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Mousset, Sabine ; Buchheidt, Dieter ; Heinz, Werner ; Ruhnke, Markus ; Cornely, Oliver Andreas ; Egerer, Gerlinde ; Krüger, William ; Link, Hartmut ; Neumann, Silke ; Ostermann, Helmut ; Panse, Jens ; Penack, Olaf ; Rieger, Christina ; Schmidt-Hieber, Martin ; Silling, Gerda ; Südhoff, Thomas ; Ullmann, Andrew J. ; Wolf, Hans-Heinrich ; Maschmeyer, Georg ; Böhme, Angelika
The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient’s risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.
Abgrall, Nicolas ; Aduszkiewicz, Antoni ; Andronov, Evgeny V. ; Antičić, Tome ; Baatar, B. ; Baszczyk, Mateusz ; Bhosale, S. ; Blondel, A. ; Bogomilov, Mariyan ; Brandin, Andrei V. ; Bravar, Alessandro ; Bryliński, Wojciech ; Brzychczyk, Janusz ; Bunyatov, S. A. ; Busygina, O. ; Bzdak, A. ; Cherif, H. ; Ćirković, M. ; Czopowicz, T. ; Damyanova, A. ; Davis, N. ; Deveaux, Michael ; Dominik, W. ; Dorosz, Piotr ; Dumarchez, J. ; Engel, Ralph ; Ereditato, A. ; Feofilov, Grigori A. ; Fields, L. ; Fodor, Zoltán ; Garibov, A. ; Gaździcki, Marek ; Golosov, Oleg ; Golubeva, Marina ; Grebieszkow, Katarzyna ; Guber, Fedor ; Haesler, A. ; Hasegawa, T. ; Hervé, A. E. ; Igolkin, Sergey N. ; Ilieva, Stoyanka ; Ivashkin, Alexander ; Johnson, S. R. ; Kadija, Krešo ; Kaptur, E. ; Kargin, N. ; Kashirin, E. ; Kiełbowicz, Mirosław ; Kireyeu, Viktar A. ; Klochkov, Viktor ; Kobayashi, Taiyo ; Kolesnikov, Vadim I. ; Kolev, D. ; Korzenev, A. ; Kovalenko, V. N. ; Kowalik, K. ; Kowalski, S. ; Koziel, Michal ; Krasnoperov, A. ; Kucewicz, Wojciech ; Kuich, M. ; Kurepin, Alexander ; Larsen, Dag Toppe ; László, A. ; Lazareva, Tatiana V. ; Lewicki, M. ; Łojek, K. ; Łysakowski, B. ; Lyubushkin, V. V. ; Maćkowiak-Pawłowska, Maja ; Majka, Zbigniew ; Maksiak, B. ; Malakhov, Aleksandr I. ; Manić, D. ; Marchionni, A. ; Marcinek, A. ; Marino, A. D. ; Marton, K. ; Mathes, H. J. ; Matulewicz, Tomasz ; Matveev, V. ; Melkumov, Georgy L. ; Merzlaya, Anastasia O. ; Messerly, B. ; Mik, Łukasz ; Mills, G. B. ; Morozov, Sergey ; Mrówczyński, Stanislaw ; Nagai, Y. ; Nakadaira, T. ; Naskręt, Michał ; Nishikawa, K. ; Ozvenchuk, Vitalii ; Paolone, V. ; Pavin, M. ; Petukhov, Oleg ; Pistillo, C. ; Płaneta, Roman ; Podlaski, P. ; Popov, B. A. ; Posiadała-Zezula, M. ; Prokhorova, D. S. ; Puławski, S. ; Puzović, Jovan ; Rauch, Wolfgang Hans ; Ravonel, M. ; Renfordt, Rainer Arno Ernst ; Richter-Wąs, E. ; Röhrich, Dieter ; Rondio, E. ; Roth, M. ; Rumberger, Brant T. ; Rustamov, Anar ; Rybczyński, Maciej ; Rybicki, Andrzej ; Sadovsky, Alexander ; Sakashita, K. ; Schmidt, K. ; Sekiguchi, T. ; Selyuzhenkov, Ilya ; Seryakov, A. Yu. ; Seyboth, Peter ; Shibata, M. ; Słodkowski, M. ; Snoch, Aleksandra ; Staszel, P. ; Stefanek, Grzegorz ; Stepaniak, J. ; Strichanov, Michail Nikolaevič ; Ströbele, Herbert ; Šuša, Tatjana ; Tada, M. ; Taranenko, Arkadiy ; Tefelska, A. ; Tefelski, Dariusz ; Tereshchenko, V. ; Toia, Alberica ; Tsenov, R. ; Turko, L. ; Ulrich, R. ; Unger, M. ; Valiev, F. F. ; Veberič, Darko ; Vechernin, V. V. ; Walewski, M. ; Wickremasinghe, A. ; Włodarczyk, Zbigniew ; Wojtaszek-Szwarc, Agnieszka ; Wyszyński, Oskar ; Zambelli, L. ; Zimmerman, E. D. ; Zwaska, Robert ; Berns, L. ; Fiorentini, G. A. ; Friend, M. ; Hartz, M. ; Vladisavljevic, T. ; Yu, M.
Measurements of the π±, K±, and proton double differential yields emitted from the surface of the 90-cm-long carbon target (T2K replica) were performed for the incoming 31 GeV/c protons with the NA61/SHINE spectrometer at the CERN SPS using data collected during 2010 run. The double differential π± yields were measured with increased precision compared to the previously published NA61/SHINE results, while the K± and proton yields were obtained for the first time. A strategy for dealing with the dependence of the results on the incoming proton beam profile is proposed. The purpose of these measurements is to reduce significantly the (anti)neutrino flux uncertainty in the T2K long-baseline neutrino experiment by constraining the production of (anti)neutrino ancestors coming from the T2K target.
Aduszkiewicz, Antoni ; Ali, Yasir ; Andronov, Evgeny V. ; Antičić, Tome ; Baatar, B. ; Baszczyk, Mateusz ; Bhosale, S. ; Blondel, A. ; Bogomilov, Mariyan ; Brandin, Andrei V. ; