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Nicolay, Jan Peter ; Thorn, Verena ; Daniel, Christoph ; Amann, Kerstin ; Siraskar, Balasaheb ; Lang, Florian ; Hillgruber, Carina ; Görge, Tobias ; Hoffmann, Stefan ; Gorzelanny, Christian ; Huck, Volker ; Mess, Christian ; Obser, Tobias ; Schneppenheim, Reinhard ; Fleming, Ingrid ; Schneider, Matthias F. ; Schneider, Stefan W.
Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.
Laban, Hebatullah ; Weigert, Andreas ; Zink, Joana Miriam ; Elgheznawy, Amro ; Schürmann, Christoph ; Günther, Lea ; Abdel Malik, Randa ; Bothur, Sabrina ; Wingert, Susanne ; Bremer, Rolf ; Rieger, Michael A. ; Brüne, Bernhard ; Brandes, Ralf ; Fleming, Ingrid ; Benz, Peter M.
In ischemic vascular diseases, leukocyte recruitment and polarization are crucial for revascularization and tissue repair. We investigated the role of vasodilator-stimulated phosphoprotein (VASP) in vascular repair. After hindlimb ischemia induction, blood flow recovery, angiogenesis, arteriogenesis, and leukocyte infiltration into ischemic muscles in VASP−/− mice were accelerated. VASP deficiency also elevated the polarization of the macrophages through increased signal transducer and activator of transcription (STAT) signaling, which augmented the release of chemokines, cytokines, and growth factors to promote leukocyte recruitment and vascular repair. Importantly, VASP deletion in bone marrow–derived cells was sufficient to mimic the increased blood flow recovery of global VASP−/− mice. In chemotaxis experiments, VASP−/− neutrophils/monocytes were significantly more responsive to M1-related chemokines than wild-type controls. Mechanistically, VASP formed complexes with the chemokine receptor CCR2 and β-arrestin-2, and CCR2 receptor internalization was significantly reduced in VASP−/− leukocytes. Our data indicate that VASP is a major regulator of leukocyte recruitment and polarization in postischemic revascularization and support a novel role of VASP in chemokine receptor trafficking.
Androgen receptor deregulation drives bromodomain-mediated chromatin alterations in prostate cancer
(2017)
Urbanucci, Alfonso ; Barfeld, Stefan J. ; Kytölä, Ville ; Itkonen, Harri M. ; Coleman, Ilsa M. ; Vodák, Daniel ; Sjöblom, Liisa ; Sheng, Xia ; Tolonen, Teemu ; Minner, Sarah ; Burdelski, Christoph ; Kivinummi, Kati K. ; Kohvakka, Annika ; Kregel, Steven ; Takhar, Mandeep ; Alshalalfa, Mohammed ; Davicioni, Elai ; Erho, Nicholas ; Lloyd, Paul ; Karnes, R. Jeffrey ; Ross, Ashley E. ; Schaeffer, Edward M. ; Vander Griend, Donald J. ; Knapp, Stefan ; Corey, Eva ; Feng, Felix Y. ; Nelson, Peter S. ; Saatcioglu, Fahri ; Knudsen, Karen E. ; Tammela, Teuvo L. J. ; Sauter, Guido ; Schlomm, Thorsten ; Nykter, Matti ; Visakorpi, Tapio ; Mills, Ian G.
Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.
Tuchscheerer, Vivian ; Eickholz, Peter ; Dannewitz, Bettina ; Ratka, Christoph Martin ; Zuhr, Otto ; Petsos, Hari
Objectives: Evaluation of surgical and non-surgical air-polishing in vitro efficacy for implant surface decontamination.
Material and methods: One hundred eighty implants were distributed to three differently angulated bone defect models (30°, 60°, 90°). Biofilm was imitated using indelible red color. Sixty implants were used for each defect, 20 of which were air-polished with three different types of glycine air powder abrasion (GAPA1–3) combinations. Within 20 equally air-polished implants, a surgical and non-surgical (with/without mucosa mask) procedure were simulated. All implants were photographed to determine the uncleaned surface. Changes in surface morphology were assessed using scanning electron micrographs (SEM).
Results: Cleaning efficacy did not show any significant differences between GAPA1–3 for surgical and non-surgical application. Within a cleaning method significant (p < 0.001) differences for GAPA2 between 30° (11.77 ± 2.73%) and 90° (7.25 ± 1.42%) in the non-surgical and 30° (8.26 ± 1.02%) and 60° (5.02 ± 0.84%) in the surgical simulation occurred. The surgical use of air-polishing (6.68 ± 1.66%) was significantly superior (p < 0.001) to the non-surgical (10.13 ± 2.75%). SEM micrographs showed no surface damages after use of GAPA.
Conclusions: Air-polishing is an efficient, surface protective method for surgical and non-surgical implant surface decontamination in this in vitro model. No method resulted in a complete cleaning of the implant surface.
Clinical relevance: Air-polishing appears to be promising for implant surface decontamination regardless of the device.
Kettner, Mattias ; Birngruber, Christoph Gerhard ; Niess, Constanze ; Baz Bartels, Marco ; Bunzel, Lena Maria ; Verhoff, Marcel A. ; Lux, Constantin Peter ; Ramsthaler, Frank
Mongolian spots (MS) are congenital dermal conditions resulting from neural crest-derived melanocytes migration to the skin during embryogenesis. MS incidences are highly variable in different populations. Morphologically, MS present as hyperpigmented maculae of varying size and form, ranging from round spots of 1 cm in diameter to extensive discolorations covering predominantly the lower back and buttocks. Due to their coloring, which is also dependent on the skin type, MS may mimic hematoma thus posing a challenge on the physician conducting examinations of children in cases of suspected child abuse. In the present study, MS incidences and distribution, as well as skin types, were documented in a collective of 253 children examined on the basis of suspected child abuse. From these data, a classification scheme was derived to document MS and to help identify cases with a need for recurrent examination for unambiguous interpretation of initial findings alongside the main decisive factors for re-examination such as general circumstances of the initial examination (e. g., experience of the examiner, lighting conditions) and given dermatological conditions of the patient (e. g., diaper rash).
Peter, Thomas ; Luo, Beiping ; Wirth, Martin ; Kiemle, Christoph ; Flentje, Harald ; Yushkov, Vladimir A. ; Khattatov, Vyacheslav ; Rudakov, Vladimir V. ; Thomas, Andreas ; Borrmann, Stephan ; Toci, Guido ; Mazzinghi, Piero ; Beuermann, Jürgen ; Schiller, Cornelius ; Cairo, Francesco ; Di Donfrancesco, Guido ; Adriani, Alberto ; Volk, C.-Michael ; Strom, Johan ; Noone, Kevin ; Mitev, Valentin ; MacKenzie, Robert A. ; Carslaw, Kenneth S. ; Trautmann, Thomas ; Santacesaria, Vincenzo ; Stefanutti, Leopoldo
Subvisible cirrus clouds (SVCs) may contribute to dehydration close to the tropical tropopause. The higher and colder SVCs and the larger their ice crystals, the more likely they represent the last efficient point of contact of the gas phase with the ice phase and, hence, the last dehydrating step, before the air enters the stratosphere. The first simultaneous in situ and remote sensing measurements of SVCs were taken during the APE-THESEO campaign in the western Indian ocean in February/March 1999. The observed clouds, termed Ultrathin Tropical Tropopause Clouds (UTTCs), belong to the geometrically and optically thinnest large-scale clouds in the Earth´s atmosphere. Individual UTTCs may exist for many hours as an only 200--300 m thick cloud layer just a few hundred meters below the tropical cold point tropopause, covering up to 105 km2. With temperatures as low as 181 K these clouds are prime representatives for defining the water mixing ratio of air entering the lower stratosphere.
Nicotinamid-3-desazapurindinucleotid * wurde aus den Teilstücken Nicotinamidmononucleotid und 3-Desazapurinribosid-5'-phosphat durch Kondensation mit Dicyclohexylcarbodiimid in wäßrigem Pyridin hergestellt1. Das Coenzymmodell war im enzymatischen Test mit verschiedenen Dehydrogenasen ebenso wirksam wie Nicotinamid-adenin-dinucleotid. Für die Funktion der Wasserstoffübertragung scheint der Stickstoff N 1 im Purinring von Bedeutung zu sein. Auffällig ist, daß die pK-Werte nichtfunktioneller Mononucleotidteile bei Coenzymmodellen, die Nicotinamid-adenin-dinucleotid im enzymatischen Test ersetzen können, über dem Wert 4 liegen. Das optische Verhalten des Coenzymmodells Nicotinamid-3-desazapurin-dinucleotid ähnelt dagegen nichtpurinhaltigen Coenzymmodellen, die sich bisher alle durch eine geringere Coenzymwirksamkeit auszeichneten. Eine schwächere intramolekulare Wechselwirkung zwischen den Heterocyclen zeichnete sich durch die Verschiebung des Dihydronicotinamid-Absorptionsmaximums in dem kurzwelligen Teil des Spektrums aus. Aus den geringeren intramolekularen Wechselwirkungen lassen sich jedoch keine Rückschlüsse auf die enzymatische Wirksamkeit ziehen. Alle nichtpurinhaltigen hydrierten Coenzymmodelle zeigen keine Änderung der Fluoreszenz nach Enzymzugabe.
Die Synthese des Coenzymmodells Flavin-benzimidazol-dinucleotid * gelang durch Kondensation von Benzimidazolribotid-imidazolid 1 oder Benzimidazolribotid-guanidiniumamidat 2 mit Flavinmononucleotid. Das Coenzymmodell war enzymatisch nicht aktiv und bildete keinen Enzym-Coenzym-Komplex. Im Absorptionsspektrum konnte eine Extinktionszunahme nach der Spaltung der Pyrophosphatbrücke nur im Bereich von 260 mμ beobachtet werden. Das Molekül liegt daher vermutlich in einer gefalteten Form vor. Ein Komplex zwischen Flavin- und Benzimidazolteil konnte nicht nachgewiesen werden. Eine Fluoreszenzunterdrückung, die im FAD durch die Komplexbildung zwischen Flavin- und Adeninteil bedingt wird, wurde im FBD-Coenzymmodell nicht beobachtet.
Luo, Beiping ; Peter, Thomas ; Wernli, Heini ; Fueglistaler, Stephan ; Wirth, Martin ; Kiemle, Christoph ; Flentje, Harald ; Yushko, Vladimir A. ; Khattatov, Vyacheslav ; Rudakov, Vladimir V. ; Thomas, Andreas ; Borrmann, Stephan ; Toci, Guido ; Mazzinghi, Piero ; Beuermann, Jürgen ; Schiller, Cornelius ; Cairo, Francesco ; Di Donfrancesco, Guido ; Adriani, Alberto ; Volk, C.-Michael ; Strom, Johan ; Noone, Kevin ; Mitev, Valentin ; MacKenzie, Robert A. ; Carslaw, Kenneth S. ; Trautmann, Thomas ; Santacesaria, Vincenzo ; Stefanutti, Leopoldo
Mechanisms by which subvisible cirrus clouds (SVCs) might contribute to dehydration close to the tropical tropopause are not well understood. Recently Ultrathin Tropical Tropopause Clouds (UTTCs) with optical depths around 10-4 have been detected in the western Indian ocean. These clouds cover thousands of square kilometers as 200-300 m thick distinct and homogeneous layer just below the tropical tropopause. In their condensed phase UTTCs contain only 1-5% of the total water, and essentially no nitric acid. A new cloud stabilization mechanism is required to explain this small fraction of the condensed water content in the clouds and their small vertical thickness. This work suggests a mechanism, which forces the particles into a thin layer, based on upwelling of the air of some mm/s to balance the ice particles, supersaturation with respect to ice above and subsaturation below the UTTC. In situ measurements suggest that these requirements are fulfilled. The basic physical properties of this mechanism are explored by means of a single particle model. Comprehensive 1-D cloud simulations demonstrate this stabilization mechanism to be robust against rapid temperature fluctuations of +/- 0.5 K. However, rapid warming (Delta T > 2 K) leads to evaporation of the UTTC, while rapid cooling (Delta T < -2 K) leads to destabilization of the particles with the potential for significant dehydration below the cloud
Gottschalk, Michael G. ; Richter, Jan ; Ziegler, Christiane ; Schiele, Miriam A. ; Mann, Julia ; Geiger, Maximilian J. ; Schartner, Christoph ; Homola, György Ádám ; Alpers, Georg W. ; Büchel, Christian ; Fehm, Lydia ; Fydrich, Thomas ; Gerlach, Alexander ; Gloster, Andrew T. ; Helbig-Lang, Sylvia ; Kalisch, Raffael ; Kircher, Tilo ; Lang, Thomas ; Lonsdorf, Tina B. ; Pané-Farré, Christiane A. ; Ströhle, Andreas ; Weber, Heike ; Zwanzger, Peter M. ; Arolt, Volker ; Romanos, Marcel ; Wittchen, Hans-Ulrich ; Hamm, Alfons ; Pauli, Paul ; Reif, Andreas ; Deckert, Jürgen ; Neufang, Susanne ; Höfler, Michael ; Domschke, Katharina
Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
Background: The flavin in its FMN and FAD forms is a versatile cofactor that is involved in catalysis of most disparate types of biological reactions. These include redox reactions such as dehydrogenations, activation of dioxygen, electron transfer, bioluminescence, blue light reception, photobiochemistry (as in photolyases), redox signaling etc. Recently, hitherto unrecognized types of biological reactions have been uncovered that do not involve redox shuffles, and might involve the reduced form of the flavin as a catalyst. The present work addresses properties of reduced flavin relevant in this context. Results: N(5)-H exchange reactions of the flavin reduced form and its pH dependence were studied using the 15N-NMR-signals of 15N-enriched, reduced flavin in the pH range from 5 to 12. The chemical shifts of the N(3) and N(5) resonances are not affected to a relevant extent in this pH range. This contrasts with the multiplicity of the N(5)-resonance, which strongly depends on pH. It is a doublet between pH 8.45 and 10.25 that coalesces into a singlet at lower and higher pH values. From the line width of the 15N(5) signal the pH-dependent rate of hydrogen exchange was deduced. The multiplicity of the 15N(5) signal and the proton exchange rates are little dependent on the buffer system used. Conclusion: The exchange rates allow an estimation of the pKa value of N(5)-H deprotonation in reduced flavin to be ≥ 20. This value imposes specific constraints for mechanisms of flavoprotein catalysis based on this process. On the other hand the pK ≈ 4 for N(5)-H protonation (to form N(5)+-H2) would be consistent with a role of N(5)-H as a base.
