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Rajan, Roopa ; Divya, K. P. ; Kandadai, Rukmini Mridula ; Yadav, Ravi ; Satagopam, Venkata P. ; Satagopam, Venkata P. ; Madhusoodanan, U. K. ; Agarwal, Pankaj ; Kumar, Niraj ; Ferreira, Teresa ; Kumar, Hrishikesh ; Prasad, A. V. Sreeram ; Shetty, Kuldeep ; Mehta, Sahil ; Desai, Soaham ; Kumar, Suresh ; Prashant, L. K. ; Bhatt, Mohit ; Wadia, Pettarusp ; Ramalingam, Sudha ; Wali, G. M. ; Pandey, Sanjay ; Bartusch, Felix ; Hannussek, Maximilian ; Krüger, Jens ; Kumar-Sreelatha, Ashwin ; Grover, Sandeep ; Lichtner, Peter ; Sturm, Marc ; Roeper, Jochen ; Busskamp, Volker ; Chandak, Giriraj R. ; Schwamborn, Jens ; Seth, Pankaj ; Gasser, Thomas ; Rieß, Olaf ; Goyal, Vinay ; Goyal, Vinay ; Pal, Pramod Kumar ; Borgohain, Rupam ; Krüger, Rejko ; Kishore, Asha ; Sharma, Manu
Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our “hub-spoke” model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.
Frey, Wiebke ; Borrmann, Stephan ; Kunkel, Daniel ; Weigel, Ralf ; Reus, Marian de ; Schlager, Hans ; Roiger, Anke ; Voigt, Christiane ; Hoor, Peter ; Curtius, Joachim ; Krämer, Martina ; Schiller, Cornelius ; Volk, C.-Michael ; Homan, Carine Dorianne ; Fierli, Federico ; Di Donfrancesco, Guido ; Ulanovsky, Alexey ; Ravegnani, Fabrizio ; Sitnikov, Nicolay M. ; Viciani, Silvia ; D'Amato, F. ; Shur, Genrikh N. ; Belyaev, Gennady ; Law, Kathy S. ; Cairo, Francesco
In situ measurements of ice crystal size distributions in tropical upper troposphere/lower stratosphere (UT/LS) clouds were performed during the SCOUT-AMMA campaign over West Africa in August 2006. The cloud properties were measured with a Forward Scattering Spectrometer Probe (FSSP-100) and a Cloud Imaging Probe (CIP) operated aboard the Russian high altitude research aircraft M-55 Geophysica with the mission base in Ouagadougou, Burkina Faso. A total of 117 ice particle size distributions were obtained from the measurements in the vicinity of Mesoscale Convective Systems (MCS). Two to four modal lognormal size distributions were fitted to the average size distributions for different potential temperature bins. The measurements showed proportionately more large ice particles compared to former measurements above maritime regions. With the help of trace gas measurements of NO, NOy, CO2, CO, and O3 and satellite images, clouds in young and aged MCS outflow were identified. These events were observed at altitudes of 11.0 km to 14.2 km corresponding to potential temperature levels of 346 K to 356 K. In a young outflow from a developing MCS ice crystal number concentrations of up to (8.3 ± 1.6) cm−3 and rimed ice particles with maximum dimensions exceeding 1.5 mm were found. A maximum ice water content of 0.05 g m−3 was observed and an effective radius of about 90 μm. In contrast the aged outflow events were more diluted and showed a maximum number concentration of 0.03 cm−3, an ice water content of 2.3 × 10−4 g m−3, an effective radius of about 18 μm, while the largest particles had a maximum dimension of 61 μm.
Close to the tropopause subvisual cirrus were encountered four times at altitudes of 15 km to 16.4 km. The mean ice particle number concentration of these encounters was 0.01 cm−3 with maximum particle sizes of 130 μm, and the mean ice water content was about 1.4 × 10−4 g m−3. All known in situ measurements of subvisual tropopause cirrus are compared and an exponential fit on the size distributions is established for modelling purposes.
A comparison of aerosol to ice crystal number concentrations, in order to obtain an estimate on how many ice particles may result from activation of the present aerosol, yielded low ratios for the subvisual cirrus cases of roughly one cloud particle per 30 000 aerosol particles, while for the MCS outflow cases this resulted in a high ratio of one cloud particle per 300 aerosol particles.
Frey, Wiebke ; Borrmann, Stephan ; Kunkel, Daniel ; Weigel, Ralf ; Reus, Marian de ; Schlager, Hans ; Roiger, Anke ; Voigt, Christiane ; Hoor, Peter ; Curtius, Joachim ; Krämer, Martina ; Schiller, Cornelius ; Volk, C.-Michael ; Homan, Carine Dorianne ; Fierli, Federico ; Di Donfrancesco, Guido ; Ulanovsky, Alexey ; Ravegnani, Fabrizio ; Sitnikov, Nicolay M. ; Viciani, Silvia ; D'Amato, Francesco ; Shur, Genrikh N. ; Belyaev, Gennady ; Law, Kathy S. ; Cairo, Francesco
In-situ measurements of ice crystal size distributions in tropical upper troposphere/lower stratosphere (UT/LS) clouds were performed during the SCOUT-AMMA campaign over West Africa in August 2006. The cloud properties were measured with a Forward Scattering Spectrometer Probe (FSSP-100) and a Cloud Imaging Probe (CIP) operated aboard the Russian high altitude research aircraft M-55 ''Geophysica'' with the mission base in Ouagadougou, Burkina Faso. A total of 117 ice particle size distributions were obtained from the measurements in the vicinity of Mesoscale Convective Systems (MCS). Two or three modal lognormal size distributions were fitted to the average size distributions for different potential temperature bins. The measurements showed proportionate more large ice particles compared to former measurements above maritime regions. With the help of trace gas measurements of NO, NOy, CO2, CO, and O3, and satellite images clouds in young and aged MCS outflow were identified. These events were observed at altitudes of 11.0 km to 14.2 km corresponding to potential temperature levels of 346 K to 356 K. In a young outflow (developing MCS) ice crystal number concentrations of up to 8.3 cm−3 and rimed ice particles with maximum dimensions exceeding 1.5 mm were found. A maximum ice water content of 0.05 g m−3 was observed and an effective radius of about 90 μm. In contrast the aged outflow events were more diluted and showed a maximum number concentration of 0.03 cm−3, an ice water content of 2.3 × 10−4 g m−3, an effective radius of about 18 μm, while the largest particles had a maximum dimension of 61 μm.
Close to the tropopause subvisual cirrus were encountered four times at altitudes of 15 km to 16.4 km. The mean ice particle number concentration of these encounters was 0.01 cm−3 with maximum particle sizes of 130 μm, and the mean ice water content was about 1.4 × 10−4 g m−3. All known in-situ measurements of subvisual tropopause cirrus are compared and an exponential fit on the size distributions is established in order to give a parameterisation for modelling.
A comparison of aerosol to ice crystal number concentrations, in order to obtain an estimate on how many ice particles result from activation of the present aerosol, yielded low activation ratios for the subvisual cirrus cases of roughly one cloud particle per 30 000 aerosol particles, while for the MCS outflow cases this resulted in a high ratio of one cloud particle per 300 aerosol particles.
Fuchs, Silke M. ; Fluhr, Joachim Wilhelm ; Bankova, Lora ; Tittelbach, Jörg ; Hoffmann, Gerd ; Elsner, Peter
Background: Common warts (verrucae vulgares) are human papilloma virus (HPV) infections with a high incidence and prevalence, most often affecting hands and feet, being able to impair quality of life. About 30 different therapeutic regimens described in literature reveal a lack of a single striking strategy. Recent publications showed positive results of photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) in the treatment of HPV-induced skin diseases, especially warts, using visible light (VIS) to stimulate an absorption band of endogenously formed protoporphyrin IX. Additional experiences adding waterfiltered infrared A (wIRA) during 5-ALA-PDT revealed positive effects. Aim of the study: First prospective randomised controlled blind study including PDT and wIRA in the treatment of recalcitrant common hand and foot warts. Comparison of "5-ALA cream (ALA) vs. placebo cream (PLC)" and "irradiation with visible light and wIRA (VIS+wIRA) vs. irradiation with visible light alone (VIS)". Methods: Pre-treatment with keratolysis (salicylic acid) and curettage. PDT treatment: topical application of 5-ALA (Medac) in "unguentum emulsificans aquosum" vs. placebo; irradiation: combination of VIS and a large amount of wIRA (Hydrosun® radiator type 501, 4 mm water cuvette, waterfiltered spectrum 590-1400 nm, contact-free, typically painless) vs. VIS alone. Post-treatment with retinoic acid ointment. One to three therapy cycles every 3 weeks. Main variable of interest: "Percent change of total wart area of each patient over the time" (18 weeks). Global judgement by patient and by physician and subjective rating of feeling/pain (visual analogue scales). 80 patients with therapy-resistant common hand and foot warts were assigned randomly into one of the four therapy groups with comparable numbers of warts at comparable sites in all groups. Results: The individual total wart area decreased during 18 weeks in group 1 (ALA+VIS+wIRA) and in group 2 (PLC+VIS+wIRA) significantly more than in both groups without wIRA (group 3 (ALA+VIS) and 4 (PLC+VIS)): medians and interquartile ranges: -94% (-100%/-84%) vs. -99% (-100%/-71%) vs. -47% (-75%/0%) vs. -73% (-92%/-27%). After 18 weeks the two groups with wIRA differed remarkably from the two groups without wIRA: 42% vs. 7% completely cured patients; 72% vs. 34% vanished warts. Global judgement by patient and by physician and subjective rating of feeling was much better in the two groups with wIRA than in the two groups without wIRA. Conclusions: The above described complete treatment scheme of hand and foot warts (keratolysis, curettage, PDT treatment, irradiation with VIS+wIRA, retinoic acid ointment; three therapy cycles every 3 weeks) proved to be effective. Within this treatment scheme wIRA as non-invasive and painless treatment modality revealed to be an important, effective factor, while photodynamic therapy with 5-ALA in the described form did not contribute recognisably - neither alone (without wIRA) nor in combination with wIRA - to a clinical improvement. For future treatment of warts an even improved scheme is proposed: one treatment cycle (keratolysis, curettage, wIRA, without PDT) once a week for six to nine weeks. © 2004 Fuchs et al; licensee German Medical Science. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL : http://www.egms.de/en/gms/volume2.shtml
Krenn, Brigitte M. ; Egorov, Andrej ; Romanovskaya-Romanko, Ekaterina ; Wolschek, Markus ; Nakowitsch, Sabine ; Ruthsatz, Tanja ; Kiefmann, Bettina ; Morokutti, Alexander ; Humer, Johannes ; Geiler, Janina ; Cinatl, Jindrich ; Michaelis, Martin ; Wressnigg, Nina ; Sturlan, Sanda ; Ferko, Boris ; Batishchev, Oleg V. ; Indenbom, Andrey V. ; Zhu, Rong ; Kastner, Markus ; Hinterdorfer, Peter ; Kiselev, Oleg A. ; Muster, Thomas ; Romanova, Julia
Background: H5N1 influenza vaccines, including live intranasal, appear to be relatively less immunogenic compared to seasonal analogs. The main influenza virus surface glycoprotein hemagglutinin (HA) of highly pathogenic avian influenza viruses (HPAIV) was shown to be more susceptible to acidic pH treatment than that of human or low pathogenic avian influenza viruses. The acidification machinery of the human nasal passageway in response to different irritation factors starts to release protons acidifying the mucosal surface (down to pH of 5.2). We hypothesized that the sensitivity of H5 HA to the acidic environment might be the reason for the low infectivity and immunogenicity of intranasal H5N1 vaccines for mammals. Methodology/Principal Findings: We demonstrate that original human influenza viruses infect primary human nasal epithelial cells at acidic pH (down to 5.4), whereas H5N1 HPAIVs lose infectivity at pH <= 5.6. The HA of A/Vietnam/1203/04 was modified by introducing the single substitution HA2 58K -> I, decreasing the pH of the HA conformational change. The H5N1 reassortants containing the indicated mutation displayed an increased resistance to acidic pH and high temperature treatment compared to those lacking modification. The mutation ensured a higher viral uptake as shown by immunohistochemistry in the respiratory tract of mice and 25 times lower mouse infectious dose50. Moreover, the reassortants keeping 58K -> I mutation designed as a live attenuated vaccine candidate lacking an NS1 gene induced superior systemic and local antibody response after the intranasal immunization of mice. Conclusion/Significance: Our finding suggests that an efficient intranasal vaccination with a live attenuated H5N1 virus may require a certain level of pH and temperature stability of HA in order to achieve an optimal virus uptake by the nasal epithelial cells and induce a sufficient immune response. The pH of the activation of the H5 HA protein may play a substantial role in the infectivity of HPAIVs for mammals.
