    Bjerregaard, Henriette; Severinsen, Kasper; Said, Saida

    2015-01-01

    Serotonergic neurotransmission is modulated by the membrane-embedded serotonin transporter (SERT). SERT mediates the reuptake of serotonin into the presynaptic neurons. Conformational changes in SERT occur upon binding of ions and substrate and are crucial for translocation of serotonin across...... the membrane. Our understanding of these conformational changes is mainly based on crystal structures of a bacterial homolog in various conformations, derived homology models of eukaryotic neurotransmitter transporters, and substituted cysteine accessibility method of SERT. However, the dynamic changes...

  5. Intramolecular interactions stabilizing compact conformations of the intrinsically disordered kinase-inhibitor domain of Sic1: a molecular dynamics investigation.

    Directory of Open Access Journals (Sweden)

    Matteo eLambrughi

    2012-11-01

    Full Text Available Cyclin-dependent kinase inhibitors (CKIs are key regulatory proteins of the eukaryotic cell cycle, which modulate cyclin-dependent kinase (Cdk activity. CKIs perform their inhibitory effect by the formation of ternary complexes with a target kinase and its cognate cyclin. These regulators generally belong to the class of intrinsically disordered proteins (IDPs, which lack a well-defined and organized three-dimensional structure in their free state, undergoing folding upon binding to specific partners. Unbound IDPs are not merely random-coil structures, but can present intrinsically folded structural units (IFSUs and collapsed conformations. These structural features can be relevant to protein function in vivo.The yeast CKI Sic1 is a 284-amino acid IDP that binds to Cdk1 in complex with the Clb5,6 cyclins, preventing phosphorylation of G1 substrates and, therefore, entrance to the S phase. Sic1 degradation, triggered by multiple phosphorylation events, promotes cell-cycle progression. Previous experimental studies pointed out a propensity of Sic1 and its isolated domains to populate both extended and compact conformations. The present contribution provides models of the compact conformations of the Sic1 kinase-inhibitory domain (KID by all-atom molecular-dynamics simulations in explicit solvent and in the absence of interactors. The results are integrated by spectroscopic and spectrometric data. Helical IFSUs are identified, along with networks of intramolecular interactions. The results identify a group of hub residues and electrostatic interactions which are likely to be involved in the stabilization of globular states.

  6. Aggregation-primed molten globule conformers of the p53 core domain provide potential tools for studying p53C aggregation in cancer.

    Science.gov (United States)

    Pedrote, Murilo M; de Oliveira, Guilherme A P; Felix, Adriani L; Mota, Michelle F; Marques, Mayra de A; Soares, Iaci N; Iqbal, Anwar; Norberto, Douglas R; Gomes, Andre M O; Gratton, Enrico; Cino, Elio A; Silva, Jerson L

    2018-05-31

    The functionality of the tumor suppressor p53 is altered in more than 50% of human cancers, and many individuals with cancer exhibit amyloid-like buildups of aggregated p53. An understanding of what triggers the pathogenic amyloid conversion of p53 is required for the further development of cancer therapies. Here, perturbation of the p53 core domain (p53C) with sub-denaturing concentrations of guanidine hydrochloride and high hydrostatic pressure revealed native-like molten globule (MG) states, a subset of which were highly prone to amyloidogenic aggregation. We found that MG conformers of p53C, likely representing population-weighted averages of multiple states, have different volumetric properties, as determined by pressure perturbation and size-exclusion chromatography. We also found that they bind the fluorescent dye 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid (bis-ANS) and have a native-like tertiary structure that occludes the single Trp residue in p53. Fluorescence experiments revealed conformational changes of the single Trp and Tyr residues before p53 unfolding and the presence of MG conformers, some of which were highly prone to aggregation. P53C exhibited marginal unfolding cooperativity, which could be modulated from unfolding to aggregation pathways with chemical or physical forces. We conclude that trapping amyloid precursor states in solution is a promising approach for understanding p53 aggregation in cancer. Our findings support the use of single-Trp fluorescence as a probe for evaluating p53 stability, effects of mutations, and the efficacy of therapeutics designed to stabilize p53. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

  7. Renyi entropy and conformal defects

    Energy Technology Data Exchange (ETDEWEB)

    Bianchi, Lorenzo [Humboldt-Univ. Berlin (Germany). Inst. fuer Physik; Hamburg Univ. (Germany). II. Inst. fuer Theoretische Physik; Meineri, Marco [Scuola Normale Superiore, Pisa (Italy); Perimeter Institute for Theoretical Physics, Waterloo, ON (Canada); Istituto Nazionale di Fisica Nucleare, Pisa (Italy); Myers, Robert C. [Perimeter Institute for Theoretical Physics, Waterloo, ON (Canada); Smolkin, Michael [California Univ., Berkely, CA (United States). Center for Theoretical Physics and Department of Physics

    2016-04-18

    We propose a field theoretic framework for calculating the dependence of Renyi entropies on the shape of the entangling surface in a conformal field theory. Our approach rests on regarding the corresponding twist operator as a conformal defect and in particular, we define the displacement operator which implements small local deformations of the entangling surface. We identify a simple constraint between the coefficient defining the two-point function of the displacement operator and the conformal weight of the twist operator, which consolidates a number of distinct conjectures on the shape dependence of the Renyi entropy. As an example, using this approach, we examine a conjecture regarding the universal coefficient associated with a conical singularity in the entangling surface for CFTs in any number of spacetime dimensions. We also provide a general formula for the second order variation of the Renyi entropy arising from small deformations of a spherical entangling surface, extending Mezei's results for the entanglement entropy.

