Publications Repository - Helmholtz-Zentrum Dresden-Rossendorf

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31844 Publications
Impact of tumour hypoxia and cancer stem cells on loco-regional control after primary radiochemotherapy in locally advanced HNSCC – results of a multicentre biomarker study of the German Cancer Consortium radiation Oncology Group
Linge, A.; Lohaus, F.; Löck, S.; Gudziol, V.; Nowak, A.; von Neubeck, C.; Tinhofer, I.; Budach, V.; Sak, A.; Stuschke, M.; Balermpas, P.; Rödel, C.; Avlar, M.; Grosu, A. L.; Abdollahi, A.; Debus, J.; Bayer, C.; Belka, C.; Pigorsch, S.; Combs, S. E.; Mönnich, D.; Zips, D.; Baretton, G. B.; Buchholz, F.; Baumann, M.; Krause, M.;
  • Abstract in refereed journal
    Oncology Research and Treatment 39(2016)Suppl.1, 22-23

Publ.-Id: 25150 - Permalink


Tumour volume, hypoxia and cancer stem cells as prognosticators for LRC after primary RCT in HNSCC
Linge, A.; Lohaus, F.; Löck, S.; Gudziol, V.; Nowak, A.; von Neubeck, C.; Tinhofer, I.; Budach, V.; Sak, A.; Stuschke, M.; Balermpas, P.; Rödel, C.; Avlar, M.; Grosu, A. L.; Abdollahi, A.; Debus, J.; Belka, C.; Pigorsch, S.; Combs, S. E.; Mönnich, D.; Zips, D.; Baretton, G. B.; Buchholz, F.; Baumann, M.; Krause, M.;

Publ.-Id: 25149 - Permalink


Fullerene Derivatives as Nano-Additives in Polymer Composites
Penkova, A. V.; Acquah, S. F. A.; Piotrovskiy, L. B.; Markelov, D.; Semisalova, A.; Kroto, H. W.;
Since their discovery, fullerenes have become one of the most recognizable molecules in science. The “beautiful molecule” described by Sir Harold Kroto has been subtly referenced in movie, and has adorned the covers of many science-based textbooks. The physical and chemical properties of fullerenes have generated a lot of interest in the science community with many opportunities to develop new avenues for scientific research. However, the difficulties in the commercial use of fullerenes, such as C60, have likely been due to issues with solubility. Fortunately, the situation has improved over the last decade with research into fullerene derivatives. Once modified, fullerenes may have applications in a variety of areas, including medicine, drug delivery, optoelectronics, and electrochemistry. The addition of low concentrations of carbon nanoparticles to polymer matrices may result in significant changes in the function of polymer-based composite materials.
This review will highlight the applications of fullerene derivatives as nano-additives for polymer composites. In this review, fullerene derivatives, such as water-soluble carbon nanoclusters (hydroxyl and carboxyl groups), and hydrophobic fullerenes, such as metallofullerenes and methanofullerenes, will be evaluated in regards to their potential impact on commercial applications, such as photovoltaic devices, fuel cells, membrane technology and biocompatible electroactive actuators.
Keywords: Fullerene, photovoltaic, sensor, antioxidant, catalyst

Publ.-Id: 25148 - Permalink


Comparison of machine-learning methods for predictive radiomic models in locally advanced HNSCC
Leger, S.; Bandurska-Luque, A.; Pilz, K.; Zöphel, K.; Baumann, M.; Troost, E. G. C.; Löck, S.; Richter, C.;

Publ.-Id: 25147 - Permalink


Hypoxie und Krebsstammzellmarker als Biomarker für die Radio(chemo)therapie von Kopf-Hals Plattenepithelkarzinomen
Krenn, C.; Linge, A.; Lohaus, F.; Löck, S.; Baumann, M.; Krause, M.;
  • Abstract in refereed journal
    Strahlentherapie und Onkologie 192(2016)Suppl.1, 121-122

Publ.-Id: 25146 - Permalink


beta1-Integrin/c-Abl Interaktion reguliert DNA Reparatur und Strahlensensibilität humaner Tumorzellen
Koppenhagen, P.; Dickreuter, E.; Cordes, N.;
  • Abstract in refereed journal
    Strahlentherapie und Onkologie 192(2016)Suppl.1, 39

Publ.-Id: 25145 - Permalink


Discoidin Domain Receptor 1 targeting impairs GBM cell invasion and mediates radiochemosensitization by induction of autophagy
Klapproth, E.; Vehlow, A.; Cordes, N.;
  • Abstract in refereed journal
    European Journal of Cancer 61(2016)Suppl.1, S160-S161

Publ.-Id: 25144 - Permalink


DDR1 reguliert Radiochemosensitivität sowie Invasivität humaner Glioblastomzellen
Klapproth, E.; Vehlow, A.; Cordes, N.;
  • Abstract in refereed journal
    Strahlentherapie und Onkologie 192(2016)Suppl.1, 42-43

Publ.-Id: 25143 - Permalink


A Bayesian network model for acute dysphagia prediction in NSCLC patients
Jochems, A. T. C.; Deist, T. M.; Troost, E. G. C.; Dekker, A.; Faivre-Finn, C.; Oberije-Dehing, C.; Lambin, P.;
  • Abstract in refereed journal
    Radiotherapy and Oncology 119(2016)Suppl.1, S118-S119

Publ.-Id: 25142 - Permalink


Re-Mining - Ressourcen aus Bergbauhalden
Büttner, P.; Gutzmer, J.;
Beitrag zum Tagungsband zur Veranstaltung "Economic Governance und Ordonomik 2016", welche in Halle im Festsaals des Siedehauses des Technischen Halloren- und Salinemuseums stattgefunden hat und auf der die Ergbnisse zum Projekt SMSB (Re-Mining) in einem Vortrag präsentiert wurden.
Keywords: Re-Mining, Halden, Tailings, Ressourcentechnologie, Resource, Rohstoffe, 3D-Model, GOCAD, Exploration, Processing, Aufbereitung, Erzgebirge, Tiefenbachhalde, Spülhalde, Davidschacht, Zero waste
  • Book chapter
    in: Economic Governance und Ordonomik: Die Nutzung von Ressourcen - mehr als eine ökonomische Fragestellung, Halle-Wittenberg: SPEEG, 2016, 978-3-86829-870-3, 213-225

Publ.-Id: 25141 - Permalink


Targeting of beta1 integrins compromises DNA damage repair for radiosensitization of head and neck cancer cells
Dickreuter, E.; Eke, I.; Krause, M.; Borgmann, K.; van Vugt, M.; Cordes, N.;
  • Abstract in refereed journal
    European Journal of Cancer 61(2016)Suppl.1, S1

Publ.-Id: 25140 - Permalink


Integration of 7T MRI into image-guided radiotherapy of glioblastoma: a feasibility study
Compter, I.; Peerlings, J.; Eekers, D. B. P.; Postma, A. A.; Ivanov, D.; Wiggins, C.; Kubben, P.; Küsters, B.; Wesseling, P.; Ackermans, L.; Schijns, O. E. M. G.; Lambin, P.; Hoffmann, A. L.;
  • Abstract in refereed journal
    Radiotherapy and Oncology 119(2016)Suppl.1, S867-S868

Publ.-Id: 25139 - Permalink


Re-Mining – Gewinnung strategischer Metalle und anderer Mineralien aus sächsischen Bergbauhalden
Büttner, P.; Gutzmer, J.;
Ein wichtiges Ziel des SMSB Projektes war es Technologien für eine möglichst effiziente und wirtschaftliche Aufbereitung strategischer Metalle und Mineralien aus Bergbauhalden mit besonders hohem Rohstoffpotential zu entwickeln. Dafür wurden verschiedene Ansätze gewählt. Es Zunächst wurde das beinhaltete Rohstoffpotential ausgewählter Haldenkörper durch Bohrungen und umfassende mineralogische und chemische Analytik konkretisiert. Dann wurden Versuche zur chemischen und biologischen Laugung an Haldenmaterial durchgeführt, aber auch moderne mechanische Aufbereitungsverfahren auf ihre Anwendbarkeit getestet. Mithilfe der nachgeschalteten Metallurgie wurden die gewonnenen Konzentrate weiter untersucht und Metalle aus diesen extrahiert. Auf die Versuche und Ergebnisse zur Aufbereitung sowie der Metallurgie wird in diesem Beitrag nicht näher eingegangen. Die Ergebnisse sind im SMSB Abschlussbericht zu finden. Aus den Resultaten von SMSB wurde ein Kataster der zwanzig bedeutendsten sächsischen Bergbauhalden erstellt. Diese Informationen wurden gemeinsam mit den Ergebnissen von zwei weiteren r³-Projekten, den Projekten ROBEHA mit Fokus Harz und ReStrateGIS mit Fokus Saarland, Ruhrgebiet und Thüringen zusammengeführt. Dabei wurde ein gemeinsames Haldenkataster erzeugt. Weiterhin wurden die Methoden zur Charakterisierung, Erkundung und Aufbereitung der Halden zusammengetragen und in einem gemeinsamen Methodenhandbuch zusammengestellt. Einige dieser Ergebnisse werden in diesem Beitrag vorgestellt.
Keywords: Re-Mining, Halden, Tailings, Ressourcentechnologie, Resource, Rohstoffe, 3D-Model, GOCAD, Exploration, Processing, Aufbereitung, Erzgebirge, Tiefenbachhalde, Spülhalde, Davidschacht
  • Book chapter
    in: Mineralische Nebenprodukte und Abfälle, Band 3, Berlin: TK Verlag Karl J. Thomé-Kozmiensky, 2016, 978-3-944310-28-2, 383-393
  • Invited lecture (Conferences)
    Berliner Konferenz mineralische Nebenprodukte und Abfälle, 20.-21.06.2016, Berlin, Germany
  • Invited lecture (Conferences)
    1st Workshop Goiano de Terras Raras, 23.-25.05.2016, Catalao, Brasil
  • Invited lecture (Conferences)
    EIT Raw Materials Brookerage Event "ReMining and process residues", 18.-19.01.2016, Berlin, Germany
  • Invited lecture (Conferences)
    Economic Governance und Ordonomik: Die Nutzung von Ressourcen - mehr als eine ökonomische Fragestellung, 17.-19.02.2016, Halle, Germany

Publ.-Id: 25138 - Permalink


SMSB - Gewinnung strategischer Metalle und Mineralien aus sächsischen Bergbauhalden
Büttner, P.; Osbahr, I.; Luhmer, R.; Pilz, C.; Uhlig, S.; Leißner, T.; Pätzold, C.; Scheel, M.; Jahns, C.; Martin, M.; Gutzmer, J.;
Projektbericht über das Projekt SMSB - Gewinnung strategischer Metalle und Mineralien aus sächsischen Bergbauhalden. Das Projekt SMSB hatte zum Ziel, die zwanzig größten Metallerzbergbauhalden Sachsens zu erfassen und in einem Kataster zusammenzufügen. Die Davidschachthalde in Freiberg und die Tiefenbachhalde in Altenberg wurden als zwei Flotations-Rückstandshalden mit besonders hohem Wertstoffpotenzial identifiziert durch jeweils 10 Bohrungen im Detail erkundet. Aus den Bohrkernen wurden insgesamt 207 Proben entnommen und ihr Stoffbestand mit verschiedenen chemischen und mineralogischen Analyseverfahren quantifiziert. Weiterhin wurden an dem gewonnen Probenmaterial verschiedene Aufbereitungsverfahren im Labormaßstab getestet. Diese Versuche hatten das Ziel, geeignete Technologien für das Abtrennen von Wertstoffen aus dem Haldenmaterial zu identifizieren. Resultate belegen, dass sich die Tiefenbachhalde insbesondere durch hohe Gehalte an Zinn, die Davidschachthalde dagegen durch hohe Konzentrationen von Indium, Blei und Zink auszeichnen. Das Zinn in der Tiefenbachhalde ist durch ein einziges Oxidmineral (Kassiterit) vertreten, während die Wertstoffe in der Davidschachthalde an eine komplexe Vergesellschaftung von Sulfiden gebunden sind. Arsen – in der Form von Arsenopyrit – ist das einzige wesentliche Schadelement in dem Material der Tiefenbachhalde. In den Rückständen der Davidschachthalde dagegen sind die Schadstoffe Arsen und Cadmium sehr eng mit den Wertstoffen assoziiert, oft vertreten in den gleichen Erzmineralien. Aufbereitungstests belegen, dass Wert- und Schadstoffe aus der Spülhalde Davidschacht sehr effizient durch biologische Laugung mobilisiert und entfernt werden können, für die Tiefenbachhalde wurde dagegen die Flotation als geeignete Aufbereitungstechnologie identifiziert.Anhand der gewonnenen Daten und erzielten Versuchsergebnisse wurden für die beiden Halden dreidimensionale Ressourcenpotenzial-Modelle erstellt, die auf Kombinationen von gewichteten aufbereitungsrelevanten Parametern fußen. Die einzelnen Parameter haben einen Einfluss darauf, wie effizient eine gewählte Aufbereitungstechnologie auf das vorhandene Haldenmaterial wirken kann.
Keywords: Re-Mining, SMSB, Resource, Freiberg, Tailings, Processing, GOCAD, 3D-Model, INTRA r³+, Resource Technology, Halden, Tiefenbachhalde, Spülhalde, Davidschacht, Aufbereitung, Exploration
  • Book chapter
    in: Innovative Technologien für Ressourceneffizienz - Strategische Metalle und Mineralien, Stuttgart: Fraunhofer Verlag, 2016, 978-8396-1102-9, 345-360

Publ.-Id: 25137 - Permalink


Biomarker für die individualisierte Strahlentherapie
Linge, A.; Lohaus, F.; Löck, S.; Krause, M.; Baumann, M.;
  • Book chapter
    Karl-Jürgen Wolf, Wolfram Knapp, Thomas Herrmann: Strahlenforschung in der Medizin – Relevanz und Perspektiven, Nova Acta Leopoldina - Neue Folge Band 121 Nummer 406, Stuttgart: Wissenschaftliche Verlagsgesellschaft, 2016, 333-344

Publ.-Id: 25136 - Permalink


The Role of Cancer Stem Cells in Tumour Radioresponse
Linge, A.; Dubrovska, A.; Baumann, M.; Krause, M.;
  • Book chapter
    Anscher, M.S., Valerie, K.: Strategies to Enhance the Therapeutic Ratio of Radiation as a Cancer Treatment, Switzerland: Springer International Publishing, 2016, 43-74

Publ.-Id: 25135 - Permalink


FMISO as a Biomarker for Clinical Radiation Oncology
Zschaeck, S.; Steinbach, J.; Troost, E. G. C.;
  • Book chapter
    Baumann, M.; Krause, M.; Cordes, N.: Molecular Radio-Oncology, Volume 198 of the series Recent results in Cancer Research,, Berlin Heidelberg: Springer Verlag, 2016, 189-201

Downloads:

Publ.-Id: 25134 - Permalink


Ambidextrous Idea Generation-Antecedents and Outcomes
Gurtner, S.; Reinhardt, R.;
Ambidexterity, defined as the capability to develop both incremental and radical innovations, is an important driver of firm success. Idea generation is an essential starting point for both types of innovation. Therefore, this study investigates whether ambidextrous idea generation, defined as the capability to actively generate both incremental and radical ideas, affects new product development (NPD) success. Analyses on the Comparative Performance Assessment Study (CPAS) data, which includes data from 453 companies distributed over 24 countries, demonstrate that ambidextrous idea generation does indeed affect NPD program success. Consequently, this study also investigates which antecedents foster ambidextrous idea generation. The innovation paradox concept predicts that achieving ambidexterity requires overcoming paradoxical antecedents. Therefore, we tested whether combinations of financial and breakthrough orientations (the paradox of strategic emphasis), a formal innovation process and an innovation culture (the paradox of innovation drivers), tight and loose customer coupling (the paradox of customer orientation), and internal development and external collaboration (the paradox of openness) affects ambidextrous idea generation. The results show that only customer orientation and openness have the expected inverted u-shaped effect. These finding are in line with construal level theory, which predicts that the organizational characteristics that influence idea-generation activity must be at the same construal level to have the desired effect. The contribution of this study is twofold. First, the analyses indicate that ambidextrous idea generation has significant repercussions for the entire NPD program. Second, the results show that resolving innovation paradoxes only has an effect if the construal level of the paradox and the activity match. This finding indicates an important boundary condition for the innovation paradox concept.

Publ.-Id: 25133 - Permalink


Fate of Plutonium Released from a Former Nuclear Weapons Test in Australia
Ikeda-Ohno, A.ORC; Mokhber-Shahin, L.; Howard, D. L.; Collins, R. N.; Payne, T. E.; Johansen, M. P.
A series of the British nuclear weapons tests conducted between 1953 and 1963 at the southeast area of the Great Victoria Desert, South Australia (Fig. 1(a)), dispersed long-lived and radioactive nuclear debris including plutonium (Pu). A reliable assessment of the environmental impact of these radioactive contaminants and their potential implications for human health requires an understanding of their physical/chemical characteristics at the molecular scale. This study focuses on the physical/chemical characterisation of the Pu contaminant, the most problematic radioactive contaminant remaining at the former testing sites, by synchrotron-based X-ray microscopy / spectroscopy.
The Pu legacy samples investigated in this study were collected at one of the former testing sites, the Taranaki site at Maralinga (Fig. 1(b)). The collected soil samples were physically sieved several times and further fractionated by heavy liquid density separation to isolate a small particle with significantly high radioactivity. The isolated particles were then transported to the X-ray fluorescence microscopy (XFM) beamline at the Australian Synchrotron. The X-ray fluorescence mapping indicates that the particle forms an inhomogeneous core-shell structure composed of a concentrated Pu core coated by the external layer containing Ca, Fe and U.1 This suggests that most of the Pu within the particle is currently unavailable for interaction with the environment, but the bioavailability of Pu could be potentially increased in the future when the particle morphology is further changed by the surface weathers. These findings also highlight the importance of the comprehensive characterization of radioactive contaminants for reliable environmental- and radiotoxicological assessment.
Keywords: actinides, plutonium, environmental radioactivity, radioactive contaminants, nuclear weapons tests, X-ray fluorescence microscopy, X-ray absorption spectroscopy, synchrotron
  • Lecture (Conference)
    Actinides 2017, 10.-14.07.2017, Sendai, Japan

Publ.-Id: 25132 - Permalink


Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation
Tinhofer, I.; Budach, V.; Saki, M.; Konschak, R.; Niehr, F.; Jöhrens, K.; Weichert, W.; Linge, A.; Lohaus, F.; Krause, M.; Neumann, K.; Endris, V.; Sak, A.; Stuschke, M.; Balermpas, P.; Rödel, C.; Avlar, M.; Grosu, A. L.; Abdollahi, A.; Debus, J.; Belka, C.; Pigorsch, S.; Combs, S. E.; Mönnich, D.; Zips, D.; Baumann, M.; DKTK-ROG;
Background
Despite clear differences in clinical presentation and outcome, squamous cell carcinomas of the head and neck (SCCHN) arising from human papilloma virus (HPV) infection or heavy tobacco/alcohol consumption are treated equally. Next-generation sequencing is expected to reveal novel targets for more individualised treatment.

Patients and methods
Tumour specimens from 208 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity, all uniformly treated with adjuvant cisplatin-based chemoradiation, were included. A customised panel covering 211 exons from 45 genes frequently altered in SCCHN was used for detection of non-synonymous point and frameshift mutations. Mutations were correlated with HPV status and treatment outcome.

Results
Mutational profiles and HPV status were successfully established for 179 cases. HPV– tumours showed an increased frequency of alterations in tumour suppressor genes compared to HPV+ cases (TP53 67% versus 4%, CDKN2A 18% versus 0%). Conversely, HPV+ carcinomas were enriched for activating mutations in driver genes compared to HPV– cases (PIK3CA 30% versus 12%, KRAS 6% versus 1%, and NRAS 4% versus 0%). Hotspot TP53 missense mutations in HPV– carcinomas correlated with an increased risk of locoregional recurrence (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.5–12.1, P = 0.006) and death (HR 2.2, 95% CI 1.1–4.4, P = 0.021). In HPV+ SCCHN, driver gene mutations were associated per trend with a higher risk of death (HR 3.9, 95% CI 0.7–21.1, P = 0.11).