Jeltsch, Florian ; Bonte, Dries ; Pe'er, Guy ; Reineking, Björn ; Leimgruber, Peter ; Balkenhol, Niko ; Schröder, Boris ; Buchmann, Carsten M. ; Mueller, Thomas ; Blaum, Niels ; Zurell, Damaris ; Böhning-Gaese, Katrin ; Wiegand, Thorsten ; Eccard, Jana A. ; Hofer, Heribert ; Reeg, Jette ; Eggers, Ute ; Bauer, Silke
Movement of organisms is one of the key mechanisms shaping biodiversity, e.g. the distribution of genes, individuals and species in space and time. Recent technological and conceptual advances have improved our ability to assess the causes and consequences of individual movement, and led to the emergence of the new field of ‘movement ecology’. Here, we outline how movement ecology can contribute to the broad field of biodiversity research, i.e. the study of processes and patterns of life among and across different scales, from genes to ecosystems, and we propose a conceptual framework linking these hitherto largely separated fields of research. Our framework builds on the concept of movement ecology for individuals, and demonstrates its importance for linking individual organismal movement with biodiversity. First, organismal movements can provide ‘mobile links’ between habitats or ecosystems, thereby connecting resources, genes, and processes among otherwise separate locations. Understanding these mobile links and their impact on biodiversity will be facilitated by movement ecology, because mobile links can be created by different modes of movement (i.e., foraging, dispersal, migration) that relate to different spatiotemporal scales and have differential effects on biodiversity. Second, organismal movements can also mediate coexistence in communities, through ‘equalizing’ and ‘stabilizing’ mechanisms. This novel integrated framework provides a conceptual starting point for a better understanding of biodiversity dynamics in light of individual movement and space-use behavior across spatiotemporal scales. By illustrating this framework with examples, we argue that the integration of movement ecology and biodiversity research will also enhance our ability to conserve diversity at the genetic, species, and ecosystem levels.
Lorenz, Nadja Irene ; Sittig, Alina C. M. ; Urban, Hans ; Luger, Anna-Luisa ; Engel, Anna Larissa ; Münch, Christian ; Steinbach, Joachim Peter ; Ronellenfitsch, Michael Wilfried
The integrated stress response (ISR) is a central cellular adaptive program that is activated by diverse stressors including ER stress, hypoxia and nutrient deprivation to orchestrate responses via activating transcription factor 4 (ATF4). We hypothesized that ATF4 is essential for the adaptation of human glioblastoma (GB) cells to the conditions of the tumor microenvironment and is contributing to therapy resistance against chemotherapy. ATF4 induction in GB cells was modulated pharmacologically and genetically and investigated in the context of temozolomide treatment as well as glucose and oxygen deprivation. The relevance of the ISR was analyzed by cell death and metabolic measurements under conditions to approximate aspects of the GB microenvironment. ATF4 protein levels were induced by temozolomide treatment. In line, ATF4 gene suppressed GB cells (ATF4sh) displayed increased cell death and decreased survival after temozolomide treatment. Similar results were observed after treatment with the ISR inhibitor ISRIB. ATF4sh and ISRIB treated GB cells were sensitized to hypoxia-induced cell death. Our experimental study provides evidence for an important role of ATF4 for the adaptation of human GB cells to conditions of the tumor microenvironment characterized by low oxygen and nutrient availability and for the development of temozolomide resistance. Inhibiting the ISR in GB cells could therefore be a promising therapeutic approach.
Coimbra, Raphael T. F. ; Winter, Sven ; Kumar, Vikas ; Koepfli, Klaus-Peter ; Gooley, Rebecca M. ; Dobrynin, Pavel ; Fennessy, Julian ; Janke, Axel
Species is the fundamental taxonomic unit in biology and its delimitation has implications for conservation. In giraffe (Giraffa spp.), multiple taxonomic classifications have been proposed since the early 1900s.1 However, one species with nine subspecies has been generally accepted,2 likely due to limited in-depth assessments, subspecies hybridizing in captivity,3,4 and anecdotal reports of hybrids in the wild.5 Giraffe taxonomy received new attention after population genetic studies using traditional genetic markers suggested at least four species.6,7 This view has been met with controversy,8 setting the stage for debate.9,10 Genomics is significantly enhancing our understanding of biodiversity and speciation relative to traditional genetic approaches and thus has important implications for species delineation and conservation.11 We present a high-quality de novo genome assembly of the critically endangered Kordofan giraffe (G. camelopardalis antiquorum)12 and a comprehensive whole-genome analysis of 50 giraffe representing all traditionally recognized subspecies. Population structure and phylogenomic analyses support four separately evolving giraffe lineages, which diverged 230–370 ka ago. These lineages underwent distinct demographic histories and show different levels of heterozygosity and inbreeding. Our results strengthen previous findings of limited gene flow and admixture among putative giraffe species6,7,9 and establish a genomic foundation for recognizing four species and seven subspecies, the latter of which should be considered as evolutionary significant units. Achieving a consensus over the number of species and subspecies in giraffe is essential for adequately assessing their threat level and will improve conservation efforts for these iconic taxa.
Quantification of circulating endothelial progenitor cells using the modified ISHAGE protocol
(2010)
Schmidt-Lucke, Caroline ; Fichtlscherer, Stephan ; Aicher, Alexandra ; Tschöpe, Carsten ; Schultheiß, Heinz-Peter ; Zeiher, Andreas M. ; Dimmeler, Stefanie
Aims: Circulating endothelial progenitor cells (EPC), involved in endothelial regeneration, neovascularisation, and determination of prognosis in cardiovascular disease can be characterised with functional assays or using immunofluorescence and flow cytometry. Combinations of markers, including CD34+KDR+ or CD133+KDR+, are used. This approach, however may not consider all characteristics of EPC. The lack of a standardised protocol with regards to reagents and gating strategies may account for the widespread inter-laboratory variations in quantification of EPC. We, therefore developed a novel protocol adapted from the standardised so-called ISHAGE protocol for enumeration of haematopoietic stem cells to enable comparison of clinical and laboratory data. Methods and Results: In 25 control subjects, 65 patients with coronary artery disease (CAD; 40 stable CAD, 25 acute coronary syndrome/acute myocardial infarction (ACS)), EPC were quantified using the following approach: Whole blood was incubated with CD45, KDR, and CD34. The ISHAGE sequential strategy was used, and finally, CD45dimCD34+ cells were quantified for KDR. A minimum of 100 CD34+ events were collected. For comparison, CD45+CD34+ and CD45-CD34+ were analysed simultaneously. The number of CD45dimCD34+KDR+ cells only were significantly higher in healthy controls compared to patients with CAD or ACS (p = 0.005 each, p<0.001 for trend). An inverse correlation of CD45dimCD34+KDR+ with disease activity (r = -0.475, p<0.001) was confirmed. Only CD45dimCD34+KDR+ correlated inversely with the number of diseased coronaries (r = -0.344; p<0.005). In a second study, a 4-week de-novo treatment of atorvastatin in stable CAD evoked an increase only of CD45dimCD34+KDR+ EPC (p<0.05). CD45+CD34+KDR+ and CD45-CD34+KDR+ were indifferent between the three groups. Conclusion: Our newly established protocol adopted from the standardised ISHAGE protocol achieved higher accuracy in EPC enumeration confirming previous findings with respect to the correlation of EPC with disease activity and the increase of EPC during statin therapy. The data of this study show the CD45dim fraction to harbour EPC.
Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial
(2021)
Niemeyer, Charlotte ; Flotho, Christian ; Lipka, Daniel ; Starý, Jan ; Rössig, Claudia ; Baruchel, André ; Klingebiel, Thomas ; Micalizzi, Concetta ; Michel, Gérard ; Nysom, Karsten ; Rives, Susana ; Schmugge Liner, Markus ; Zecca, Marco ; Schönung, Maximilian ; Baumann, Irith ; Nöllke, Peter ; Benettaib, Bouchra ; Biserna, Noha ; Poon, Jennifer ; Simcock, Mathew ; Patturajan, Meera ; Menezes, Daniel ; Gaudy, Allison ; Heuvel-Eibrink, Marry M. van den ; Locatelli, Franco
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration-–time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.
Voskens, Caroline J. ; Goldinger, Simone M. ; Loquai, Carmen ; Robert, Caroline ; Kähler, Katharina C. ; Berking, Carola ; Bergmann, Tanja Regina ; Bockmeyer, Clemens Luitpold ; Eigentler, Thomas Kurt ; Fluck, Michael ; Garbe, Claus ; Gutzmer, Ralf ; Grabbe, Stephan ; Hauschild, Axel ; Hein, Rüdiger ; Hundorfean, Gheorghe ; Justich, Armin ; Keller, Ullrich ; Klein, Christina ; Mateus, Christine ; Mohr, Peter ; Pätzold, Sylvie ; Satzger, Imke ; Schadendorf, Dirk ; Schlaeppi, Marc ; Schuler, Gerold ; Schuler-Thurner, Beatrice ; Trefzer, Uwe ; Ulrich, Jens ; Vaubel, Julia ; Moos, Roger von ; Weder, Patrik ; Wilhelm, Tabea ; Göppner, Daniela ; Dummer, Reinhard ; Heinzerling, Lucie
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
Tombach, Bernd ; Bohndorf, Klaus ; Brodtrager, Wolfgang ; Claussen, Claus D. ; Düber, Christoph ; Galanski, Michael ; Grabbe, Eckhardt ; Gortenuti, Giacomo ; Kuhn, Michael ; Gross-Fengels, Walter ; Hammerstingl, Renate Maria ; Happel, Brigitte ; Heinz-Peer, Gertraud ; Jung, Gregor ; Kittner, Thomas ; Lagalla, Roberto ; Lengsfeld, Philipp ; Loose, Reinhard ; Oyen, Raymond H. G. ; Pavlica, Pietro ; Pering, Christiane ; Pozzi-Mucelli, Roberto ; Persigehl, Thorsten ; Reimer, Peter ; Renken, Nomdo S. ; Richter, Götz M. ; Rummeny, Ernst J. ; Schäfer, Fritz ; Szczerbo-Trojanowska, Malgorzata ; Urbanik, Andrzej ; Vogl, Thomas J. ; Hajek, Paul
The purpose of this phase III clinical trial was to compare two different extracellular contrast agents, 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine, for magnetic resonance imaging (MRI) in patients with known or suspected focal renal lesions. Using a multicenter, single-blind, interindividual, randomized study design, both contrast agents were compared in a total of 471 patients regarding their diagnostic accuracy, sensitivity, and specificity to correctly classify focal lesions of the kidney. To test for noninferiority the diagnostic accuracy rates for both contrast agents were compared with CT results based on a blinded reading. The average diagnostic accuracy across the three blinded readers (‘average reader’) was 83.7% for gadobutrol and 87.3% for gadopentate dimeglumine. The increase in accuracy from precontrast to combined precontrast and postcontrast MRI was 8.0% for gadobutrol and 6.9% for gadopentate dimeglumine. Sensitivity of the average reader was 85.2% for gadobutrol and 88.7% for gadopentate dimeglumine. Specificity of the average reader was 82.1% for gadobutrol and 86.1% for gadopentate dimeglumine. In conclusion, this study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentate dimeglumine in the diagnostic assessment of renal lesions with CE-MRI.