  8. Conformal dimension theory and application

    CERN Document Server

    Mackay, John M

    2010-01-01

    Conformal dimension measures the extent to which the Hausdorff dimension of a metric space can be lowered by quasisymmetric deformations. Introduced by Pansu in 1989, this concept has proved extremely fruitful in a diverse range of areas, including geometric function theory, conformal dynamics, and geometric group theory. This survey leads the reader from the definitions and basic theory through to active research applications in geometric function theory, Gromov hyperbolic geometry, and the dynamics of rational maps, amongst other areas. It reviews the theory of dimension in metric spaces and of deformations of metric spaces. It summarizes the basic tools for estimating conformal dimension and illustrates their application to concrete problems of independent interest. Numerous examples and proofs are provided. Working from basic definitions through to current research areas, this book can be used as a guide for graduate students interested in this field, or as a helpful survey for experts. Background needed ...

  9. Elementary introduction to conformal invariance

    International Nuclear Information System (INIS)

    Grandati, Y.

    1992-01-01

    These notes constitute an elementary introduction to the concept of conformal invariance and its applications to the study of bidimensional critical phenomena. The aim is to give an access as pedestrian as possible to this vast subject. After a brief account of the general properties of conformal transformation in D dimensions, we study more specifically the case D = 2. The center of the discussion is then the consequences of the action of this symmetry group on bidimensional field theories, and in particular the links between the representations of the Virasoro algebra and the structure of the correlation functions of conformal field theories. Finally after showing how the Ising model reduces to a Majorana fermionic field theory, we see how the general formalism previously discussed can be applied to the Ising case at the critical point. (orig.)

  10. Conformal geometry and quasiregular mappings

    CERN Document Server

    Vuorinen, Matti

    1988-01-01

    This book is an introduction to the theory of spatial quasiregular mappings intended for the uninitiated reader. At the same time the book also addresses specialists in classical analysis and, in particular, geometric function theory. The text leads the reader to the frontier of current research and covers some most recent developments in the subject, previously scatterd through the literature. A major role in this monograph is played by certain conformal invariants which are solutions of extremal problems related to extremal lengths of curve families. These invariants are then applied to prove sharp distortion theorems for quasiregular mappings. One of these extremal problems of conformal geometry generalizes a classical two-dimensional problem of O. Teichmüller. The novel feature of the exposition is the way in which conformal invariants are applied and the sharp results obtained should be of considerable interest even in the two-dimensional particular case. This book combines the features of a textbook an...

  11. Renyi entropy and conformal defects

    International Nuclear Information System (INIS)

    Bianchi, Lorenzo; Myers, Robert C.; Smolkin, Michael

    2016-01-01

    We propose a field theoretic framework for calculating the dependence of Renyi entropies on the shape of the entangling surface in a conformal field theory. Our approach rests on regarding the corresponding twist operator as a conformal defect and in particular, we define the displacement operator which implements small local deformations of the entangling surface. We identify a simple constraint between the coefficient defining the two-point function of the displacement operator and the conformal weight of the twist operator, which consolidates a number of distinct conjectures on the shape dependence of the Renyi entropy. As an example, using this approach, we examine a conjecture regarding the universal coefficient associated with a conical singularity in the entangling surface for CFTs in any number of spacetime dimensions. We also provide a general formula for the second order variation of the Renyi entropy arising from small deformations of a spherical entangling surface, extending Mezei's results for the entanglement entropy.

  12. Residues and duality for singularity categories of isolated Gorenstein singularities

    OpenAIRE

    Murfet, Daniel

    2009-01-01

    We study Serre duality in the singularity category of an isolated Gorenstein singularity and find an explicit formula for the duality pairing in terms of generalised fractions and residues. For hypersurfaces we recover the residue formula of the string theorists Kapustin and Li. These results are obtained from an explicit construction of complete injective resolutions of maximal Cohen-Macaulay modules.

  13. How cholesterol constrains glycolipid conformation for optimal recognition of Alzheimer's beta amyloid peptide (Abeta1-40).