Conclusions
Distinct mutation profiles in HPV– and HPV+ SCCHN identify subgroups with poor outcome after adjuvant chemoradiation. Mutant p53 and the phosphoinositide 3-kinase pathway were identified as potential druggable targets for subgroup-specific treatment optimisation.
Keywords: Head and neck cancer; Human papilloma virus; Mutation profiles; Adjuvant chemoradiation; Cisplatin

Publ.-Id: 25131 - Permalink


A Compton camera prototype for prompt gamma medical imaging
Thirolf, P. G.; Aldawood, S.; Böhmer, M.; Bortfeldt, J.; Castelhano, I.; Dedes, G.; Fiedler, F.; Gernhäuser, R.; Golnik, C.; Helmbrecht, S.; Hueso-González, F.; von D. Kolff, H.; Kormoll, T.; Lang, C.; Liprandi, S.; Lutter, R.; Marinšek, T.; Maier, L.; Pausch, G.; Petzoldt, J.; Römer, K.; Schaart, D.; Parodi, K.;
Compton camera prototype for a position-sensitive detection of prompt γ rays from proton-induced nuclear reactions is being developed in Garching. The detector system allows to track the Comptonscattered electrons. The camera consists of a monolithic LaBr3:Ce scintillation absorber crystal, read out by a multi-anode PMT, preceded by a stacked array of 6 double-sided silicon strip detectors acting as scatterers. The LaBr3:Ce crystal has been characterized with radioactive sources. Online commissioning measurements were performed with a pulsed deuteron beam at the Garching Tandem accelerator and with a clinical proton beam at the OncoRay facility in Dresden. The determination of the interaction point of the photons in the monolithic crystal was investigated.

Publ.-Id: 25130 - Permalink


The impact of CDK9 on radiosensitivity, DNA damage repair and cell cycling of HNSCC cancer cells
Storch, K.; Cordes, N.;
Cyclin-dependent kinase 9 (CDK9), mainly involved in regulation of transcription, has recently been shown to impact on cell cycling and DNA repair. Despite the fact that CDK9 has been proposed as potential cancer target, it remains largely elusive whether CDK9 targeting alters tumor cell radiosensitivity. Five human head and neck squamous cell carcinoma (HNSCC) cell lines (SAS, FaDu, HSC4, Cal33, UTSCC5) as well as SAS cells stably transfected with CDK9-EGFP-N1 plasmid or empty vector controls were used. Upon either CDK9 small interfering RNA knockdown or treatment with a pan-CDK inhibitor (ZK304709), colony formation, DNA double strand breaks (DSBs), apoptosis, cell cycling, and expression and phosphorylation of major cell cycle and DNA damage repair proteins were examined. While CDK9 overexpression mediated radioprotection, CDK9 depletion clearly enhanced the radiosensitivity of HNSCC cells without an induction of apoptosis. While the cell cycle and cell cycle proteins were significantly modulated by CDK9 depletion, no further alterations in these parameters were observed after combined CDK9 knockdown with irradiation. ZK304709 showed concentration-dependent cytotoxicity but failed to radiosensitize HNSCC cells. Our findings suggest a potential role of CDK9 in the radiation response of HNSCC cells. Additional studies are warranted to clarify the usefulness to target CDK9 in the clinic.

Publ.-Id: 25129 - Permalink


ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.
Offersen, B. V.; Boersma, L. J.; Kirkove, C.; Hol, S.; Aznar, M. C.; Sola, A. B.; Kirova, Y. M.; Pignol, J.-P.; Remouchamps, V.; Verhoeven, K.; Weltens, C.; Arenas, M.; Gabrys, D.; Kopek, N.; Krause, M.; Lundstedt, D.; Marinko, T.; Montero, A.; Yarnold, J.; Poortmans, P.;

Publ.-Id: 25128 - Permalink


Independent validation of the prognostic value of cancer stem cell marker expression and hypoxia-induced gene expression for patients with locally advanced HNSCC after postoperative radiotherapy
Linge, A.; Löck, S.; Krenn, C.; Appold, S.; Lohaus, F.; Nowak, A.; Gudziol, V.; Baretton, G. B.; Buchholz, F.; Baumann, M.; Krause, M.;
Objective

To validate the impact of HPV status, cancer stem cell (CSC) marker expression and tumour hypoxia status in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received postoperative radiotherapy. The results of the exploration cohort have previously been reported by the German Cancer Consortium Radiation Oncology Group (DKTK-ROG; Lohaus et al., 2014; Linge et al., 2016).

Materials and methods

For 152 patients with locally advanced HNSCC the impact of HPV16 DNA status, CSC marker expression and hypoxia-associated gene signatures on outcome of postoperative radiotherapy were retrospectively analysed. Out of them, 40 patients received postoperative radiochemotherapy. Cox models presented in a previous study were validated using the concordance index as a performance measure. The primary endpoint of this study was loco-regional control. Results were compared to those previously reported by DKTK-ROG.

Results

Loco-regional control, freedom from distant metastases and overall survival were inferior to the previously reported cohort. Despite of this, the prognostic value of the combination of HPV infection status, CSC marker expression (SLC3A2) and tumour hypoxia status could be validated in univariate analyses using an independent validation cohort. For multivariate models, the concordance index was between 0.58 and 0.69 in validation, indicating a good prognostic performance of the models. The inclusion of CD44 and the 15-gene hypoxia signature moderately improved the performance compared to a baseline model without CSC markers or hypoxia classifiers.

Conclusions

The HPV status, CSC marker expression of CD44 and SLC3A2 as well as hypoxia status are potential prognostic biomarkers for patients with locally advanced HNSCC treated by postoperative radiotherapy.
Keywords: Biomarker; Cancer stem cells; HNSCC; HPV; Hypoxia; Postoperative radiochemotherapy; Validation

Publ.-Id: 25127 - Permalink


Clinical trials for personalized glioblastoma radiotherapy: Markers for efficacy and late toxicity but often delayed treatment – Does that matter?
Lattermann, A.; Baumann, M.; Krause, M.;

Publ.-Id: 25126 - Permalink


Targeting of β1 integrins impairs DNA repair for radiosensitization of head and neck cancer cells
Dickreuter, E.; Eke, I.; Krause, M.; Borgmann, K.; van Vugt, M. A.; Cordes, N.;
β1 Integrin-mediated cell–extracellular matrix interactions allow cancer cell survival and confer therapy resistance. It was shown that inhibition of β1 integrins sensitizes cells to radiotherapy. Here, we examined the impact of β1 integrin targeting on the repair of radiation-induced DNA double-strand breaks (DSBs). β1 Integrin inhibition was accomplished using the monoclonal antibody AIIB2 and experiments were performed in three-dimensional cell cultures and tumor xenografts of human head and neck squamous cell carcinoma (HNSCC) cell lines. AIIB2, X-ray irradiation, small interfering RNA-mediated knockdown and Olaparib treatment were performed and residual DSB number, protein and gene expression, non-homologous end joining (NHEJ) activity as well as clonogenic survival were determined. β1 Integrin targeting impaired repair of radiogenic DSB (γH2AX/53BP1, pDNA-PKcs T2609 foci) in vitro and in vivo and reduced the protein expression of Ku70, Rad50 and Nbs1. Further, we identified Ku70, Ku80 and DNA-PKcs but not poly(ADP-ribose) polymerase (PARP)-1 to reside in the β1 integrin pathway. Intriguingly, combined inhibition of β1 integrin and PARP using Olaparib was significantly more effective than either treatment alone in non-irradiated and irradiated HNSCC cells. Here, we support β1 integrins as potential cancer targets and highlight a regulatory role for β1 integrins in the repair of radiogenic DNA damage via classical NHEJ. Further, the data suggest combined targeting of β1 integrin and PARP as promising approach for radiosensitization of HNSCC.

Publ.-Id: 25125 - Permalink


Bridging the valley of death: The new Radiotherapy & Oncology section “First in man - Translational innovations in radiation oncology.”
Baumann, M.; Overgaard, J.;

Publ.-Id: 25124 - Permalink


Potential modeling with uncertain covariables
Schaeben, H.; Tolosana Delgado, R.; van den Boogaart, K. G.;
Published potential mapping procedures usually presume that the covariables are known.
However, covariables are usually interpolated by kriging. In sparsely covered regions reported covariables can seriously differ from the actual situation on the ground. When regressing to the mean we often nd the variation of covariables underestimated, leading to an overestimation of dependence. Similar effects can be observed when the fitted model is applied to prediction: The potential seems promising, but is underestimated in sparsely observed regions.
In earlier publications it has been shown that a Cox regression model is more general than weights of evidence methods, and also independent of a grid with a user defined resolution.
Therefore our investigation is based on this model class. Here we compare four different estimation procedures for Cox regression models: (i) the pseudolikelihood method put forward by Baddeley, (ii) a numerical solution of the full Maximum Likelihood approach based on kriged covariables, (iii) an approximation of the full Maximum Likelihood approach based on the conditional distribution of the covariables, and (iv) the MCMC based Bayesian solution.
The first two methods neglect the uncertainty of the covariables, the latter two account for it. For simulated examples with known true parameters we can show a substantial decrease of estimation errors when the uncertainty is considered.
It can be shown that the estimation error reported by the methods neglecting the uncertainty of covariables seriously underestimates the actual uncertainty of the parameter estimate.
Keywords: Exploration, Potential Modelling, Metropolis Hastings, Markov Chain Monte Carlo Method for geostatistical data
  • Lecture (Conference)
    18th Annual Conference IAMG2017, 03.-09.09.2017, Perth, Australia

Publ.-Id: 25123 - Permalink


Model based multiple point statistics and training model estimation
van den Boogaart, K. G.; Tolosana Delgado, R.; Ortiz, J.;
We would like to put the workflows of two point geostats and multi point geostatistics in a common framework of model estimation, model selection, algorithmic parameter selection and than finally simulation and prediction. This workflow is well established in to point geostats. In this contribution we extend it to multi point geostatistics. In this way we can improve the performance by better choices for the all method parameters.
Two point geostatistics typically puts three decisions ahead of each estimation or simulation: Based on the observations we choose a variogram model, estimate its parameters, and select a kriging neighbourhood to weigh between computational speed and algorithmic accuracy.
For Multiple Point statistics simulation methods we typically provide all knowledge about the spatial dependence by a fixed training image. Three different ways for generating training images have been proposed: Real maps or 3D models of the phenomenon, constructed images capturing our knowledge, and realisations of random field models. The random field model used for the simulation could be understood as our model of the distribution of the random field we would like to interpolate. The simulation of the training image and the following multiple point simulation is an imperfect numerical algorithm computing the conditional distribution based on that model. Just like two point geostatistics it again has the patterns as algorithmic parameters describing a geostatistical neighbourhood.
Like with variogram models, for any more complicated random fields models, we have model parameters. Depending on them different sets of observations will have different likelihoods. I.e. like with classical variogram estimation we can estimate the model parameters from the observations. As the likelihoods are typically not computable and variogram based methods can only capture two point dependences, we propose a quasilikelihood based multi point approach for the estimation of these parameters. Analog to variogram model comparison we also propose cross validation based methods to check the fit of the model and the performance of the simulation algorithm on the model. In analogy to the selection of search neighbourhood the simulation performance of the algorithm can be checked against the model.
Keywords: Nonlinear Geostatistics, Training models, Training Images, Parameter Estimation
  • Contribution to proceedings
    18th Annual Conference IAMG2017, 03.-09.09.2017, Perth, Australia
    Proceedings of IAMG2017

Publ.-Id: 25122 - Permalink


Block Predictions of Compositional Data with high order geostatistics
Tolosana Delgado, R.; Talebi, H.; Mueller, U.; van den Boogaart, K. G.;
Block kriging of compositional data is a challenge even in the case of classical linear statistics. Compositional kriging is not unbiased with respect to the quantity used additively in block integration. Classical block kriging can leave the compositional simplex. Compositional data cannot directly be integrated in a block, when the material density varies within the block. For full compositions the density might be a function of the composition. For subcomposition it is typically still correlated. In a previous publication we developed a geostatistical block prediction of compositional data relying on the additive lognormal property of the compositional random field. This assumption is however not always met. Especially in case of multiple facies, we see bimodal distributions leading to substantially different distribution of block values. Due to the non lognormality of the residuals typical lognormal kriging type bias corrections are not appropriate.
For this situation we propose to apply conditional distribution based type of multiple point geostatistics. Based on a training image or a training model, we generate joint dataset of the observations of the block integral value incorporating all relevant corrections (like density correction). The conditional distribution is described by a very general version of a generalized linear model for the conditional distribution. The parameters of this regression model are estimated from the training dataset. Compositional, Euclidean expected values can be computed from the resulting prediction.
The method has the following properties: The Expected difference of true value and prediction is 0. The method provides the full conditional distribution. Not only the mean, but more selected nonlinear functionals can be predict on average correct from the conditional distribution. Due to its underlying Baysian nature the method can in principle outperform averages over conditional simulations with mps or ordinary kriging.

Keywords: Block Kriging, Conditional Distribution, Geostatistik
  • Lecture (Conference)
    18th Annual Conference of the International Association for Mathematical Geoscience - IAMG 2017, 03.-09.09.2017, Perth, Australia

Publ.-Id: 25121 - Permalink


Shining light on the beauty of f-electron systems: principles and perspectives of X-ray spectroscopy
Kvashnina, K. O.;
Investigations of the electronic structure of different systems have been the subject of continuous research efforts over the last 100 years. Parallel to the technical developments and experimental discoveries, the theoretical models, describing the observed phenomena, have advanced. The challenges arise in the studies of exotic systems, where the most extraordinary behaviors need to be understood in detail. To improve our understanding, we search for the most extreme experimental methods, testing strange combinations of theoretical approximations; there are still many questions that remain unknown. This is the case of f-electron systems.

The aim of this HDR thesis is to demonstrate the applicability of X-ray spectroscopy for determining the electronic structure of f-electron systems, and to show the importance of theoretical simulations in understanding the experimental results. Special attention has been paid to the high-energy resolution fluorescence detection (HERFD) X-ray absorption near edge structure (XANES), X-ray emission spectroscopy (XES) and resonant inelastic X-ray scattering (RIXS) methods. It is shown here that a combination of high-quality experimental data and theoretical calculations can provide unprecedented detailed information about the electronic structure of actinide and lanthanide systems
  • Other
    Univerisite Grenoble Alpes (UGA), 2017
    Mentor: Andreas Scheinost

Publ.-Id: 25120 - Permalink


Resonant x-ray spectroscopy of uranium intermetallics at the U M4,5 edges
Kvashnina, K. O.; Walker, H. C.; Magnani, N.; Lander, G. H.; Caciuffo, R.;
We present resonant x-ray emission spectroscopic (RXES) data from the uranium intermetallics UPd3, USb, USn3 and URu2Si2 at the U M4,5 edges and compare the data to those from the well-localized 5f2 semiconductor UO2. The technique is especially sensitive to any oxidation of the surface, and this was found on the USb sample, thus preventing a good comparison with a material known to be 5f3. We have found a small energy shift between UO2 and UPd3, both known to have localized 5f2 configurations, which we ascribe to the effect of conduction electrons in UPd3. The spectra from UPd3 and URu2Si2 are similar, strongly suggesting a predominant 5f2 configuration for URu2Si2. The valence-band resonant inelastic x-ray scattering (RIXS) provides information on the U P3 transitions (at about 18 eV) between the U 5f and U 6p states, as well as transitions of between 3 and 7 eV from the valence band into the unoccupied 5f states. These transitions are primarily involving mixed ligand states (O 2p or Pd, Ru 4d) and U 5f states. Calculations are able to reproduce both these low-energy transitions reasonably well.

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Publ.-Id: 25118 - Permalink


Polyphenols delivery by polymeric materials: challenges in cancer treatment.
Vittorio, O.; Curcio, M.; Cojoc, M.; Goya, G.; Hampel, S.; Iemma, F.; Dubrovska, A.; Cirillo, G.;
Nanotechnology can offer different solutions for enhancing the therapeutic efficiency of polyphenols, a class of natural products widely explored for a potential applicability for the treatment of different diseases including cancer. While possessing interesting anticancer properties, polyphenols suffer from low stability and unfavorable pharmacokinetics, and thus suitable carriers are required when planning a therapeutic protocol. In the present review, an overview of the different strategies based on polymeric materials is presented, with the aim to highlight the strengths and the weaknesses of each approach and offer a platform of ideas for researchers working in the field.
Keywords: Nanocarrier, polyphenols, cancer therapy, polymeric materials

Publ.-Id: 25117 - Permalink


Nanoparticles for radiooncology: Mission, vision, challenges.
Kunz-Schughart, L.; Dubrovska, A.; Peitzsch, C.; Ewe, A.; Aigner, A.; Schellenburg, S.; Muders, M.; Hampel, S.; Cirillo, G.; Iemmae, F.; Tietze, R.; Alexiou, C.; Stephan, H.; Zarschlerg, K.; Vittorio, O.; Kavallaris, M.; Parak, W.; Mädler, L.; Pokhrel, S.;
Cancer is one of the leading non-communicable diseases with highest mortality rates worldwide. About half of all cancer patients receive radiation treatment in the course of their disease. However, treatment outcome and curative potential of radiotherapy is often impeded by genetically and/or environmentally driven mechanisms of tumor radioresistance and normal tissue radiotoxicity. While nanomedicine-based tools for imaging, dosimetry and treatment are potential keys to the improvement of therapeutic efficacy and reducing side effects, radiotherapy is an established technique to eradicate the tumor cells. In order to progress the introduction of nanoparticles in radiooncology, due to the highly interdisciplinary nature, expertise in chemistry, radiobiology and translational research is needed. In this report recent insights and promising policies to design nanotechnology-based therapeutics for tumor radiosensitization will be discussed. An attempt is made to cover the entire field from preclinical development to clinical studies. Hence, this report illustrates (1) the radio- and tumor-biological rationales for combining nanostructures with radiotherapy, (2) tumor-site targeting strategies and mechanisms of cellular uptake, (3) biological response hypotheses for new nanomaterials of interest, and (4) challenges to translate the research findings into clinical trials.
Keywords: Flame spray pyrolysis; Magnetic particles; Nanoparticles; Radiooncology; Radiosensitizers; Radiotherapy

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Publ.-Id: 25116 - Permalink


Epigenetic targeting therapy for tumor radiosensitization
Schniewind, I.; Peitzsch, C.; von Neubeck, C.; Baumann, M.; Krause, M.; Dubrovska, A.;
Introduction: A malignant tumor is composed of a hierarchically organized, heterogeneous pool of cells in various stages of differentiation including cancer stem cells (CSCs) as the main cell population responsible for tumor initiation, growth and relapse as well as for metastasis formation and therapy resistance. Preliminary work of our group showed that photon irradiation of prostate cancer cells induces an augmentation of the CSC population that can be attributed to an epigenetic reprogramming of non-CSCs into CSCs. The combination of the histone methyltransferase EZH2 inhibitor 3-Deazaneplanocin A (DZNep) with x-ray irradiation leads to a radiosensitization and prevention of the cellular reprogramming of prostate cancer cells in vitro, in vivo and in ex vivo treated primary prostate cancer samples.

Objectives: The aim of this study is (1) the investigation of potential radiosensitizing effects of epigenetic inhibitors for different tumor entities including prostate cancer, head and neck squamous cell carcinoma (HNSCC) and glioblastoma multiforme (GBM); (2) a high throughput screening (HTS) using a chemical library with epigenetic targeting substances to identify novel epigenetic targeting agents for tumor radiosensitization and (3) the correlation of radiation-induced CSC and epigenetic markers after photon versus 150MeV proton irradiation to identify biomarkers for a personalized proton therapy.

Methods: Evaluation of the cytotoxicity (MTT-Assay, CellTiterGlo®-Assay), radiosensitivity (colony formation assay), DNA repair capacity (γH2AX foci assay), CSC marker expression (Flow cytometry) and histone modifications (Western blot) for prostate cancer (DU145, PC3), HNSCC (FaDu, Cal33) and GBM (LN229, U87MG) cell lines using different clinically relevant epigenetic modulators in combination with irradiation.

Results: Our results show that epigenetic marks including histone modifications are modulated after ionizing radiation in the different tumor entities including prostate cancer, HNSCC and GBM and that treatment with some epigenetic inhibitors leads to the radiosensitization of cancer cells. Furthermore, we found differences in CSC marker expression and epigenetic modulation after photon versus proton irradiation.