The solution structure of the lantibiotic immunity protein NisI and its interactions with nisin
(2015)
Hacker, Carolin ; Christ, Nina A. ; Duchardt-Ferner, Elke ; Korn, Sophie ; Göbl, Christoph ; Berninger, Lucija ; Düsterhus, Stefanie ; Hellmich, Ute ; Madl, Tobias ; Kötter, Peter ; Entian, Karl-Dieter ; Wöhnert, Jens
Many Gram-positive bacteria produce lantibiotics, genetically encoded and posttranslationally modified peptide antibiotics, which inhibit the growth of other Gram-positive bacteria. To protect themselves against their own lantibiotics these bacteria express a variety of immunity proteins including the LanI lipoproteins. The structural and mechanistic basis for LanI-mediated lantibiotic immunity is not yet understood. Lactococcus lactis produces the lantibiotic nisin, which is widely used as a food preservative. Its LanI protein NisI provides immunity against nisin but not against structurally very similar lantibiotics from other species such as subtilin from Bacillus subtilis. To understand the structural basis for LanI-mediated immunity and their specificity we investigated the structure of NisI. We found that NisI is a two-domain protein. Surprisingly, each of the two NisI domains has the same structure as the LanI protein from B. subtilis, SpaI, despite the lack of significant sequence homology. The two NisI domains and SpaI differ strongly in their surface properties and function. Additionally, SpaI-mediated lantibiotic immunity depends on the presence of a basic unstructured N-terminal region that tethers SpaI to the membrane. Such a region is absent from NisI. Instead, the N-terminal domain of NisI interacts with membranes but not with nisin. In contrast, the C-terminal domain specifically binds nisin and modulates the membrane affinity of the N-terminal domain. Thus, our results reveal an unexpected structural relationship between NisI and SpaI and shed light on the structural basis for LanI mediated lantibiotic immunity.
Hecht, Nils Nicholas ; Wessels, Lars ; Werft, Finn-Ove ; Schneider, Ulf Christoph ; Czabanka, Marcus Alexander ; Vajkoczy, Peter
Background: To investigate whether patients with critical emergency conditions are seeking or receiving the medical care that they require we characterized the reality of care for patients presenting with Neuro-emergencies during the first phase of the COVID-19 pandemic.
Methods: In this observational, longitudinal cohort study, all neurosurgical admissions that presented to our Department between February 1st and April 15th during the COVID-19 pandemic and during the same time-period in 2019 were identified and categorized according to the presence of a Neuro-emergency, the route of admission, management, and the category of disease. Further, the clinical course of patients with chronic subdural hematoma (cSDH) was investigated as a Neuro-emergency representative for a wide variety of semi-urgent symptoms.
Results: During the pandemic, the percentage of Neuro-emergencies among all neurosurgical admissions remained similar as in 2019 but a larger proportion presented through the emergency department than through the outpatient clinic or by referral (*p=0.009). The total number of Neuro-emergencies was significantly reduced (*p=0.0007) across all types of disease, particularly in severe vascular (*p=0.036) but also in spinal (*p=0.007) and hydrocephalus (*p=0.048) emergencies. Strikingly, elderly patients with cSDH and mild to moderate symptoms presented less frequently, with more severe symptoms (*p=0.046) and were less likely to reach favorable outcome (*p=0.003).
Conclusions: Despite pandemic-related restrictive measures and reallocation of resources, patients with Neuro-emergencies should be encouraged to present regardless of the severity of symptoms because deferred presentation may result in adverse outcome. Thus, conservation of critical healthcare resources remains essential in spite fighting COVID-19.
Peter, Alina ; Stauch, Benjamin J. ; Shapcott, Katharine A. ; Kouroupaki, Kleopatra ; Schmiedt, Joscha Tapani ; Klein, Liane ; Klon-Lipok, Johanna ; Dowdall, Jarrod Robert ; Schölvinck, Marieke L. ; Vinck, Martin ; Singer, Wolf ; Schmid, Michael Christoph ; Fries, Pascal
When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here, we show in awake macaque area V1 that both repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects show some persistence on the timescale of minutes. Gamma increases are specific to the presented stimulus location. Further, repetition effects on gamma and on firing rates generalize to images of natural objects. These findings support the notion that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters.
Baumgardt, Christian ; Stephan, Christoph ; Haberl, Annette Elisabeth ; Brodt, Hans-Reinhard ; Stürmer, Martin ; Klauke, Stefan ; Gute, Peter ; Bickel, Markus ; Khaykin, Pavel ; Hentig, Nils von ; Staszewski, Schlomo
Poster presentation: Purpose of the study To compare the virological, immunological and clinical response to three boosted double protease inhibitor (PI) regimens of saquinavir and ritonavir in combination with lopinavir (LOPSAQ), atazanavir (ATSAQ) or fosamprenavir (FOSAQ) without reverse transcriptase inhibitors (RTI) in HIV-positive patients with limited RTI treatment options. ...