    Science.gov (United States)

    Yahi, Nouara; Aulas, Anaïs; Fantini, Jacques

    2010-02-05

    Membrane lipids play a pivotal role in the pathogenesis of Alzheimer's disease, which is associated with conformational changes, oligomerization and/or aggregation of Alzheimer's beta-amyloid (Abeta) peptides. Yet conflicting data have been reported on the respective effect of cholesterol and glycosphingolipids (GSLs) on the supramolecular assembly of Abeta peptides. The aim of the present study was to unravel the molecular mechanisms by which cholesterol modulates the interaction between Abeta(1-40) and chemically defined GSLs (GalCer, LacCer, GM1, GM3). Using the Langmuir monolayer technique, we show that Abeta(1-40) selectively binds to GSLs containing a 2-OH group in the acyl chain of the ceramide backbone (HFA-GSLs). In contrast, Abeta(1-40) did not interact with GSLs containing a nonhydroxylated fatty acid (NFA-GSLs). Cholesterol inhibited the interaction of Abeta(1-40) with HFA-GSLs, through dilution of the GSL in the monolayer, but rendered the initially inactive NFA-GSLs competent for Abeta(1-40) binding. Both crystallographic data and molecular dynamics simulations suggested that the active conformation of HFA-GSL involves a H-bond network that restricts the orientation of the sugar group of GSLs in a parallel orientation with respect to the membrane. This particular conformation is stabilized by the 2-OH group of the GSL. Correspondingly, the interaction of Abeta(1-40) with HFA-GSLs is strongly inhibited by NaF, an efficient competitor of H-bond formation. For NFA-GSLs, this is the OH group of cholesterol that constrains the glycolipid to adopt the active L-shape conformation compatible with sugar-aromatic CH-pi stacking interactions involving residue Y10 of Abeta(1-40). We conclude that cholesterol can either inhibit or facilitate membrane-Abeta interactions through fine tuning of glycosphingolipid conformation. These data shed some light on the complex molecular interplay between cell surface GSLs, cholesterol and Abeta peptides, and on the influence

  14. How cholesterol constrains glycolipid conformation for optimal recognition of Alzheimer's beta amyloid peptide (Abeta1-40.

    Directory of Open Access Journals (Sweden)

    Nouara Yahi

    Full Text Available Membrane lipids play a pivotal role in the pathogenesis of Alzheimer's disease, which is associated with conformational changes, oligomerization and/or aggregation of Alzheimer's beta-amyloid (Abeta peptides. Yet conflicting data have been reported on the respective effect of cholesterol and glycosphingolipids (GSLs on the supramolecular assembly of Abeta peptides. The aim of the present study was to unravel the molecular mechanisms by which cholesterol modulates the interaction between Abeta(1-40 and chemically defined GSLs (GalCer, LacCer, GM1, GM3. Using the Langmuir monolayer technique, we show that Abeta(1-40 selectively binds to GSLs containing a 2-OH group in the acyl chain of the ceramide backbone (HFA-GSLs. In contrast, Abeta(1-40 did not interact with GSLs containing a nonhydroxylated fatty acid (NFA-GSLs. Cholesterol inhibited the interaction of Abeta(1-40 with HFA-GSLs, through dilution of the GSL in the monolayer, but rendered the initially inactive NFA-GSLs competent for Abeta(1-40 binding. Both crystallographic data and molecular dynamics simulations suggested that the active conformation of HFA-GSL involves a H-bond network that restricts the orientation of the sugar group of GSLs in a parallel orientation with respect to the membrane. This particular conformation is stabilized by the 2-OH group of the GSL. Correspondingly, the interaction of Abeta(1-40 with HFA-GSLs is strongly inhibited by NaF, an efficient competitor of H-bond formation. For NFA-GSLs, this is the OH group of cholesterol that constrains the glycolipid to adopt the active L-shape conformation compatible with sugar-aromatic CH-pi stacking interactions involving residue Y10 of Abeta(1-40. We conclude that cholesterol can either inhibit or facilitate membrane-Abeta interactions through fine tuning of glycosphingolipid conformation. These data shed some light on the complex molecular interplay between cell surface GSLs, cholesterol and Abeta peptides, and on the

  15. Saturating representation of loop conformational fragments in structure databanks

    Directory of Open Access Journals (Sweden)

    Fiser András

    2006-07-01

    Full Text Available Abstract Background Short fragments of proteins are fundamental starting points in various structure prediction applications, such as in fragment based loop modeling methods but also in various full structure build-up procedures. The applicability and performance of these approaches depend on the availability of short fragments in structure databanks. Results We studied the representation of protein loop fragments up to 14 residues in length. All possible query fragments found in sequence databases (Sequence Space were clustered and cross referenced with available structural fragments in Protein Data Bank (Structure Space. We found that the expansion of PDB in the last few years resulted in a dense coverage of loop conformational fragments. For each loops of length 8 in the current Sequence Space there is at least one loop in Structure Space with 50% or higher sequence identity. By correlating sequence and structure clusters of loops we found that a 50% sequence identity generally guarantees structural similarity. These percentages of coverage at 50% sequence cutoff drop to 96, 94, 68, 53, 33 and 13% for loops of length 9, 10, 11, 12, 13, and 14, respectively. There is not a single loop in the current Sequence Space at any length up to 14 residues that is not matched with a conformational segment that shares at least 20% sequence identity. This minimum observed identity is 40% for loops of 12 residues or shorter and is as high as 50% for 10 residue or shorter loops. We also assessed the impact of rapidly growing sequence databanks on the estimated number of new loop conformations and found that while the number of sequentially unique sequence segments increased about six folds during the last five years there are almost no unique conformational segments among these up to 12 residues long fragments. Conclusion The results suggest that fragment based prediction approaches are not limited any more by the completeness of fragments in databanks but