Conclusion: Epigenetic targeting therapy may be useful as a co-therapy strategy to prevent tumor cell reprogramming and promote radiosensitization of the different tumor entities. Moreover, CSC and histone mark-based biomarkers can be potentially used as predictive markers for a personalized radiotherapy.
Keywords: epigenetics, radioresistance, DNA repair
  • Contribution to proceedings
    23. DEGRO-Jahrestagung 2017, 15.-18.02.2017, Berlin, Deutschland
    Strahlentherapie und Onkologie 193, S182
  • Abstract in refereed journal
    Strahlentherapie und Onkologie 193(2017), S182-S183
    DOI: 10.1007/s00066-017-1137-6

Publ.-Id: 25115 - Permalink


CD98hc a potential biomarker for therapy outcome and a putative therapeutical target for radiosensitization of head and neck squamous cell carcinoma
Digomann, D.; Kurth, I.; Linge, A.; Hein, L.; Heiden, S.; Baumann, M.; Dubrovska, A.;
Retrospective analyses of CSC-related biomarkers followed by prospective validation studies in patients with locally advanced HNSCC are currently being performed in an ongoing multicentre retrospective – prospective trial conducted by the Radiation Oncology Group of the German Cancer Consortium (DKTK-ROG) For the patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with a curatively intended cisplatin-based postoperative radiochemotherapy or primary radiochemotherapy, the expression level of SLC3A2 (Solute Carrier Family 3 member 2), a putative cancer stem cell marker was positively correlated with poor locoregional control in locally advanced (HNSCC) [1, 2].
The human gene SLC3A2 encodes the heavy chain of CD98; a ~125 kDa heterodimeric L-type amino acid transporter. CD98hc also interacts with integrin β subunit and has a putative role in regulating integrin signaling, which controls cell proliferation, survival, migration, and epithelial adhesion [3].
The aim of this study is to elucidate the potential role of stem cell marker CD98hc in regulation of the HNSCC radiosensitivity.
The expression levels of CD98 in nine HNSCC cell lines measured by western blot analysis and flow cytometry were positively correlated with their respective in vivo tumor control dose 50 (TCD50) values (ref). An increase of CD98hc expression was also detected by Western blotting in the radioresistant derivatives of the established HNSCC cells as compared to their parental counterparts. In addition, expression of CD98hs was induced in the parental HNSCC cells after single dose irradiation of HNSCC cells with 4Gy of X-ray.
To analyze a functional role of CD98hc in the regulation of HNSCC radioresistance, SLC3A2 (gene of CD98hc) was knocked down via siRNA in Cal33, Fadu, UT5 and SAS cells, which then were subjected to the radiobiological colony formation assays. A knockdown of SLC3A2 in HNSCC cells followed by irradiation decreased the capability for colony formation compared to the cells transfected with scrambled siRNA.
For further in vitro and in vivo experiments, cell lines with a low CD98hc level were established using CRISPR/Cas9 technology. Off-targets were reduced using a modified CRISPR/Cas9-variant that was confirmed by PCR and sequencing experiments.
In addition, a recombinant neutralizing antibody against CD98hc is currently tested as possible CD98hc targeted and radiosensitizing therapy.
Finally, publicly available TCGA-gene dataset for HNSCC patients treated with and without radiotherapy was used to analyze a potential correlation of SLC3A2 expression with expression of other genes and clinical outcome of the HNSCC patients.
The results support the hypothesis that CD98hc is playing a role in the regulation of HNSCC radioresistance. In the future CD98hc may be used as a prognostic marker and become a potential target for combined radiochemotherapy in locally advanced HNSCC.

References:
[1] Linge, A., Lock, S., Gudziol, V., Nowak, A., Lohaus, F., von Neubeck, C., Jutz, M., Abdollahi, A.,
Debus, J., Tinhofer, I., et al. (2016). Low CSC marker expression and low hypoxia identify good
prognosis subgroups in HPV(-)HNSCC after postoperative radiochemotherapy: a multicenter study
of the DKTK-ROG. Clin. Cancer Res.
[2]. https://www.ncbi.nlm.nih.gov/pubmed/27913065
[3]Cantor, J.M., Ginsberg, M.H., 2012. CD98 at the crossroads of adaptive immunity and cancer. J Cell Sci 125, 1373–1382. doi:10.1242/jcs.096040
Keywords: CD98, HNSCC, Radioresistance
  • Contribution to proceedings
    DEGRO Akademie: 26. Symposium Experimentelle Strahlentherapie und Klinische Strahlenbiologie, 09.-11.02.2017, Universitätsklinikum Tübingen, Deutschland
  • Abstract in refereed journal
    Strahlentherapie und Onkologie 192(2016)Suppl.1, 124

Publ.-Id: 25114 - Permalink


CD98hc as a potential marker of radioresistance in head and neck squamous cell carcinoma
Digomann, D.; Kurth, I.; Linge, A.; Löck, S.; Koi, L.; Hein, L.; Heiden, S.; Krause, M.; Baumann, M.; Dubrovska, A.;
Background: CD98hc protein is encoded by the SLC3A2 (solute carrier family 3 member 2) gene. CD98hc contributes to the amino acid transport and regulation of the integrin signaling pathway, and is a putative marker of cancer stem cells (CSCs). Recent retrospective analyses showed a correlation of high SLC3A2 expression with poor locoregional control in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with a curatively intended cisplatin-based postoperative radiochemotherapy or primary radiochemotherapy. The aim of this study is the investigation of potential molecular mechanisms of action of CD98hc as a regulator of HNSCC radioresistance. Methods: The expression levels of CD98 in nine HNSCC cell lines were measured by Western blot analysis and correlated with corresponding tumor control dose 50 (TCD50) values. The fractions of plasma membrane proteins from Cal33 and FaDu cells and their radioresistant sublines established by fractionated irradiation with a total dose of ≥50Gy of X-rays were enriched by differential centrifugation and quantitatively analyzed by tandem mass spectrometry. To determine the role of SLC3A2 in the regulation of cell radioresistance, HNSCC cell lines and their respective irradiated sublines were transfected with SLC3A2 siRNAs and analysed by 2D and/or 3D radiobiological clonogenic assays after X-ray irradiation. The CRISPR/Cas9 system was used for the stable monoallelic knock-out of SLC3A2 in HNSCC cells. The efficiency of DNA repair after irradiation was examined by γH2A.X foci analysis. The Cancer Genome Atlas (TCGA) gene dataset for HNSCC patients treated with and without radiotherapy was used to analyse a potential correlation of SLC3A2 expression with expression of other genes and with clinical outcome of the HNSCC patients. Results and Discussion: The data of proteomic profiling, the results of Western blot analysis correlated to TCD50 values, the functional assessment of the SLC3A2 knockdown and knockout cells along with analysis of the TCGA datasets confirmed a connection between the CD98hc expression level and the cancer cell radiosensitivity in vitro and in vivo. These results support the hypothesis that CD98hc is a regulator of HNSCC radioresistance. The ongoing experimental studies will reveal if CD98hc may be used as potential target for HNSCC radiosensitization.
Keywords: CD98, HNSCC, radioresistance
  • Contribution to proceedings
    The 15th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology, 17.-19.06.2017, CH-8272 Ermatingen, Switzerland

Publ.-Id: 25113 - Permalink


Interaktion von Stammzelleigenschaften und DNA Reparatur bestimmen die strahlensensitivierende Wirkung nach Inhibition von CHK1, RAD51 und PARP1 in TNBCs
Meyer, F.; Becker, S.; Niecke, A.; Werner, S.; Peitzsch, C.; Hein, L.; Dubrovska, A.; Goy, Y.; Parplys, A.; Petersen, C.; Riepen, B.; Zielinski, A.; Rothkamm, K.; Borgmann, K.;
Fragestellung: Das Mammakarzinom fasst eine heterogene Gruppe von Tumoren zusammen von denen etwa 20% als Triple-negativ (TNBC) bezüglich des Rezeptorstatus bezeichnet werden. Wichtige Parameter und therapeutische Angriffspunkte der TNBC Biologie sind eine hohe Proliferationsaktivität, ein Basal-artiger und mesenchymaler Phänotyp und ein Defekt im DNA Reparaturweg Homologe Rekombination (HR) welcher eine erhöhte chromosomale Instabilität dieser Tumore begünstigt. TNBCs weisen darüber hinaus eine Anreicherung von Tumorstammzellen und Therapieresistenz auf. Ziel des Projektes ist es Strategien unter gleichzeitiger Ausnutzung von HR-Defizienz und Stammzelleigenschaften durch spezifische Inhibition zur Intensivierung der Therapie weiter zu entwickeln. Dies wurde für die Inhibition von RAD51-, CHK1- und PARP1 nach Bestrahlung untersucht. Dafür wurde eine TNBC-Zelllinie (MDA-231 WT), zwei isogenen Sublinien, die präferentiell in Knochen (-SA) und Gehirn (-BR) metastasieren im Vergleich zu einer luminalen Zelllinie (MCF7) eingesetzt.
Methodik: In MDA-MB-231 WT/BR/SA und MCF7-Zellen wurde die Expression bezüglich HR (RAD51, BRCA1, PTEN, CHK1, MRE11, ATR, ATM) und Stammzelleigenschaften (ZEB1, E-Cadherin, ß-Catenin, ALDH1) charakterisiert, HR mittels RAD51-Foci, MMC-Sensitivität und Reporterplasmiden eingeordnet, Replikationsprozesse analysiert und die Migrationsfähigkeit überprüft. Strahlenempfindlichkeit wurde unter Gabe verschiedener Inhibitoren im Kolonietest dokumentiert und mit der Metabric Datenbank (952 TNBC) hinsichtlich des chromosomalen Instabilitätsindex (CIN) korreliert.
Ergebnisse: Es zeigten sich klare Unterschiede in der Expression von Reparaturproteinen, mit einem Anstieg von CHK1, MRE11 und ATM in BR und SA. Beide Linien zeigten Stammzell-übliche Expressionsprofile, entsprechend eine stärkere Migrationsfähigkeit und in der SA Linie eine verbesserte HR (2,5-fach), Resistenz gegen MMC (IC50 von 1,6µg/ml im Vergleich zu 0,75µg/ml in BR und 2,1 µg/ml in SA) und geringere DNA Schäden (0,75-fach). Nach Bestrahlung zeigte sich kein Überlebensvorteil für BR und SA. Dies deutet darauf hin, dass nicht HR, sondern übergeordnet CHK1-vermittelte Prozesse für die Strahlenempfindlichkeit verantwortlich sind. Bestätigt wird dies durch die deutliche Strahlensensitivierung nach CHK1i, wobei die strahlenresistenteste Linie sich am stärksten sensitivieren ließ, mit VF von 3. Dies spiegelt sich auch in den Replikationsprozessen wieder, je sensitiver, desto stärker inhibiert. Momentan wird der Einfluss weiterer Inhibitoren auf die zelluläre Strahlenempfindlichkeit überprüft. Topkandidat ist RAD51i, da in einer Metabric-Analyse TNBC mit hohem CIN, also besonders aggressiven Tumoren, RAD51 und CHK1 deutlich stärker exprimiert werden als in TNBCs mit niedrigem CIN.
Schlussfolgerung: Eine veränderte Expression von HR-Proteinen und ein Stammzell-artiger Phänotyp hängen eng zusammen und determinieren gemeinsam die Therapieresistenz.
Keywords: Mammakarzinom, Homologe Rekombination (HR), DNA Reparaturweg
  • Contribution to proceedings
    DEGRO Akademie: 26. Symposium Experimentelle Strahlentherapie und Klinische Strahlenbiologie, 09.-11.02.2017, Universitätsklinikum Tübingen, Deutschland
    Abstracts DEGRO 2017. Strahlenther Onkol(2017) (Suppl) 193:S1–S194
    DOI: 10.1007/s00066-017-1137-6

Publ.-Id: 25112 - Permalink


Glutamine metabolism as potential target for prostate cancer radiosensitization
Tyutyunnykova, A.; Chen, O.; Richter, S.; Eisenhofer, G.; Toma, M.; Hein, L.; Novotny, V.; Zschaeck, S.; Wirth, M.; Kunz-Schughart, L.; Krause, M.; Baumann, M.; Peitzsch, C.; Dubrovska, A.;
Background: A major reprogramming of cellular energy metabolism is a hallmark of tumor cells. In addition to an increased glucose uptake, highly proliferative cancer cells require additional supplies for their biosynthesis and energy production such as glutamine. Glutaminolysis also contributes to the ROS scavenging and activation of the pro-survival signaling pathways. Tumors with enhanced MYC expression, such as prostate cancer have a particularly high demand for glutamine. Herein, we investigated the role of glutamine metabolism pathways for prostate cancer radioresistance. Methods: Prostate cancer cell lines DU145, PC3, LNCaP and their radioresistant sublines (RR) were analyzed by metabolomic and gene expression profiling. The relative cell sensitivity to the inhibition of glutaminolysis was measured by analysis of viability (MTT), apoptosis and necrosis (flow cytometry and Western blotting), levels of ROS and glutathione (flow cytometry), radiosensitivity (colony formation assay, CFA), DNA repair (γH2A.X foci) and tumorigenicity in mice. Primary cell cultures from 12 tumor biopsies and matched benign tissues from prostates cancer patients were characterized by radiobiological 3D CFA and by gene expression profiling, and relative radioresistance was correlated with expression levels of the genes regulating glutaminolysis. The Cancer Genome Atlas (TCGA) datasets were analyzed for correlation of the gene expression levels and patients outcome. Results: Glutaminolysis is upregulated in RR cells, where glutamine is mostly used for production of α-ketoglutarate, which is involved in ROS scavenging and epigenetic resetting by regulation of the histone methylation, whereas α-ketoglutarate utilization for Krebs cycle is suppressed. Deprivation of glutamine or siRNA mediated inhibition of glutaminolysis leads to the induction of endoplasmic reticulum (ER) stress and inhibition of the DNA repair, clonogenicity and in vivo tumorigenicity after irradiation with a more pronounced effect for RR cells. Analysis of the TCGA datasets revealed that a high expression of the genes regulating prostate cancer glutaminolysis is significantly associated with a decrease in relapse free survival after radiotherapy. Discussion: Prostate cancer cell radioresistance is associated with alterations of glutaminolysis, whose inhibition increases the cytotoxic effects of radiation in prostate tumor cells. Expression of the proteins involved in glutaminolysis can be potentially used to predict clinical outcome after radiation therapy.
Keywords: cancer stem cells, radioresistance, glutamine metabolism, prostate cancer
  • Contribution to proceedings
    The 15th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology, 17.-19.06.2017, CH-8272 Ermatingen, Switzerland

Publ.-Id: 25111 - Permalink


Interplay of DNA repair and stem-like phenotype determines the sensitizing effect of CHK1, RAD51 and PARP1 inhibition in TNBC
Meyer, F.; Becker, S.; Niecke, A.; Riepen, B.; Zielinski, A.; Werner, S.; Peitzsch, C.; Hein, L.; Dubrovska, A.; Wikman, H.; Windhorst, S.; Goy, Y.; Parplys, A.; Petersen, C.; Rothkamm, K.; Borgmann, K.;
Breast cancer comprises a heterogeneous group of tumors of whom 20% are categorized as triple-negative (TNBC). Important biological characteristics and potential therapeutic targets of TNBC include high proliferation, a basal-like and mesenchymal phenotype and a defect in the DNA repair pathway Homologous Recombination (HR), which feeds the observed elevated chromosomal instability in these tumors. TNBCs show an enrichment of cancer stem cells and therapy resistance. This project aims to develop treatment intensification strategies based on the simultaneous exploitation of the HR-deficiency and the stem-like phenotype, using specific inhibitors for RAD51, CHK1 and PARP1 in combination with irradiation.
Expression of HR-related (RAD51, BRCA1, PTEN, CHK1, MRE11, ATR, ATM) and stem-like factors (ZEB1, E-Cadherin, ß-Catenin, ALDH1) as well as HR functionality (via RAD51 foci, MMC-sensitivity and plasmid reporter assay) were determined in the TNBC line MDA-231 WT, its two sublines preferentially metastasizing to brain (BR) or bone (SA) and in the luminal BC line MCF7. DNA replication (fiber assay) and migration assay were also tested. Radiosensitivity and the radiosensitizing effect of different inhibitors was analyzed by colony assay and correlated to the CIN in the METABRIC database.
Distinct differences in the expression of HR-related proteins were observed, with an elevated expression of CHK1, MRE11 and ATM in BR and SA relative to WT and MCF7. BR and SA showed a typical stem cell-like protein expression profile, together with a higher migration capacity, increased HR-capacity, resistance against MMC and less DNA damage. After irradiation no advantage in survival for the BR and SA cell lines was observed, suggesting that not HR, but superordinate CHK1 signaling promotes radioresistance. This was confirmed by a distinct radiosensitization after CHK1i; the most radioresistant WT cell line was most strongly sensitized, by a factor of 3. The extent of sensitization was also linked to the extent of replication inhibition. The effect of other inhibitors on radiosensitivity is currently being investigated. A second promising target is RAD51, because a METABRIC analysis (952 TNBCs) showed that in TNBC with high CIN RAD51 and CHK1 are significantly stronger expressed than in TNBC with low CIN.
In conclusion the results presented here show that DNA repair and a stem-like phenotype collude to determine resistance to tumor therapy of TNBCs with high CIN.
Keywords: Breast cancer, Homologous Recombination, DNA repair
  • Contribution to proceedings
    The 15th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology, 17.-19.06.2017, Ermatingen, Switzerland
    Program 15th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology

Publ.-Id: 25110 - Permalink


Cancer stemness: What is it and why is it important
Dubrovska, A.;
no abstract available
Keywords: cancer stem cells, therapy resistance, metastasis initiating cells

Publ.-Id: 25109 - Permalink


Radiolabeling of nanoparticles as a versatile tool in safety research
Franke, K.; Schymura, S.; Hildebrand, H.;
Identification and quantification of nanoparticulate materials in living and non-living media is mandatory for a thorough nanosafety research. However, the online and in-situ monitoring of nanoparticles in such complex natural systems as soil, natural waters, plants, sewage sludge, etc. is highly challenging, especially at environmentally relevant concentrations. Radiolabeling offers a robust method for these complex studies within a wide range concentration of nanoparticles even in the presence of background concentrations of the respective elements.

Depending on the nature of the nanoparticle and the process of interest we applied different methods for the radiolabeling of common nanoparticles, like the synthesis of the nanoparticles using radioactive starting materials, the binding of the radiotracer to the nanoparticles, the activation of the nanoparticles using proton irradiation, the recoil labeling utilizing the recoil of a nuclear reaction to implant a radiotracer into the nanoparticle, and the in-diffusion of radiotracers into the nanoparticles.

For our recent studies we produced [105Ag]Ag, [110mAg]Ag, [44Ti]TiO2, [45Ti]TiO2, [48V]TiO2, [64Cu]CuS, [64Cu]SiO2, [65Zn]CdSe/ZnS, [124I]CNTs, [125I]CNTs, [131I]CNTs, [7Be]MWCNT, [139Ce]CeO2 and [194Au]Pt nanoparticles (including radiolabeled commercial nanoparticle samples). Due to the choice of the used radionuclide (half-life, decay-mode) and the activity concentrations it was possible to enable different detection methods and time scales for the investigations. All these methods go along with a careful characterization of the radiolabeled nanoparticles in respect of the radiolabeling stability and nanoparticle properties.

The radiolabeled nanoparticles can easily be detected down to ng/L range and have been successfully used in investigations of the uptake of nanoparticles in plants, the distribution and mobility of nanoparticles in sewage sludge, fate of nanoparticles in wastewater treatment processes and in release studies.
Keywords: Radiolabeling Nanoparticle
  • Lecture (Conference)
    5th-International Nuclear Chemistry Congress, 27.08.-01.09.2017, Göteborg, Schweden

Publ.-Id: 25108 - Permalink


Feasibility of proton pencil beam scanning treatment of free-breathing lung cancer patients
Jakobi, A.; Perrin, R.; Knopf, A.; Richter, C.ORC
Background
The interplay effect might degrade the dose of pencil beam scanning proton therapy to a degree that free-breathing treatment might be impossible without further motion mitigation techniques, which complicate and prolong the treatment. We assessed whether treatment of free-breathing patients without motion mitigation is feasible.
Material/Methods
For 40 lung cancer patients, 4DCT datasets and individual breathing patterns were used to simulate 4D dynamic dose distributions of 3D treatment plans over 33 fractions delivered with an IBA universal nozzle. Evaluation was done by assessing under- and overdosage in the target structure using the parameters V90, V95, V98, D98, D2, V107 and V110. The impact of using beam-specific target volumes and the impact of changes in motion and patient anatomy in control 4DCTs were assessed.
Results
Almost half of the patients had tumour motion amplitudes of less than 5mm. Under- and overdosage was significantly smaller for patients with tumour motion below 5mm compared to patients with larger motion (2% versus 13% average absolute reduction of V95, 2% versus 8% average increase in V107, p<0.01). Simulating a 33-fraction treatment, the dose degradation was reduced but persisted for patients with tumour motion above 5mm (average ΔV95 of <1% vs 3%, p<0.01). Beam-specific target volumes reduced the dose degradation in a fractionated treatment, but were more relevant for large motion. Repeated 4DCT revealed that changes in tumour motion during treatment might result in unexpected large dose degradations.
Conclusion
Tumour motion amplitude is an indicator of dose degradation caused by the interplay effect. Fractionation reduces the dose degradation allowing the unmitigated treatment of patients with small tumour motions of less than 5mm. The beam-specific target approach improves the dose coverage. The tumour motion and position needs to be assessed during treatment for all patients, to quickly react to possible changes which might require treatment adaptation.
Keywords: proton therapy, pencil beam scanning, lung cancer, interplay, motion

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Publ.-Id: 25107 - Permalink


Time-of-Flight Telescope for ERDA at the HZDR
Julin, J.ORC; Heller, R.
Elastic Recoil Detection Analysis (ERDA) is a near-surface heavy ion beam based elemental characterization technique, known especially for its suitability for light element analysis of thin films. The elemental composition of an unknown sample can be determined quantitatively in a single measurement, without resorting to the use of standards or information from additional measurements or models.