Peter, Alina ; Stauch, Benjamin J. ; Shapcott, Katharine A. ; Kouroupaki, Kleopatra ; Schmiedt, Joscha Tapani ; Klein, Liane ; Klon-Lipok, Johanna ; Dowdall, Jarrod Robert ; Schölvinck, Marieke L. ; Vinck, Martin ; Singer, Wolf ; Schmid, Michael Christoph ; Fries, Pascal
When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here we show in awake macaque area V1 that both, repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects showed some persistence on the timescale of minutes. Further, gamma increases were specific to the presented stimulus location. Importantly, repetition effects on gamma and on firing rates generalized to natural images. These findings suggest that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters, both for generating efficient stimulus responses and possibly for memory formation.
Adamczewski-Musch, Jörn ; Agakishiev, Geydar ; Arnold, Oliver Werner ; Atomssa, Ermias T. ; Behnke, Claudia ; Berger-Chen, Jia-Chii ; Biernat, Jacek ; Blanco, Alberto ; Blume, Christoph ; Böhmer, Michael ; Bordalo, Paula ; Chernenko, Sergey P. ; Deveaux, Christina Anna ; Dybczak, Adrian ; Epple, Eliane ; Fabbietti, Laura ; Fateev, Oleg ; Fonte, Paulo ; Franco, Celso ; Friese, Jürgen ; Fröhlich, Ingo ; Galatyuk, Tetyana ; Garzón, Juan A. ; Gernhäuser, Roman ; Gill, Katharina ; Golubeva, Marina ; Guber, Fedor ; Gumberidze, Malgorzata ; Harabasz, Szymon ; Hennino, Thierry ; Hlaváč, Stanislav ; Höhne, Claudia ; Holzmann, Romain ; Ierusalimov, Alexander P. ; Ivashkin, Alexander ; Jurkovič, Martin ; Kämpfer, Burkhard ; Karavicheva, Tatiana L. ; Kardan, Behruz ; Koenig, Ilse ; Koenig, W. ; Kolb, Burkhard W. ; Korcyl, Grzegorz ; Kornakov, Georgy ; Kotte, Roland ; Krása, Antonin ; Krebs, Erik ; Kuc, Hubert ; Kugler, Andrej ; Kunz, Tobias ; Kurepin, Alexander ; Kurilkin, Aleksey K. ; Kurilkin, Pavel ; Ladygin, Vladimir P. ; Lalik, Rafał Tomasz ; Lapidus, Kirill ; Lebedev, Alexei ; Lopes, Luis Alberto Vieira ; Lorenz, Manuel ; Mahmoud, Tariq ; Maier, Ludwig W. ; Maurus, Steffen ; Mangiarotti, Alessio ; Markert, Jochen ; Metag, Volker ; Michel, Jan ; Müntz, Christian ; Münzer, Robert Helmut ; Naumann, Lothar ; Palka, Marek ; Parpottas, Yannis ; Pechenov, Vladimir ; Pechenova, Olga ; Petousis, Vlasios ; Pietraszko, Jerzy ; Przygoda, Witold ; Ramos, S. ; Ramstein, Béatrice ; Rehnisch, Laura ; Reshetin, Andrey ; Rost, Adrian ; Rustamov, Anar ; Sadovsky, Alexander ; Salabura, Piotr ; Scheib, Timo ; Schmidt-Sommerfeld, Korbinian ; Schuldes, Heidi ; Sellheim, Patrick ; Siebenson, Johannes Stephan ; Silva, L. ; Sobolev, Yuri G. ; Spataro, Stefano ; Ströbele, Herbert ; Stroth, Joachim ; Strzempek, Paweł ; Sturm, C. ; Svoboda, Ondřej ; Tarantola Peloni, Attilio ; Teilab, Khaled ; Tlustý, Pavel ; Traxler, Michael ; Tsertos, Haralabos ; Vasiliev, Taras A. ; Wagner, Vladimir ; Wendisch, Christian ; Wirth, Joana ; Wüstenfeld, Jörn ; Zanevsky, Yuri V. ; Zumbruch, Peter W.
The production of Σ0 baryons in the nuclear reaction p (3.5 GeV) + Nb (corresponding to sNN=3.18 GeV) is studied with the detector set-up HADES at GSI, Darmstadt. Σ0s were identified via the decay Σ0→Λγ with subsequent decays Λ→pπ− in coincidence with a e+e− pair from either external (γ→e+e−) or internal (Dalitz decay γ⁎→e+e−) gamma conversions. The differential Σ0 cross section integrated over the detector acceptance, i.e. the rapidity interval 0.5<y<1.1, has been extracted as ΔσΣ0=2.3±(0.2)stat±(−0.6+0.6)sys±(0.2)norm mb, yielding the inclusive production cross section in full phase space σΣ0total=5.8±(0.5)stat±(−1.4+1.4)sys±(0.6)norm±(1.7)extrapol mb by averaging over different extrapolation methods. The Λall/Σ0 ratio within the HADES acceptance is equal to 2.3±(0.2)stat±(−0.6+0.6)sys. The obtained rapidity and momentum distributions are compared to transport model calculations. The Σ0 yield agrees with the statistical model of particle production in nuclear reactions. Keywords: Hyperons, Strangeness, Proton, Nucleus.
Lauber, Simone F. ; Yaramyshev, Stepan ; Basten, Markus ; Aulenbacher, Kurt ; Barth, Winfried ; Burandt, Christoph ; Droba, Martin ; Dziuba, Florian ; Forck, Peter ; Gettmann, Viktor ; Kürzeder, Thorsten ; List, Julian A. ; Miski-Oglu, Maksym ; Podlech, Holger ; Rubin, Anna ; Schwarz, Malte
The new heavy ion superconducting continuous wave HElmholtz LInear ACcelerator (HELIAC) is under construction at GSI. A normal conducting injector, comprising an ECR ion source, an RFQ and a DTL, is recently in development. The new Interdigital H-mode DTL, presented in this paper, accelerates the heavy ion beam from 300 to 1400 keV/u, applying an Alternating Phase Focusing (APF) beam dynamics scheme. This APF section, consisting of two separately controlled tanks, has to provide for stable routine operation with assistance of dedicated beam diagnostics devices in the Intertank section. The installed quadrupole lenses and beam steerers installed there ensure full transmission in a wide range of input beam parameters.