  16. SUSY Unparticle and Conformal Sequestering

    Energy Technology Data Exchange (ETDEWEB)

    Nakayama, Yu; Nakayama, Yu

    2007-07-17

    We investigate unparticle physics with supersymmetry (SUSY). The SUSY breaking effects due to the gravity mediation induce soft masses for the SUSY unparticles and hence break the conformal invariance. The unparticle physics observable in near future experiments is only consistent if the SUSY breakingeffects from the hidden sector to the standard model sector are dominated by the gauge mediation, or if the SUSY breaking effects to the unparticle sector are sufficiently sequestered. We argue that the natural realization of the latter possibility is the conformal sequestering scenario.

  17. Topics in conformal field theory

    International Nuclear Information System (INIS)

    Kiritsis, E.B.

    1988-01-01

    In this work two major topics in Conformal Field Theory are discussed. First a detailed investigation of N = 2 Superconformal theories is presented. The structure of the representations of the N = 2 superconformal algebras is investigated and the character formulae are calculated. The general structure of N = 2 superconformal theories is elucidated and the operator algebra of the minimal models is derived. The first minimal system is discussed in more detail. Second, applications of the conformal techniques are studied in the Ashkin-Teller model. The c = 1 as well as the c = 1/2 critical lines are discussed in detail

  18. A real-time web-based optimal Biomass Site Assessment Tool (BioSAT): Module 1. An economic assessment of mill residues for the southern U.S.

    Science.gov (United States)

    Timothy M. Young; James H. Perdue; Andy Hartsell; Robert C. Abt; Donald Hodges; Timothy G. Rials

    2009-01-01

    Optimal locations for biomass facilities that use mill residues are identified for 13 southern U.S. states. The Biomass Site Assessment Tool (BioSAT) model is used to identify the top 20 locations for 13 southern U.S. states. The trucking cost model of BioSAT is used with Timber Mart South 2009 price data to estimate the total cost, average cost, and marginal costs for...

  19. Immirzi parameter without Immirzi ambiguity: Conformal loop quantization of scalar-tensor gravity

    Science.gov (United States)

    Veraguth, Olivier J.; Wang, Charles H.-T.

    2017-10-01

    Conformal loop quantum gravity provides an approach to loop quantization through an underlying conformal structure i.e. conformally equivalent class of metrics. The property that general relativity itself has no conformal invariance is reinstated with a constrained scalar field setting the physical scale. Conformally equivalent metrics have recently been shown to be amenable to loop quantization including matter coupling. It has been suggested that conformal geometry may provide an extended symmetry to allow a reformulated Immirzi parameter necessary for loop quantization to behave like an arbitrary group parameter that requires no further fixing as its present standard form does. Here, we find that this can be naturally realized via conformal frame transformations in scalar-tensor gravity. Such a theory generally incorporates a dynamical scalar gravitational field and reduces to general relativity when the scalar field becomes a pure gauge. In particular, we introduce a conformal Einstein frame in which loop quantization is implemented. We then discuss how different Immirzi parameters under this description may be related by conformal frame transformations and yet share the same quantization having, for example, the same area gaps, modulated by the scalar gravitational field.

  20. Direct electrical control of IgG conformation and functional activity at surfaces

    Science.gov (United States)

    Ghisellini, Paola; Caiazzo, Marialuisa; Alessandrini, Andrea; Eggenhöffner, Roberto; Vassalli, Massimo; Facci, Paolo

    2016-11-01

    We have devised a supramolecular edifice involving His-tagged protein A and antibodies to yield surface immobilized, uniformly oriented, IgG-type, antibody layers with Fab fragments exposed off an electrode surface. We demonstrate here that we can affect the conformation of IgGs, likely pushing/pulling electrostatically Fab fragments towards/from the electrode surface. A potential difference between electrode and solution acts on IgGs’ charged aminoacids modulating the accessibility of the specific recognition regions of Fab fragments by antigens in solution. Consequently, antibody-antigen affinity is affected by the sign of the applied potential: a positive potential enables an effective capture of antigens; a negative one pulls the fragments towards the electrode, where steric hindrance caused by neighboring molecules largely hampers the capture of antigens. Different experimental techniques (electrochemical quartz crystal microbalance, electrochemical impedance spectroscopy, fluorescence confocal microscopy and electrochemical atomic force spectroscopy) were used to evaluate binding kinetics, surface coverage, effect of the applied electric field on IgGs, and role of charged residues on the phenomenon described. These findings expand the concept of electrical control of biological reactions and can be used to gate electrically specific recognition reactions with impact in biosensors, bioactuators, smart biodevices, nanomedicine, and fundamental studies related to chemical reaction kinetics.

  1. Prion protein β2-α2 loop conformational landscape.

    Science.gov (United States)

    Caldarulo, Enrico; Barducci, Alessandro; Wüthrich, Kurt; Parrinello, Michele

    2017-09-05

    In transmissible spongiform encephalopathies (TSEs), which are lethal neurodegenerative diseases that affect humans and a wide range of other mammalian species, the normal "cellular" prion protein ([Formula: see text]) is transformed into amyloid aggregates representing the "scrapie form" of the protein ([Formula: see text]). Continued research on this system is of keen interest, since new information on the physiological function of [Formula: see text] in healthy organisms is emerging, as well as new data on the mechanism of the transformation of [Formula: see text] to [Formula: see text] In this paper we used two different approaches: a combination of the well-tempered ensemble (WTE) and parallel tempering (PT) schemes and metadynamics (MetaD) to characterize the conformational free-energy surface of [Formula: see text] The focus of the data analysis was on an 11-residue polypeptide segment in mouse [Formula: see text](121-231) that includes the [Formula: see text]2-[Formula: see text]2 loop of residues 167-170, for which a correlation between structure and susceptibility to prion disease has previously been described. This study includes wild-type mouse [Formula: see text] and a variant with the single-residue replacement Y169A. The resulting detailed conformational landscapes complement in an integrative manner the available experimental data on [Formula: see text], providing quantitative insights into the nature of the structural transition-related function of the [Formula: see text]2-[Formula: see text]2 loop.

  2. Spin-4 extended conformal algebras

    International Nuclear Information System (INIS)

    Kakas, A.C.

    1988-01-01

    We construct spin-4 extended conformal algebras using the second hamiltonian structure of the KdV hierarchy. In the presence of a U(1) current a family of spin-4 algebras exists but the additional requirement that the spin-1 and spin-4 currents commute fixes the algebra uniquely. (orig.)

  3. Defects in conformal field theory

    International Nuclear Information System (INIS)

    Billò, Marco; Gonçalves, Vasco; Lauria, Edoardo; Meineri, Marco

    2016-01-01

    We discuss consequences of the breaking of conformal symmetry by a flat or spherical extended operator. We adapt the embedding formalism to the study of correlation functions of symmetric traceless tensors in the presence of the defect. Two-point functions of a bulk and a defect primary are fixed by conformal invariance up to a set of OPE coefficients, and we identify the allowed tensor structures. A correlator of two bulk primaries depends on two cross-ratios, and we study its conformal block decomposition in the case of external scalars. The Casimir equation in the defect channel reduces to a hypergeometric equation, while the bulk channel blocks are recursively determined in the light-cone limit. In the special case of a defect of codimension two, we map the Casimir equation in the bulk channel to the one of a four-point function without defect. Finally, we analyze the contact terms of the stress-tensor with the extended operator, and we deduce constraints on the CFT data. In two dimensions, we relate the displacement operator, which appears among the contact terms, to the reflection coefficient of a conformal interface, and we find unitarity bounds for the latter.

  4. Conformal symmetry and holographic cosmology

    NARCIS (Netherlands)

    Bzowski, A.W.

    2013-01-01

    This thesis presents a novel approach to cosmology using gauge/gravity duality. Analysis of the implications of conformal invariance in field theories leads to quantitative cosmological predictions which are in agreement with current data. Furthermore, holographic cosmology extends the theory of

  5. Checking behavioral conformance of artifacts

    NARCIS (Netherlands)

    Fahland, D.; Leoni, de M.; Dongen, van B.F.; Aalst, van der W.M.P.

    2011-01-01

    The usefulness of process models (e.g., for analysis, improvement, or execution) strongly depends on their ability to describe reality. Conformance checking is a technique to validate how good a given process model describes recorded executions of the actual process. Recently, artifacts have been

  6. Conformation analysis of oligomeric flavanoids

    Science.gov (United States)

    Jan P. Steynberg; E. Vincent Brandt; Daneel Ferreira; Carin A. Helfer; Wayne L. Mattice; Dominika Gornik; Richard W. Hemingway

    1995-01-01

    The profisetinidins are the most important polyflavanoids of commerce, making up the major constituents of wattle and quebracho tannins. Within the dimeric profisetinidins, substantial complexity exists because of stereo-, regio, rotational and conformational isomers. Definition of the stereochemistry of the upper and lower flavan units, the location of the...

  7. Conformational analysis of oligomeric flavanoids

    Science.gov (United States)

    Jan P. Steynberg; E. Vincent Brandt; Daneel Ferreira; Carin A. Helfer; Wayne L. Mattice; Dominika Gornik; Richard W. Hemingway

    1995-01-01

    The profisetinidins are the most important polyflavanoids of commerce, making up the major constituents of wattle and quebracho tannins. Even within the dimeric profisetinidins, substantial complexity exists because of stereo-, regio-, rotational and conformational isomers. Definition of the stereochemistry of the upper and lower flavan units, the location of the...

