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Eke I.,OncoRay National Center for Radiation Research in Oncology | Dickreuter E.,OncoRay National Center for Radiation Research in Oncology | Cordes N.,OncoRay National Center for Radiation Research in Oncology | Cordes N.,National Center for Radiation Research And Technology
Radiotherapy and Oncology | Year: 2012

Purpose: Integrin-mediated adhesion to extracellular matrix (ECM) contributes to the regulation of the cellular radiation response in various tumor entities. To evaluate whether targeting of β1 integrin enhances the radiosensitivity of head and neck SCC cell lines (HNSCC) was assessed using either inhibitory anti-β1 integrin antibodies or specific β1 integrin small interfering RNA (siRNA). Materials and methods: The HNSCC cell lines FaDu, UTSCC15 and UTSCC14 were used. Upon β1 integrin inhibition, colony formation, proliferation, DNA double strand breaks, adhesion, and migration as well as protein expression and phosphorylation of integrin downstream targets like Focal Adhesion Kinase and AKT were determined. Results: We found that siRNA- and antibody-mediated targeting of β1 integrin result in a dose- and cell line-dependent radiosensitization that was accompanied by a decreased cell proliferation and an increased number of radiogenic DNA double strand breaks. Analysis of signal transduction events revealed a dephosphorylation of focal adhesion proteins, prevention of radiation-induced phosphorylation of pro-survival protein kinases and impaired cell adhesion and migration upon blocking of β1 integrins. Conclusions: Our data suggest that β1 integrin critically contributes to the cellular radioresistance of HNSCC. Further studies are warranted to evaluate whether targeting β1 integrin emerges as novel approach to improve radiotherapy patients' outcome. © 2012 Elsevier Ireland Ltd. All rights reserved.


Saki M.,University of Tübingen | Toulany M.,University of Tübingen | Sihver W.,Helmholtz Center Dresden | Zenker M.,Helmholtz Center Dresden | And 6 more authors.
Strahlentherapie und Onkologie | Year: 2012

Purpose. Anti-EGFR antibody cetuximab (C225) is used in combination with radiotherapy of head and neck squamous cell carcinoma (HNSCC) patients. We investigated whether conjugation of cetuximab with trans-cyclohexyl-diethylene- triamine-pentaacetic acid (CHX-A''-DTPA) and radiolabeling with 90Yttrium affect the molecular and cellular function of cetuximab and improve its combined effect with external-beam irradiation (EBI).Methods. The following cell lines were used: HNSCC UT5, SAS, FaDu, as well as A43, Chinese hamster ovary cells (CHO), and human skin fibroblast HSF7. Binding affinity and kinetics, specificity, retention, and the combination of 90Y- cetuximab with EBI were evaluated.Results. Control cetuximab and CHX-A''-DTPA-cetuximab blocked the proliferation activity of UT5 cells. In combination with EBI, CHX-A''-DTPA-cetuximab increased the radiosensitivity of UT5 to a similar degree as control cetuximab did. In contrast, in SAS and HSF7 cells neither proliferation nor radiosensitivity was affected by either of the antibodies. Binding [ 90Y]Y-CHX-A''-DTPA-cetuximab ( 90Y-cetuximab) to EGFR in HNSCC cells occurred time dependently with a maximum binding at 24 h. Retention of 90Y-cetuximab was similar in both HNSCC cell lines; 24 h after treatment, approximately 90% of bound activity remained in the cell layer. Competition assays, using cell membranes in the absence of an internalized fraction of cetuximab, showed that the cetuximab affinity is not lost as a result of conjugation with CHX-A''-DTPA. Cetuximab and CHX-A''-DTPA-cetuximab blocked EGF-induced Y1068 phosphorylation of EGFR. The lack of an effect of cetuximab on EGF-induced Akt and ERK1/2 phosphorylation and the inhibition of irradiation (IR)-induced Akt and ERK1/2 phosphorylation by cetuximab were not affected by DTPA conjugation. 90Y-cetuximab in combination with EBI resulted in a pronounced inhibition of colony formation of HNSCC cells.Conclusions. Conjugation of CHX-A''-DTPA to cetuximab does not alter the cellular and biological function of cetuximab. 90Y-labeling of cetuximab in combination with EBI may improve radiotherapy outcome. © Springer-Verlag 2012.