Stegmann, Yannik ; Schiele, Miriam A. ; Schümann, Dirk ; Lonsdorf, Tina B. ; Zwanzger, Peter M. ; Romanos, Marcel ; Reif, Andreas ; Domschke, Katharina ; Deckert, Jürgen ; Gamer, Matthias ; Pauli, Paul
Previous research indicates that anxiety disorders are characterized by an overgeneralization of conditioned fear as compared with healthy participants. Therefore, fear generalization is considered a key mechanism for the development of anxiety disorders. However, systematic investigations on the variance in fear generalization are lacking. Therefore, the current study aims at identifying distinctive phenotypes of fear generalization among healthy participants. To this end, 1175 participants completed a differential fear conditioning phase followed by a generalization test. To identify patterns of fear generalization, we used a k-means clustering algorithm based on individual arousal generalization gradients. Subsequently, we examined the reliability and validity of the clusters and phenotypical differences between subgroups on the basis of psychometric data and markers of fear expression. Cluster analysis reliably revealed five clusters that systematically differed in mean responses, differentiation between conditioned threat and safety, and linearity of the generalization gradients, though mean response levels accounted for most variance. Remarkably, the patterns of mean responses were already evident during fear acquisition and corresponded most closely to psychometric measures of anxiety traits. The identified clusters reliably described subgroups of healthy individuals with distinct response characteristics in a fear generalization test. Following a dimensional view of psychopathology, these clusters likely delineate risk factors for anxiety disorders. As crucial group characteristics were already evident during fear acquisition, our results emphasize the importance of average fear responses and differentiation between conditioned threat and safety as risk factors for anxiety disorders.
Jarick, Ivonne ; Volckmar, Anna-Lena ; Pütter, Carolin ; Pechlivanis, Sonali ; Nguyen, Trang T. ; Dauvermann, Maria R. ; Beck, Sebastian ; Albayrak, Özgür ; Scherag, Susann ; Gilsbach, Susanne ; Cichon, Sven ; Hoffmann, Per ; Degenhardt, Franziska ; Nöthen, Markus Maria ; Schreiber, Stefan ; Wichmann, Heinz Erich ; Jöckel, Karl-Heinz ; Heinrich, Joachim ; Tiesler, Carla Marie Thérèse ; Faraone, Stephen V. ; Walitza, Susanne ; Sinzig, Judith ; Freitag, Christine M. ; Meyer, Jobst ; Herpertz-Dahlmann, Beate ; Lehmkuh, Gerd ; Renner, Tobias J. ; Warnke, Andreas ; Romanos, Marcel ; Lesch, Klaus-Peter J. ; Reif, Andreas ; Schimmelmann, Benno G. ; Hebebrand, Johannes ; Scherag, André ; Hinney, Anke
Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
Hahn, Tim ; Marquand, Andre F. ; Plichta, Michael M. ; Ehlis, Ann-Christine ; Schecklmann, Martin ; Dresler, Thomas ; Jarczok, Tomasz Antoni ; Eirich, Elisa ; Leonhard, Christine ; Reif, Andreas ; Lesch, Klaus-Peter J. ; Brammer, Michael J. ; Mourão-Miranda, Janaina ; Fallgatter, Andreas Jochen
Pattern recognition approaches to the analysis of neuroimaging data have brought new applications such as the classification of patients and healthy controls within reach. In our view, the reliance on expensive neuroimaging techniques which are not well tolerated by many patient groups and the inability of most current biomarker algorithms to accommodate information about prior class frequencies (such as a disorder's prevalence in the general population) are key factors limiting practical application. To overcome both limitations, we propose a probabilistic pattern recognition approach based on cheap and easy-to-use multi-channel near-infrared spectroscopy (fNIRS) measurements. We show the validity of our method by applying it to data from healthy controls (n = 14) enabling differentiation between the conditions of a visual checkerboard task. Second, we show that high-accuracy single subject classification of patients with schizophrenia (n = 40) and healthy controls (n = 40) is possible based on temporal patterns of fNIRS data measured during a working memory task. For classification, we integrate spatial and temporal information at each channel to estimate overall classification accuracy. This yields an overall accuracy of 76% which is comparable to the highest ever achieved in biomarker-based classification of patients with schizophrenia. In summary, the proposed algorithm in combination with fNIRS measurements enables the analysis of sub-second, multivariate temporal patterns of BOLD responses and high-accuracy predictions based on low-cost, easy-to-use fNIRS patterns. In addition, our approach can easily compensate for variable class priors, which is highly advantageous in making predictions in a wide range of clinical neuroimaging applications. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.
Gottlieb, Alice B. ; Merola, Joseph F. ; Reich, Kristian ; Behrens, Frank ; Nash, Peter ; Griffiths, Christopher E. M. ; Bao, Weibin ; Pellet, Pascale ; Pricop, Luminita ; McInnes, Iain
Background: Secukinumab [an interleukin (IL)‐17A inhibitor] has demonstrated significantly higher efficacy vs. etanercept (a tumour necrosis factor inhibitor) and ustekinumab (an IL‐12/23 inhibitor) in patients with moderate‐to‐severe plaque psoriasis.
Objectives: To report 52‐week results from a prespecified analysis of patients with active psoriatic arthritis (PsA) having concomitant moderate‐to‐severe plaque psoriasis from the head‐to‐head EXCEED monotherapy study comparing secukinumab with adalimumab.
Methods: Patients were randomized to receive secukinumab 300 mg via subcutaneous injection at baseline, week 1–4, and then every 4 weeks until week 48 or adalimumab 40 mg via subcutaneous injection every 2 weeks from baseline until week 50. Assessments in patients with concomitant moderate‐to‐severe psoriasis, defined as having affected body surface area > 10% or Psoriasis Area and Severity Index (PASI) ≥ 10 at baseline, included musculoskeletal, skin and quality‐of‐life outcomes. Missing data were handled using multiple imputation.
Results: Of the 853 patients [secukinumab (N = 426), adalimumab (N = 427)], 211 (24·7%) had concomitant moderate‐to‐severe psoriasis [secukinumab (N = 110, 25·8%), adalimumab (N = 101, 23·7%)]. Up to week 50, 5·5% of patients discontinued secukinumab vs.17·8% in the adalimumab group. The proportion of patients who achieved American College of Rheumatology (ACR) 20 response was 76·4% with secukinumab vs. 68·3% with adalimumab (P = 0·175), PASI 100 response was 39·1% vs. 23·8% (P = 0·013), and simultaneous improvement in ACR 50 and PASI 100 response at week 52 was 28·2% vs. 17·7%, respectively (P = 0·06). Secukinumab demonstrated consistently higher responses vs. adalimumab across skin endpoints.
Conclusions: This prespecified analysis in PsA patients with concomitant moderate‐to‐severe plaque psoriasis in the EXCEED study provides further evidence that IL‐17 inhibitors offer a comprehensive biological treatment to manage the concomitant features of psoriasis and PsA.
Baudena, Mara ; Dekker, Stefan C. ; Bodegom, Peter M. van ; Cuesta, Barbara ; Higgins, Steven Ian ; Lehsten, Veiko ; Reick, Christian H. ; Rietkerk, Max ; Scheiter, Simon ; Yin, Zun ; Zavala, Miguel Ángel de ; Brovkin, Victor
The forest, savanna, and grassland biomes, and the transitions between them, are expected to undergo major changes in the future due to global climate change. Dynamic global vegetation models (DGVMs) are very useful for understanding vegetation dynamics under the present climate, and for predicting its changes under future conditions. However, several DGVMs display high uncertainty in predicting vegetation in tropical areas. Here we perform a comparative analysis of three different DGVMs (JSBACH, LPJ-GUESS-SPITFIRE and aDGVM) with regard to their representation of the ecological mechanisms and feedbacks that determine the forest, savanna, and grassland biomes, in an attempt to bridge the knowledge gap between ecology and global modeling. The outcomes of the models, which include different mechanisms, are compared to observed tree cover along a mean annual precipitation gradient in Africa. By drawing on the large number of recent studies that have delivered new insights into the ecology of tropical ecosystems in general, and of savannas in particular, we identify two main mechanisms that need improved representation in the examined DGVMs. The first mechanism includes water limitation to tree growth, and tree–grass competition for water, which are key factors in determining savanna presence in arid and semi-arid areas. The second is a grass–fire feedback, which maintains both forest and savanna presence in mesic areas. Grasses constitute the majority of the fuel load, and at the same time benefit from the openness of the landscape after fires, since they recover faster than trees. Additionally, these two mechanisms are better represented when the models also include tree life stages (adults and seedlings), and distinguish between fire-prone and shade-tolerant forest trees, and fire-resistant and shade-intolerant savanna trees. Including these basic elements could improve the predictive ability of the DGVMs, not only under current climate conditions but also and especially under future scenarios.
Baudena, Mara ; Dekker, Stefan C. ; Bodegom, Peter M. van ; Cuesta, Barbara ; Higgins, Steven Ian ; Lehsten, Veiko ; Reick, Christian H. ; Rietkerk, Max ; Scheiter, Simon ; Yin, Zun ; Zavala, Miguel Ángel de ; Brovkin, Victor
The forest, savanna, and grassland biomes, and the transitions between them, are expected to undergo major changes in the future, due to global climate change. Dynamic Global Vegetation Models (DGVMs) are very useful to understand vegetation dynamics under present climate, and to predict its changes under future conditions. However, several DGVMs display high uncertainty in predicting vegetation in tropical areas. Here we perform a comparative analysis of three different DGVMs (JSBACH, LPJ-GUESS-SPITFIRE and aDGVM) with regard to their representation of the ecological mechanisms and feedbacks that determine the forest, savanna and grassland biomes, in an attempt to bridge the knowledge gap between ecology and global modelling. Model outcomes, obtained including different mechanisms, are compared to observed tree cover along a mean annual precipitation gradient in Africa. Through these comparisons, and by drawing on the large number of recent studies that have delivered new insights into the ecology of tropical ecosystems in general, and of savannas in particular, we identify two main mechanisms that need an improved representation in the DGVMs. The first mechanism includes water limitation to tree growth, and tree-grass competition for water, which are key factors in determining savanna presence in arid and semi-arid areas. The second is a grass-fire feedback, which maintains both forest and savanna occurrences in mesic areas. Grasses constitute the majority of the fuel load, and at the same time benefit from the openness of the landscape after fires, since they recover faster than trees. Additionally, these two mechanisms are better represented when the models also include tree life stages (adults and seedlings), and distinguish between fire-prone and shade-tolerant savanna trees, and fire-resistant and shade-intolerant forest trees. Including these basic elements could improve the predictive ability of the DGVMs, not only under current climate conditions but also and especially under future scenarios.