  8. Inversion theory and conformal mapping

    CERN Document Server

    Blair, David E

    2000-01-01

    It is rarely taught in an undergraduate or even graduate curriculum that the only conformal maps in Euclidean space of dimension greater than two are those generated by similarities and inversions in spheres. This is in stark contrast to the wealth of conformal maps in the plane. The principal aim of this text is to give a treatment of this paucity of conformal maps in higher dimensions. The exposition includes both an analytic proof in general dimension and a differential-geometric proof in dimension three. For completeness, enough complex analysis is developed to prove the abundance of conformal maps in the plane. In addition, the book develops inversion theory as a subject, along with the auxiliary theme of circle-preserving maps. A particular feature is the inclusion of a paper by Carath�odory with the remarkable result that any circle-preserving transformation is necessarily a M�bius transformation, not even the continuity of the transformation is assumed. The text is at the level of advanced undergr...

  9. Defects in conformal field theory

    Energy Technology Data Exchange (ETDEWEB)

    Billò, Marco [Dipartimento di Fisica, Università di Torino, and Istituto Nazionale di Fisica Nucleare - sezione di Torino,Via P. Giuria 1 I-10125 Torino (Italy); Gonçalves, Vasco [Centro de Física do Porto,Departamento de Física e Astronomia Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto (Portugal); ICTP South American Institute for Fundamental Research Instituto de Física Teórica,UNESP - University Estadual Paulista,Rua Dr. Bento T. Ferraz 271, 01140-070, São Paulo, SP (Brazil); Lauria, Edoardo [Institute for Theoretical Physics, KU Leuven, Celestijnenlaan 200D, B-3001 Leuven (Belgium); Meineri, Marco [Perimeter Institute for Theoretical Physics,Waterloo, Ontario, N2L 2Y5 (Canada); Scuola Normale Superiore, and Istituto Nazionale di Fisica Nucleare - sezione di Pisa,Piazza dei Cavalieri 7 I-56126 Pisa (Italy)

    2016-04-15

    We discuss consequences of the breaking of conformal symmetry by a flat or spherical extended operator. We adapt the embedding formalism to the study of correlation functions of symmetric traceless tensors in the presence of the defect. Two-point functions of a bulk and a defect primary are fixed by conformal invariance up to a set of OPE coefficients, and we identify the allowed tensor structures. A correlator of two bulk primaries depends on two cross-ratios, and we study its conformal block decomposition in the case of external scalars. The Casimir equation in the defect channel reduces to a hypergeometric equation, while the bulk channel blocks are recursively determined in the light-cone limit. In the special case of a defect of codimension two, we map the Casimir equation in the bulk channel to the one of a four-point function without defect. Finally, we analyze the contact terms of the stress-tensor with the extended operator, and we deduce constraints on the CFT data. In two dimensions, we relate the displacement operator, which appears among the contact terms, to the reflection coefficient of a conformal interface, and we find unitarity bounds for the latter.

  10. Supertwistor connection and conformal supergravity

    International Nuclear Information System (INIS)

    Merkulov, S.A.

    1985-01-01

    Supersymmetry expansion of the geometry of local twistors is suggested. Definition of the space of local supertwistors is given and its differential geometry is formulated. Variational principles are discussed, and it is shown that corresponding Euler-Lagrange equations also coincide and result in superzero equations of N=1 conformal supergravitation, which generalize Bach equations

  11. Conformal symmetry and string theories

    International Nuclear Information System (INIS)

    Kumar, A.

    1987-01-01

    This thesis is devoted to the study of various aspects of the 2-dimensional conformal field theory and its applications to strings. We make a short review of the conformal field theory and its supersymmetric extension, called superconformal field theory. We present an elegant superspace formulation of these theories and solve the condition for the closure of the superconformal algebra. The we go on to classify the superconformal field theories according to these solutions. We prove that N ≥ 5 superconformal algebra, with N being the number of supersymmetries, does not have central charge. We find the primary representations of all the interesting superconformal algebra. We study the quantization of the superconformal theories and derive the constraints on the central charge of the algebra that has to be satisfied for a consistent quantum theory. This quantization process also determines the ground state energy of the system and the spectrum of the model. We study the global aspects of the conformal symmetry and its role in the construction of consistent heterotic string theories. We prove the uniqueness of heterotic superstring theories in 10 dimensions in the fermionic constructions. We show how the vertex operators are closely associated with the primary field representation of the conformal algebra. We utilize these vertex operator constructions to obtain tree amplitudes in the 10-dimensional heterotic string theory. We show by explicit calculation at the 3-point level that the scattering amplitudes derived from the heterotic superstring are same as the ones obtained from 10-dimensional supergravity theories

  12. Exceptional and Spinorial Conformal Windows

    DEFF Research Database (Denmark)

    Mojaza, Matin; Pica, Claudio; Ryttov, Thomas

    2012-01-01

    We study the conformal window of gauge theories containing fermionic matter fields, where the gauge group is any of the exceptional groups with the fermions transforming according to the fundamental and adjoint representations and the orthogonal groups where the fermions transform according...