In the Ion Beam Center (IBC) of the Helmholtz-Zentrum Dresden-Rossendorf a Bragg Ionization Chamber (BIC) based ERDA setup has been operated successfully for many years. In the past there has also been a time-of-flight telescope installed in the same chamber. During 2017 this instrument will be upgraded with new detectors, bringing it up to date with latest experimental developments in the field.

The goal for the project is first and foremost to construct a user-friendly instrument, which can be operated reliably. Special emphasis will be put to the achievable depth resolution, without sacrificing performance in other areas. The instrument can be operated with a relatively broad energy range, with lower incident beam energy (< 10 MeV) enabling high depth resolution (2 nm) near the surface and higher energies, e.g. 20 MeV, enable excellent mass separation and better probing depth for thicker films.

In this contribution we will present the basic idea of the new setup and give some particular details on the design, expected performance and a realization time line.
  • Poster
    Workshop Ionenstrahlphysik, 13.-15.02.2017, Göttingen, Deutschland

Publ.-Id: 25106 - Permalink


Astrophysical S-factor of the 14N(p,γ)15O reaction at 0.4 – 1.3MeV
Wagner, L.; Akhmadaliev, S.; Anders, M.; Bemmerer, D.; Caciolli, A.; Gohl, S.; Grieger, M.; Junghans, A.; Marta, M.; Munnik, F.; Reinhardt, T. P.; Reinicke, S.; Röder, M.; Schmidt, K.; Schwengner, R.; Serfling, M.; Takács, M. P.; Szücs, T.; Vomiero, A.; Wagner, A.; Zuber, K.;
The 14N(p,γ)15O reaction is the slowest reaction of the carbon-nitrogen cycle of hydrogen burning and thus determines its rate. The precise knowledge of its rate is required to correctly model hydrogen burning in asymptotic giant branch stars. In addition, it is a necessary ingredient for a possible solution of the solar abundance problem by using the solar 13N and 15O neutrino fluxes as probes of the carbon and nitrogen abundances in the solar core. After the downward revision of its cross section due to a much lower contribution by one particular transition, capture to the ground state in 15O, the evaluated total uncertainty is still 8%, in part due to an unsatisfactory knowledge of the excitation function over a wide energy range. The present work reports precise S-factor data at twelve energies between 0.357-1.292 MeV for the strongest transition, capture to the 6.79 MeV excited state in 15O, and at ten energies between 0.479-1.202 MeV for the second strongest transition, capture to the ground state in 15O. A simple R-matrix fit is performed to gauge the impact of the new data on astrophysical energies. The recently suggested slight enhancement of the ground state transition at low energy could not be confirmed. The present extrapolated zero-energy S-factors are S679(0) = 1.24±0.11 keVbarn and SGS(0) = 0.19±0.06 keVbarn.
Keywords: Nuclear Astrophysics CNO cycle Hydrogen burning

Publ.-Id: 25105 - Permalink


X-ray Structures of Succinimidyl Halobenzoates
Mamat, C.; Weiss, D.-H.; Köckerling, M.;
The crystal and molecular structures of five succinimidyl halobenzoates are reported. Corresponding derivatives with the respective halo-radionuclide (18F, 76Br, 123I/124I/125I/131I) were prepared and used for the radiolabeling of biologically active (macro-)molecules (peptides, proteins, antibodies) under mild labeling conditions. All compounds crystalized from petroleum ether/ethyl acetate mixtures.
Keywords: building block; radiolabeling; [18F]SFB; SIB; SBrB

Publ.-Id: 25104 - Permalink


Charge Collection Efficiency in a segmented semiconductor detector interstrip region
Alarcon-Diez, V.; Vickridge, I.; Jakšić, M.; Grilj, V.; Schmidt, B.; Lange, H.;
Charged particle semiconductor detectors have been used in Ion Beam Analysis (IBA) for over four decades without great changes in either design or fabrication. However one area where improvement is desirable would be to increase the detector solid angle so as to improve spectrum statistics for a given incident beam fluence. This would allow the use of very low fluences opening the way, for example, to increase the time resolution in real-time RBS or for analysis of materials that are highly sensitive to beam damage. In order to achieve this goal without incurring the costs of degraded resolution due to kinematic broadening or large detector capacitance, a single-chip segmented detector (SEGDET) was designed and built within the SPIRIT EU infrastructure project. In this work we present the Charge Collection Efficiency (CCE) in the vicinity between two adjacent segments focusing on the interstrip zone. Microbeam Ion Beam Induced Charge (IBIC) measurements with different ion masses and energies were used to perform X-Y mapping of (CCE), as a function of detector operating conditions (bias voltage changes, detector housing possibilities and guard ring configuration). We show the (CCE) in the edge region of the active area and have also mapped the charge from the interstrip region, shared between adjacent segments. The results indicate that the electrical extent of the interstrip region is very close to the physical extent of the interstrip and guard ring structure with interstrip impacts contributing very little to the complete spectrum. The interstrip contributions to the spectra that do occur, can be substantially reduced by an offline anti-coincidence criterion applied to list mode data, which should also be easy to implement directly in the data acquisition software.
Keywords: Segmented detector; IBIC; Charge Collection Efficiency; Interstrip

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Publ.-Id: 25103 - Permalink


Effect of glutamic acid on copper sorption onto kaolinite - batch experiments and surface complexation modeling
Karimzadeh, L.; Barthen, R.; Stockmann, M.; Gruendig, M.; Franke, K.; Lippmann-Pipke, J.;
High carbonate content of the European Kupferschiefer ore deposits is a challenge for acid copper leaching (pH ≤ 2). Therefore investigating the mobility behavior of Cu(II) under conditions related to an alternative, neutrophil biohydrometallurgical Cu(II) leaching approach is of interest. As glutamic acid (Glu) might be present as a component in the growth media, we studied its effects on the adsorption of Cu(II) onto kaolinite. The binary and ternary batch sorption measurements of Cu(II) and Glu onto kaolinite were performed in the presence of 10 mM NaClO4 as background electrolyte and at a pH range from 4 to 9. Sorption experiments were modeled by the charge-distribution multi-site ion complexation (CD-MUSIC) model by using single sorption site (≡SOH) and monodentate surface complexation reactions. Glu sorption on kaolinite is weak (<10%) and independent of pH. Furthermore, Glu slightly enhances the Cu(II) sorption at low pH but strongly hinders (up to 50%) the sorption at higher pH and therewith enhances copper mobility. The results of isotherms show that Cu(II)-Glu sorption onto kaolinite mimics the Freundlich model. The proposed CD-MUSIC model provides a close fit to the experimental data and predicts the sorption of Cu(II), Cu(II)-Glu and Glu onto kaolinite as well as the effect of Glu on Cu(II) mobility.
Keywords: Copper mobility, Glutamic acid, Kaolinite, Sorption, Surface complexation modeling

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Publ.-Id: 25102 - Permalink


Provenance of uranium in a sediment core from a natural reservoir, South China: Application of Pb stable isotope analysis
Liu, J.; Luo, X.; Wang, J.; Xiao, T.; Yin, M.; Belshaw, N. S.; Lippold, H.; Kong, L.; Xiao, E.; Bao, Z.; Li, N.; Chen, Y.; Linghu, W.;
As part of ongoing environmental investigations of U mining impacts, forty-two sediment samples of a nearly-half-meter-long sediment core retrieved from a natural reservoir near an active uranium (U) mining site, South China were analyzed to quantify the extent of U release and identify U release mechanism within the riverine catchment. Enrichment levels of U was dispersed not only in the surface sediments but also in deep sediments across the depth profile. Further analysis by SEM-EDS and XRD indicated that U partitioning in the depth profile was possibly controlled by complicated interplay of leaching and precipitation cycles of U-bearing minerals. Even with the relative complexity of U dispersal processes within the catchment, the Pb isotopic fingerprinting techniques allowed quantification of source inputs of the sediments by using a binary mixing model. The results revealed that along the depth profile, only 6%–50% of the sediment material is anthropogenically derived from the U ore tailing, with the other predominant proportions originated from geogenically natural weathering of granitic bedrocks. This study highlights the use of Pb isotopes as a powerful tool for quantitatively fingerprinting the sources of U dispersal in the sediment core, and natural-occurring U contamination that may become a hidden geoenvironmental health hazard in this area.
Keywords: uranium; Pb isotopes; source apportionment; binary mixing; radiogenic

Publ.-Id: 25100 - Permalink


Self-Organized Semiconductor Patterning by Polyatomic Broad Beam Ion Irradiation
Pilz, W.; Bischoff, L.; Böttger, R.; Laufer, P.; Tajmar, M.;
Surface patterning based on self-organized nano-structures on i.e. semiconductor materials formed by heavy mono - and polyatomic ion irradiation from Liquid Metal (Alloy) Ion Sources (LMAIS) is a very promising technique. To overcome the lack of only very small treated areas by applying a Focused Ion Beam (FIB) instrument this technology was transferred into larger single-end ion beam systems like an ion implanter. Main component is an ion beam injector based on high current LMAIS, developed for space propulsion systems combined with suited ion optics allocating ion currents in the µA range in a nearly parallel beam of a few mm in diameter. The mass selection of the needed ion species can be performed either by an introduced ExB mass separator (Wien filter) and/or the existing magnet of the ion implanter itself which also can define the final ion energy up to 200 keV.
Different types of LMAIS (needle, porous emitter, capillary) are presented and characterized. The ion beam injector design is specified as well as the implementation of this module into a high current ion implanter (Danfysik Series 1090) operating at the HZDR Ion Beam Center (IBC). Finally the obtained results of large area surface modification of Ge using Bi2+ polyatomic ions from a GaBi capillary LMAIS at room temperature will be presented and discussed.
Keywords: Self-Organized Patterning; Polyatomic Ions; Broad Beam Ion Irradiation
  • Lecture (Conference)
    Nationales Treffen der deutschen Ionenstrahl-PhysikerInnen und -MaterialwissenschaftlerInnen, 12.-15.02.2017, Göttingen, Germany

Publ.-Id: 25099 - Permalink


Defect-induced magnetism in SiC probed by nuclear magnetic resonance
Zhang, Z. T.; Dmytriieva, D.; Molatta, S.; Wosnitza, J.; Wang, Y.; Helm, M.; Zhou, S.; Kühne, H.;
We give evidence for intrinsic defect-induced bulk paramagnetism in SiC by means of 13C and 29Si nuclear magnetic resonance (NMR) spectroscopy. The temperature dependence of the internal dipole-field distribution, probed by the spin part of the NMR Knight shift and the spectral linewidth, follows the Curie law and scales very well with the macroscopic dc susceptibility. In order to quantitatively analyze the NMR spectra, a microscopic model based on dipole-dipole interactions was developed. The very good agreement between these simulations and the NMR data establishes a direct relation between the frequency distribution of the spectral intensity and the corresponding real-space volumes of nuclear spins. The presented approach by NMR can be applied to a variety of similar materials and, thus, opens a new avenue for the microscopic exploration and exploitation of diluted bulk magnetism in semiconductors.

Publ.-Id: 25098 - Permalink


Thallium contamination in arable soils and vegetables around a steel plant – A newly-found significant source of Tl pollution in South China
Liu, J.; Luo, X.; Wang, J.; Xiao, T.; Chen, D.; Sheng, G.; Yin, M.; Lippold, H.; Wang, C.; Chen, Y.;
Thallium (Tl) is a highly toxic rare element. Severe Tl poisoning can cause neurological brain damage or even death. The present study was designed to investigate contents of Tl and other associated heavy metals in arable soils and twelve common vegetables cultivated around a steel plant in South China, a newly-found initiator of Tl pollution. Potential health risks of these metals to exposed population via consumption of vegetables were examined by calculating hazard quotients (HQ). The soils showed a significant contamination with Tl at a mean concentration of 1.34 mg/kg. The Tl levels in most vegetables (such as leaf lettuce, chard and pak choy) surpassed the maximum permissible level (0.5 mg/kg) according to the environmental quality standards for food in Germany. Vegetables like leaf lettuce, chard, pak choy, romaine lettuce and Indian beans all exhibited bioconcentration factors (BCF) and transfer factors (TF) for Tl higher than 1, indicating a hyperaccumulation of Tl in these plants. Although the elevated Tl levels in the vegetables at present will not immediately pose significant non-carcinogenic health risks to residents, it highlights the necessity of a permanent monitoring of Tl contamination in the steel-making areas.
Keywords: thallium; soil; vegetable; ecological risk; steel plant

Publ.-Id: 25097 - Permalink


Surface science using radioactive ions at ISOLDE: from metal surfaces to 2-dimensional materials
Potzger, K.; Molholt, T. E.; Fenta, A. S.; Pereira, L. M. C.;
We review the research carried out using the apparatus for surface physics and interfaces (ASPIC), at ISOLDE, CERN. We give an overview of the research highlights since 2000, focusing on magnetic and non-magnetic metallic surfaces, and introduce the scientific program that will follow the upgrade which is currently underway, focusing on 2-dimensional materials.
ASPIC was formerly used for the growth of ultrathin metallic films and their characterization by means of perturbed angular correlation spectroscopy. Past research has mainly focused on the determination of the magnetic hyperfine field at the probe atom located on different sites at the surface such as terraces, kinks, steps as well as on the investigation of the static magnetic polarization at the interface between ferromagnetic and paramagnetic layers.
Future research on 2-dimensional materials using ASPIC is foreseen to focus on the investigation of structural and electronic properties of adatoms (adsorption sites, hybridization effects, intra-atomic charge transfer, magnetic moments, etc.). We emphasize, in this context, the exceptional capabilities of ASPIC in terms of broad applicability, high precision and low detection limits.
Keywords: Perturbed angular correlation spectroscopy, nuclear solid state physics

Publ.-Id: 25096 - Permalink


Backward-forward reaction asymmetry of neutron elastic scattering on deuterium
Pirovano, E.; Beyer, R.; Junghans, A. R.; Nankov, N.; Nolte, R.; Nyman, M.; Plompen, A. J. M.;
A new measurement of the angular distribution of neutron elastic scattering on deuterium was carried out at the neutron time-of-flight facility nELBE. The backward-forward asymmetry of the reaction was investigated via the direct detection of neutrons scattered at the laboratory angle of 15◦ and 165◦ from a polyethylene sample enriched with deuterium. In order to extend the measurement to neutron energies below 1 MeV, 6Li glass scintillators were employed. The data were corrected for the background and the multiple scattering in the target, the events due to scattering on deuterium were separated from those due to carbon, and the ratio of the differential cross section at 15◦ and 165◦ was determined. The results, covering the energy range from 200 keV to 2 MeV, were found to be in agreement with the theoretical predictions calculated by Canton et al. [Eur. Phys. J. A 14, 225 (2002)] and by Golak et al. [Eur. Phys. J. A 50, 177 (2014)]. The comparison with the evaluated nuclear data libraries indicated CENDL-3.1, JEFF-3.2, and JENDL-4.0 as the evaluations that best describe the asymmetry of n-d scattering.
ENDF/B-VII.1 is compatible with the data for energies below 700 keV, but above the backward to forward ratio is higher than measured. ROSFOND-2010 and BROND-2.2 resulted to have little compatibility with the data.
Keywords: nELBE, neutron, time-of-flight, elastic scattering, deuterium

Publ.-Id: 25095 - Permalink


Guidelines to Design Electrolytes for Lithium-ion Batteries: Environmental Impact, Physicochemical and Electrochemical Properties
Flamme, B.; Rodriguez-Garcia, G.ORC; Weil, M.; Haddad, M.; Phansavath, P.; Ratovelomanana-Vidal, V.; Chagnes, A.
Electrolytes for lithium-ion batteries (LiBs) have been put aside for too long because few new solvents have been designed to match electrolyte specifications. Conversely, more attention has been paid to synthesize new electrode materials, and more especially positive electrodes. Particularly, most of the studies dedicated to the investigation of electrolytes for LiBs have been focused on mixing different molecules. Nowadays, the development of high-voltage materials for LiBs stimulates the synthesis of new solvents and new salts more stable against oxidation. Despite the challenges, only few teams are active in this field in developing a rational approach combining physicochemistry, electrochemistry and modelling from the molecular to the macromolecular levels. After assembling a critical collection of physicochemical and electrochemical data from the literature, this paper highlights the main trends between the chemical structure of organic dipolar aprotic solvents and their physicochemical and electrochemical properties in order to provide a guide for the chemists to design new electrolytes for LiBs. This guide also includes indicators to take into account the environmental impact of solvent production by including the life cycle assessment of eight different solvents.

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Publ.-Id: 25094 - Permalink


Elastic Moduli in Cadmium Selenide Doped with Chromium
Averkiev, N. S.; Bersuker, I. B.; Gudkov, V. V.; Zhevstovskikh, I. V.; Sarychev, M. N.; Zherlitsyn, S.; Yasin, S.; Korostelin, Y. V.;
Temperature dependence of elastic moduli (C11 − C12 ) / 2 , C33 , and C44, the latter for the piezo-active and non-piezo-active versions, have been measured in the interval of 4 - 180 K at 28 - 262 MHz in a CdSe: Cr2+ crystal. Anomalies below 40 K have been found for all the moduli, except C33 . The interpretation of the results has been carried out involving the Jahn-Teller effect and relaxation between the equivalent distortions of the tetrahedral CrSe4 centers.

Publ.-Id: 25092 - Permalink


On the Interpretation of Principal Balances for Compositional Data Sets
Martin-Fernandez, J. A.; Pawlowsky-Glahn, V.; Egozcue, J. J.; Tolosana-Delgado, R.;
To analyse compositional data (CoDa) sets it is advisable to apply the principle of working on orthonormal coordinates. Sequential Binary Partition (SBP) is a technique to construct an interpretable basis. The provided coordinates are called balances, and they are complemented with a descriptive tool, the CoDa-dendrogram. The goal of a Principal Balances method is to identify an orthonormal basis of the simplex such that the coordinates are balances approaching the properties of principal component analysis (PCA) of CoDa. PCA is one of the main tools for exploratory analysis and modelling of CoDa. However, the main shortcoming of PC's is the difficulty in interpreting the resulting coordinates because a PC is a function of all the original parts. Balances are log-contrasts resulting from a logratio of two geometric means of two groups of parts. Their interpretation is considerably simpler than the interpretation of PC's. The resulting procedures provide tools improving interpretability and intuitive dimension reduction. The algorithm to compute principal balances requires an exhaustive search along all possible sets of orthonormal balances. The consumption of computational time may be considerable for even a small number of parts. Here, to reduce this time, the sets of possible partitions for up to 15 parts is stored. For comparison, two suboptimal, but feasible, algorithms are introduced: (i) searching for balances following a constraint PC's approach; and (ii) a hierarchical cluster analysis of variables based on the Aitchison distance between parts. The properties and performance of these three algorithms are illustrated using a data set of geochemical composition of glacial sediments. Results obtained corroborate the theoretical properties of the methods: they approximate reasonably well the PC's improving the interpretability. However, the price payed is a smaller amount of variance explained by the first balances and the lack of uncorrelation between the coordinates.
  • Poster
    18th Annual Conference IAMG2017, 02.-09.09.2017, Perth, Australia

Publ.-Id: 25091 - Permalink


Ultrafast observation of lattice dynamics in laser-irradiated gold foils
Hartley, N. J.ORC; Ozaki, N.; Matsuoka, T.; Albertazzi, B.; Faenov, A.; Fujimoto, Y.; Habara, H.; Harmand, M.; Inubushi, Y.; Katayama, T.; Koenig, M.; Krygier, A.; Mabey, P.; Matsumura, Y.; Matsuyama, S.; Mcbride, E. E.; Miyanishi, K.; Morard, G.; Okuchi, T.; Pikuz, T.; Sakata, O.; Sano, Y.; Sato, T.; Sekine, T.; Seto, Y.; Takahashi, K.; Tanaka, K. A.; Tange, Y.; Togashi, T.; Umeda, Y.; Vinci, T.; Yabashi, M.; Yabuuchi, T.; Yamauchi, K.; Kodama, R.
We have observed lattice expansion before the onset of compression in an optical-laser-driven target, using diffraction of femtosecond X-ray beams generated by the SACLA X-ray Free Electron Laser. The change in diffraction angle provides a direct measure of the lattice spacing, allowing the density to be calculated with a precision of +-1%. From known equation of state relations this allows estimation of the temperature responsible for the expansion as <1000 K. The subsequent ablation-driven compression was observed with a clear rise in density at later times. This demonstrates the feasibility of studying the dynamics of preheating and shock formation with unprecedented detail.
Keywords: XFEL, Diffraction, Laser-matter interaction

Publ.-Id: 25090 - Permalink


Energy dependence of the electron-boson coupling strength in the electron-doped cuprate superconductor Pr1.85Ce0.15CuO4−δ
Beck, M.; Klammer, M.; Rousseau, I.; Obergfell, M.; Leiderer, P.; Helm, M.; Kabanov, V. V.; Diamant, I.; Rabinowicz, A.; Dagan, Y.; Demsar, J.;
The quest for a pairing boson in cuprate high-temperature superconductors is one of the outstanding Tasks of solid-state physics. Numerous time-resolved studies of pair breaking, related to pairing by time-reversal symmetry, have been performed using femtosecond optical pulses. By considering energy Relaxation pathways between charge, spin, and lattice degrees of freedom, evidence for both phonon and antiferromagnetic fluctuationmediated pairing has been obtained. Here we present a study of the superconducting-state depletion process in an electron-doped cuprate Pr1.85Ce0.15CuO4−δ , where the superconducting gap is smaller than the energy of relevant bosonic excitations. When pumping with above-gap terahertz pulses, we find that the absorbed energy density required to deplete superconductivity, Adep, matches the thermodynamic condensation energy. On the contrary, by near-infrared pumping, Adep is an order of Magnitude higher, as in the case of hole-doped, large-gap cuprates. These results imply that only a small subset of bosons, which are generated during the relaxation of optically excited carriers, contributes to pairing. This observation implies that, contrary to the common assumptions, electron-boson coupling in cuprates is strongly energy dependent.
Keywords: superconductor, terahertz, free electron laser

Publ.-Id: 25089 - Permalink


Field-induced gapless electron pocket in the superconducting vortex phase of YNi2B2C as probed by magnetoacoustic quantum oscillations
Nössler, J.; Seerig, R.; Yasin, S.; Uhlarz, M.; Zherlitsyn, S.; Behr, G.; Drechsler, S.-L.; Fuchs, G.; Rosner, H.; Wosnitza, J.;
By use of ultrasound studies we resolved magnetoacoustic quantum oscillation deep into the mixed state of the multiband nonmagnetic superconductor YNi2B2C. Below the upper critical field, only a very weak additional damping appears that can be well explained by the field inhomogeneity caused by the flux-line lattice in the mixed state. This is clear evidence for no or a vanishingly small gap for one of the bands, namely, the spheroidal α band. This contrasts de Haas–van Alphen data obtained by use of torque magnetometry for the same sample, with a rapidly vanishing oscillation signal in the mixed state. This points to a strongly distorted flux-line lattice in the latter case that, in general, can hamper a reliable extraction of gap parameters by use of such techniques.