Comparing projections of future changes in runoff from hydrological and biome models in ISI-MIP
(2013)
Davie, Jemma C. S. ; Falloon, Peter D. ; Kahana, Ron ; Dankers, Rutger ; Betts, Richard ; Portmann, Felix Theodor ; Wisser, Dominik ; Clark, Douglas B. ; Itoh, Akihiko ; Masaki, Yoshimitsu ; Nishina, Kazuya ; Fekete, Balazs M. ; Tessler, Zachary ; Wada, Yoshihide ; Liu, Xingcai ; Tang, Qiuhong ; Hagemann, Stefan ; Stacke, Tobias ; Pavlick, Ryan ; Schaphoff, Sibyll ; Gosling, Simon N. ; Franssen, Wietse ; Arnell, Nigel
Future changes in runoff can have important implications for water resources and flooding. In this study, runoff projections from ISI-MIP (Inter-sectoral Impact Model Intercomparison Project) simulations forced with HadGEM2-ES bias-corrected climate data under the Representative Concentration Pathway 8.5 have been analysed for differences between impact models. Projections of change from a baseline period (1981–2010) to the future (2070–2099) from 12 impacts models which contributed to the hydrological and biomes sectors of ISI-MIP were studied. The biome models differed from the hydrological models by the inclusion of CO2 impacts and most also included a dynamic vegetation distribution. The biome and hydrological models agreed on the sign of runoff change for most regions of the world. However, in West Africa, the hydrological models projected drying, and the biome models a moistening. The biome models tended to produce larger increases and smaller decreases in regionally averaged runoff than the hydrological models, although there is large inter-model spread. The timing of runoff change was similar, but there were differences in magnitude, particularly at peak runoff. The impact of vegetation distribution change was much smaller than the projected change over time, while elevated CO2 had an effect as large as the magnitude of change over time projected by some models in some regions. The effect of CO2 on runoff was not consistent across the models, with two models showing increases and two decreases. There was also more spread in projections from the runs with elevated CO2 than with constant CO2. The biome models which gave increased runoff from elevated CO2 were also those which differed most from the hydrological models. Spatially, regions with most difference between model types tended to be projected to have most effect from elevated CO2, and seasonal differences were also similar, so elevated CO2 can partly explain the differences between hydrological and biome model runoff change projections. Therefore, this shows that a range of impact models should be considered to give the full range of uncertainty in impacts studies.
Davie, Jemma C. S. ; Falloon, Peter D. ; Kahana, Ron ; Dankers, Rutger ; Betts, Richard ; Portmann, Felix Theodor ; Clark, Douglas B. ; Itoh, Akihiko ; Masaki, Yoshimitsu ; Nishina, Kazuya ; Fekete, Balazs M. ; Tessler, Zachary ; Liu, Xingcai ; Tang, Qiuhong ; Hagemann, Stefan ; Stacke, Tobias ; Pavlick, Ryan ; Schaphoff, Sibyll ; Gosling, Simon N. ; Franssen, Wietse ; Arnell, Nigel
Projections of future changes in runoff can have important implications for water resources and flooding. In this study, runoff projections from ISI-MIP (Inter-sectoral Impact Model Intercomparison Project) simulations forced with HadGEM2-ES bias-corrected climate data under the Representative Concentration Pathway 8.5 have been analysed. Projections of change from the baseline period (1981–2010) to the future (2070–2099) from a number of different ecosystems and hydrological models were studied. The differences between projections from the two types of model were looked at globally and regionally. Typically, across different regions the ecosystem models tended to project larger increases and smaller decreases in runoff than the hydrological models. However, the differences varied both regionally and seasonally. Sensitivity experiments were also used to investigate the contributions of varying CO2 and allowing vegetation distribution to evolve on projected changes in runoff. In two out of four models which had data available from CO2 sensitivity experiments, allowing CO2 to vary was found to increase runoff more than keeping CO2 constant, while in two models runoff decreased. This suggests more uncertainty in runoff responses to elevated CO2 than previously considered. As CO2 effects on evapotranspiration via stomatal conductance and leaf-area index are more commonly included in ecosystems models than in hydrological models, this may partially explain some of the difference between model types. Keeping the vegetation distribution static in JULES runs had much less effect on runoff projections than varying CO2, but this may be more pronounced if looked at over a longer timescale as vegetation changes may take longer to reach a new state.
Molina, Carlos ; Rotter, Björn ; Horres, Ralf ; Udupa, Sripada M. ; Besser, Bert ; Bellarmino, Luis ; Baum, Michael ; Matsumura, Hideo ; Terauchi, Ryohei ; Kahl, Günter ; Winter, Peter
Background Drought is the major constraint to increase yield in chickpea (Cicer arietinum). Improving drought tolerance is therefore of outmost importance for breeding. However, the complexity of the trait allowed only marginal progress. A solution to the current stagnation is expected from innovative molecular tools such as transcriptome analyses providing insight into stress-related gene activity, which combined with molecular markers and expression (e)QTL mapping, may accelerate knowledge-based breeding. SuperSAGE, an improved version of the serial analysis of gene expression (SAGE) technique, generating genome-wide, high-quality transcription profiles from any eukaryote, has been employed in the present study. The method produces 26 bp long fragments (26 bp tags) from defined positions in cDNAs, providing sufficient sequence information to unambiguously characterize the mRNAs. Further, SuperSAGE tags may be immediately used to produce microarrays and probes for real-time-PCR, thereby overcoming the lack of genomic tools in non-model organisms. Results We applied SuperSAGE to the analysis of gene expression in chickpea roots in response to drought. To this end, we sequenced 80,238 26 bp tags representing 17,493 unique transcripts (UniTags) from drought-stressed and non-stressed control roots. A total of 7,532 (43%) UniTags were more than 2.7-fold differentially expressed, and 880 (5.0%) were regulated more than 8-fold upon stress. Their large size enabled the unambiguous annotation of 3,858 (22%) UniTags to genes or proteins in public data bases and thus to stress-response processes. We designed a microarray carrying 3,000 of these 26 bp tags. The chip data confirmed 79% of the tag-based results, whereas RT-PCR confirmed the SuperSAGE data in all cases. Conclusion This study represents the most comprehensive analysis of the drought-response transcriptome of chickpea available to date. It demonstrates that – inter alias – signal transduction, transcription regulation, osmolyte accumulation, and ROS scavenging undergo strong transcriptional remodelling in chickpea roots already 6 h after drought stress. Certain transcript isoforms characterizing these processes are potential targets for breeding for drought tolerance. We demonstrate that these can be easily accessed by micro-arrays and RT-PCR assays readily produced downstream of SuperSAGE. Our study proves that SuperSAGE owns potential for molecular breeding also in non-model crops.
Müller, Sören ; Rycak, Lukas ; Afonso-Grunz, Fabian ; Winter, Peter ; Zawada, Adam M. ; Damrath, Ewa ; Scheider, Jessica ; Schmäh, Juliane ; Koch, Ina ; Kahl, Günter ; Rotter, Björn
Alternative polyadenylation (APA) is a widespread mechanism that contributes to the sophisticated dynamics of gene regulation. Approximately 50% of all protein-coding human genes harbor multiple polyadenylation (PA) sites; their selective and combinatorial use gives rise to transcript variants with differing length of their 3' untranslated region (3'UTR). Shortened variants escape UTR-mediated regulation by microRNAs (miRNAs), especially in cancer, where global 3'UTR shortening accelerates disease progression, dedifferentiation and proliferation. Here we present APADB, a database of vertebrate PA sites determined by 3' end sequencing, using massive analysis of complementary DNA ends. APADB provides (A)PA sites for coding and non-coding transcripts of human, mouse and chicken genes. For human and mouse, several tissue types, including different cancer specimens, are available. APADB records the loss of predicted miRNA binding sites and visualizes next-generation sequencing reads that support each PA site in a genome browser. The database tables can either be browsed according to organism and tissue or alternatively searched for a gene of interest. APADB is the largest database of APA in human, chicken and mouse. The stored information provides experimental evidence for thousands of PA sites and APA events. APADB combines 3' end sequencing data with prediction algorithms of miRNA binding sites, allowing to further improve prediction algorithms. Current databases lack correct information about 3'UTR lengths, especially for chicken, and APADB provides necessary information to close this gap. Database URL: http://tools.genxpro.net/apadb/
Willems, Laurent M. ; Hochbaum, Maja ; Frey, Katharina ; Schulz, Juliane ; Menzler, Katja ; Langenbruch, Lisa Marie ; Kovać, Stjepana ; Immisch, Ilka ; Podewils, Felix von ; Hamacher, Mario ; Siebenbrodt, Kai ; Rosenow, Felix ; Reese, Jens-Peter ; Strzelczyk, Adam
Objective: This study was undertaken to quantify epilepsy-related costs of illness (COI) in Germany and identify cost-driving factors.
Methods: COI were calculated among adults with epilepsy of different etiologies and severities. Multiple regression analysis was applied to determine any epilepsy-related and sociodemographic factors that serve as cost-driving factors.
Results: In total, 486 patients were included, with a mean age of 40.5 ± 15.5 years (range = 18–83 years, 58.2% women). Mean 3-month COI were estimated at €4911, €2782, and €2598 for focal, genetic generalized, and unclassified epilepsy, respectively. The mean COI for patients with drug-refractory epilepsy (DRE; €7850) were higher than those for patients with non-DRE (€4720), patients with occasional seizures (€3596), or patients with seizures in remission for >1 year (€2409). Identified cost-driving factors for total COI included relevant disability (unstandardized regression coefficient b = €2218), poorer education (b = €2114), living alone (b = €2612), DRE (b = €1831), and frequent seizures (b = €2385). Younger age groups of 18–24 years (b = −€2945) and 25–34 years (b = −€1418) were found to have lower overall expenditures. A relevant disability (b = €441), DRE (b = €1253), frequent seizures (b = €735), and the need for specialized daycare (b = €749) were associated with higher direct COI, and poorer education (b = €1969), living alone (b = €2612), the presence of a relevant disability (b = €1809), DRE (b = €1831), and frequent seizures (b = €2385) were associated with higher indirect COI.
Significance: This analysis provides up-to-date COI data for use in further health economics analyses, highlighting the high economic impacts associated with disease severity, disability, and disease-related loss of productivity among adult patients with epilepsy. The identified cost drivers could be used as therapeutic and socioeconomic targets for future cost-containment strategies.
Scheiper-Welling, Stefanie ; Tabunscik, Monika ; Groß, Theresa Elisa ; Jenewein, Tina ; Beckmann, Britt-Maria ; Niess, Constanze ; Gradhand, Elise ; Wunder, Cora ; Schneider, Peter M. ; Rothschild, Markus A. ; Verhoff, Marcel A. ; Kauferstein, Silke
Sudden cardiac death (SCD) in adolescents and young adults may be the first manifestation of an inherited arrhythmic syndrome. Thus identification of a genetic origin in sudden death cases deemed inconclusive after a comprehensive autopsy and may help to reduce the risk of lethal episodes in the remaining family. Using next-generation sequencing (NGS), a large number of variants of unknown significance (VUS) are detected. In the majority of cases, there is insufficient evidence of pathogenicity, representing a huge dilemma in current genetic investigations. Misinterpretation of such variants may lead to inaccurate genetic diagnoses and/or the adoption of unnecessary and/or inappropriate therapeutic approaches. In our study, we applied current (ACMG) recommendations for variant classification in post-mortem genetic screening of a cohort of 56 SCD victims. We identified a total 53 rare protein-altering variants (MAF < 0.2%) classified as VUS or worse. Twelve percent of the cases exhibited a clinically actionable variant (pathogenic, likely pathogenic or VUS – potentially pathogenic) that would warrant cascade genetic screening in relatives. Most of the variants detected by means of the post-mortem genetic investigations were VUS. Thus, genetic testing by itself might be fairly meaningless without supporting background data. This data reinforces the need for an experienced multidisciplinary team for obtaining reliable and accountable interpretations of variant significance for elucidating potential causes for SCDs in the young. This enables the early identification of relatives at risk or excludes family members as genetic carriers. Also, development of adequate forensic guidelines to enable appropriate interpretation of rare genetic variants is fundamental.