  13. Anomalous Dimensions of Conformal Baryons

    DEFF Research Database (Denmark)

    Pica, Claudio; Sannino, Francesco

    2016-01-01

    We determine the anomalous dimensions of baryon operators for the three color theory as function of the number of massless flavours within the conformal window to the maximum known order in perturbation theory. We show that the anomalous dimension of the baryon is controllably small, within...

  14. The Dynameomics Entropy Dictionary: A Large-Scale Assessment of Conformational Entropy across Protein Fold Space.

    Science.gov (United States)

    Towse, Clare-Louise; Akke, Mikael; Daggett, Valerie

    2017-04-27

    Molecular dynamics (MD) simulations contain considerable information with regard to the motions and fluctuations of a protein, the magnitude of which can be used to estimate conformational entropy. Here we survey conformational entropy across protein fold space using the Dynameomics database, which represents the largest existing data set of protein MD simulations for representatives of essentially all known protein folds. We provide an overview of MD-derived entropies accounting for all possible degrees of dihedral freedom on an unprecedented scale. Although different side chains might be expected to impose varying restrictions on the conformational space that the backbone can sample, we found that the backbone entropy and side chain size are not strictly coupled. An outcome of these analyses is the Dynameomics Entropy Dictionary, the contents of which have been compared with entropies derived by other theoretical approaches and experiment. As might be expected, the conformational entropies scale linearly with the number of residues, demonstrating that conformational entropy is an extensive property of proteins. The calculated conformational entropies of folding agree well with previous estimates. Detailed analysis of specific cases identifies deviations in conformational entropy from the average values that highlight how conformational entropy varies with sequence, secondary structure, and tertiary fold. Notably, α-helices have lower entropy on average than do β-sheets, and both are lower than coil regions.

  15. Modulation of prion polymerization and toxicity by rationally designed peptidomimetics.

    Science.gov (United States)

    Srivastava, Ankit; Sharma, Sakshi; Sadanandan, Sandhya; Gupta, Sakshi; Singh, Jasdeep; Gupta, Sarika; Haridas, V; Kundu, Bishwajit

    2017-01-01

    Misfolding and aggregation of cellular prion protein is associated with a large array of neurological disorders commonly called the transmissible spongiform encephalopathies. Designing inhibitors against prions has remained a daunting task owing to limited information about mechanism(s) of their pathogenic self-assembly. Here, we explore the anti-prion properties of a combinatorial library of bispidine-based peptidomimetics (BPMs) that conjugate amino acids with hydrophobic and aromatic side chains. Keeping the bispidine unit unaltered, a series of structurally diverse BPMs were synthesized and tested for their prion-modulating properties. Administration of Leu- and Trp-BPMs delayed and completely inhibited the amyloidogenic conversion of human prion protein (HuPrP), respectively. We found that each BPM induced the HuPrP to form unique oligomeric nanostructures differing in their biophysical properties, cellular toxicities and response to conformation-specific antibodies. While Leu-BPMs were found to stabilize the oligomers, Trp-BPMs effected transient oligomerization, resulting in the formation of non-toxic, non-fibrillar aggregates. Yet another aromatic residue, Phe, however, accelerated the aggregation process in HuPrP. Molecular insights obtained through MD (molecular dynamics) simulations suggested that each BPM differently engages a conserved Tyr 169 residue at the α2-β2 loop of HuPrP and affects the stability of α2 and α3 helices. Our results demonstrate that this new class of molecules having chemical scaffolds conjugating hydrophobic/aromatic residues could effectively modulate prion aggregation and toxicity. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  16. Molecular Dynamics Simulations of Insulin: Elucidating the Conformational Changes that Enable Its Binding.

    Directory of Open Access Journals (Sweden)

    Anastasios Papaioannou

    Full Text Available A sequence of complex conformational changes is required for insulin to bind to the insulin receptor. Recent experimental evidence points to the B chain C-terminal (BC-CT as the location of these changes in insulin. Here, we present molecular dynamics simulations of insulin that reveal new insights into the structural changes occurring in the BC-CT. We find three key results: 1 The opening of the BC-CT is inherently stochastic and progresses through an open and then a "wide-open" conformation--the wide-open conformation is essential for receptor binding, but occurs only rarely. 2 The BC-CT opens with a zipper-like mechanism, with a hinge at the Phe24 residue, and is maintained in the dominant closed/inactive state by hydrophobic interactions of the neighboring Tyr26, the critical residue where opening of the BC-CT (activation of insulin is initiated. 3 The mutation Y26N is a potential candidate as a therapeutic insulin analogue. Overall, our results suggest that the binding of insulin to its receptor is a highly dynamic and stochastic process, where initial docking occurs in an open conformation and full binding is facilitated through interactions of insulin receptor residues with insulin in its wide-open conformation.