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Publ.-Id: 25088 - Permalink


Interatomic coulombic decay - the mechanism for rapid deexcitation of hollow atoms
Wilhelm, R. A.ORC; Gruber, E.; Schwestka, J.; Kozubek, R.; Madeira, T. I.; Marques, J. P.; Kobus, J.; Krasheninnikov, A. V.; Schleberger, M.; Aumayr, F.
The impact of highly charged ions onto a solid gives rise to charge exchange between the ions and target atoms, so that slow ions get neutralized in the vicinity of the surface. Using highly charged Ar and Xe ions and the surface-only material graphene as a target, we show that the neutralization and de-excitation of the ions proceeds on a sub-10 fs time scale. We further demonstrate that a multiple interatomic coulombic decay (ICD) model of highly charged ions can describe the observed ultrafast de-excitation. Other de-excitation mechanisms involving non-radiative decay and quasi- molecular orbitals formation during the impact are not important, as follows from the comparison of our experimental data with the results of first-principles calculations. Our method also enables the estimation of ICD rates directly.
Keywords: slow highly charged ion, HCI, graphene, interatomic coulombic decay, ICD
  • Open Access LogoPhysical Review Letters 119(2017)10, 103401
    DOI: 10.1103/PhysRevLett.119.103401
  • Poster
    28th International Conference on Atomic Collisions in Solids - ICACS 2018, 01.-06.07.2018, Caen, Frankreich
  • Invited lecture (Conferences)
    19th International Conferences on the Physics of Highly Charged Ions - HCI 2018, 02.-07.09.2018, Lissabon, Portugal
  • Lecture (Conference)
    The International Conference on Many Particle Spectroscopy of Atoms, Molecules, Clusters and Surfaces - MPS 2018, 21.-24.08.2018, Budapest, Ungarn
  • Poster
    German Conference for Research with Synchrotron Radiation, Neutrons and Ion Beams at Large Facilities, 17.-19.09.2018, München, Deutschland

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Publ.-Id: 25087 - Permalink


Fluor-18-markierte Substrat-basierte Radiotracer zur In-vivo-Bildgebung der Lysyloxidase
Kuchar, M.;
Die Bedeutung von Lysyloxidasen im Zusammenhang mit Krebserkrankungen begründet die Notwendigkeit der nichtinvasiven bildgebenden Darstellung dieser Enzyme mittels PET.
Bisher wurde über die ln-vivo-Bildgebung von Lysyloxidasen mittels PET nicht berichtet, wodurch die in dieser Arbeit verfolgten Ansätze einen hohen Neuigkeitswert aufweisen. Allgemein haben sich in der molekularen Bildgebung Radiotracer, deren Anreicherungsmechanismen auf irreversiblen kovalenten Wechselwirkungen beruhen, als sehr erfolgreich erwiesen. Demzufolge erschien das Konzept, Bildgebungssonden auf der Basis von Substraten der Lysyloxidase zu entwickeln, die nach enzymatischem Umsatz potentiell einer kovalenten Fixierung an Matrixproteinen unterliegen können, vielversprechend. Daher wurden Peptide (Abb. 78) für die ln-vivo-Bildgebung derextrazellulären Lysyloxidase auf Grundlage des alpha1(I)-N-Telopeptids als substratbasierte Radiotracer ausgewählt und im Rahmen dieser Arbeit als Präkursaren und Referenzverbindungen synthetisiert und ausführlich charakterisiert.
Diese Markierungsmethode wurde auf weitere, für die molekulare Bildgebung potentiell interessante Peptide übertragen und evaluiert.
Um als Substrate gegenüber Lysyloxidasen zu fungieren, müssen die als Radiotracer zum Einsatz kommenden Peptide in jedem Fall einen Lysinrest aufweisen. Der für die Radiomarkierung ausgewählte Markierungsbaustein N-Succinimidyi-4-[18F]fluorbenzoat resultiert in einer 18F-Fiuorbenzoylierung von primären Aminofunktionen, wie sie am N-Terminus bzw. den Lysinseitenketten zu finden sind. Aus diesem Grund wurde eine Methode etabliert, die die 18F-Markierung selektiv an einer spezifischen Aminofunktion, die keinem enzymatischen Umsatz unterliegt, ermöglicht.
Für die Radiomarkierung wurden folgende vier Markierungsstrategien ausgewählt und hinsichtlich ihrer Selektivität beurteilt:
I. Synthese in Lösung, Steuerung der fvlarkierungsposition über den pH-Wert
II. Synthese in Lösung mit vollständigem Seitenkettenschutz
III. Synthese in Lösung mit geschütztem LOX-relevanten Lysin
IV. Synthese an der festen Phase mit variablem Seitenkettenschutz.
Durch den Einsatz der mikrowellengestützten Festphasenpeptidsynthese (SPPS) wurde die Mehrzahl der Peptide und deren Vorläufer unkompliziert hergestellt. Notwendige Modifikationen wurden in hohen Ausbeuten mittels manueller SPPS durchgeführt. Neben den Synthesen der Peptide als Präkurseren und Referenzverbindungn für die Markierungsstrategien, wurden weitere Peptidderivate für die Entwicklung von funktionellen Assays hergestellt.
Markierungsstrategie I lieferte unabhängig vom gewählten pH-Wert ein Gemisch der mono-18F-fluorbenzoylierten Regioisomere. Neben den radiomarkierten Spezies befanden sich in jeder Produktmischung zwei Zersetzungsprodukte, die während der [18F]SFB-Synthese entstanden waren. Diese Produktzusammensetzung hatte nicht nur eine aufwendige Reinigung zur Folge, sondern brachte einen großen Ausbeuteverlust mit sich.
Für Markierungsstrategie II war die Präkursorsynthese nicht praktikabel, daher wurde diese Strategie nicht weiter verfolgt.
Markierungsstrategie III führte zu geringen Ausbeuten des Rohprodukts und erforderte zusätzlich zu Strategie I einen Entschützungsschritt.
Markierungsstrategie IV erwies sich als effektivste Variante, über welche reproduzierbar die markierten Peptide mit hoher Ausbeute und radiochemischer Reinheit synthetisiert werden konnten.
Es wurde gezeigt, dass mit Markierungsstrategie IV der N-Terminus bzw. jede beliebige primäre Aminofunktion selektiv markiert werden kann. Sie ist damit eine universelle Methode, welche auf andere Peptide mit ähnlicher Fragestellung übertragen werden kann. Zur Evaluierung der Markierungsstrategie IV wurden zusätzlich drei pharmakologisch relevante Beispielpeptide (SNEW als Peptid mit für die Ligandenaffinität essentiellem N-Terminus, k7-Fragment als Peptid mit 7 Lysinresten sowie das Fragment 290-319 des Clostridium perfringens-Enterotoxins als Peptid bestehend aus 30 Aminosäuren) ausgewählt.
Die spezifische Aktivität der markierten und gereinigten Peptide lag zwischen 1-3 GBq/µmol ausgehend von ca. 3 GBq [18F]SFB mit einer spezifischen Aktivität von 20-40 GBq/µmol.
ln der Literatur sind keine Angaben zur Stärke der Telopeptid-Kollagen-lnteraktion verfügbar. Aus diesem Grund wurde die Wechselwirkung der LOX-adressierenden Peptide mit Atelokollagen mithilfe der Oberflächenplasmonresonanz-Spektroskopie quantifiziert. Bei diesen Experimenten wurden KD-Werte im oberen mikromolaren Bereich für das originale alpha1(I)-N-Telopeptid 1a ermittelt. Affinitäten in diesem Bereich legen nahe, dass nicht mit einer spezifischen Anreicherung von n.c.a.-Radiotracern auf Basis der Telopeptid-Kollagen-lnteraktion zu rechnen ist. Dieser Befund ist als günstig zu betrachten, da es Ziel war, mithilfe von 18F-markierten Telepeptidderivaten die Voraussetzung zur Bildgebung der enzymatischen Aktivität von Lysyloxidasen zu entwickeln. Eine Anreicherung der Peptide an das in Säugetieren nahezu ubiquitär vorhandene Typ I-Kollagen ist nach diesen Ergebnissen ohne enzymatische Aktivität der Lysyloxidase nicht erwünscht und es ist damit nicht zu rechnen. Die abgeleiteten Derivate des alpha1(I)-N-Telopeptids besitzen eine geringfügig höhere Affinität zum Kollagen als das authentische N-Telopeptid. Dieses Resultat ist ebenso als positiv für den Einsatz der Peptide als Radiotracer zur Visualisierung der LOX-Aktivität zu werten.
Es wurden LOX-exprimierende Tumorzelllinien ausgewählt, zum einen für die Entwicklung von Tumormodellen und zum anderen, um diese als mögliche Quellen für die Präparation des LOX-Enzyms zu nutzen. Wegen der großen Bedeutung sowohl der LOX als auch der LOXL2 im Prozess der Tumorbildung und Metastasierung wurden die Experimente auch parallel für die LOXL2 durchgeführt. Die Vorauswahl resultierte in Zelltypen aus sechs verschiedenen Tumorzelllinien (A375, FaDu, EMT-6, MDA-MB- 231 , HT-29 und MCF-7). Western-Slot-Analysen zum Nachweis der LOX in diesen Zellen ergaben für das Enzym ein charakteristisches Bandenmuster, das sich über die verschiedenen Zelllinien hinweg als konstant erwies. Die LOXL2 wurde vor allem in A375- und FaDu-Zellen als Einzelbande nachgewiesen.
Vier dieser Zelllinien wurden auf Veränderungen der Expression und Sekretion sowohl der LOX als auch der LOXL2 unter hypoxischen Kulturbedingungen untersucht (A375, EMT-6, MDA-MB-231 und MCF-7). Im Ergebnis dieser Vergleiche wurde festgestellt, dass alle getesteten Zelllinien unabhängig von den Kulturbedingungen gleichmäßig LOX exprimieren. Jedoch reichte die Expression der LOX nicht für eine Isolierung. Für die LOXL2 gelang der Nachweis einer gesteigerten Sekretion in der Zelllinie MDA-MB-231 unter hypoxischen Bedingungen.
Zusätzlich wurde die Assoziation der LOX/LOXL2 mit Proteinen der Zellmembran bzw. extrazellulären Matrix untersucht. Die Ergebnisse dieser Experimente ließen eine Assoziation der LOX mit den genannten Proteinen vermuten, während für die LOXL2 dafür keine Anhaltspunkte vorlagen. Eine Internalisierung der Tracerpeptide wurde anhand von Zellaufnahmeexperimenten ausgeschlossen.
Aus den vier Zelllinien A375, EMT-6, MDA-MB-231 und MCF-7 wurden Tumortiermodelle durch Xenotransplantation entwickelt, zwei weitere Modelle der Zelllinien FaDu und HT-29 waren im Institut verfügbar. Western-Blot-Analysen der Tumorlysate bestätigten die Untersuchungen zur LOX-Expression der kultivierten Tumorzellen in vitro. Der Nachweis der LOXL2-Expression gelang nur für A375-Tumoren mit hoher Intensität. Die LOX- und LOXL2-Expression und deren Lokalisation im A375-Tumor wurden weiterhin mittels histochemischer Untersuchungen belegt.
Die radiopharmakologische Charakterisierung der drei Tracerpeptide [18F]1c, [18F]2b und [18F]3b in gesunden männlichen Wistar-Ratten zeigte eine kurze Blutverweildauer, eine zügige renale Ausscheidung und keine Anreicherung in bestimmten Organen und Geweben. Die Untersuchungen zum Metabolisierungsverhalten der drei Tracerpeptide haben das Cyclohexapeptid [18F]3b als metabolisch inert ausgewiesen, während das N-Telopeptid [18F]1c nach 5 min zu 50% metabolisiert war. Das DPK-Peptid [18F]2b erwies sich als überraschend stabil, denn bei den ln-vivo-Studien waren nach 60 min noch über 50% intaktes Peptid nachweisbar.
Mit A375-tumortragenden NMRI-(nu/nu)-Mäusen wurden Experimente zur Aufnahme der radiomarkierten Peptide in den Tumor durchgeführt. Die Auswertung der dynamischen Kleintier-PET-Messungen und Autoradiogramme zeigten einen temporären Anstieg der Aktivität in den Tumoren, welcher sich aber deutlich von den Werten im jeweiligen Vergleichsmuskelgewebe abhob. Die höchsten SUV und ein günstiges Tumor-zu-Muskel-Verhältnis ergaben sich für DPK-Peptid [18F]2b, welches daraufhin in weiteren fünf Tumormodellen untersucht wurde; wobei analoge Ergebnisse erzielt wurden. Insgesamt wurden die größten Unterschiede des Tumor-zu-Muskel-Verhältnisses in den A375-, EMT-6- und MDA-MB-231-Tumormodellen gefunden.
Um einen Bezug der katalytischen Aktivität der LOX zur Tumoraufnahme von [18F]2b herzustellen, wurden Hemmexperimente an A375- und EMT-6-tumorentragenden Mäusen durchgeführt. Zur Hemmung der aktiven Lysyloxidase wurde den Versuchstieren vier und 24 Stunden vor Injektion von [18F]2b der Inhibitor ß-Aminopropionitril verabreicht. ln beiden Fällen wurde eine Hemmung beobachtet, wobei die Hemmung vier Stunden vor Injektion effektiver ist. Dies deutet auf einen direkten Zusammenhang zwischen Tumoraufnahme der Tracerpeptide und LOX-Aktivität hin.
  • Doctoral thesis
    TU Dresden, 2016
    Mentor: Dr. Reik Löser
    262 Seiten

Publ.-Id: 25086 - Permalink


Interaction of uranium (VI) with cellulose degradation products
Brinkmann, H.; Moll, H.;
Cellulosic material is present in low and intermediate level wastes in considerable amounts. In the case of ground water ingressing into cementitious backfill material a hyperalkaline environment will be established. Since cellulose will be relatively fast degraded under alkaline conditions, there is a high risk that small organic, water soluble molecules will be formed. These molecules can act as complexing agents for radionuclides and thereby affecting their sorption behavior and solubility adversely. Therefore the focus of current investigations is on the interaction of uranium (VI) with Isosaccharinic acid as main degradation product as well as with acetate. The progress and results of these investigations as part of the MIND project (work package 1) will be presented.
Keywords: Cellulose, Isosaccharinic acid, Acetate, Uranium
  • Lecture (others)
    TD-315 Joint BN, GD, HT, MA Meeting 2017, 06.-07.02.2017, St. Ursanne, Schweiz

Publ.-Id: 25085 - Permalink


Combined fractionated external radiotherapy and internal irradiation using 90Y-labelled-Cetuximab: optimization of treatment scheduling and proof of curative potential
Dietrich, A.; Andreeff, M.; Koi, L.; Schubert, M.; Schreiner, L.; Bergmann, R.; Löck, S.; Sihver, W.; Faulhaber, D.; Pietzsch, H.-J.; Steinbach, J.; Kotzerke, J.; Baumann, M.; Krause, M.;
Solid tumors can be precisely targeted with external beam radiotherapy (EBRT) but dose is limited by the surrounding tissue. The combination with radioimmunotherapy (= combination of internal and external radiotherapy - CIERT) mediates additional internal irradiation with the potential to strike also distant metastases but affecting different organs at risk. Furthermore, patient stratification is possible using corresponding PET-tracers [1].
We showed the effectiveness of CIERT using 90Y-labelled Cetuximab ([90Y]Y-Cet) and single dose EBRT in a head and neck squamous cell carcinoma xenograft model (FaDu, [2]). The presented project aimed to investigate CIERT using clinical relevant fractionated EBRT with 30 fractions (fx) over 6 weeks. However, the timing of [90Y]Y-Cet is crucial in such settings and was first optimized by modeling [90Y]Y-Cet uptake with near-infrared-labeled Cetuximab (NIR-Cet). The tracer was injected in FaDu-bearing mice at different time points during fxEBRT with differing doses. NIR-Cet uptake was longitudinally followed by in vivo optical imaging to find the optimal schedule for tumor control probability experiments to test the curative potential of CIERT.
NIR-Cet uptake was enhanced after applying low to moderate doses of fxEBRT. Thus, [90Y]Y-Cet was injected after 10 fx of EBRT in CIERT efficacy experiments. CIERT massively increased local control probability compared to EBRT alone or in combination with unlabeled Cetuximab. In the group with the lowest external dose (1 Gy/fx, total dose = 30 Gy) plus [90Y]Y-Cet all tumors were still permanently controlled (observation period = 120 d). In contrast, the total EBRT dose to cure 50% of the tumors without additional [90Y]Y-Cet injection was 63.9 Gy [58.7, 73.9].
Our results indicate a remarkably potential to improve treatment outcome if radiolabeled therapeutics are combined with fractionated external radiotherapy in a clinical relevant setting. Tumor uptake may be improved by application of some EBRT dose prior to injection. This scheduling would also enable patient stratification via a corresponding PET-tracer during ongoing therapy.