Karsch L.,OncoRay National Center for Radiation Research in Oncology | Pawelke J.,OncoRay National Center for Radiation Research in Oncology
Zeitschrift fur Medizinische Physik | Year: 2014

In ionization chambers, not all released charge is collected due to the recombination of charge carriers. This effect is taken into account by the saturation correction factor kS. A physical description of the correction factor has been established for pulsed radiation. However, it is only accurate when the pulse length is short compared with the collection time of the ionization chamber.In this paper we develop a description of the saturation correction for radiation pulses of arbitrary length. For this, a system of partial differential equations is solved iteratively. The numerical solutions are verified experimentally for a Roos ionization chamber (PTW TM34001) exposed to a pulsed electron beam.The results of this iterative procedure describe the experimental data well. The calculations are also possible for beam structures which are experimentally hard to get and thereby contribute to a better understanding and correct description of the saturation correction at arbitrary pulse length. Among other things the pulse length dependent distributions of the charge carriers in the ionization chamber is calculated, inclusive of the transition to the conditions prevailing in the case of continuous irradiation.Furthermore is shown that the formula for kS established by Hochhäuser and Balk [1] is applicable even at arbitrary pulse length, if pulse duration dependent effective values are used for the parameters a and p. These effective values have been determined for the Roos chamber at pulse lengths up to 300μs. © 2013.


Karsch L.,OncoRay National Center for Radiation Research in Oncology | Richter C.,Helmholtz Center Dresden | Pawelke J.,OncoRay National Center for Radiation Research in Oncology
Zeitschrift fur Medizinische Physik | Year: 2011

In gas-filled ionization chambers as radiation detectors, the collection of the charge carriers is affected by the recombination effect. In dosimetry this effect must be accounted for by the saturation correction factor k S. The physical description of the correction factor by Boag, Hochhäuser and Balk for pulsed radiation is well established. However, this description is only accurate when the pulse length is short compared to the collection time of the ionization chamber. In this work experimental investigations of the saturation correction factor have been made for pulses of 4μs up to pulse doses of about 230 mGy, and the theory of Boag, Hochhäuser and Balk was again confirmed. For longer pulses, however, the correction factor decreases and at a pulse duration of about 200μs reaches 75% of the value valid for short pulses. This reduced influence of the ion recombination is interpreted by the reaction kinetics of ion recombination as a second-order reaction. This effect is negligible for PTW Roos chambers at clinical linear accelerators with 4μs pulse duration for pulse doses up to 120 mGy. © 2010.


Wink K.,Maastricht University | Roelofs E.,Maastricht University | Solberg T.,University of Pennsylvania | Lin L.,University of Pennsylvania | And 8 more authors.
Frontiers in Oncology | Year: 2014

This review article provides a systematic overview of the currently available evidence on the clinical effectiveness of particle therapy for the treatment of NSCLC and summarizes findings of in silico comparative planning studies. Furthermore, technical issues and dosimetric uncertainties with respect to thoracic pa rticle therapy are discussed. © 2014 Wink, Roelofs, Solberg, Lin, Simone_ii, Jakobi, Richter, Lambin and Troost.


Karsch L.,OncoRay National Center for Radiation Research in Oncology
Physics in Medicine and Biology | Year: 2016

Gas-filled ionization chambers are widely used radiation detectors in radiotherapy. A quantitative description and correction of the recombination effects exists for two cases, for continuous radiation exposure and for pulsed radiation fields with short single pulses. This work gives a derivation of a formula for pulsed beams with arbitrary pulse rate for which the prerequisites of the two existing descriptions are not fulfilled. Furthermore, an extension of the validity of the two known cases is investigated. The temporal evolution of idealized charge density distributions within a plane parallel chamber volume is described for pulsed beams of vanishing pulse duration and arbitrary pulse repetition rate. First, the radiation induced release, movement and collection of the charge carriers without recombination are considered. Then, charge recombination is calculated basing on these simplified charge distributions and the time dependent spatial overlap of positive and negative charge carrier distributions. Finally, a formula for the calculation of the saturation correction factor is derived by calculation and simplification of the first two terms of a Taylor expansion for small recombination. The new formula of saturation correction contains the two existing cases, descriptions for exposure by single pulses and continuous irradiation, as limiting cases. Furthermore, it is possible to determine the pulse rate range for which each of the three descriptions is applicable by comparing the dependencies of the new formula with the two existing cases. As long as the time between two pulses is lower than one third of the collection time of the chamber, the formalism for a continuous exposure can be used. The known description for single pulse irradiation is only valid if the repetition rate is less than 1.2 times the inverse collection time. For all other repetition rates in between the new formula should be used. The experimental determination by Jaffe diagrams can be applied for all repetition rates which are not single pulse irradiation but will result in a small deviation from the correct saturation correction value. © 2016 Institute of Physics and Engineering in Medicine.


Iwanowska J.,National Center for Nuclear Research | Swiderski L.,National Center for Nuclear Research | Krakowski T.,National Center for Nuclear Research | Moszynski M.,National Center for Nuclear Research | And 2 more authors.
Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment | Year: 2015

The purpose of this work is to present a measurement method for determining the neutron responses of various liquid organic scintillators using a time-of-flight technique in conjunction with a D-T neutron generator. The method is based on fast-neutron scattering on protons in a liquid-scintillator medium and on the acquisition of the neutron response of the medium as a function of the proton-recoil energy. This method can be applied to all scintillators that utilize fast-neutron elastic scattering. © 2015 Elsevier B.V.