Lauber, Simone F. ; Aulenbacher, Kurt ; Barth, Winfried ; Basten, Markus ; Burandt, Christoph ; Dziuba, Florian ; Forck, Peter ; Gettmann, Viktor ; Heilmann, Manuel ; Kürzeder, Thorsten ; List, Julian A. ; Miski-Oglu, Maksym ; Podlech, Holger ; Rubin, Anna ; Schwarz, Malte ; Sieber, Thomas ; Yaramyshev, Stepan
The upcoming commissioning of the superconducting (SC) continuous wave Helmholtz linear accelerators first of series cryomodule is going to demand precise alignment of the four internal SC cavities and two SC solenoids. For optimal results, a beam-based alignment method is used to reduce the misalignment of the whole cryomodule, as well as its individual components. A symmetric beam of low transverse emittance is required for this method, which is to be formed by a collimation system. It consists of two separate plates with milled slits, aligned in the horizontal and vertical direction. The collimation system and alignment measurements are proposed, investigated, and realized. The complete setup of this system and its integration into the existing environment at the GSI High Charge State Injector are presented, as well as the results of the recent reference measurements.
Mendoza Cembranos, Emilio ; Cano-Ott, Daniel ; Altstadt, Sebastian ; Andriamonje, Samuel ; Andrzejewski, Józef ; Audouin, Laurent ; Balibrea Correa, Javier ; Bécares, Vicente ; Barbagallo, Massimo ; Bečvář, František ; Belloni, Fabio ; Berthier, B. ; Berthoumieux, Eric ; Billowes, Jonathan ; Boccone, Vittorio ; Bosnar, Damir ; Brugger, Markus ; Calviño Tavares, Francisco ; Calviani, Marco ; Carrapiço, Carlos ; Cerutti, Francesco ; Chiaveri, Enrico ; Chin, Michael ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Diakaki, Maria ; Dillmann, Iris ; Domingo-Pardo, César ; Durán, Ignacio ; Dzysiuk, Nataliia ; Eleftheriadis, Christos ; Fernández-Ordóñez, M. ; 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 ; Gramegna, F. ; 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 ; Mastromarco, Mario ; 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 A. ; 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. ; Versaci, Roberto ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Ware, Timothy ; Weigand, Mario ; Weiss, Christian ; Wright, Tobias ; Žugec, Petar
New neutron cross section measurements of minor actinides have been performed recently in order to reduce the uncertainties in the evaluated data, which is important for the design of advanced nuclear reactors and, in particular, for determining their performance in the transmutation of nuclear waste. We have measured the 241Am(n,γ) cross section at the n_TOF facility between 0.2 eV and 10 keV with a BaF2 Total Absorption Calorimeter, and the analysis of the measurement has been recently concluded. Our results are in reasonable agreement below 20 eV with the ones published by C. Lampoudis et al. in 2013, who reported a 22% larger capture cross section up to 110 eV compared to experimental and evaluated data published before. Our results also indicate that the 241Am(n,γ) cross section is underestimated in the present evaluated libraries between 20 eV and 2 keV by 25%, on average, and up to 35% for certain evaluations and energy ranges.
Balibrea Correa, Javier ; Mendoza Cembranos, Emilio ; Cano-Ott, Daniel ; Krtička, Milan ; 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 ; 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 ; Guerrero Sánchez, Carlos ; Gómez Hornillos, María Belén ; Ganesan, Srinivasan ; García Ríos, Aczel Regino ; Giubrone, Giuseppe ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Goverdovski, Andrey ; Griesmayer, Erich ; Gunsing, Frank ; 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 ; Kivel, Nikolay ; Koehler, Paul ; Kokkoris, Michael ; Kroll, Jiří ; Lampoudis, Christos ; Langer, Christoph ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Leong, Lou Sai ; Lerendegui-Marco, Jorge ; Licata, Mauro ; Losito, Roberto ; Mallick, Amod Kishore ; Manousos, Athanasios ; Marganiec, Justyna ; Martı́nez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; 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 ; Rubbia, Carlo ; Ryan, James A. ; 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, Christian ; Wright, Tobias ; Žugec, Petar
The accuracy on neutron capture cross section of fissile isotopes must be improved for the design of future nuclear systems such as Gen-IV reactors and Accelerator Driven Systems. The High Priority Request List of the Nuclear Energy Agency, which lists the most important nuclear data requirements, includes also the neutron capture cross sections of fissile isotopes such as 233,235U and 239,241Pu. A specific experimental setup has been used at the CERN n_TOF facility for the measurement of the neutron capture cross section of 235U by a set of micromegas fission detectors placed inside a segmented BaF2 Total Absorption Calorimeter.
Zamora Cardona, Juan Carlos ; Aumann, Thomas ; Bagchi, Soumya ; Bönig, Esther Sabine ; Csatlós, Margit ; Dillmann, Iris ; Dimopoulou, Christina ; Egelhof, Peter ; Eremin, Vladimir ; Furuno, Tatsuya ; Geissel, Hans ; Gernhäuser, Roman ; Harakeh, Muhsin N. ; Hartig, Anna-Lena ; Ilieva, Stoyanka ; Kalantar-Nayestanaki, Nasser ; Kiselev, Oleg A. ; Kollmus, Holger ; Kozhuharov, Christophor ; Krasznahorkay, Attila ; Kröll, Thorsten ; Kuilman, Maartje ; Litvinov, Sergey A. ; Litvinov, Yuri A. ; Mahjour-Shafiei, Masoud ; Mutterer, Manfred ; Nagae, Daisuke ; Najafi, Mohammad Ali ; Nociforo, Chiara ; Nolden, Fritz ; Popp, Ulrich ; Rigollet, Catherine ; Roy, Subhankar ; Scheidenberger, Christoph ; Schmid, Mirko von ; Steck, Markus ; Streicher, Branislav ; Stuhl, László ; Thürauf, Michael Friedrich Erhard ; Uesaka, Tomohiro ; Weick, Helmut ; Winfield, John S. ; Winters, Danyal Ferdinant Alexander ; Woods, Philip John ; Yamaguchi, Takayuki ; Yue, Ke ; Zenihiro, Juzo
A new technique developed for measuring nuclear reactions at low momentum transfer with stored beams in inverse kinematics was successfully used to study isoscalar giant resonances. The experiment was carried out at the experimental heavy-ion storage ring (ESR) at the GSI facility using a stored 58Ni beam at 100 MeV/u and an internal helium gas-jet target. In these measurements, inelastically scattered α-recoils at very forward center-of-mass angles (θcm ≤ 1.5°) were detected with a dedicated setup, including ultra-high vacuum compatible detectors. Experimental results indicate a dominant contribution of the isoscalar giant monopole resonance at this very forward angular range. It was found that the monopole contribution exhausts 79+12−11% of the energy-weighted sum rule (EWSR), which agrees with measurements performed in normal kinematics. This opens up the opportunity to investigate the giant resonances in a large domain of unstable and exotic nuclei in the near future. It is a fundamental milestone towards new nuclear reaction studies with stored ion beams.
Medema, Marnix H. ; Kottmann, Renzo ; Yilmaz, Pelin ; Cummings, Matthew ; Biggins, John B. ; Kai, Blin ; de Bruijn, Irene ; Chooi, Yit Heng ; Claesen, Jan ; Coates, R. Cameron ; Cruz-Morales, Pablo ; Duddela, Srikanth ; Düsterhus, Stephanie ; Edwards, Daniel J. ; Fewer, David P. ; Garg, Neha ; Geiger, Christoph ; Gomez-Escribano, Juan Pablo ; Greule, Anja ; Hadjithomas, Michalis ; Haines, Anthony S. ; Helfrich, Eric J. N. ; Hillwig, Matthew L. ; Ishida, Keishi ; Jones, Adam C. ; Jones, Carla S. ; Jungmann, Katrin ; Kegler, Carsten ; Kim, Hyun Uk ; Kötter, Peter ; Krug, Daniel ; Masschelein, Joleen ; Melnik, Alexey V. ; Mantovan, Simone M. ; Monroe, Emily A. ; Moore, Marcus ; Moss, Nathan ; Nützmann, Hans-Wilhelm ; Pan, Guohui ; Pati, Amrita ; Petras, Daniel ; Reen, F. Jerry ; Rosconi, Federico ; Rui, Zhe ; Tian, Zhenhua ; Tobias, Nicholas J. ; Tsunematsu, Yuta ; Wiemann, Philipp ; Wyckoff, Elizabeth ; Yan, Xiaohui ; Yim, Grace ; Yu, Fengan ; Xie, Yunchang ; Aigle, Bertrand ; Apel, Alexander K. ; Balibar, Carl J. ; Balskus, Emily P. ; Barona-Gómez, Francisco ; Bechthold, Andreas ; Bode, Helge Björn ; Borriss, Rainer ; Brady, Sean F. ; Brakhage, Axel A. ; Caffrey, Patrick ; Cheng, Yi-Qiang ; Clardy, Jon ; Cox, Russell J. ; De Mot, René ; Donadio, Stefano ; Donia, Mohamed S. ; van der Donk, Wilfred A. ; Dorrestein, Pieter C. ; Doyle, Sean ; Driessen, Arnold J. M. ; Ehling-Schulz, Monika ; Entian, Karl-Dieter ; Fischbach, Michael A. ; Gerwick, Lena ; Gerwick, William H. ; Gross, Harald ; Gust, Bertolt ; Hertweck, Christian ; Höfte, Monica ; Jensen, Susan E. ; Ju, Jianhua ; Katz, Leonard ; Kaysser, Leonard ; Klassen, Jonathan L. ; Keller, Nancy P. ; Kormanec, Jan ; Kuipers, Oscar P. ; Kuzuyama, Tomohisa ; Kyrpides, Nikos C. ; Kwon, Hyung-Jin ; Lautru, Sylvie ; Lavigne, Rob ; Lee, Chia Y. ; Linquan, Bai ; Liu, Xinyu ; Liu, Wen ; Luzhetskyy, Andriy ; Mahmud, Taifo ; Mast, Yvonne ; Méndez, Carmen ; Metsä-Ketelä, Mikko ; Micklefield, Jason ; Mitchell, Douglas A. ; Moore, Bradley S. ; Moreira, Leonilde M. ; Müller, Rolf ; Neilan, Brett A. ; Nett, Markus ; Nielsen, Jens ; O’Gara, Fergal ; Oikawa, Hideaki ; Osbourn, Anne ; Osburne, Marcia S. ; Ostash, Bohdan ; Payne, Shelley M. ; Pernodet, Jean-Luc ; Petricek, Miroslav ; Piel, Jörn ; Ploux, Olivier ; Raaijmakers, Jos M. ; Salas, José A. ; Schmitt, Esther K. ; Scott, Barry ; Seipke, Ryan F. ; Shen, Ben ; Sherman, David H. ; Sivonen, Kaarina ; Smanski, Michael J. ; Sosio, Margherita ; Stegmann, Evi ; Süssmuth, Roderich D. ; Tahlan, Kapil ; Thomas, Christopher M. ; Tang, Yi ; Truman, Andrew W. ; Viaud, Muriel ; Walton, Jonathan D. ; Walsh, Christopher T. ; Weber, Tilmann ; van Wezel, Gilles P. ; Wilkinson, Barrie ; Willey, Joanne M. ; Wohlleben, Wolfgang ; Wright, Gerard D. ; Ziemert, Nadine ; Zhang, Changsheng ; Zotchev, Sergey B. ; Breitling, Rainer ; Takano, Eriko ; Glöckner, Frank Oliver
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
Wiegand, Steffen B. ; Heidrich, Benjamin ; Susser, Simone ; Rogalska-Taranta, Magdalena ; Petersen, Jörg ; Böker, Klaus H. W. ; Grigorian, Natalia ; Link, Ralph ; Naumann, Uwe ; John, Christine ; Lüth, Stefan ; Malfertheiner, Peter ; Manns, Michael P. ; Wedemeyer, Heiner ; Sarrazin, Christoph ; Cornberg, Markus
Background: SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3.
Methods: We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631).
Results: Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%).
Conclusion: IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.