[1] A. Dietrich, L. Koi, K. Zöphel, W. Sihver, J. Kotzerke, M. Baumann, M. Krause, Br. J. Radiol. 2015, 88, 20150042
[2] L. Koi, R. Bergmann, K. Brüchner, J. Pietzsch, H.-J. Pietzsch, M. Krause, J. Steinbach, D. Zips, M. Baumann, Radiother. Oncol. 2014, 110, 362-369
  • Contribution to proceedings
    Wolfsberg Meeting 2017, 17.-19.06.2017, Ermatingen, Schweiz

Publ.-Id: 25084 - Permalink


High power laser-driven particle acceleration for radiotherapy
Pawelke, J.; Beyreuther, E.; Cowan, T. E.; Enghardt, W.; Gotz, M.; Herrmannsdörfer, T.; Karsch, L.; Kraft, S.; Krause, M.; Kroll, F.; Masood, U.; Sauerbrey, R.; Schramm, U.; Schürer, M.; Wilkens, J. J.; Zeil, K.;
The current status of developing ultra-high intensity laser-based particle acceleration for more compact and cost effective ion therapy facilities will be presented.
  • Invited lecture (Conferences)
    Conference on Lasers and Electro-Optics Europe (CLEO/Europe) & European Quantum Electronics Conference (EQEC), 25.-29.06.2017, München, Germany

Publ.-Id: 25083 - Permalink


Status of the development of compact laser-driven ion beam therapy
Pawelke, J.;
For a decade we have been developing laser-based particle acceleration for more compact and cost effective ion therapy facilities. The current status will be presented, discussing not only high power laser systems and laser targets to generate therapeutically applicable beams but also technical solutions for dosimetry, beam transport and dose delivery along with the radiobiological consequences of the short ultra-intense pulses of laser-driven beams.
  • Invited lecture (Conferences)
    32nd Conference on Clinical and Experimental Research in Radiation Oncology, 14.-21.01.2017, Les Menuires, France

Publ.-Id: 25082 - Permalink


Ab initio study of interaction of helium with edge and screw dislocations in tungsten
Bakaev, A.; Terentyev, D.; Grigorev, P.; Posselt, M.; Zhurkin, E. E.;
The interaction of a single He atom with edge and screw dislocations in tungsten has been studied using ab initio calculations. It was revealed that He is strongly attracted to the core of both dislocations with the interaction energy of -1.3 and -3.0 eV for screw and edge dislocations, respectively, which corresponds to the detrapping temperature in thermal desorption spectroscopy experiments of about 500 K and 1050 K, respectively. The lowest energy positions for He around the dislocation cores are identified and the atomic structures are rationalized on the basis of elasticity theory considerations. Both types of dislocations exhibit a higher binding energy for He as compared to the He-He binding (known as self-trapping) and are weaker traps as compared to a single vacancy. It is, thus, concluded that the strong attraction to dislocation lines can contribute to the nucleation of He clusters in the temperature range which already excludes He self-trapping.
Keywords: Dislocations Helium Tungsten Ab initio

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Publ.-Id: 25081 - Permalink


Visualization of the global flow structure in a modified Rayleigh-Bénard setup using contactless inductive flow tomography
Wondrak, T.; Pal, J.; Stefani, F.; Galindo, V.; Eckert, S.;
Rayleigh-Bénard convection is not only a classical problem in fluid dynamics but plays also an important role in many metallurgical and crystal growth applications. The measurement of the flow field and of the dynamics of the emerging large-scale circulation in liquid metals is a challenging task due to the opaqueness and the high temperature of the melts. Contactless inductive flow tomography is a technique to visualize the mean three-dimensional flow structure in liquid metals by measuring the flow induced magnetic field perturbations under the influence of one or several applied magnetic fields. In this paper, we present first measurements of the flow induced magnetic field in a Rayleigh-Bénard setup, which are also used to investigate the dynamics of the large-scale circulation. Additionally, we investigate numerically the quality of the reconstruction of the three-dimensional flow field for different sensor configurations.
Keywords: Rayleigh-Bénard convection, contactless inductive flow tomography

Publ.-Id: 25080 - Permalink


Zwitterionic Modification of Ultra-Small Iron Oxide Nanoparticles for Reduced Protein Corona Formation
Pombo-Garcia, K.; Rühl, C.; Lam, R.; Ang, C.-S.; Scammells, P. J.; Comba, P.; Spiccia, L.; Graham, B.; Joshi, T.; Stephan, H.ORC
Polyacrylic acid-coated ultra-small super-paramagnetic iron oxide nanoparticles have been surface-modified with low-molecular weight sulfobetaines or N,N-diethylaminopropylamine in order to generate nanoparticles with zwitterionic character (ZW-NPs). The ZW-NPs proved highly resistant to serum protein corona formation in vitro, as revealed by AFM, SDS-PAGE and proteomics analysis, and exhibited low cytotoxicity towards A431 and HEK293 cells. The presence of unreacted carboxylic acid groups enabled additional functionalization with fluorescent (Cy5) and radioactive (64Cu-dmptacn) moieties. Overall, the ZW-NPs represent promising platforms for the development of new multi-modal diagnostic/therapeutic agents possessing “stealth” properties.
Keywords: iron oxide nanoparticles • multimodal imaging • protein corona • proteomics • zwitterionic coatings

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Publ.-Id: 25079 - Permalink


Do spiroindolines have the potential to replace vesamicol as lead compound for the development of radioligands targeting the vesicular acetylcholine transporter?
Lindemann, M.; Deuther-Conrad, W.; Moldovan, R.; Sekhar, K. V. G. C.; Brust, P.; Wenzel, B.;
The vesicular acetylcholine transporter (VAChT) is an important target for in vivo imaging of neurodegenerative processes using positron-emission-tomography. So far the development of VAChT radioligands is based on the single known lead compound vesamicol. In this study we investigated a recently published spiroindoline compound class (Sluder et al. 2012), which was suggested to have potential in the development of VAChT ligands. Therefore, we synthesized a small series of spiroindoline derivatives and determined their in vitro binding affinities toward the VAChT. In order to investigate the selectivity, the off-target binding toward 1 and 2 receptors were determined. The compounds possessed VAChT affinities with Ki values in the range of 39 to 376 nM. Binding affinities toward the 1 and 2 receptors are in a similar range indicating that the strong structural difference between the spiroindolines and vesamicol did not improve the selectivity. The observed potential to additionally bind to  receptors let us assume that the herein investigated spiroindolines are not suitable to replace vesamicol as lead compound for the development of VAChT ligands.
Keywords: VAChT, Vesamicol, Spiroindolines, PET, sigma receptors

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Publ.-Id: 25078 - Permalink


A fluorescence anisotropy‐based assay to determine the activity of tissue transglutaminase in human cancer cell lines
Ullm, S.; Wodtke, R.; Pietzsch, J.; Löser, R.;
High activity of tissue transglutaminase (TGase 2) in various tumors is associated with both their increased metastatic and invasive potential and their resistance towards chemotherapy and radiation. This renders TGase 2 an attractive target for the development of agents that are capable of targeting the tumor-associated TGase 2 for both imaging and therapeutic approaches [1].
To identify Inhibitor-based compounds for these purposes, the establishment of activity assays that allow their characterization both in vitro and at the cellular level is essential. We previously reported a kinetic fluorescence anisotropy (FA)-based assay to determine the transamidase activity of guinea pig TGase 2 [2] which follows the incorporation of fluorescently labeled (either fluoresceine or rhodamine B) cadaverine derivatives into N,N-dimethylated casein (DMC) over time. Using this assay, we were able to show that the method of FA ensures the absence of background signal and a high reproducibility in a homogenous assay design.
Here we apply the FA assay using DMC and a newly developed rhodamine B-cadaverine conjugate to recombinant human TGase 2 for the kinetic characterization of selected inhibitors and the active-site titration of the enzyme. Due to the favorable signal-to-noise ratio, it was furthermore possible to apply the FA assay for determining cellular TGase 2 in 25 human cell models by measuring the enzyme activity in the whole cell lysate and calculating the respective protein amount. The obtained results were compared with those of a densitometric Western Blot analysis, showing a clear correlation between the two data sets. The human lung cancer cell line NCI-H292 and the human breast cancer cell line MDA-MB-231 were found to exhibit the highest amount of activatable TGase 2 among the tested cancer cell lines, whereas the human cerebral endothelial cell line hCMEC-D3 showed the highest activity among the tested non-cancerous cell lines. To prove that the observed FA signal is caused by TGase 2 activity, N2-phenylacetyl-N6-acryloyl-lysine-4-(6-methylpyridine-2-yl)piperazide [3], which has previously been characterized as irreversible inactivator of this enzyme, was utilized. Application of this inhibitor resulted in a substantial reduction of the FA signal.

References:
[1] Pietsch et al. Bioorg. Med. Chem. Lett. 2013, 23, 6528.
[2] Hauser et al. Amino Acids 2016 DOI: 10.1007/s00726-00016-02192-00725.
[3] Wityak et al. ACS Med. Chem. Lett. 2012, 3, 1024.
  • Poster
    Transglutaminases in Human Disease Processes, 10.-15.07.2016, Girona, Spanien

Publ.-Id: 25077 - Permalink


Expression and Activity of Tissue Transglutaminase in the Response to Gelatin-based Hydrogels in vitro and in vivo
Ullm, S.; Wodtke, R.; Tondera, C.; Löser, R.; Pietzsch, J.;
Tissue transglutaminase (TGase 2) is proposed to be important for biomaterial-cell or -tissue interactions due to its presence and versatile functions in the extracellular environment. For example, TGase 2 catalyzes the crosslinking of proteins of the extracellular matrix through its Ca2+-dependent transamidase activity or enhances the interactions between fibronectin, integrins, and syndecan-4 via its role as scaffold protein. Through these functions, TGase 2 mediates the adhesion, migration and motility of cells. Additionally, TGase 2 is a key player during the development of fibrosis. Consequently, TGase 2 might be a potential target for the improvement and visualization of tissue regeneration following biomaterial implantation. Here, we studied the expression pattern and activity of TGase 2 in the response to gelatin-based hydrogels with tailorable elastic properties and degradation behavior due to different degrees of crosslinking.
Solutions of 10 wt.-% gelatin were crosslinked with 3- (G10_LNCO3) or 8-fold (G10_LNCO8) excess of isocyanate groups of lysine diisocyanate ethyl ester compared to amino groups of gelatin. Primary human aortic endothelial cells (HAEC) and human leukemia THP-1 and HL-60 cells, differentiated to macrophages (Mɸ) or granulocytes (Gɸ), were seeded either directly on the hydrogel films or cultivated with material eluates in order to simulate hydrolytic or enzymatic hydrogel degradation in vivo. Expression levels of intracellular and secreted TGase 2 were analyzed via Western blotting [1]. Additionally, hydrogels were implanted subcutaneously in immunocompetent, hairless SKH-1 mice. TGase 2 expression at the implantation site was detected ex vivo by immunohistochemistry at several time points up to 112 days after implantation. The presence of activatable TGase 2 in tissue sections was confirmed in vitro by incorporation of fluorescently labelled cadaverine derivatives [2] at sites of TGase 2 expression. To prove that the incorporation is caused by TGase 2, the staining was performed in the presence and absence of a recently described irreversible inhibitor for TGase 2 [3].
HAEC showed high expression and secretion of TGase 2, independent from hydrogel contact. THP-1 Mɸ highly expressed TGase 2, and increased its secretion after direct hydrogel contact. In contrast, HL-60 Mɸ and Gɸ exhibited enhanced expression of TGase 2 after direct contact to the hydrogels, without secreting TGase 2. These results demonstrate that TGase 2 expression and secretion by Mɸ and Gɸ are influenced by contact to the hydrogel surface structure and not by hydrogel degradation products. Additionally, the hydrogels with higher content of diurealysine junction units (G10_LNCO8) induced higher effects than G10_LNCO3. Ex vivo analysis of tissue sections by immunohistochemistry revealed enhanced expression levels of activatable TGase 2 around the hydrogels 14 and 21 days after implantation, indicating a role of TGase 2 in hydrogel integration and tissue remodelling.
Our results revealed that contact to the gelatin-based hydrogels influenced TGase 2 expression and secretion by Mɸ and Gɸ in vitro, as well as expression of activatable TGase 2 in vivo. This underlines TGase 2 to be a promising theranostic target during processes of biomaterial integration.
References:
[1] Ullm et al. Biomaterials 2014, 35, 9755-9766
[2] Hauser et al. Amino Acids 2016, DOI 10.1007/s00726-00016-02192-00725
[3] Wityak et al. ACS Med. Chem. Lett. 2012, 3, 1024-1028
  • Poster
    Transglutaminases in Human Disease Processes, 10.-15.07.2016, Girona, Spanien

Publ.-Id: 25076 - Permalink


N6-Acryloyl-lysine piperazides as irreversible inhibitors of transglutaminase 2 ― synthesis and structure activity relationships
Wodtke, R.; Jäckel, E.; Wong, A.; Lohse, M.; Bauer, D.; Ullm, S.; Steinbach, J.; Pietzsch, J.; Löser, R.;
Various kinds of tumour entities are characterised by an increased activity of transglutaminase 2 (TGase 2), which contributes to an enhanced invasive potential of the tumour cells and their resistance to chemo- and radiotherapy. Therefore, this enzyme represents an interesting target for the development of PET tracers for functional imaging of tumours in vivo [1].
Among the TGase 2 inhibitors described in the literature, N6-acryloyl-lysine-4-arylpiperazides reported by Wityak et al. [2] seem to be most suitable for radiotracer development as these compounds exhibit both strong inhibitory potential and selectivity towards human TGase 2 and show favourable pharmacokinetic properties. Based on this class of compounds, derivatives that allow for labelling with radionuclides such as fluorine-18 and iodine-124 were prepared and their inhibitory potential towards TGase 2 was evaluated.
The N2-acyl-N6-acryloyl-lysine-4-pyridylpiperazides were synthesised in a sequence consisting of N6-acrylation, PyBOP-mediated amide bond formation, Boc deprotection and N2-acylation starting from N2-Boc-lysine. The required pyridylpiperazines were obtained commercially or prepared in a few steps. All final compounds were evaluated in two independent kinetic assays, which detect either the transamidase [3] or hydrolase activity [4] of TGase 2, respectively, with N2-phenylacetyl-N6-acryloyl-lysine-4-(6-methylpyridine-2-yl)piperazide [2] serving as benchmark inhibitor.
Using the outlined synthetic route a series of more than 50 N2-acyl-N6-acryloyl-lysine-4-pyridylpiperazides was prepared in good yields. The kinetic characterisation of the compounds revealed some interesting structure-activity relationships. For example, replacing the 6-methylpyridine-2-yl moiety of the benchmark inhibitor by a 2-nitro-5-pyridyl moiety led to a significantly increased inhibitory effect towards human TGase 2. Furthermore, substitution of the methyl group by hydrogen or a halogen atom (F, Cl, Br and I) revealed a direct correlation between the van der Waals radius of the substituent and the inhibitory effect towards human TGase 2, with the inhibitor containing iodine being even more potent than the benchmark inhibitor. Covalent docking studies provided information about the binding mode of this inhibitor class for the first time and, thus, allowed for explaining the trends observed in the activity assays and give hints for further improvement of inhibitory potency by specific structural variations.
In addition to their interaction with TGase 2, the inhibitors are characterised for their pharmacokinetic properties by the determination of appropriate parameters in vitro.
References:
[1] Pietsch et al. Bioorg. Med. Chem. Lett. 2013, 23, 6528. [2] Wityak et al. ACS Med. Chem. Lett. 2012, 3, 1024. [3] Hauser et al. Amino Acids 2016 DOI 10.1007/s00726-00016-02192-00725. [4] Wodtke et al. ChemBioChem 2016 DOI 10.1002/cbic.201600048
  • Poster
    Transglutaminases in Human Disease Processes, 10.-15.07.2016, Girona, Spanien

Publ.-Id: 25075 - Permalink


Comparative analysis of radiolabeled monoclonal antibodies and antibody fragments for immunotherapy of Prostate Stem Cell Antigen expressing tumors
Oertel, F.; Arndt, C.; Feldmann, A.; Bachmann, M.; Bergmann, R.; Steinbach, J.; Pietzsch, H.-J.;
Aim: Advances in antibody engineering have led to the development of a multiplicity of antibody types for radioimmunotherapy. Predominantly, this development was concentrated on generating variations in the antibody size, which evidently influences the pharmacokinetics and tumor uptake. However, it is still discussed, which size has most suitable properties for radioimmunotherapy approaches. Here, two different antibody types, monoclonal antibodies (mAbs, 150 kDa) and thereof derived single-chain variable fragments (scFv, 35 kDa), were compared, that are directed against the prostate stem cell antigen (PSCA). Due to its overexpression on the surface of various cancers, including prostate, pancreas and bladder cancer, PSCA is proposed to be a promising tumor target structure for antibody-based immunotherapy.

Methods: In this study, two different anti-PSCA mAb clones, RD1 and RD2, as well as their respective anti-PSCA scFvs were compared with regard to their binding properties towards PSCA, using flow cytometry analysis. Above, the anti-PSCA mAbs were conjugated with the radionuclide chelating agent CHX-A’'-DTPA and subsequently radiolabeled with 177Lu. The radiolabeled mAb-conjugates were, then, characterized regarding binding properties on PC3-PSCA cells in vitro.

Results: As determined by flow cytometry, non-radiolabeled anti-PSCA mAbs RD1 and RD2 show a high affinity, with a dissociation constant of 10 and 6 nM, respectively. Even though, the scFvs of RD1 and RD2 exhibit a lower affinity in comparison to their mAbs counterpart, they maintain a moderate Kd-value (170 and 98 nM) that is sufficient to proceed with conjugation and radiolabeling analogous to the mAbs. Conjugation of three CHX-A’’-DTPA-chelators to the mAbs had no influence on binding affinity towards the PSCA. Subsequent radiolabeling of the mAb-conjugates could be performed with high radiochemical purity (> 95%). Similar to the non-radiolabeled mAbs, the binding affinity of 177Lu-labeled (CHX-A’’-DTPA)3-RD1 or RD2 was high with 12 and 19 nM, respectively. Summing up, both anti-PSCA mAb were successfully radiolabeled with 177Lu without losing their binding properties to PSCA. Thus, these molecules are attractive candidates for radioimmunotherapy of PSCA-positive cancers.
  • Lecture (Conference)
    24. Jahrestagung der Arbeitsgemeinschaft Radiochemie/Radiopharmazie 2016, 29.09.-01.10.2016, Morschach, Schweiz

Publ.-Id: 25074 - Permalink


Toward high-energy laser-driven ion beams: Nanostructured double-layer targets
Passoni, M.; Sgattoni, A.; Prencipe, I.; Fedeli, L.; Dellasega, D.; Cialfi, L.; Choi, I. W.; Kim, I. J.; Janulewicz, K. A.; Lee, H. W.; Sung, J. H.; Lee, S. K.; Nam, C. H.;
The development of novel target concepts is crucial to make laser-driven acceleration of ion beams suitable for applications. We tested double-layer targets formed of an ultralow density nanostructured carbon layer (∼7  mg/cm3, 8–12  μm–thick) deposited on a μm–thick solid Al foil. A systematic increase in the total number of the accelerated ions (protons and C6+) as well as enhancement of both their maximum and average energies was observed with respect to bare solid foil targets. Maximum proton energies up to 30 MeV were recorded. Dedicated three-dimensional particle-in-cell simulations were in remarkable agreement with the experimental results, giving clear indication of the role played by the target nanostructures in the interaction process.