  17. 3-D conformal radiation therapy - Part I: Treatment planning

    International Nuclear Information System (INIS)

    Burman, Chandra M.; Mageras, Gikas S.

    1997-01-01

    Objective: In this presentation we will look into the basic components of 3-dimensional conformal treatment planning, and will discuss planning for some selected sites. We will also review some current and future trends in 3-D treatment planning. External beam radiation therapy is one of the arms of cancer treatment. In the recent years 3-D conformal therapy had significant impact on the practice of external beam radiation therapy. Conformal radiation therapy shapes the high-dose volume so as to conform to the target volume while minimizing the dose to the surrounding normal tissues. The advances that have been achieved in conformal therapy are in part due to the development of 3-D treatment planning, which in turn has capitalized on 3-D imaging for tumor and normal tissue localization, as well as on available computational power for the calculation of 3-D dose distributions, visualization of anatomical and dose volumes, and numerical evaluation of treatment plans. In this course we will give an overview of how 3-D conformal treatments are designed and transferred to the patient. Topics will include: 1) description of the major components of a 3-D treatment planning system, 2) techniques for designing treatments, 3) evaluation of treatment plans using dose distribution displays, dose-volume histograms and normal tissue complication probabilities, 4) implementation of treatments using shaped blocks and multileaf collimators, 5) verification of treatment delivery using portal films and electronic portal imaging devices. We will also discuss some current and future trends in 3-D treatment planning, such as field shaping with multileaf collimation, computerized treatment plan optimization, including the use of nonuniform beam profiles (intensity modulation), and incorporating treatment uncertainties due to patient positioning errors and organ motion into treatment planning process

  18. Conformal consistency relations for single-field inflation

    International Nuclear Information System (INIS)

    Creminelli, Paolo; Noreña, Jorge; Simonović, Marko

    2012-01-01

    We generalize the single-field consistency relations to capture not only the leading term in the squeezed limit — going as 1/q 3 , where q is the small wavevector — but also the subleading one, going as 1/q 2 . This term, for an (n+1)-point function, is fixed in terms of the variation of the n-point function under a special conformal transformation; this parallels the fact that the 1/q 3 term is related with the scale dependence of the n-point function. For the squeezed limit of the 3-point function, this conformal consistency relation implies that there are no terms going as 1/q 2 . We verify that the squeezed limit of the 4-point function is related to the conformal variation of the 3-point function both in the case of canonical slow-roll inflation and in models with reduced speed of sound. In the second case the conformal consistency conditions capture, at the level of observables, the relation among operators induced by the non-linear realization of Lorentz invariance in the Lagrangian. These results mean that, in any single-field model, primordial correlation functions of ζ are endowed with an SO(4,1) symmetry, with dilations and special conformal transformations non-linearly realized by ζ. We also verify the conformal consistency relations for any n-point function in models with a modulation of the inflaton potential, where the scale dependence is not negligible. Finally, we generalize (some of) the consistency relations involving tensors and soft internal momenta

  19. Residual gas analysis

    International Nuclear Information System (INIS)

    Berecz, I.

    1982-01-01

    Determination of the residual gas composition in vacuum systems by a special mass spectrometric method was presented. The quadrupole mass spectrometer (QMS) and its application in thin film technology was discussed. Results, partial pressure versus time curves as well as the line spectra of the residual gases in case of the vaporization of a Ti-Pd-Au alloy were demonstrated together with the possible construction schemes of QMS residual gas analysers. (Sz.J.)

  20. Conformational changes of the amyloid beta-peptide (1-40) adsorbed on solid surfaces

    NARCIS (Netherlands)

    Giacomelli, CE; Norde, W

    2005-01-01

    The conformational change of the 39-43 residues of the amyloid beta-peptide (A beta) toward a beta-sheet enriched state promotes self-aggregation of the peptide molecules and constitutes the major peptide component of the amyloid plaques in Alzheimer patients. The crucial question behind the

  1. Conformational changes of the amyloid beta-peptide (1-40) adsorbed on solid surfaces

    NARCIS (Netherlands)

    Giacomelli, C.E.; Norde, W.

    2005-01-01

    The conformational change of the 39-43 residues of the amyloid beta -peptide (A beta) toward a beta -sheet enriched state promotes self-aggregation of the peptide molecules and constitutes the major peptide component of the amyloid plaques in Alzheimer patients. The crucial question behind the

  2. Clinical Applications of 3-D Conformal Radiotherapy

    Science.gov (United States)

    Miralbell, Raymond

    Although a significant improvement in cancer cure (i.e. 20% increment) has been obtained in the last 2-3 decades, 30-40% of patients still fail locally after curative radiotherapy. In order to improve local tumor control rates with radiotherapy high doses to the tumor volume are frequently necessary. Three-dimensional conformal radiation therapy (3-D CRT) is used to denote a spectrum of radiation planning and deliver