Bachmann, Friederike ; Schreder, Martin ; Engelhardt, Monika ; Langer, Christian ; Wolleschak, Denise ; Mügge, Lars-Olof ; Dürk, Heinz ; Schäfer-Eckart, Kerstin ; Blau, Igor-Wolfgang ; Gramatzki, Martin ; Liebisch, Peter ; Grube, Matthias ; Metzler, Ivana von ; Bassermann, Florian ; Metzner, Bernd ; Röllig, Christoph ; Hertenstein, Bernd ; Khandanpour, Cyrus ; Dechow, Tobias ; Hebart, Holger ; Jung, Wolfram ; Theurich, Sebastian ; Maschmeyer, Georg ; Salwender, Hans ; Hess, Georg ; Bittrich, Max ; Rasche, Leo ; Brioli, Annamaria ; Eckardt, Kai-Uwe ; Straka, Christian ; Held, Swantje ; Einsele, Hermann ; Knop, Stefan
Simple Summary: Renal insufficiency is frequently seen in newly diagnosed multiple myeloma and can be due to the disease itself but also caused by medical interventions or infections. Patients with severe renal insufficiency are known to have an adverse prognosis, but recently, it was shown that even moderately impaired kidney function can have long-term sequelae. Achieving quick disease control by effective antimyeloma therapy can lead to the recovery of renal function. We investigated the kidney-specific variables in a large cohort of 770 myeloma patients receiving three different three-drug regimens for initial myeloma treatment to learn more about the differential effects on kidney function in an early disease phase. All regimens had a positive impact on kidney function without a difference in the proportion of patients who reached normal renal function after three cycles. Interestingly, patients who received bortezomib, lenalidomide, and dexamethasone tended to have higher risk for a worse renal function following induction when compared to the initial values.
Abstract: Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3% at baseline to 1.9% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined “renal complete response (CRrenal)” was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd (p = 0.4747). Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment “renal fitness” in the latter group.
Grammatikos, Georgios ; Lange, Christian ; Susser, Simone ; Schwendy, Susanne ; Dikopoulos, Nektarios ; Buggisch, Peter ; Encke, Jens ; Teuber, Gerlinde ; Goeser, Tobias ; Thimme, Robert ; Klinker, Hartwig ; Boecher, Wulf O. ; Schulte-Frohlinde, Ewert ; Penna Martinez, Marissa ; Badenhoop, Klaus ; Zeuzem, Stefan ; Berg, Thomas ; Sarrazin, Christoph
Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed.
Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24–72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome.
Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002–1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975–0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000–1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073–2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271–4.695, P = 0.007) constituted the strongest predictors of treatment response.
Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.
Dultz, Georg ; Seelhof, Martin ; Herrmann, Eva ; Welker, Martin-Walter ; Friedrich-Rust, Mireen ; Teuber, Gerlinde ; Kronenberger, Bernd ; Wagner, Michael von ; Vermehren, Johannes ; Sarrazin, Christoph ; Zeuzem, Stefan ; Hofmann, Wolf-Peter
Background and Aims: In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined.
Methods: In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks).
Results: Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p = 0.015), mean platelets (102.64 vs. 138.95/nl, p = 0.014) and mean leukocytes (4.02 vs. 5.68/nl, p = 0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18–2.07; p = 0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6–9, 10–13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001).
Conclusions: Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.
Barucca, Gianni ; Davì, F. ; Lancioni, G. ; Mengucci, P. ; Montalto, L. ; Natali, P. P. ; Paone, N. ; Rinaldi, D. ; Scalise, L. ; Erni, W. ; Krusche, B. ; Steinacher, M. ; Walford, N. ; Cao, N. ; Liu, Z. ; Liu, C. ; Liu, B. ; Shen, X. ; Sun, S. ; Tao, J. ; Xiong, X. A. ; Zhao, G. ; Zhao, J. ; Albrecht, Malte ; Alkakhi, W. ; Bökelmann, S. ; Coen, S. ; Feldbauer, Florian ; Fink, M. ; Frech, J. ; Freudenreich, V. ; Fritsch, Miriam ; Grochowski, J. ; Hagdorn, R. ; Heinsius, Fritz-Herbert ; Held, T. ; Holtmann, Tobias ; Keshk, Iman ; Koch, H. ; Kopf, Bertram ; Kuhlmann, M. ; Kümmel, M. ; Küßner, M. ; Li, J. ; Linzen, L. ; Maldaner, Stephan ; Oppotsch, J. ; Pankonin, S. ; Pelizäus, Marc ; Pflüger, S. ; Pitka, A. ; Reher, J. ; Reicherz, G. ; Schnier, Claudius ; Steinke, M. ; Triffterer, T. ; Wenzel, C. ; Wiedner, Ulrich ; Denizli, H. ; Er, N. ; Keskin, U. ; Olgun, A. T. ; Yerlikaya, S. ; Yilmaz, A. ; Beck, R. ; Hammann, C. ; Hartmann, J. ; Ketzer, Bernhard ; Müllers, J. ; Rossbach, M. ; Salisbury, B. ; Schmidt, Christian Joachim ; Thoma, U. ; Urban, M. ; Bianconi, A. ; Bragadireanu, Mario ; Pantea, D. ; Domagala, M. ; Filo, G. ; Lisowski, E. ; Lisowski, F. ; Michałek, M. ; Poznański, P. ; Płażek, J. ; Korcyl, K. ; Kozela, A. ; Lebiedowicz, P. ; Pysz, K. ; Schäfer, W. ; Szczurek, A. ; Firlej, M. ; Fiutowski, T. ; Idzik, M. ; Moron, J. ; Swientek, K. ; Terlecki, P. ; Korcyl, G. ; Lalik, R. ; Malige, A. ; Moskal, P. ; Nowakowski, K. ; Przygoda, W. ; Rathod, N. ; Rudy, Z. ; Salabura, P. ; Smyrski, J. ; Augustin, I. ; Böhm, R. ; Lehmann, I. ; Schmitt, L. ; Varentsov, V. ; Al-Turany, Mohammad ; Belias, A. ; Deppe, H. ; Dzhygadlo, R. ; Flemming, H. ; Gerhardt, A. ; Götzen, Klaus ; Heinz, Andreas ; Jiang, P. ; Karabowicz, R. ; Koch, S. ; Kurilla, U. ; Lehmann, D. ; Lühning, J. ; Lynen, U. ; Orth, H. ; Peters, Klaus ; Saito, T. ; Schepers, G. ; Schmidt, C. J. ; Schwarz, C. ; Schwiening, J. ; Täschner, Alexander ; Traxler, M. ; Voss, B. ; Wieczorek, P. ; Abazov, V. ; Alexeev, G. ; Arefiev, V. A. ; Astakhov, V. ; Barabanov, M. Yu. ; Batyunya, B. V. ; Dodokhov, V. Kh. ; Efremov, A. ; Fechtchenko, A. ; Galoyan, A. ; Golovanov, G. ; Koshurnikov, E. K. ; Lobanov, Y. Yu. ; Olshevskiy, A. G. ; Piskun, A. A. ; Samartsev, A. ; Shimanski, S. ; Skachkov, N. B. ; Skachkova, A. N. ; Strokovsky, E. A. ; Tokmenin, V. ; Uzhinsky, V. ; Verkheev, A. ; Vodopianov, A. ; Zhuravlev, N. I. ; Branford, D. ; Watts, D. ; Böhm, M. ; Eyrich, W. ; Lehmann, A. ; Miehling, D. ; Pfaffinger, M. ; Quin, N. ; Robison, L. ; Seth, K. ; Xiao, T. ; Bettoni, Diego ; Ali, A. ; Hamdi, A. ; Himmelreich, Mathilde ; Krebs, M. ; Nakhoul, S. ; Nerling, Frank ; Belousov, A. ; Kisel, Ivan ; Kozlov, Grigory ; Pugach, M. ; Zyzak, Maksym ; Bianchi, Nicola ; Gianotti, Paola ; Lucherini, V. ; Bracco, G. ; Bettner, Y. ; Bodenschatz, S. ; Brinkmann, K. 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This paper reports on Monte Carlo simulation results for future measurements of the moduli of time-like proton electromagnetic form factors, |GE | and |GM|, using the ¯pp → μ+μ− reaction at PANDA (FAIR). The electromagnetic form factors are fundamental quantities parameterizing the electric and magnetic structure of hadrons. This work estimates the statistical and total accuracy with which the form factors can be measured at PANDA, using an analysis of simulated data within the PandaRoot software framework. The most crucial background channel is ¯pp → π+π−,due to the very similar behavior of muons and pions in the detector. The suppression factors are evaluated for this and all other relevant background channels at different values of antiproton beam momentum. The signal/background separation is based on a multivariate analysis, using the Boosted Decision Trees method. An expected background subtraction is included in this study, based on realistic angular distribuations of the background contribution. Systematic uncertainties are considered and the relative total uncertainties of the form factor measurements are presented.