Schnitzbauer, Andreas ; Zuelke, Carl ; Graeb, Christian ; Rochon, Justine ; Bilbao, Itxarone ; Burra, Patrizia ; de Jong, Koert P. ; Duvoux, Christophe ; Kneteman, Norman M. ; Adam, Rene ; Bechstein, Wolf Otto ; Becker, Thomas ; Beckebaum, Susanne ; Chazouilleres, Olivier ; Cillo, Umberto ; Colledan, Michele ; Fandrich, Fred ; Gugenheim, Jean ; Hauss, Johann P. ; Heise, Michael ; Hidalgo, Ernest ; Jamieson, Neville ; Königsrainer, Alfred ; Lamby, Philipp E. ; Lerut, Jan P. ; Makisalo, Heikki ; Margreiter, Raimund ; Mazzaferro, Vincenzo ; Mutzbauer, Ingrid ; Otto, Gerd ; Pageaux, Georges-Philippe ; Pinna, Antonio D. ; Pirenne, Jacques ; Rizell, Magnus ; Rossi, Giorgio ; Rostaing, Lionel ; Roy, Andre ; Turrion, Victor Sanchez ; Schmidt, Jan ; Troisi, Roberto I. ; Hoek, Bart van ; Valente, Umberto ; Wolf, Philippe ; Wolters, Heiner ; Mirza, Darius F. ; Scholz, Tim ; Steininger, Rudolf ; Soderdahl, Gunnar ; Strasser, Simone I. ; Jauch, Karl-Walter ; Neuhaus, Peter ; Schlitt, Hans J. ; Geissler, Edward K.
Background: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. Methods: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 3-year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. Discussion: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. (trial registered at www.clinicaltrials.gov: NCT00355862) (EudraCT Number: 2005-005362-36)
Ehrhart, Sebastian ; Ickes, Luisa ; Almeida, Joao ; Amorim, Antonio ; Barmet, Peter ; Bianchi, Federico ; Dommen, Josef ; Dunne, Eimear M. ; Duplissy, Jonathan ; Franchin, Alessandro ; Kangasluoma, Juha ; Kirkby, Jasper ; Kürten, Christoph Andreas ; Kupc, Agnieszka ; Lehtipalo, Katrianne ; Nieminen, Tuomo ; Riccobono, Francesco ; Rondo, Linda ; Schobesberger, Siegfried ; Steiner, Gerhard ; Tomé, Antonio ; Wimmer, Daniela ; Baltensperger, Urs ; Wagner, Paul E. ; Curtius, Joachim
Binary nucleation of sulphuric acid-water particles is expected to be an important process in the free troposphere at low temperatures. SAWNUC (Sulphuric Acid Water Nucleation) is a model of binary nucleation that is based on laboratory measurements of the binding energies of sulphuric acid and water in charged and neutral clusters. Predictions of SAWNUC are compared for the first time comprehensively with experimental binary nucleation data from the CLOUD chamber at European Organization for Nuclear Research. The experimental measurements span a temperature range of 208–292 K, sulphuric acid concentrations from 1·106 to 1·109 cm−3, and distinguish between ion-induced and neutral nucleation. Good agreement, within a factor of 5, is found between the experimental and modeled formation rates for ion-induced nucleation at 278 K and below and for neutral nucleation at 208 and 223 K. Differences at warm temperatures are attributed to ammonia contamination which was indicated by the presence of ammonia-sulphuric acid clusters, detected by an Atmospheric Pressure Interface Time of Flight (APi-TOF) mass spectrometer. APi-TOF measurements of the sulphuric acid ion cluster distributions (math formula with i = 0, 1, ..., 10) show qualitative agreement with the SAWNUC ion cluster distributions. Remaining differences between the measured and modeled distributions are most likely due to fragmentation in the APi-TOF. The CLOUD results are in good agreement with previously measured cluster binding energies and show the SAWNUC model to be a good representation of ion-induced and neutral binary nucleation of sulphuric acid-water clusters in the middle and upper troposphere.
Levine, John E. ; Grupp, Stephan ; Pulsipher, Michael A. ; Dietz, Andrew C. ; Rives, Susana ; Myers, G. Douglas ; August, Keith J. ; Verneris, Michael R. ; Büchner, Jochen ; Laetsch, Theodore W. ; Bittencourt, Henrique ; Baruchel, Andre ; Boyer, Michael W. ; De Moerloose, Barbara ; Qayed, Muna ; Davies, Stella M. ; Phillips, Christine L. ; Driscoll, Timothy A. ; Bader, Peter ; Schlis, Krysta ; Wood, Patricia A ; Mody, Rajen ; Yi, Lan ; Leung, Mimi ; Eldjerou, Lamis K. ; June, Carl H. ; Maude, Shannon L
Background: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse.
Methods: A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel.
Results: Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion.
Conclusions: This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.
VASP is a member of the Enabled/VASP protein family that is involved in cortical actin dynamics and may also contribute to the formation of gap junctions. In vessels, gap junctional coupling allows the transfer of signals along the vessel wall and coordinates vascular behavior. Moreover, VASP is reportedly a mediator of NO-induced inhibition of platelet aggregation. Therefore, we hypothesized that VASP exerts also important physiologic functions in arterioles. We examined the spread of vasodilations enabled by gap junctional coupling in endothelial cells as well as NO-induced arteriolar dilations in VASP-deficient mice by intravital microscopy of the microcirculation in a skeletal muscle in anesthetized mice. Conducted dilations were initiated by brief, locally confined stimulation of the arterioles with acetylcholine. The maximal diameters of the arterioles under study ranged from 30 to 40 μm. Brief stimulation with acetylcholine induced a short dilation at the local site that was also observed at remote, upstream sites without an attenuation of the amplitude up to a distance of 1.2 mm in control animals (wild-type). In contrast, remote dilations were reduced in VASP-deficient mice despite a similar local dilation indicating an impairment of conducted dilations. Superfusion of NOdonors induced a concentration-dependent dilation in wild-type mice. However, these dilations were slightly reduced in VASP-deficient animals. In contrast, dilations induced by the endothelial stimulator acetylcholine were fully preserved in VASP-deficient mice. In summary, this study suggests that VASP exerts critical functions in arteriolar diameter control. It is crucial for the conduction of dilator signals along the endothelial cell layer. The impairment possibly reflects a perturbed formation of gap junctions in the endothelial cell membrane. VASP also participates in the full dilatory potential of NOdonors although the effect of its deficiency is only subtle. In contrast, VASP is not required for dilations initiated by endothelial stimulation which are mediated in the murine microcirculation by an EDH-mechanism.
Christian Thurn ; Eibisch, Paul ; Ata, Arif ; Winkler, Maximilian ; Lunkenheimer, Peter ; Kézsmárki, István ; Tutsch, Ulrich ; Saito, Yohei ; Hartmann, Steffi ; Zimmermann, Jan ; R. N. Hanna, Abanoub ; Islam, A. T. M. Nazmul ; Chillal, Shravani ; Lake, Bella ; Wolf, Bernd ; Lang, Michael
Geometrical frustration among interacting spins combined with strong quantum fluctuations destabilize long-range magnetic order in favor of more exotic states such as spin liquids. By following this guiding principle, a number of spin liquid candidate systems were identified in quasi-two-dimensional (quasi-2D) systems. For 3D, however, the situation is less favorable as quantum fluctuations are reduced and competing states become more relevant. Here we report a comprehensive study of thermodynamic, magnetic and dielectric properties on single crystalline and pressed-powder samples of PbCuTe2O6, a candidate material for a 3D frustrated quantum spin liquid featuring a hyperkagome lattice. Whereas the low-temperature properties of the powder samples are consistent with the recently proposed quantum spin liquid state, an even more exotic behavior is revealed for the single crystals. These crystals show ferroelectric order at TFE ≈ 1 K, accompanied by strong lattice distortions, and a modified magnetic response—still consistent with a quantum spin liquid—but with clear indications for quantum critical behavior.
Laukens, Bram ; Jennewein, Claudia ; Schenk, Barbara ; Vanlangenakker, Nele ; Schier, Alexander ; Cristofanon, Silvia ; Zobel, Kerry ; Deshayes, Kurt ; Vucic, Domagoj ; Jeremias, Irmela ; Bertrand, Mathieu J. M. ; Vandenabeele, Peter ; Fulda, Simone
Searching for new strategies to bypass apoptosis resistance, we investigated the potential of the Smac mimetic BV6 in Jurkat leukemia cells deficient in key molecules of the death receptor pathway. Here, we demonstrate for the first time that Smac mimetic primes apoptosis-resistant, FADD- or caspase-8-deficient leukemia cells for TNFα-induced necroptosis in a synergistic manner. In contrast to TNFα, Smac mimetic significantly enhances CD95-induced apoptosis in wild-type but not in FADD-deficient cells. Interestingly, Smac mimetic- and TNFα-mediated cell death occurs without characteristic features of apoptosis (i.e., caspase activation, DNA fragmentation) in FADD-deficient cells. By comparison, Smac mimetic and TNFα trigger activation of caspase-8, -9, and -3 and DNA fragmentation in wild-type cells. Consistently, the caspase inhibitor zVAD.fmk fails to block Smac mimetic- and TNFα-triggered cell death in FADD- or caspase-8-deficient cells, while it confers protection in wild-type cells. By comparison, necrostatin-1, an RIP1 kinase inhibitor, abolishes Smac mimetic- and TNFα-induced cell death in FADD- or caspase-8-deficient. Thus, Smac mimetic enhances TNFα-induced cell death in leukemia cells via two distinct pathways in a context-dependent manner: it primes apoptosis-resistant cells lacking FADD or caspase-8 to TNFα-induced, RIP1-dependent and caspase-independent necroptosis, whereas it sensitizes apoptosis-proficient cells to TNFα-mediated, caspase-dependent apoptosis. These findings have important implications for the therapeutic exploitation of necroptosis as an alternative cell death program to overcome apoptosis resistance.
A new species belonging to the crustacean class Remipedia is described from an anchialine cave system on the island of Cozumel (Mexico), and is illustrated and compared morphologically and molecularly (CO1 and 16S) with closely related taxa. Xibalbanus cozumelensis sp. nov., the first remipede described from Cozumel, is morphologically similar to Xibalbanus tulumensis (Yager, 1987) from the Yucatán Peninsula, but the two species are genetically separate from each other (about 10% in CO1). A phylogenetic (Bayesian) analysis of Yucatán remipede populations based on CO1 and 16S placed them in a monophyletic Xibalbanus (in Xibalbanidae fam. nov.), with X. cozumelensis as most closely related to X. tulumensis. The Yucatán Peninsula and Cozumel have been separate since approx. early Cenozoic (~65 Ma), which suggests allopatric speciation for X. cozumelensis sp. nov. and X. tulumensis. However, the comparatively low genetic divergence between the two species may indicate that there has been gene flow between ‘mainland’ Yucatán and Cozumel long after the geological separation of the two landmasses, e.g., in cave systems under the sea bed, either continuously or sporadically, for example during the Last Glacial Maximum when the sea level was about 120 m lower than today.
Barbagallo, Massimo ; Mastromarco, Mario ; Colonna, Nicola ; Altstadt, Sebastian ; Andrzejewski, Józef ; Audouin, Laurent ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brugger, Markus ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Durán, Ignacio ; Dressler, Rugard ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Hernández Prieto, Álvaro ; Jenkins, David ; Jericha, Erwin ; Kadi, Yacine ; Käppeler, Franz ; Karadimos, Dimitri ; Kivel, Nikolay ; Koehler, Paul ; Krtička, Milan ; Kroll, Jiří ; Lampoudis, Christos ; Langer, Christoph ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Losito, Roberto ; Manousos, Athanasios ; Marganiec, Justyna ; Martínez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Mondalaers, Willy ; Paradela Dobarro, Carlos ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Rubbia, Carlo ; Sabaté-Gilarte, Marta ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarrío Vilas, Diego ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias ; Žugec, Petar
The study of neutron-induced reactions is of high relevance in a wide variety of fields, ranging from stellar nucleosynthesis and fundamental nuclear physics to applications of nuclear technology. In nuclear energy, high accuracy neutron data are needed for the development of Generation IV fast reactors and accelerator driven systems, these last aimed specifically at nuclear waste incineration, as well as for research on innovative fuel cycles. In this context, a high luminosity Neutron Time Of Flight facility, n_TOF, is operating at CERN since more than a decade, with the aim of providing new, high accuracy and high resolution neutron cross-sections. Thanks to the features of the neutron beam, a rich experimental program relevant to nuclear technology has been carried out so far. The program will be further expanded in the near future, thanks in particular to a new high-flux experimental area, now under construction.
High precision measurement of the radiative capture cross section of 238U at the n_TOF CERN facility
(2017)
Mingrone, Federica ; Altstadt, Sebastian ; Andrzejewski, Józef ; Audouin, Laurent ; Bécares, Vicente ; Barbagallo, Massimo ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Boccone, Vittorio ; Bosnar, Damir ; Brugger, Markus ; Calviño Tavares, Francisco ; Calviani, Marco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Durán, Ignacio ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Furman, Valter ; Göbel, Kathrin ; Gómez Hornillos, María Belén ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Goverdovski, Andrey ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Heftrich, Tanja ; Hernández Prieto, Álvaro ; Heyse, Jan ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Karadimos, Dimitri ; Katabuchi, Tatsuya ; Ketlerov, Vladimir ; Khryachkov, Vitaly ; Kivel, Nikolay ; Koehler, Paul ; Kokkoris, Michael ; Kroll, Jiří ; Krtička, Milan ; Lampoudis, Christos ; Langer, Christoph ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Lerendegui-Marco, Jorge ; Losito, Roberto ; Mallick, Amod Kishore ; Manousos, Athanasios ; Marganiec, Justyna ; Martı́nez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mirea, Mihail ; Mondelaers, Willy ; Paradela Dobarro, Carlos ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Robles Manzano, Maria Soledad ; Rubbia, Carlo ; Ryan, James ; Sabaté-Gilarte, Marta ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tarrío Vilas, Diego ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias ; Žugec, Petar
The importance of improving the accuracy on the capture cross-section of 238U has been addressed by the Nuclear Energy Agency, since its uncertainty significantly affects the uncertainties of key design parameters for both fast and thermal nuclear reactors. Within the 7th framework programme ANDES of the European Commission three different measurements have been carried out with the aim of providing the 238U(n,γ) cross-section with an accuracy which varies from 1 to 5%, depending on the energy range. Hereby the final results of the measurement performed at the n_TOF CERN facility in a wide energy range from 1 eV to 700 keV will be presented.
Leal Cidoncha, Esther ; Durán, Ignacio ; Paradela Dobarro, Carlos ; Tarrío Vilas, Diego ; Leong, Lou Sai ; Tassan-Got, Laurent ; Audouin, Laurent ; Altstadt, Sebastian ; Andrzejewski, Józef ; Barbagallo, Massimo ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Boccone, Vittorio ; Bosnar, Damir ; Brugger, Markus ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Dzysiuk, Nataliia ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gómez Hornillos, María Belén ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Gurusamy, Perumal ; Hernández Prieto, Álvaro ; Jenkins, David ; Jericha, Erwin ; Kadi, Yacine ; Käppeler, Franz ; Karadimos, Dimitri ; Kivel, Nikolay ; Koehler, Paul ; Kokkoris, Michael ; Krtička, Milan ; Kroll, Jiří ; Lampoudis, Christos ; Langer, Christoph ; Lederer, Claudia ; Leeb, Helmut ; Lo Meo, Sergio ; Losito, Roberto ; Mallick, Amod Kishore ; Manousos, Athanasios ; Marganiec, Justyna ; Martı́nez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Meaze, AKM Moinul Haque ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Mondelaers, Willy ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Robles Manzano, Maria Soledad ; Roman, Faustin Laurenţiu ; Rubbia, Carlo ; Sabaté-Gilarte, Marta ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Versaci, Roberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias ; Žugec, Petar
Neutron-induced fission cross sections of 238U and 235U are used as standards in the fast neutron region up to 200 MeV. A high accuracy of the standards is relevant to experimentally determine other neutron reaction cross sections. Therefore, the detection effciency should be corrected by using the angular distribution of the fission fragments (FFAD), which are barely known above 20 MeV. In addition, the angular distribution of the fragments produced in the fission of highly excited and deformed nuclei is an important observable to investigate the nuclear fission process.
In order to measure the FFAD of neutron-induced reactions, a fission detection setup based on parallel-plate avalanche counters (PPACs) has been developed and successfully used at the CERN-n_TOF facility. In this work, we present the preliminary results on the analysis of new 235U(n,f) and 238U(n,f) data in the extended energy range up to 200 MeV compared to the existing experimental data.
Barbagallo, Massimo ; Colonna, Nicola ; Altstadt, Sebastian ; Andrzejewski, Józef ; Audouin, Laurent ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brugger, Markus ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Durán, Ignacio ; Dressler, Rugard ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Hernández Prieto, Álvaro ; Jenkins, David ; Jericha, Erwin ; Kadi, Yacine ; Käppeler, Franz ; Karadimos, Dimitri ; Kivel, Nikolay ; Koehler, Paul ; Krtička, Milan ; Kroll, Jiří ; Lampoudis, Christos ; Langer, Christoph ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Losito, Roberto ; Manousos, Athanasios ; Marganiec, Justyna ; Martı́nez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Mondalaers, Willy ; Paradela Dobarro, Carlos ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Rubbia, Carlo ; Sabaté-Gilarte, Marta ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarrío Vilas, Diego ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias ; Žugec, Petar
The n_TOF facility operates at CERN with the aim of addressing the request of high accuracy nuclear data for advanced nuclear energy systems as well as for nuclear astrophysics. Thanks to the features of the neutron beam, important results have been obtained on neutron induced fission and capture cross sections of U, Pu and minor actinides. Recently the construction of another beam line has started; the new line will be complementary to the first one, allowing to further extend the experimental program foreseen for next measurement campaigns.
Mingrone, Federica ; Massimi, Cristian ; Vannini, Gianni ; Colonna, Nicola ; Gunsing, Frank ; Žugec, Petar ; Altstadt, Sebastian ; Andrzejewski, Józef ; Audouin, Laurent ; Barbagallo, Massimo ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brugger, Markus ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Durán, Ignacio ; Dressler, Rugard ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Hernández Prieto, Álvaro ; Jenkins, David ; Jericha, Erwin ; Kadi, Yacine ; Käppeler, Franz ; Karadimos, Dimitri ; Kivel, Nikolay ; Koehler, Paul ; Kokkoris, Michael ; Krtička, Milan ; Kroll, Jiří ; Lampoudis, Christos ; Langer, Christoph ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Lo Meo, Sergio ; Losito, Roberto ; Mallick, Amod Kishore ; Manousos, Athanasios ; Marganiec, Justyna ; Martı́nez, Trinitario ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mirea, Mihail ; Mondalaers, Willy ; Paradela Dobarro, Carlos ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Robles Manzano, Maria Soledad ; Rubbia, Carlo ; Sabaté-Gilarte, Marta ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarrío Vilas, Diego ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias
The aim of this work is to provide a precise and accurate measurement of the 238U(n,γ) reaction cross section in the energy region from 1 eV to 700 keV. This reaction is of fundamental importance for the design calculations of nuclear reactors, governing the behavior of the reactor core. In particular, fast reactors, which are experiencing a growing interest for their ability to burn radioactive waste, operate in the high energy region of the neutron spectrum. In this energy region most recent evaluations disagree due to inconsistencies in the existing measurements of up to 15%. In addition, the assessment of nuclear data uncertainty performed for innovative reactor systems shows that the uncertainty in the radiative capture cross section of 238U should be further reduced to 1–3% in the energy region from 20 eV to 25 keV. To this purpose, addressed by the Nuclear Energy Agency as a priority nuclear data need, complementary experiments, one at the GELINA and two at the n_TOF facility, were proposed and carried out within the 7th Framework Project ANDES of the European Commission. The results of one of these 238U(n,γ) measurements performed at the n_TOF CERN facility are presented in this work. The γ-ray cascade following the radiative neutron capture has been detected exploiting a setup of two C6D6 liquid scintillators. Resonance parameters obtained from this work are on average in excellent agreement with the ones reported in evaluated libraries. In the unresolved resonance region, this work yields a cross section in agreement with evaluated libraries up to 80 keV, while for higher energies our results are significantly higher.
Leal Cidoncha, Esther ; Durán, Ignacio ; Paradela Dobarro, Carlos ; Tassan-Got, Laurent ; Audouin, Laurent ; Leal, Luiz C. ; Le Naour, Claire ; Noguere, Gilles ; Tarrío Vilas, Diego ; Leong, Lou Sai ; Altstadt, Sebastian ; Andrzejewski, Józef ; Barbagallo, Massimo ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Boccone, Vittorio ; Bosnar, Damir ; Brugger, Markus ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gómez Hornillos, María Belén ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Gurusamy, Perumal ; Hernández Prieto, Álvaro ; Jenkins, David ; Jericha, Erwin ; Kadi, Yacine ; Käppeler, Franz ; Karadimos, Dimitri ; Kivel, Nikolay ; Kokkoris, Michael ; Krtička, Milan ; Kroll, Jiří ; Lampoudis, Christos ; Langer, Christoph ; Lederer, Claudia ; Leeb, Helmut ; Losito, Roberto ; Mallick, Amod Kishore ; Manousos, Athanasios ; Marganiec, Justyna ; Martı́nez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Meaze, AKM Moinul Haque ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Mondelaers, Willy ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Robles Manzano, Maria Soledad ; Roman, Faustin Laurenţiu ; Rubbia, Carlo ; Sabaté-Gilarte, Marta ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Versaci, Roberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias ; Žugec, Petar
New results are presented of the 234U neutron-induced fission cross section, obtained with high accuracy in the resonance region by means of two methods using the 235U(n,f) as reference. The recent evaluation of the 235U(n,f) obtained with SAMMY by L. C. Leal et al. (these Proceedings), based on previous n_TOF data [1], has been used to calculate the 234U(n,f) cross section through the 234U/235U ratio, being here compared with the results obtained by using the n_TOF neutron flux.
Mastromarco, Mario ; Barbagallo, Massimo ; Vermeulen, Mark J. ; Colonna, Nicola ; Altstadt, Sebastian ; Andrzejewski, Józef ; Audouin, Laurent ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brugger, Markus ; Calviño Tavares, Francisco ; Calviani, Marco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Durán, Ignacio ; Dzysiuk, Nataliia ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Furman, Valter ; Gómez Hornillos, María Belén ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Goverdovski, Andrey ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Gurusamy, Perumal ; Heftrich, Tanja ; Heinitz, Stephan ; Hernández Prieto, Álvaro ; Heyse, Jan ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Karadimos, Dimitri ; Katabuchi, Tatsuya ; Ketlerov, Vladimir ; Khryachkov, Vitaly ; Koehler, Paul ; Kokkoris, Michael ; Kroll, Jiří ; Krtička, Milan ; Lampoudis, Christos ; Langer, Christoph ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Lerendegui-Marco, Jorge ; Licata, Mauro ; Losito, Roberto ; Manousos, Athanasios ; Marganiec, Justyna ; Martı́nez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Mondelaers, Willy ; Paradela Dobarro, Carlos ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Robles Manzano, Maria Soledad ; Roman, Faustin Laurenţiu ; Rubbia, Carlo ; Ryan, James ; Sabaté-Gilarte, Marta ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tarrío Vilas, Diego ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Versaci, Roberto ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias ; Žugec, Petar
The 236U isotope plays an important role in nuclear systems, both for future and currently operating ones. The actual knowledge of the capture reaction of this isotope is satisfactory in the thermal region, but it is considered insufficient for Fast Reactor and ADS applications. For this reason the 236U(n, γ) reaction cross-section has been measured for the first time in the whole energy region from thermal energy up to 1 MeV at the n_TOF facility with two different detection systems: an array of C6D6 detectors, employing the total energy deposited method, and a FX1 total absorption calorimeter (TAC), made of 40 BaF2 crystals. The two n_TOF data sets agree with each other within the statistical uncertainty in the Resolved Resonance Region up to 800 eV, while sizable differences (up to ≃ 20%) are found relative to the current evaluated data libraries. Moreover two new resonances have been found in the n_TOF data. In the Unresolved Resonance Region up to 200 keV, the n_TOF results show a reasonable agreement with previous measurements and evaluated data.