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Publ.-Id: 25073 - Permalink


Investigation of microbial community in extreme saline environments
Franze, M.; Cherkouk, A.;
In Germany, three kinds of potential host rock systems (clay, crystalline and rock salt) are considered for the long-term storage of highly radioactive waste in a deep geological repository. In this study the focus is on the habitat rock salt to get a more detailed understanding of the way of life of the microorganisms occurring there. Next to bacteria and fungi, extreme halophilic archaea are dominating this habitat. It is of interest to know what kind of microorganisms are living there, how active they are under repository relevant conditions and how these microorganisms can influence the safe storage of the waste. The microbial diversity of two different types of samples (rock salt from Germany & saline soil sample from Israel) was investigated with a combination of culture-dependent and -independent methods. From the two samples DNA was extracted, purified for PCR amplifications of 16S rRNA genes and finally sequenced with Illumina MiSeq by RTL Genomics. Additionally, a specific portion of each sample was incubated in three different sodium chloride concentrations of modified R2A resuscitation buffer and subsequently spread on corresponding agar plates (37°C) to get isolates which were further characterized. Different halophilic microorganisms could be isolated from both kinds of samples. The isolates from rock salt can all be assigned to different Halobacterium species. Whereas from the saline soil samples different archaeal genera such as Natrinema, Halorubrum as well as Halobacterium could be isolated. Bacterial isolates were related to different Bacilli such as Halobacillus and Aquibacillus species. The obtained isolates can be further used for investigations e.g. regarding their activity under repository relevant conditions.
  • Poster
    MiCom 6th International Conference on Microbial Communication for Young Scientists, 20.-23.03.2017, Jena, Deutschland

Publ.-Id: 25070 - Permalink


Towards atomic physics in particle in cell on GPUs (PIConGPU), photon scattering and nanometer and femtosecond probing of hot dense matter with SAXS
Kluge, T.;
Ultrafast heating of solids or solid density plasmas can provide a unique, transient and non-thermal state of matter that enables the study e.g. of ultrafast ionization and excitation, recombination, photon and electron transport. Heating can be achieved directly and indirectly by irradiation with ultra-intense optical lasers or volumetrically with XFELs. Yet, the state-of-the-art theoretical description needed to simulate those processes in particle in cell (PIC) simulations is based on average and effective simplistic assumptions, and hence not reliable for ultrashort, non-thermal states. We present our approach and status of implementing explicit atomic physics in PIConGPU, and introduce the first spin-off tool ParaTAXIS that simulates explicitly photon scattering using PIC methods. This enables implementation of arbitrary scattering physics, multiple scattering, full treatment of X-ray beam properties and fast plasma dynamics. We also demonstrate a novel experimental method based on Small Angle X-ray Scattering to probe such physics on a few nanometer and few femtosecond level simultaneously in ultra-intensity optical laser heated solids.
  • Poster
    Radiative Properties of Hot Dense Matter Workshop, 05.-09.12.2016, Santa Barbara, USA (CA)

Publ.-Id: 25069 - Permalink


Nanometer-scale characterization of laser-driven plasmas, compression, shocks and phase transitions, by coherent small angle x-ray scattering
Kluge, T.; Rödel, M.; Pelka, A.; Mcbride, E. E.; Bussmann, M.; Fletcher, L.; Galtier, E.; Laso Garcia, A.; Gutt, C.; Lee, H. J.; Nagler, B.; Rödel, C.; Glenzer, S.; Schramm, U.; Cowan, T. E.;
Combining ultra-intense short-pulse and high-energy long-pulse lasers, with hard X-ray FELs, such as the Helmholtz International Beamline for Extreme Fields (HIBEF) [1] at European XFEL [2], or MEC at LCLS [3], holds the promise to revolutionize our understanding of many High Energy Density Physics phenomena. Examples include the relativistic electron generation, transport, and bulk plasma response [4], and ionization dynamics and heating [5] in relativistic laser-matter interactions, or the dynamics of laser-driven shocks, quasi-isentropic compression, and the kinetics of phase transitions at high pressure [3,6]. Particularly interesting is Small Angle X-ray Scattering [4] and resonant scattering [5]. Their feasibility in laser-driven matter will be discussed for ultra-intense short pulse drive lasers and nanosecond lasers, including first results from demonstration experiments at LCLS (SLAC). Very sharp density changes from laser-driven compression are observed, having a step width of <10 nm, comparing to a resolution of several hundred nm achieved previously [6] with phase contrast imaging.
[1] www.hibef.eu
[2] www.xfel.eu
[3] J. Synchrotron Rad. 22, 520 (2015)
[4] Phys. Plasmas 21, 033110 (2014)
[5] http://arxiv.org/abs/1508.03988
[6] Sci. Rep. 3, 1633 (2013)
  • Invited lecture (Conferences)
    43rd EPS Conference on Plasma Physics, 04.-08.07.2016, Leuven, Belgium

Publ.-Id: 25068 - Permalink


Prospective Validation of a Prognostic Computed Tomography-Based Radiomic Signature in Stage IV Non-Small Cell Lung Cancer
de Jong, E.; van Elmpt, W.; Leijenaar, R. T. H.; Carvalho, S.; Troost, E. G. C.; Hendriks, L. E. L.; Dingemans, A. M. C.; Lambin, P.;
there ist no abstract
  • Abstract in refereed journal
    International Journal of Radiation Oncology Biology Physics 96(2016)2, S192
    DOI: 10.1016/j.ijrobp.2016.06.480

Publ.-Id: 25067 - Permalink


Toward Shared Decision: Validated Clinical Nomogram for Personalized Long-Term Survival Prediction After Radiosurgery for Brain Metastases
Zindler, J. D.; Jochems, A.; Beumer, R.; Troost, E. G.; Lagerwaard, F.; Eekers, D. B.; Compter, I.; van der Toorn, P. P.; Essers, M.; Oei, B.; Hurkmans, C.; Bruynzeel, A.; Bosmans, G.; Lambin, P.;
there ist no abstract
  • Abstract in refereed journal
    International Journal of Radiation Oncology Biology Physics 96(2016)2, S181
    DOI: 10.1016/j.ijrobp.2016.06.453

Publ.-Id: 25066 - Permalink


Toward Distributed Conduction of Large-Scale Studies in Radiation Therapy and Oncology: Open-Source System Integration Approach
Skripcak, T.; Just, U.; Simon, M.; Buttner, D.; Lühr, A.; Baumann, M.; Krause, M.;
The conduct of multicenter studies in the field of radiation therapy and oncology is one of the key prerequisites for stimulating translational research and accelerating the application of healthcare innovations into day to day patient treatment. To effectively run such studies, the participating research institutions need access to radiotherapy-specific information technology (IT), which enables collection of case report forms (eCRFs) linked with medical imaging and treatment planning data. Existing commercial systems that provide multimodal data collection features may fit for industry funded clinical trials but do not consider academia needs for long-lasting and affordable IT infrastructure. This paper presents an alternative way for development of a sustainable clinical research IT platform based on open-source systems. The platform design is driven by an integration of its core components, namely, electronic data capture system (EDC), medical image archive (PACS), and patient identity management system (PIDG). Three deployment scenarios are described that allow setting up the platform in a central, virtually hosted or decentralized environment. The first production implementation of this infrastructure was established as RadiationDosePlan-Image/Biomarker-Outcome-platform (RadPlanBio) in September 2013. It is maintained by the German Cancer Consortium (DKTK), Dresden and the German Cancer Research Center (DKFZ), Heidelberg. Until now, it manages 9 studies across 11 sites with 600 enrolled subjects. This paper shows how the integration of open-source systems can drive the development of sustainable clinical research IT environment supporting translational research projects in the field of radiation therapy and oncology. © 2015 IEEE.
Keywords: Digital imaging and communication in medicine (DICOM); electronic data capture (EDC); open source; radiotherapy studies; software integration

Publ.-Id: 25065 - Permalink


Personalized radiation oncology: Epidermal growth factor receptor and other receptor tyrosine kinase inhibitors
Higgins, G. S.; Krause, M.; Mckenna, W. G.; Baumann, M.;
Molecular biomarkers are currently evaluated in preclinical and clinical studies in order to establish predictors for treatment decisions in radiation oncology. The receptor tyrosine kinases (RTK) are described in the following text. Among them, the most data are available for the epidermal growth factor receptor (EGFR) that plays a major role for prognosis of patients after radiotherapy, but seems also to be involved in mechanisms of radioresistance, specifically in repopulation of tumour cells between radiotherapy fractions. Monoclonal antibodies against the EGFR improve locoregional tumour control and survival when applied during radiotherapy, however, the effects are heterogeneous and biomarkers for patient selection are warranted. Also other RTK’s such as c-Met and IGF-1R seem to play important roles in tumour radioresistance. Beside the potential to select patients for molecular targeting approaches combined with radiotherapy, studies are also needed to evluate radiotherapy adaptation approaches for selected patients, i.e. adaptation of radiation dose, or, more sophisticated, of target volumes. © Springer-Verlag Berlin Heidelberg 2016.
Keywords: Biomarker; EGFR; HER-2; Radiotherapy; Receptor tyrosine kinases
  • Book chapter
    Baumann, M.; Krause, M.; Cordes, N.: Molecular Radio-Oncology, Volume 198 of the series Recent results in Cancer Research, Berlin Heidelberg: Springer Verlag, 2016, 107-122
    DOI: 10.1007/978-3-662-49651-0_5

Publ.-Id: 25063 - Permalink


Low Cancer Stem Cell Marker Expression and Low Hypoxia Identify Good Prognosis Subgroups in HPV(-) HNSCC after Postoperative Radiochemotherapy: A Multicenter Study of the DKTK-ROG.
Linge, A.; Löck, S.; Gudziol, V.; Nowak, A.; Lohaus, F.; von Neubeck, C.; Jütz, M.; Abdollahi, A.; Debus, J.; Tinhofer, I.; Budach, V.; Sak, A.; Stuschke, M.; Balermpas, P.; Rödel, C.; Avlar, M.; Grosu, A. L.; Bayer, C.; Belka, C.; Pigorsch, S.; Combs, S. E.; Welz, S.; Zips, D.; Buchholz, F.; Aust, D. E.; Baretton, G. B.; Thames, H. D.; Dubrovska, A.; Alsner, J.; Overgaard, J.; Baumann, M.; Krause, M.;
PURPOSE:

To investigate the impact of hypoxia-induced gene expression and cancer stem cell (CSC) marker expression on outcome of postoperative cisplatin-based radiochemotherapy (PORT-C) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).
EXPERIMENTAL DESIGN:

Expression of the CSC markers CD44, MET, and SLC3A2, and hypoxia gene signatures were analyzed in the resected primary tumors using RT-PCR and nanoString technology in a multicenter retrospective cohort of 195 patients. CD44 protein expression was further analyzed in tissue microarrays. Primary endpoint was locoregional tumor control.
RESULTS:

Univariate analysis showed that hypoxia-induced gene expression was significantly associated with a high risk of locoregional recurrence using the 15-gene signature (P = 0.010) or the 26-gene signature (P = 0.002). In multivariate analyses, in patients with HPV16 DNA-negative but not with HPV16 DNA-positive tumors the effect of hypoxia-induced genes on locoregional control was apparent (15-gene signature: HR 4.54, P = 0.006; 26-gene signature: HR 10.27, P = 0.024). Furthermore, MET, SLC3A2, CD44, and CD44 protein showed an association with locoregional tumor control in multivariate analyses (MET: HR 3.71, P = 0.016; SLC3A2: HR 8.54, P = 0.037; CD44: HR 3.36, P = 0.054; CD44 protein n/a because of no event in the CD44-negative group) in the HPV16 DNA-negative subgroup.
CONCLUSIONS:

We have shown for the first time that high hypoxia-induced gene expression and high CSC marker expression levels correlate with tumor recurrence after PORT-C in patients with HPV16 DNA-negative HNSCC. After validation in a currently ongoing prospective trial, these parameters may help to further stratify patients for individualized treatment de-escalation or intensification strategies. Clin Cancer Res; 22(11); 2639-49. ©2016 AACR.

Publ.-Id: 25060 - Permalink


Correlation of FMISO simulations with pimonidazole-stained tumor xenografts: A question of O2 consumption?
Wack, L. J.; Mönnich, D.; Yaromina, A.; Zips, D.; Baumann, M.; Thorwarth, D.;
PURPOSE:

To compare a dedicated simulation model for hypoxia PET against tumor microsections stained for different parameters of the tumor microenvironment. The model can readily be adapted to a variety of conditions, such as different human head and neck squamous cell carcinoma (HNSCC) xenograft tumors.
METHODS:

Nine different HNSCC tumor models were transplanted subcutaneously into nude mice. Tumors were excised and immunoflourescently labeled with pimonidazole, Hoechst 33342, and CD31, providing information on hypoxia, perfusion, and vessel distribution, respectively. Hoechst and CD31 images were used to generate maps of perfused blood vessels on which tissue oxygenation and the accumulation of the hypoxia tracer FMISO were mathematically simulated. The model includes a Michaelis-Menten relation to describe the oxygen consumption inside tissue. The maximum oxygen consumption rate M0 was chosen as the parameter for a tumor-specific optimization as it strongly influences tracer distribution. M0 was optimized on each tumor slice to reach optimum correlations between FMISO concentration 4 h postinjection and pimonidazole staining intensity.
RESULTS:

After optimization, high pixel-based correlations up to R(2) = 0.85 were found for individual tissue sections. Experimental pimonidazole images and FMISO simulations showed good visual agreement, confirming the validity of the approach. Median correlations per tumor model varied significantly (p < 0.05), with R(2) ranging from 0.20 to 0.54. The optimum maximum oxygen consumption rate M0 differed significantly (p < 0.05) between tumor models, ranging from 2.4 to 5.2 mm Hg/s.
CONCLUSIONS:

It is feasible to simulate FMISO distributions that match the pimonidazole retention patterns observed in vivo. Good agreement was obtained for multiple tumor models by optimizing the oxygen consumption rate, M0, whose optimum value differed significantly between tumor models.

Publ.-Id: 25058 - Permalink


Room-temperature short-wavelength infrared Si photodetector
Berencén, Y.; Prucnal, S.; Liu, F.; Skorupa, I.; Hübner, R.; Rebohle, L.; Zhou, S.; Schneider, H.; Helm, M.; Skorupa, W.;
The optoelectronic applications of Si are restricted to the visible and near-infrared spectral range due to its 1.12 eV-indirect band gap. Sub-band gap light detection in Si, for instance, has been a long-standing scientific challenge for many decades since most photons with sub-band gap energies pass through Si unabsorbed. This fundamental shortcoming, however, can be overcome by introducing non-equilibrium deep-level dopant concentrations into Si, which results in the formation of an impurity band allowing for strong sub-band gap absorption. Here, we present steady-state room-temperature short-wavelength infrared p-n photodiodes from single-crystalline Si hyperdoped with Se concentrations as high as 9×1020 cm-3, which are introduced by a robust and reliable non-equilibrium processing consisting of ion implantation followed by millisecond-range flash lamp annealing. We provide a detailed description of the material properties, working principle and performance of the photodiodes as well as the main features in the studied wavelength region. This work fundamentally contributes to establish the short-wavelength infrared detection by hyperdoped Si in the forefront of the state-of-the-art of short-IR Si photonics.
Keywords: Extended Si photodetector, Hyperdoped Si, Chalcogens, FLA, non-equilibrium processing

Publ.-Id: 25057 - Permalink


Local flow measurement in a continuous casting model test stand
Hernández, D.; Wondrak, T.; Karcher, C.;
Local Lorentz force velocimetry (LFV) is a contactless local velocity measurement technique for liquid metals. Due to the interaction between an electrically moving liquid and an applied magnetic field, eddy currents and flow-braking Lorentz forces are induced within the fluid. Due to Newton’s third law, a counter force of the same magnitude acts on the source of the applied magnetic field which is in our case a permanent magnet. The magnet is connected to a new generation force/torque sensor that has been especially developed to record all force and torque components. This sensor has already been tested at a continuous casting model with a 15 mm cubic magnet providing an insight of the 3-D velocity distribution of GaInSn near the wide face of the mold [1]. For a better understanding of these results, especially regarding torque sensing, we propose a kinematic approach of ohm’s law where the velocity field is already given. In this case we avoid the variability and noise of the measurements meaning that the force depends just on the velocity distribution of the liquid metal. In this paper we present a comparison between our numerical model and the previous experiments.
  • Contribution to proceedings
    Workshop Elektroprozesstechnik, 22.-23.09.2016, Ilmenau, Deutschland
  • Lecture (Conference)
    Workshop Elektroprozesstechnik, 22.-23.09.2016, Ilmenau, Deutschland

Publ.-Id: 25056 - Permalink


Elucidating the role of dissolution in CeO2 nanoparticle plant uptake by smart radiolabeling
Schymura, S.; Fricke, T.; Hildebrand, H.; Franke, K.;
The identification of major uptake pathways in plants is an important factor when evaluation the fate of manufactured nanoparticles in the environment and the associated risks. Using different radiolabeling techniques we were able to show a predominantly particulate uptake for CeO2 nanoparticles (NPs) in contrast to a possible uptake in the form of ionic cerium.
Keywords: Radiomarkierung, Radiolabeling Nanopartikel, Nanoparticle CeO2, CeO2 Pflanzenaufnahme, plant uptake

Downloads:

  • Secondary publication expected

Publ.-Id: 25055 - Permalink


Representing topology and geometry of 3D ore microstructures with GMaps
Menzel, P.; Teichmann, J.; van den Boogaart, K. G.;
The determination of optimal processing chains of specific and complex ores is one of the main tasks in mineral processing. For this purpose, we want to simulate the complete process chain from ore body to flotation to optimize for specific input materials. The key issue is the knowledge of the 3D ore microstructure as starting point for crushing into mineral particles.
Based on statistical information of 2D samples from MLA images (mineral liberation analysis), 3D microstructure models founded on random mosaics are fitted using stochastic geometry.
Then again, simulated MLA data sets can be created from this 3D microstructure model and compared to real data to optimize simulation.
To represent the geometry and the topology of the microstucture models, a data structure is needed to perform the following main tasks. Firstly, we need to build a comprehensive, topologically consistent cell structure. Secondly, we need easy access to all geometric features for all k-cells (e.g. volume, surface, contact faces). Furthermore, operations like the breakup along defined particle borders, the creation of profiles along planes and the dual graph have to be provided in an eficient way. We decided to use our own Java-based implementation of the Generalized Maps (GMaps) data structure that supports the requested operations.
The opportunity of the GMaps concept is, that it only uses one specific data type, called Dart, and several associations between incident Darts, called involutions, to describe the complete topology. Thus, it allows an efficient traversal through all topological elements of our microstructure models.
The simulated microstructure, represented by a GMap, can be used for a milling simulation and the resulting particle streams might undergo, e.g., a flotation simulation. The 3D microstructure models are the essential linkage between the analytical and the processing part of our mineral processing simulation.
Keywords: GMaps, microsructures, stochastic geometry, data structures
  • Lecture (Conference)
    18th Annual Conference IAMG2017, 02.-09.09.2017, Fremantle, Australia

Publ.-Id: 25053 - Permalink


Numerical calibration of a multicomponent local lorentz force flowmeter
Hernández, D.; Böck, T.; Karcher, C.; Wondrak, T.;
Local Lorentz force velocimetry is a local velocity measurement technique for liquid metals. Due to the interaction between an electrically conductive liquid and an applied magnetic field, eddy currents and flow-braking Lorentz forces are induced within the fluid. Due to Newtons’s third law, a force of the same magnitude acts on the source of the applied magnetic field, which is a permanent magnet in our case. The magnet is attached to a gauge that has been especially developed to record all three force and three torque components acting on the magnet. This new-generation local Lorentz force flowmeter (L2F2) has already been tested at a test stand for continuous casting with a 15mm cubic magnet providing an insight into the three-dimensional velocity distribution of the model melt GaInSn near the wide face of the mold. For a better understanding of these results, especially regarding torque sensing, we propose dry experiments which consist in replacing the flowing liquid by a moving solid. Here, as the velocity field is fixed and steady, we are able to decrease considerably the variability and the noise of the measurements providing an accurate calibration of the system. In this paper we present a numerical study of this dry calibration proposal using a rotating disk made of aluminum and two different magnet systems that can be shifted along the rotation axis as well as in radial direction.
Keywords: local lorentz force velocimetry
  • Magnetohydrodynamics 53(2017)2, 233-243

Publ.-Id: 25052 - Permalink


Synthese von Transglutaminase 2-Inhibitoren und Präkursoren für deren Markierung mit Fluor-18
Bauer, D.;
Kein Abstract vorhanden
  • Master thesis
    TU Dresden, 2016
    Mentor: Dr. Reik Löser
    181 Seiten

Publ.-Id: 25051 - Permalink


Germanium Recovery from Optical Fiber Waste
Recksiek, V.; Scharf, C.;
Germanium is an essential element for the European information technology. The increasing demand for high speed internet connections requires the application of optical fibers, which cannot be produced without Germanium. Because of high supply risks, the European Union added Germanium to the list of critical raw materials in 2010. The world refinery production of Germanium was approximately 165 metric tons in 2014. Thirty percent of this amount was used for the manufacturing of optical fibers. In the production process various Germanium containing scraps are generated, from some of these Germanium is not yet recovered.
This poster outlines methods for the recovery of Germanium from these waste materials. The necessary mechanical processing and a possible pyrometallurgical recovery process are discussed.
Keywords: Germanium, recovery, distillation, reduction, chlorination
  • Poster
    European Resources Forum, Nationales Ressourcen-Forum, 09.-11.11.2016, Berlin, Deutschland
  • Lecture (Conference)
    Aufbereitung und Recycling, 11.-12.11.2015, Freiberg, Deutschland

Publ.-Id: 25050 - Permalink


Local Hydrodynamics, Mixing and Mass Transfer in Bubble Columns with Internals
Möller, F.; Macisaac, A.; Seiler, T.; Hampel, U.; Schubert, M.;
Abstract
Bubble column reactors (BCRs) are apparatuses of choice for the chemical process industry due to their excellent heat and mass transport as well as their simple manufacturing and design without any moving part. They are commonly used for reactions, such as Fischer-Tropsch and methanol synthesis. Most of the reactions carried out in these devices are of exothermic nature and require an efficient heat removal, which can be achieved via internally placed tube bundle heat exchangers. For the Fischer-Tropsch synthesis, a specific heat exchanging surface area between 30 and 40 m²/m³ is needed, which can be provided, for instance, with dense tube bundles inserted in the reactor. Accordingly, the hydrodynamic behavior of the reactor is strongly affected and subsequently, mixing and mass transfer processes are altered, too. Hitherto, the influence of the most common configurations used for the design of shell and tube heat exchangers, i.e. triangular and square pitches, has not been subject of a comparative analysis. Therefore, a study was conducted to reveal global and local hydrodynamics in the equipped bubble column covering a comprehensive sub-channel analysis as well as to disclose the pattern’s influence on gas-liquid mass transfer and liquid mixing behavior.