PubMed | OncoRay National Center for Radiation Research in Oncology
Type: Evaluation Studies | Journal: Zeitschrift fur medizinische Physik | Year: 2014

In ionization chambers, not all released charge is collected due to the recombination of charge carriers. This effect is taken into account by the saturation correction factor kS. A physical description of the correction factor has been established for pulsed radiation. However, it is only accurate when the pulse length is short compared with the collection time of the ionization chamber. In this paper we develop a description of the saturation correction for radiation pulses of arbitrary length. For this, a system of partial differential equations is solved iteratively. The numerical solutions are verified experimentally for a Roos ionization chamber (PTW TM34001) exposed to a pulsed electron beam. The results of this iterative procedure describe the experimental data well. The calculations are also possible for beam structures which are experimentally hard to get and thereby contribute to a better understanding and correct description of the saturation correction at arbitrary pulse length. Among other things the pulse length dependent distributions of the charge carriers in the ionization chamber is calculated, inclusive of the transition to the conditions prevailing in the case of continuous irradiation. Furthermore is shown that the formula for kS established by Hochhuser and Balk is applicable even at arbitrary pulse length, if pulse duration dependent effective values are used for the parameters a and p. These effective values have been determined for the Roos chamber at pulse lengths up to 300 s.


PubMed | Nottinghamshire Healthcare NHS Trust, Lawson Health Research Institute, OncoRay National Center for Radiation Research in Oncology and University of Nottingham
Type: | Journal: NeuroImage | Year: 2016

Repetitive transcranial magnetic stimulation (rTMS) has been used worldwide to treat depression. However, the exact physiological effects are not well understood. Pathophysiology of depression involves crucial limbic structures (e.g. insula), and it is still not clear if these structures can be modulated through neurostimulation of surface regions (e.g. dorsolateral prefrontal cortex, DLPFC), and whether rTMS-induced excitatory/inhibitory transmission alterations relate to fronto-limbic connectivity changes. Therefore, we sought proof-of-concept for neuromodulation of insula via prefrontal intermittent theta-burst stimulation (iTBS), and how these effects relate to GABAergic and glutamatergic systems. In 27 healthy controls, we employed a single-blind crossover randomised-controlled trial comparing placebo and real iTBS using resting-state functional MRI and magnetic resonance spectroscopy. Granger causal analysis was seeded from right anterior insula (rAI) to locate individualized left DLPFC rTMS targets. Effective connectivity coefficients within rAI and DLPFC were calculated, and levels of GABA/Glx, GABA/Cr and Glx/Cr in DLPFC and anterior cingulate voxels were also measured. ITBS significantly dampened fronto-insular connectivity and reduced GABA/Glx in both voxels. GABA/Glx had a significant mediating effect on iTBS-induced changes in DLPFC-to-rAI connectivity. We demonstrate modulation of the rAI using targeted iTBS through alterations of excitatory/inhibitory interactions, which may underlie therapeutic effects of rTMS, offering promise for rTMS treatment optimization.


PubMed | OncoRay National Center for Radiation Research in Oncology
Type: Journal Article | Journal: Medical physics | Year: 2016

Gas-filled ionization chambers are the most important radiation detectors in radiotherapy. The collected charge at the electrodes does not represent the total released charge due to the unavoidable recombination processes. This needs to be considered for precise dose measurements. A quantitative description and correction of the recombination effects is established for two cases: continuous radiation exposure and pulsed radiation fields of single pulses with vanishing pulse duration. This work derives formulas for calculating the saturation correction for pulsed beams of nonvanishing pulse duration.Recursive formulas are derived describing the spatio-temporal development of the charge density distributions in plane-parallel ionization chambers starting at neglected recombination. Pulse duration dependent effective chamber parameters are calculated, by comparing the coefficients of a series expansion for small recombination effects. These parameters are used afterward in the known formula for the saturation correction factor for pulsed irradiation with increased recombination effects which was established with the assumption of vanishing pulse duration.The formulas should be valid for pulse durations shorter than half the collection time of the chamber. They allow calculating the saturation correction factor for pulsed beams of nonvanishing pulse duration and arbitrary pulse dose, if chamber, beam, and filling gas parameters are known. The filling gas parameters could be determined from experimental data. The calculation results are in good agreement with already published experimental and simulated results for a Roos chamber.The new formulas can be applied to determine the expected saturation correction for pulsed beams of different pulse duration and pulse dose including new beams at accelerators of new technologies. More experimental validation by using other chambers and an extension of the new formalism to pulse durations longer than half the collection time of the chamber is desired.

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