Mingrone, Federica ; Massimi, Cristian ; Vannini, Gianni ; Altstadt, Sebastian ; Andrzejewski, Józef ; Audouin, Ludmila ; Barbagallo, Massimo ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brugger, Markus ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Mary ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Durán, Ignacio ; Dressler, Rugard ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Hernández Prieto, Álvaro ; Jenkins, David ; Jericha, Erwin ; Kadi, Yacine ; Käppeler, Franz ; Karadimos, Dimitri ; Kivel, Nikolay ; Koehler, Paul Edward ; Krtička, Milan ; Kroll, Jiří ; Lampoudis, Christos ; Langer, Christoph ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Losito, Roberto ; Mallick, Amod Kishore ; Manousos, Athanasios ; Marganiec, Justyna ; Martínez, Trinitario ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mirea, Mihail ; Mondalaers, Willy ; Paradela Dobarro, Carlos ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Robles, Marisol S. ; Rubbia, Carlo ; Sabaté Gilarte, Marta ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Sebastian ; Schumann, Dorothea ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarrío Vilas, Diego ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias ; Žugec, Petar
The radiative capture cross section of 238U is very important for the developing of new reactor technologies and the safety of existing ones. Here the preliminary results of the 238U(n,γ) cross section measurement performed at n_TOF with C6D6 scintillation detectors are presented, paying particular attention to data reduction and background subtraction.
Stamatopoulos, Athanasios ; Tsinganis, Andrea ; Colonna, Nicola ; Vlastou, Rosa ; Kokkoris, Michael ; Schillebeeckx, Peter ; Plompen, Arjan J. M. ; Heyse, Jan ; Žugec, Petar ; Barbagallo, Massimo ; Calviani, Marco ; Berthoumieux, Eric ; Chiaveri, Enrico ; Aberle, Oliver ; Andrzejewski, Józef ; Audouin, Laurent ; Bécares, Vicente ; Bacak, Michael ; Balibrea Correa, Javier ; Barros, Susana C.C. ; Bečvář, František ; Beinrucker, Clemens ; Belloni, Fabio ; Billowes, Jonathan ; Boccone, Vittorio ; Bosnar, Damir ; Brugger, Markus ; Caamaño, Manuel ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Cerutti, Francesco ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Damone, Lucia Anna ; Deo, Kapil ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Dupont, Emmeric ; Durán, Ignacio ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Ferreira, Pedro G. ; Finocchiaro, Paolo ; Frost, Robert J. W. ; Furman, Valter ; Göbel, Kathrin ; Gómez Hornillos, María Belén ; García Ríos, Aczel Regino ; Gheorghe, Ioana ; Glodariu, Tudor ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Goverdovski, Andrey ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Harada, Hideo ; Heftrich, Tanja ; Heinitz, Stephan ; Hernández Prieto, Álvaro ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Katabuchi, Tatsuya ; Kavrigin, Pavel ; Ketlerov, Vladimir ; Khryachkov, Vitaly ; Kimura, Atsushi ; Kivel, Nikolay ; Krtička, Milan ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Lerendegui-Marco, Jorge ; Licata, Mauro ; Lo Meo, Sergio ; Losito, Roberto ; Macina, Daniela ; Marganiec, Justyna ; Martı́nez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Matteucci, Francesca ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Montesano, Simone ; Musumarra, Agatino ; Nolte, Ralf ; Palomo Pinto, Francisco Rogelio ; Paradela Dobarro, Carlos ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Robles Manzano, Maria Soledad ; Rubbia, Carlo ; Ryan, James ; Sabaté-Gilarte, Marta ; Saxena, Alok ; Schmidt, Stefan ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Smith, Alastair Gavin ; Suryanarayana, Saraswatula Venkata ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tassan-Got, Laurent ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vlachoudis, Vasilis ; Wallner, Anton ; Warren, Stephen J. ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias
The accurate knowledge of the neutron-induced fission cross-sections of actinides and other isotopes involved in the nuclear fuel cycle is essential for the design of advanced nuclear systems, such as Generation-IV nuclear reactors. Such experimental data can also provide the necessary feedback for the adjustment of nuclear model parameters used in the evaluation process, resulting in the further development of nuclear fission models. In the present work, the 240Pu(n,f) cross-section was measured at CERN's n_TOF facility relative to the well-known 235U(n,f) cross section, over a wide range of neutron energies, from meV to almost MeV, using the time-of-flight technique and a set-up based on Micromegas detectors. This measurement was the first experiment to be performed at n_TOF's new experimental area (EAR-2), which offers a significantly higher neutron flux compared to the already existing experimental area (EAR-1). Preliminary results as well as the experimental procedure, including a description of the facility and the data handling and analysis, are presented.
Massimi, Cristian ; Koehler, Paul Edward ; Kopecky, Stefan ; Mingrone, Federica ; Schillebeeckx, Peter ; Vannini, Gianni ; Altstadt, Sebastian ; Andrzejewski, Józef ; Audouin, Ludmila ; Barbagallo, Massimo ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brugger, Markus ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Mary ; Colonna, Nicola ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Hernández Prieto, Álvaro ; Jenkins, David ; Jericha, Erwin ; Kadi, Yacine ; Käppeler, Franz ; Karadimos, Dimitri ; Kivel, Nikolay ; Krtička, Milan ; Kroll, Jiří ; Lampoudis, Christos ; Langer, Christoph ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Losito, Roberto ; Mallick, Amod Kishore ; Manousos, Athanasios ; Marganiec, Justyna ; Martínez, Trinitario ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mirea, Mihail ; Mondalaers, Willy ; Paradela Dobarro, Carlos ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Robles, Marisol S. ; Rubbia, Carlo ; Sabaté Gilarte, Marta ; Sarmento, Raul ; Saxena, Alok ; Schmidt, Sebastian ; Schumann, Dorothea ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarrío Vilas, Diego ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias ; Žugec, Petar
We have measured the radiative neutron-capture cross section and the total neutron-induced cross section of one of the most important isotopes for the s process, the 25Mg. The measurements have been carried out at the neutron time-of-flight facilities n_TOF at CERN (Switzerland) and GELINA installed at the EC-JRC-IRMM (Belgium). The cross sections as a function of neutron energy have been measured up to approximately 300 keV, covering the energy region of interest to the s process. The data analysis is ongoing and preliminary results show the potential relevance for the s process.
Leong, Lou Sai ; Tassan-Got, Laurent ; Tarrío Vilas, Diego ; Audouin, Laurent ; Paradela Dobarro, Carlos ; Durán, Ignacio ; Le Naour, Claire ; Altstadt, Sebastian ; Andrzejewsky, Jozef ; Barbagallo, Massimo ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Boccone, Vittorio ; Bosnar, Damir ; Brugger, Markus ; Calviño Tavares, Francisco ; Calviani, Marco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Dzysiuk, Nataliia ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gómez Hornillos, María Belén ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Gurusamy, Perumal ; Jenkins, David ; Jericha, Erwin ; Kadi, E. ; Käppeler, Franz ; Karadimos, Dimitri ; Kivel, Nikolay ; Koehler, Paul ; Kokkoris, Michael ; Korschinek, Gunther ; Kroll, Jiří ; Krtička, Milan ; Langer, Christoph ; Lederer, Claudia ; Leeb, Helmut ; Losito, Roberto ; Manousos, Athanasios ; Marganiec, Justyna ; Massimi, Cristian ; Martı́nez, Trinitario ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Meaze, AKM Moinul Haque ; Mengon, A. ; Mendoza Cembranos, Emilio ; Milazzo, Paolo Maria ; Mingrone, T. ; Mirea, Mihail ; Mondelaers, Willy ; Pavlik, Andreas ; Perkowski, Jarosław ; Pignatari, Marco ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifhart, R. ; Riego Pérez, Albert ; Roman, Faustin Laurenţiu ; Rubbia, Carlo ; Sarmento, Raul ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Taı́n Enríquez, Jose Luis ; Tagliente, Giuseppe ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Versaci, Roberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, V. ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias ; Žugec, Petar
Above 1 MeV of incident neutron energy the fission fragment angular distribution (FFAD) has generally a strong anisotropic behavior due to the combination of the incident orbital momentum and the intrinsic spin of the fissioning nucleus. This effect has to be taken into account for the efficiency estimation of devices used for fission cross section measurements. In addition it bears information on the spin deposition mechanism and on the structure of transitional states. We designed and constructed a detection device, based on Parallel Plate Avalanche Counters (PPAC), for measuring the fission fragment angular distributions of several isotopes, in particular 232Th. The measurement has been performed at n_TOF at CERN taking advantage of the very broad energy spectrum of the neutron beam. Fission events were recognized by back to back detection in coincidence in two position-sensitive detectors surrounding the targets. The detection efficiency, depending mostly on the stopping of fission fragments in backings and electrodes, has been computed with a Geant4 simulation and validated by the comparison to the measured case of 235U below 3 keV where the emission is isotropic. In the case of 232Th, the result is in good agreement with previous data below 10 MeV, with a good reproduction of the structures associated to vibrational states and the opening of second chance fission. In the 14 MeV region our data are much more accurate than previous ones which are broadly scattered.
Hübner, Hanna ; Kurbacher, Christian M. ; Kuesters, Geoffrey ; Hartkopf, Andreas D. ; Lux, Michael P. ; Huober, Jens ; Volz, Bernhard ; Ţăran, Florin-Andrei ; Overkamp, Friedrich ; Tesch, Hans ; Häberle, Lothar ; Lüftner, Diana ; Wallwiener, Markus ; Müller, Volkmar ; Beckmann, Matthias Wilhelm ; Belleville, Erik ; Rübner, Matthias ; Untch, Michael ; Fasching, Peter Andreas ; Janni, Wolfgang ; Fehm, Tanja ; Kolberg, Hans-Christian ; Wallwiener, Diethelm ; Brucker, Sara Y. ; Schneeweiss, Andreas ; Ettl, Johannes
Background: Eligibility criteria are a critical part of clinical trials, as they define the patient population under investigation. Besides certain patient characteristics, clinical trials often include biomarker testing for eligibility. However, patient-identification mostly relies on the trial site itself and is often a time-consuming procedure, which could result in missing out on potentially eligible patients. Pre-selection of those patients using a registry could facilitate the process of eligibility testing and increase the number of identified patients. One aim with the PRAEGNANT registry (NCT02338167) is to identify patients for therapies based on clinical and molecular data. Here, we report eligibility testing for the SHERBOC trial using the German PRAEGNANT registry.
Methods:Heregulin (HRG) has been reported to identify patients with better responses to therapy with the anti-HER3 monoclonal antibody seribantumab (MM-121). The SHERBOC trial investigated adding seribantumab (MM-121) to standard therapy in patients with advanced HER2-negative, hormone receptor–positive (HR-positive) breast cancer and HRG overexpression. The PRAEGNANT registry was used for identification and tumor testing, helping to link potential HRG positive patients to the trial. Patients enrolled in PRAEGNANT have invasive and metastatic or locally advanced, inoperable breast cancer. Patients eligible for SHERBOC were identified by using the registry. Study aims were to describe the HRG positivity rate, screening procedures, and patient characteristics associated with inclusion and exclusion criteria.
Results: Among 2769 unselected advanced breast cancer patients, 650 were HER2-negative, HR-positive and currently receiving first- or second-line treatment, thus potentially eligible for SHERBOC at the end of current treatment; 125 patients also met further clinical eligibility criteria (e.g. menopausal status, ECOG). In the first/second treatment lines, patients selected for SHERBOC based on further eligibility criteria had a more favorable prognosis than those not selected. HRG status was tested in 38 patients, 14 of whom (36.8%) proved to be HRG-positive.
Conclusion: Using a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials.
Trial registration: Clinicaltrials, NCT02338167, Registered 14 January 2015 - retrospectively registered.
Lux, Michael Patrick ; Nabieva, Naiba ; Hartkopf, Andreas ; Huober, Jens ; Volz, Bernhard ; Ţăran, Florin-Andrei ; Overkamp, Friedrich ; Kolberg, Hans-Christian ; Hadji, Peyman ; Tesch, Hans ; Häberle, Lothar ; Ettl, Johannes ; Lüftner, Diana ; Wallwiener, Markus ; Müller, Volkmar ; Beckmann, Matthias Wilhelm ; Belleville, Erik ; Wimberger, Pauline ; Hielscher, Carsten ; Geberth, Matthias ; Abenhardt, Wolfgang ; Kurbacher, Christian M. ; Würstlein, Rachel ; Thomssen, Christoph ; Untch, Michael ; Fasching, Peter Andreas ; Janni, Wolfgang ; Fehm, Tanja ; Wallwiener, Diethelm ; Schneeweiss, Andreas ; Brucker, Sara
This study presents comprehensive real-world data on the use of anti-human epidermal growth factor receptor 2 (HER2) therapies in patients with HER2-positive metastatic breast cancer (MBC). Specifically, it describes therapy patterns with trastuzumab (H), pertuzumab + trastuzumab (PH), lapatinib (L), and trastuzumab emtansine (T-DM1). The PRAEGNANT study is a real-time, real-world registry for MBC patients. All therapy lines are documented. This analysis describes the utilization of anti-HER2 therapies as well as therapy sequences. Among 1936 patients in PRAEGNANT, 451 were HER2-positive (23.3%). In the analysis set (417 patients), 53% of whom were included in PRAEGNANT in the first-line setting, 241 were treated with H, 237 with PH, 85 with L, and 125 with T-DM1 during the course of their therapies. The sequence PH → T-DM1 was administered in 51 patients. Higher Eastern Cooperative Oncology Group (ECOG) scores, negative hormone receptor status, and visceral or brain metastases were associated with more frequent use of this therapy sequence. Most patients received T-DM1 after treatment with pertuzumab. Both novel therapies (PH and T-DM1) are utilized in a high proportion of HER2-positive breast cancer patients. As most patients receive T-DM1 after PH, real-world data may help to clarify whether the efficacy of this sequence is similar to that in the approval study.
Wernicke, Caroline M. ; Grunewald, Thomas G. P. ; Juenger, Hendrik ; Kuçi, Selim ; Kuçi, Zyrafete ; Köhl, Ulrike ; Mueller, Ingo ; Döring, Michaela ; Peters, Christina ; Lawitschka, Anita ; Kolb, Hans-Jochem ; Bader, Peter ; Burdach, Stefan ; Teichert- von Lüttichau, Irene
Severe acute graft versus host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. Human mesenchymal stromal cells (MSCs) play an important role in endogenous tissue repair and possess strong immune-modulatory properties making them a promising tool for the treatment of steroid-refractory GvHD. To date, a few reports exist on the use of MSCs in treatment of GvHD in children indicating that children tend to respond better than adults, albeit with heterogeneous results. We here present a review of the literature and the clinical course of two instructive pediatric patients with acute steroid-refractory GvHD after haploidentical stem cell transplantation, which exemplify the beneficial effects of third-party transplanted MSCs in treatment of acute steroid-refractory GvHD. Moreover, we provide a meta-analysis of clinical studies addressing the outcome of patients with steroid-refractory GvHD and treatment with MSCs in adults and in children (n = 183; 122 adults, 61 children). Our meta-analysis demonstrates that the overall response-rate is high (73.8%) and confirms, for the first time, that children indeed respond better to treatment of GvHD with MSCs than adults (complete response 57.4% vs. 45.1%, respectively). These data emphasize the significance of this therapeutic approach especially in children and indicate that future prospective studies are needed to assess the reasons for the observed differential response-rates in pediatric and adult patients. Additional file 1: MSCs expansion and release criteria.his file contains a detailed description of the MSCs expansion and release criteria for Case A and Case B.
Rothbauer, Mario ; Bachmann, Barbara E. M. ; Eilenberger, Christoph ; Kratz, Sebastian R. A. ; Spitz, Sarah ; Höll, Gregor ; Ertl, Peter
Organ-on-a-chip technology has the potential to accelerate pharmaceutical drug development, improve the clinical translation of basic research, and provide personalized intervention strategies. In the last decade, big pharma has engaged in many academic research cooperations to develop organ-on-a-chip systems for future drug discoveries. Although most organ-on-a-chip systems present proof-of-concept studies, miniaturized organ systems still need to demonstrate translational relevance and predictive power in clinical and pharmaceutical settings. This review explores whether microfluidic technology succeeded in paving the way for developing physiologically relevant human in vitro models for pharmacology and toxicology in biomedical research within the last decade. Individual organ-on-a-chip systems are discussed, focusing on relevant applications and highlighting their ability to tackle current challenges in pharmacological research.
Zawada, Adam M. ; Rogacev, Kyrill S. ; Müller, Sören ; Rotter, Björn ; Winter, Peter ; Fliser, Danilo ; Heine, Gunnar H.
Epigenetic dysregulation contributes to the high cardiovascular disease burden in chronic kidney disease (CKD) patients. Although microRNAs (miRNAs) are central epigenetic regulators, which substantially affect the development and progression of cardiovascular disease (CVD), no data on miRNA dysregulation in CKD-associated CVD are available until now. We now performed high-throughput miRNA sequencing of peripheral blood mononuclear cells from ten clinically stable hemodialysis (HD) patients and ten healthy controls, which allowed us to identify 182 differentially expressed miRNAs (e.g., miR-21, miR-26b, miR-146b, miR-155). To test biological relevance, we aimed to connect miRNA dysregulation to differential gene expression. Genome-wide gene expression profiling by MACE (Massive Analysis of cDNA Ends) identified 80 genes to be differentially expressed between HD patients and controls, which could be linked to cardiovascular disease (e.g., KLF6, DUSP6, KLF4), to infection / immune disease (e.g., ZFP36, SOCS3, JUND), and to distinct proatherogenic pathways such as the Toll-like receptor signaling pathway (e.g., IL1B, MYD88, TICAM2), the MAPK signaling pathway (e.g., DUSP1, FOS, HSPA1A), and the chemokine signaling pathway (e.g., RHOA, PAK1, CXCL5). Formal interaction network analysis proved biological relevance of miRNA dysregulation, as 68 differentially expressed miRNAs could be connected to 47 reciprocally expressed target genes. Our study is the first comprehensive miRNA analysis in CKD that links dysregulated miRNA expression with differential expression of genes connected to inflammation and CVD. After recent animal data suggested that targeting miRNAs is beneficial in experimental CVD, our data may now spur further research in the field of CKD-associated human CVD.
Statistical analysis on various stocks reveals long range dependence behavior of the stock prices that is not consistent with the classical Black and Scholes model. This memory or nondeterministic trend behavior is often seen as a reflection of market sentiments and causes that the historical volatility estimator becomes unreliable in practice. We propose an extension of the Black and Scholes model by adding a term to the original Wiener term involving a smoother process which accounts for these effects. The problem of arbitrage will be discussed. Using a generalized stochastic integration theory [8], we show that it is possible to construct a self financing replicating portfolio for a European option without any further knowledge of the extension and that, as a consequence, the classical concept of volatility needs to be re-interpreted.
AMS subject classifications: 60H05, 60H10, 90A09.
Madritsch, Silvia ; Wischnitzki, Elisabeth ; Kotrade, Peter ; Ashoub, Ahmed ; Burg, Agnes ; Fluch, Silvia ; Brüggemann, Wolfgang ; Sehr, Eva M.
The impact of climate change that comes with a dramatic increase of long periods of extreme summer drought associated with heat is a fundamental challenge for European forests. As a result, forests are expected to shift their distribution patterns toward north-east, which may lead to a dramatic loss in value of European forest land. Consequently, unraveling key processes that underlie drought stress tolerance is not only of great scientific but also of utmost economic importance for forests to withstand future heat and drought wave scenarios. To reveal drought stress-related molecular patterns we applied cross-species comparative transcriptomics of three major European oak species: the less tolerant deciduous pedunculate oak (Quercus robur), the deciduous but quite tolerant pubescent oak (Q. pubescens), and the very tolerant evergreen holm oak (Q. ilex). We found 415, 79, and 222 differentially expressed genes during drought stress in Q. robur, Q. pubescens, and Q. ilex, respectively, indicating species-specific response mechanisms. Further, by comparative orthologous gene family analysis, 517 orthologous genes could be characterized that may play an important role in drought stress adaptation on the genus level. New regulatory candidate pathways and genes in the context of drought stress response were identified, highlighting the importance of the antioxidant capacity, the mitochondrial respiration machinery, the lignification of the water transport system, and the suppression of drought-induced senescence - providing a valuable knowledge base that could be integrated in breeding programs in the face of climate change.
Žugec, Petar ; Colonna, Nicola ; Bosnar, Damir ; Altstadt, Sebastian ; Andrzejewski, Józef ; Audouin, Laurent ; Barbagallo, Massimo ; Bécares, Vicente ; Bečvář, František ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Boccone, Vittorio ; Brugger, Markus ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Durán, Ignacio ; Dzysiuk, Nataliia ; Eleftheriadis, Christos ; Ferrari, Alfredo ; Fraval, Kevin ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gómez Hornillos, María Belén ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Gurusamy, Perumal ; Heinitz, Stephan ; Jenkins, David ; Jericha, Erwin ; Kadi, Yacine ; Käppeler, Franz ; Karadimos, Dimitri ; Kivel, Nikolay ; Koehler, Paul ; Kokkoris, Michael ; Krtička, Milan ; Kroll, Jiří ; Langer, Christoph ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Lo Meo, Sergio ; Losito, Roberto ; Manousos, Athanasios ; Marganiec, Justyna ; Martínez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Meaze, AKM Moinul Haque ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Mondalaers, Willy ; Paradela Dobarro, Carlos ; Pavlik, Andreas ; Perkowski, Jarosław ; Plompen, Arjan J. M. ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Roman, Faustin Laurenţiu ; Rubbia, Carlo ; Sarmento, Raul ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarrío Vilas, Diego ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Versaci, Roberto ; Vermeulen, Mark J. ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias
The neutron sensitivity of the C6D6 detector setup used at n_TOF facility for capture measurements has been studied by means of detailed GEANT4 simulations. A realistic software replica of the entire n_TOF experimental hall, including the neutron beam line, sample, detector supports and the walls of the experimental area has been implemented in the simulations. The simulations have been analyzed in the same manner as experimental data, in particular by applying the Pulse Height Weighting Technique. The simulations have been validated against a measurement of the neutron background performed with a natC sample, showing an excellent agreement above 1 keV. At lower energies, an additional component in the measured natC yield has been discovered, which prevents the use of natC data for neutron background estimates at neutron energies below a few hundred eV. The origin and time structure of the neutron background have been derived from the simulations. Examples of the neutron background for two different samples are demonstrating the important role of accurate simulations of the neutron background in capture cross-section measurements.