Figure 1: a) Bubble column reactor with internals, b) with spacer layouts, and c) summary of the studied tube bundle configurations.
A bubble column reactor with an internal diameter of 0.1 m (ID) and 2 m height (clear liquid height of 1.1 m) was employed and operated with deionized water and air. For the internal tube bundles, two configurations, namely, triangular and square tube pitch of two tube diameters (8 and 13 mm), ensuring a similar cross-sectional coverage were chosen (Figure 1).
The ultrafast X-ray tomography was used to disclose the hydrodynamic parameters bubble size and gas holdup. In particular, characteristic sub-channels along the reactor diameter were analyzed (Fig. 2a) to study the effect of the sub-channel position compared with the cross-sectional averaged data in order to examine whether a single sub-channel analysis is sufficient to describe the whole bubble column behavior. In addition, a fast-responding oxygen needle probe was used for mass transfer measurements (Fig. 2b) and wire-mesh sensors (WMS) were applied to track the dispersion of conductive tracers throughout the column’s cross-sectional area (Fig. 2c). The study covered homogenous and heterogeneous flow conditions (2 – 20 cm s-1) in order to also reveal the influence of different regimes.

Figure 2: a) Sub-channel flow structure, b) Mixing analysis based on 2D tracer distributions and c) mass transfer evaluation via oxygen saturation.
The hydrodynamic behavior within the sub-channels was found to depend strongly on their position within the reactor’s cross-sectional area. Furthermore, the influence of tube pattern is also very pronounced. The square configurations show advantageous hydrodynamic behavior with regard to the gas-liquid mass transfer. The small bubbles of narrow size distribution are evenly-distributed over the cross-sectional area and rise with lower velocity, thus, resulting in higher gas holdup and longer bubble-liquid contact time. Triangular configurations, however, introduce a strong flow resistance for the moving bubbles and cause flow asymmetries.
The mixing behavior in the columns with internals was quantified considering axial and radial dispersion of the tracer (Forret et al., 2003). The resulting axial dispersion coefficient was subsequently used for the estimation of the overall volumetric mass transfer coefficient. The dispersion coefficient depends strongly on the internals’ geometry as well as on the bottom structure, i.e. mixing is strongly increased when U-tube bottom ends are used. The mass transfer, however, is lower, with respect to an empty BCR, when internals are inserted due to turbulence dampening.
References
A. Forret, J.-M. Schweitzer, T. Gauthier, R. Krishna and D. Schweich, Liquid Dispersion in Large Diameter Bubble Columns, with and without Internals, The Canadian Journal of Chemical Engineering, Volume 81, June-August 2003, 360-366
  • Lecture (Conference)
    13th International Conference on Gas–Liquid and Gas–Liquid–Solid Reactor Engineering (GLS-13), 20.-23.08.2017, Brussels, Belgium

Publ.-Id: 25049 - Permalink


Synthese Lysin-abgeleiteter Inhibitoren der Transglutaminase 2 als potentielle Radiotracer zur funktionellen Charakterisierung dieses Enzyms
Lohse, M.;
In der vorliegenden Bachelorarbeit wird die Synthese von irreversiblen Transglutaminase 2-Inhibitoren basierend auf einem N6-Acryloyl-L-lysin-Grundgerüst beschrieben. Dafür konnte ausgehend von einem N6-Acryloyl-L-lysin eine Reaktionssequenz aus den drei Schritten Amidkupplung, Boc-Entschützung und N2-Acylierung angewendet werden. Auf diesem Weg erfolgte die Synthese von 23 Inhibitoren mit einer Gesamtausbeute zwischen 2% und 17%. Die Inhibitoren sollen für die Ermittlung von Struktur-Aktivitätsbeziehungen sowie als Vorläuferverbindungen und Referenzverbindungen für PET-Radiotracer verwendet werden.
Weiterhin wird die Synthese eines Fluorophor-konjugierten Substrats der TGase 2 beschrieben. Die Festphasensynthese von 2’-((5-Aminopentyl)isonipecotyl)rhodamin B erfolgte durch eine dreistufige Synthese ausgehend von dem an das 2-Chlortritylchlorid-Harz angebundenen Cadaverin mit einer Gesamtausbeute von 24%. Diese Verbindung soll für ein Fluoreszenzpolarisations-Assay zur Ermittlung der inhibitorischen Potenz (IC50) der irreversiblen TGase 2-Inhibitoren verwendet werden.
  • Bachelor thesis
    Hochschule Zittau/Görlitz, 2016
    Mentor: Dr. Reik Löser
    147 Seiten

Publ.-Id: 25048 - Permalink


Molecular Targeting of Integrins and Integrin-Associated Signaling Networks in Radiation Oncology.
Vehlow, A.; Storch, K.; Matzke, D.; Cordes, N.;
Radiation and chemotherapy are the main pillars of the current multimodal treatment concept for cancer patients. However, tumor recurrences and resistances still hamper treatment success regardless of advances in radiation beam application, particle radiotherapy, and optimized chemotherapeutics. To specifically intervene at key recurrence- and resistance-promoting molecular processes, the development of potent and specific molecular-targeted agents is demanded for an efficient, safe, and simultaneous integration into current standard of care regimens. Potential targets for such an approach are integrins conferring structural and biochemical communication between cells and their microenvironment. Integrin binding to extracellular matrix activates intracellular signaling for regulating essential cellular functions such as survival, proliferation, differentiation, adhesion, and cell motility. Tumor-associated characteristics such as invasion, metastasis, and radiochemoresistance also highly depend on integrin function. Owing to their dual functionality and their overexpression in the majority of human malignancies, integrins present ideal and accessible targets for cancer therapy. In the following chapter, the current knowledge on aspects of the tumor microenvironment, the molecular regulation of integrin-dependent radiochemoresistance and current approaches to integrin targeting are summarized.
Keywords: Focal adhesion signaling; Integrins; Molecular targeting; Radiochemosensitization
  • Book chapter
    Baumann, M.; Krause, M.; Cordes, N: Molecular Radio-Oncology, Volume 198 of the series Recent results in Cancer Research, Berlin Heidelberg: Springer Verlag, 2016, 89-106
    DOI: 10.1007/978-3-662-49651-0_4

Publ.-Id: 25047 - Permalink


Optimisation of Cathepsin B Endopeptidase Substrates as Potential Cleavage Sites for Activatable Cell-Penetrating Peptides (ACPP)
Kuhne, K.; Behring, L.; Belter, B.; Wodtke, R.; Steinbach, J.; Pietzsch, J.; Löser, R.;
High activity of the cysteine protease cathepsin B correlates with increased metastasis, therapy resistance, and a generally poor prognosis in neoplastic diseases [1,2] Therefore, the development of substrate-based radiotracers for in vivo imaging of this protease will be beneficial towards better diagnosis and improved therapy regimens. We aim at developingsuch a probe by combination of a polyarginine-based, activatable cell penetrating peptide, as described by Tsien and others, and newly optimised endopeptidase substrates for cathepsin B [3]. A unique feature of cathepsin B within the cysteine cathepsin family is the occluding loop, a flexible element consisting of 20 amino acids (aa), which is able to cover the active site of the enzyme and thereby regulates the substrate specificity in a pH-dependent manner [1,2]. This phenomenon is mediated by two histidine residues within the occluding loop, which play a crucial role in positioning a potential substrate for carboxydipeptidolytic cleavage.
Starting point for the development of endopeptidase substrates was the carboxydipeptidase substrate Abz‑GIVRAK(Dnp)‑OH (Abz - aminobenzoyl, Dnp - dinitrophenyl) described by Cotrin et al. in 2004, with the fluorophores Abz and Dnp constituting a FRET pair to enable fluorometric detection of the proteolytic cleavage [4]. Two structural changes were introduced to convert the exopeptidase substrate into an endopeptidase substrate for later use as an activator sequence in an aCPP: Firstly, C‑terminal amidation was performed to interrupt the interaction between the terminal carboxyl group and the two His residues within the occluding loop. This resulted in a reduced specificity constant (kcat/Km = 1179 mM‑1s‑1 vs. 139 mM‑1s‑1), indicating attenuated electrostatic/hydrogen bond interactions. Secondly, the peptide sequence was C‑terminally elongated to test longer substrates. Interestingly, the C‑terminal elongation resulted in a hysteretic progress of the enzymatic cleavage, likely a result of the steric displacement of the occluding loop. To evaluate the influence of size, polarity and charge of the C‑terminal aa on the enzymatic hysteresis, 14 variations of this position were synthesized and analysed for their kinetic parameters. The peptide Abz‑GIVRAK(Dnp)G‑V‑NH2 was determined to exhibit the highest specificity constant (kcat/Km = 260 mM‑1s‑1).
The optimised octapeptide sequence is currently inserted as recognition site in a fluorophore-labelled aCPP for monitoring cathepsin B-mediated activation and subsequent cellular uptake, and for investigating kinetics and in vitro stability analysis in future
experiments.
[1] Aggarwal and Sloane, Proteomics Clin. Appl. 2014, 8(5-6), 427-437
[2] Löser and Pietzsch, Front. Chem. 2015, 3, article 37
[3] Jiang et al., PNAS, 2004, 101(51), 17867-17872
[4] Cotrin et al., Anal. Biochem. 2004, 335, 244-252
  • Poster
    34th European Peptide Symposium, 04.-09.09.2016, Leipzig, Deutschland
  • Abstract in refereed journal
    Journal of Peptide Science 22(2016)S2, 177-178
    DOI: 10.1002/psc.2950

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Publ.-Id: 25046 - Permalink


N6-Acryloyl-lysine piperazides as irreversible inhibitors of transglutaminase 2 - synthesis and structure activity relationships
Wodtke, R.; Jäckel, E.; Wong, A.; Lohse, M.; Bauer, D.; Ullm, S.; Steinbach, J.; Pietzsch, J.; Löser, R.;
Various kinds of tumour entities are characterised by an increased activity of transglutaminase 2 (TGase 2), which contributes to an enhanced invasive potential of the tumour cells and their resistance to chemo- and radiotherapy. Therefore, this enzyme represents an interesting target for the development of PET tracers for functional imaging of tumours in vivo [1].
Among the TGase 2 inhibitors described in the literature, N6-acryloyl-lysine-4-arylpiperazides reported by Wityak et al. [2] seem to be most suitable for radiotracer development as these compounds exhibit both strong inhibitory potential and selectivity towards human TGase 2 and show favourable pharmacokinetic properties. Based on this class of compounds, derivatives that allow for labelling with radionuclides such as fluorine-18 and iodine-124 were prepared and their inhibitory potential towards TGase 2 was evaluated.
The N2-acyl-N6-acryloyl-lysine-4-pyridylpiperazides were synthesised in a sequence consisting of N6-acrylation, PyBOP-mediated amide bond formation, Boc deprotection and N2-acylation starting from N2-Boc-lysine. The required pyridylpiperazines were obtained commercially or prepared in a few steps. All final compounds were evaluated in two independent kinetic assays, which detect either the transamidase or hydrolase activity of TGase 2, respectively, with N2-phenylacetyl-N6-acryloyl-lysine-4-(6-methylpyridine-2-yl)piperazide [2] serving as benchmark inhibitor.
Using the outlined synthetic route a series of more than 40 N2-acyl-N6-acryloyl-lysine-4-pyridylpiperazides were prepared in good yields. The kinetic characterisation of the compounds revealed some interesting structure-activity relationships. For example, replacing the 6-methylpyridine-2-yl moiety of the benchmark inhibitor by a 2-nitro-5-pyridyl moiety led to a significantly increased inhibitory effect towards human TGase 2.
Furthermore, substitution of the methyl group by hydrogen or a halogen atom (F, Cl, Br and I) revealed a direct correlation between the van der Waals radius of the substituent and the inhibitory effect towards human TGase 2, with the inhibitor containing iodine being even more potent than the benchmark inhibitor. Covalent docking studies provided information about the binding mode of this inhibitor class for the first time and, thus, allowed for explaining the trends observed in the activity assays and give hints for further improvement of inhibitory potency by specific structural variations.
References:
[1] Pietsch etal. Bioorg. Med. Chern. Lett. 2013, 23, 6528. [2] Wityak etal. ACS Med. Chem. Lett. 2012, 3, 1024.
  • Poster
    Frontiers in Medicinal Chemistry, 13.-16.03.2016, Bonn, Deutschland

Publ.-Id: 25045 - Permalink


Erbium ion implantation into diamond – measurement and modelling of the crystal structure
Cajzl, J.; Nekvindová, P.; Mackova, A.; Malinský, P.; Sedmidubsky, D.; Hušák, M.; Remeš, Z.; Varga, M.; Kromka, A.; Böttger, R.; Oswald, J.;
Diamond is proposed as extraordinary material usable for interdisciplinary fields, especially for optics and photonics. In this contribution we focus on the doping of diamond with erbium as optically active centre. In the theoretical part of study based on DFT simulations we have developed two Er-doped diamond structure models with 0 to 4 carbon vacancies in the vicinity of Er atom and performed geometry optimizations with calculation of cohesive energies and defect formation energies. The theoretical results showed an excellent agreement between the calculated and experimental cohesive energy for the parent diamond. The highest values of cohesive energies and lowest values of defect formation energies were obtained for models with erbium in the substitutional carbon position with 1 or 3 vacancies in the vicinity of erbium atom. From the geometry optimization the structure model with 1 vacancy had an octahedral symmetry whereas the model with 3 vacancies had a coordination of 10 forming a trigonal structure with hexagonal ring. In the experimental part, erbium doped diamond crystal samples were prepared by ion implantation of Er+ ions using ion implantation fluences ranging from 1×1014 ions/cm2 to 5×1015 ions/cm2. The experimental results revealed a high degree of diamond structure damage after the ion implantation process reaching up to 69% of disordered atoms in the samples. The prepared Er-doped diamond samples annealed at the temperatures of 400, 600 and 800 °C in vacuum revealed clear luminescence, where the 〈110〉 cut sample was having approximately 6-7 times higher luminescence intensity than 〈001〉 cut sample with the same ion implantation fluence. The reported results are the first demonstration of the Er luminescence in the single crystal diamond structure for the near-infrared spectral region.
Keywords: diamond, erbium, ion implantation, luminescence, DFT

Publ.-Id: 25044 - Permalink


Evaluation of tumour hypoxia during radiotherapy using [18F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer
Zegers, C. M. L.; Hoebers, F. J. P.; van Elmpt, W.; Bons, J. A.; Öllers, M. C.; Troost, E. G. C.; Eekers, D.; Balmaekers, L.; Arts-Pechtold, M.; Mottaghy, F. M.; Lambin, P.;
BACKGROUND AND PURPOSE:

Increased tumour hypoxia is associated with a worse overall survival in patients with head and neck squamous cell carcinoma (HNSCC). The aims of this study were to evaluate treatment-associated changes in [18F]HX4-PET, hypoxia-related blood biomarkers, and their interdependence.
MATERIAL AND METHODS:

[18F]HX4-PET/CT scans of 20 patients with HNSCC were acquired at baseline and after ±20Gy of radiotherapy. Within the gross-tumour-volumes (GTV; primary and lymph nodes), mean and maximum standardized uptake values, the hypoxic fraction (HF) and volume (HV) were calculated. Also, the changes in spatial uptake pattern were evaluated using [18F]HX4-PET/CT imaging. For all patients, the plasma concentration of CAIX, osteopontin and VEGF was assessed.
RESULTS:

At baseline, tumour hypoxia was detected in 69 % (22/32) of the GTVs. During therapy, we observed a significant decrease in all image parameters. The HF decreased from 21.7 ± 19.8 % (baseline) to 3.6 ± 10.0 % (during treatment; P < 0.001). Only two patients had a HV > 1 cm3 during treatment, which was located for >98 % within the baseline HV. During treatment, no significant changes in plasma CAIX or VEGF were observed, while osteopontin was increased.
CONCLUSIONS:

[18F]HX4-PET/CT imaging allows monitoring changes in hypoxia during (chemo)radiotherapy whereas the blood biomarkers were not able to detect a treatment-associated decrease in hypoxia.
Keywords: CAIX; Hypoxia; Osteopontin; PET; VEGF

Publ.-Id: 25043 - Permalink


Synthese und enzymkinetische Prüfung von N6-Acryloyllysinpiperaziden als potentielle Radiotracer zur Bildgebung der Transglutaminase 2 (TGase 2)
Wodtke, R.; Hauser, C.; Jäckel, E.; Ruiz-Gomez, G.; Ullm, S.; Wong, A.; Lohse, M.; Steinbach, J.; Pietzsch, J.; Pietsch, M.; Löser, R.;
Ziel/Aim: Zahlreiche Krebsarten zeichnen sich durch eine deutlich erhöhte Aktivität der TGase 2 aus, die vor allem mit einer gesteigerter Chemo- und Strahlenresistenz der Krebszellen korreliert. Daher stellt dieses Enzym ein interessantes Target für die Entwicklung von PET-Tracern zur funktionellen Bildgebung derartiger Tumoren dar. Unter den bekannten Inhibitoren der TGase 2 erscheinen die N6-Acryloyllysin-4-arylpiperazide für die Entwicklung von Radiotracern als besonders geeignet, da sie über eine hohe inhibitorische Potenz und Selektivität verfügen (1). Daher sollten ausgehend von dieser Verbindungsklasse Derivate zugänglich gemacht werden, die eine Markierung mit Radionukliden wie F-18 oder Radioiod erlauben.
Methodik/Methods: Ausgehend von N2-Boc-Lysin wurden in einer Sequenz bestehend aus N6-Acrylierung, Amidknüpfung, Boc-Entschützung und N2-Acylierung verschiedene N2-Acyl-N6-acryloyllysin-4-arylpiperazide synthetisiert. Alle Zielverbindungen wurden in zwei unabhängigen enzymkinetischen Assays, welche die Transamidase- bzw. Hydrolaseaktivität der TGase 2 erfassen, evaluiert.
Ergebnisse/Results: Bisher wurde eine Serie von mehr als 40 Inhibitoren synthetisiert, deren enzymkinetische Charakterisierung interessante Struktur-Wirkungsbeziehungen aufdeckte. So führt der Ersatz des 6-Methyl-2-pyridyl-Restes im literaturbekannten Referenzinhibitor N2-Phenylacetyl-N6-acryloyllysin-4-(6-methylpyridin-2-yl)piperazid gegen einen 2-Nitro-5 pyridyl-Rest zu einer deutlich höheren Hemmwirkung gegenüber der TGase 2. Untersuchungen zum kovalenten Docking der Inhibitoren im aktiven Zentrum der TGase 2 geben erstmals Aufschluss über deren Bindungsmodus.
Schlussfolgerungen/Conclusions: Die gefundenen Struktur-Wirkungs-Beziehungen können gezielt genutzt werden, um potentielle Radiotracer hinsichtlich ihrer Hemmkinetik zu verbessern, was für ihre Anwendung zur molekularen Bildgebung in vivo vorteilhaft ist.
Literatur/References:
[1] Wityak et al. ACS Med. Chem. Lett. 2012, 3, 1024.
  • Poster
    54. Jahrestagung der Deutschen Gesellschaft für Nuklearmedizin, 20.-23.04.2016, Dresden, Deutschland
  • Abstract in refereed journal
    Nuklearmedizin 55(2016)2, A77-A77

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Publ.-Id: 25042 - Permalink


Simulating laser wakefield acceleration with PIConGPU - from modeling the laser plasma dynamic to in-situ radiation calculation
Pausch, R.; Debus, A.; Burau, H.; Huebl, A.; Garten, M.; Steiniger, K.; Widera, R.; Bussmann, M.; Schramm, U.;
We recent simulations of laser wakefield acceleration on recent experiments performed at HZDR. We focus on how to best approximate the experimental setup using newly developed laser-models, as well as particle creation- and ionization-methods. Furthermore, we elaborate on predicting experimentally observable radiation signatures from the simulation.

We discuss in detail the influence of various ionization mechanisms, including BSI, ADK and Keldysh, and how to model the initial gas or plasma distribution. Furthermore, we present recent improvements in the laser implementation, that added Laguerre-Gauss modes, which drastically reduces discrepancies between previous simulations and experiments. On top of simulating plasma dynamics, we present how to predict experimental observables using PIConGPU’s in-situ synthetic diagnostics, especially the classical Liénard-Wiechert potential- and QED-based radiation. It allows predicting both coherent and incoherent radiation spectrally from infrared to x-rays and provides the capability to resolve the radiation polarization as well as determine its temporal and spatial origin.

On the examples of a large-scale LWFA simulation, we illustrate how we reduce the gap between simulated plasma dynamics and radiation observed in experiments and discuss valuable spectral signatures which allow conclusions on the micrometer femtosecond electron dynamics occurring during acceleration.
Keywords: PIConGPU, LWFA, radiation, GPU, ionization, laser, synthetic diagnostics
  • Poster
    3rd Annual Matter and Technologies Meeting, Darmstadt 2017, 30.01.-02.02.2017, Darmstadt, Deutschland
  • Lecture (Conference)
    3rd Annual Matter and Technologies Meeting, Darmstadt 2017, 30.01.-02.02.2017, Darmstadt, Deutschland

Publ.-Id: 25041 - Permalink


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