Graf, Christiana ; Mondorf, Antonia Maria ; Knop, Viola ; Peiffer, Kai-Henrik ; Dietz, Julia ; Friess, Julia ; Wedemeyer, Heiner ; Buggisch, Peter ; Mauß, Stefan ; Berg, Thomas ; Rausch, Michael ; Sprinzl, Martin F. ; Klinker, Hartwig ; Hinrichsen, Holger ; Bronowicki, Jean-Pierre ; Haag, Sebastian ; Hüppe, Dietrich ; Lutz, Thomas ; Poynard, Thierry ; Zeuzem, Stefan ; Friedrich-Rust, Mireen ; Sarrazin, Christoph ; Vermehren, Johannes
Background: Accurate assessment of hepatic fibrosis in patients with chronic HBeAg-negative Hepatitis B is of crucial importance not only to predict the long-term clinical course, but also to evaluate antiviral therapy indication. The aim of this study was to prospectively assess the utility of point shear wave elastography (pSWE) for longitudinal non-invasive fibrosis assessment in a large cohort of untreated patients with chronic HBeAg-negative hepatitis B virus (HBV) infection.
Methods: 407 consecutive patients with HBeAg-negative HBV infection who underwent pSWE, transient elastography (TE) as well as laboratory fibrosis markers, including fibrosis index based on four factors (FIB-4), aspartate to platelet ratio index (APRI) and FibroTest, on the same day were prospectively followed up for six years. Patients were classified into one of the three groups: inactive carriers (IC; HBV-DNA <2000 IU/mL and ALT <40 U/L); grey zone group 1 (GZ-1; HBV DNA <2000 IU/mL and ALT >40 U/L); grey zone group 2 (GZ-2; HBV-DNA >2000 IU/mL and ALT <40 U/L).
Results: pSWE results were significantly correlated with TE (r = 0.29, p < 0.001) and APRI (r = 0.17; p = 0.005). Median pSWE values did not differ between IC, GZ-1 and GZ-2 patients (p = 0.82, p = 0.17, p = 0.34). During six years of follow-up, median pSWE and TE values did not differ significantly over time (TE: p = 0.27; pSWE: p = 0.05).
Conclusion: Our data indicate that pSWE could be useful for non-invasive fibrosis assessment and follow-up in patients with HBeAg-negative chronic HBV infection.
Radiographic and safety details of vertebral body stenting : results from a multicenter chart review
(2013)
Diel, Peter ; Röder, Christoph ; Perler, Gosia ; Vordemvenne, Thomas ; Scholz, Matti ; Kandziora, Frank ; Fürderer, Sebastian ; Eiskjaer, Soren ; Maestretti, Gianluca ; Rotter, Robert ; Benneker, Lorin Michael ; Heini, Paul Friedhelm
Background: Up to one third of BKP treated cases shows no appreciable height restoration due to loss of both restored height and kyphotic realignment after balloon deflation. This shortcoming has called for an improved method that maintains the height and realignment reached by the fully inflated balloon until stabilization of the vertebral body by PMMA-based cementation. Restoration of the physiological vertebral body height for pain relief and for preventing further fractures of adjacent and distant vertebral bodies must be the main aim for such a method. A new vertebral body stenting system (VBS) stabilizes the vertebral body after balloon deflation until cementation. The radiographic and safety results of the first 100 cases where VBS was applied are presented.
Methods: During the planning phase of an ongoing international multicenter RCT, radiographic, procedural and followup details were retrospectively transcribed from charts and xrays for developing and testing the case report forms. Radiographs were centrally assessed at the institution of the first/senior author.
Results: 100 patients (62 with osteoporosis) with a total of 103 fractured vertebral bodies were treated with the VBS system. 49 were females with a mean age of 73.2 years; males were 66.7 years old. The mean preoperative anterior-middle-posterior heights were 20.3-17.6-28.0 mm, respectively. The mean local kyphotic angle was 13.1°. The mean preoperative Beck Index (anterior edge height/posterior edge height) was 0.73, the mean alternative Beck Index (middle height/posterior edge height) was 0.63. The mean postoperative heights were restored to 24.5-24.6-30.4 mm, respectively. The mean local kyphotic angle was reduced to 8.9°. The mean postoperative Beck Index was 0.81, the mean alternative one was 0.82. The overall extrusion rate was 29.1%, the symptomatic one was 1%. In the osteoporosis subgroup there were 23.8% extrusions. Within the three months followup interval there were 9% of adjacent and 4% of remote new fractures, all in the osteoporotic group.
Conclusions: VBS showed its strengths especially in realignment of crush and biconcave fractures. Given that fracture mobility is present, the realignment potential is sound and increases with the severity of preoperative vertebral body deformation.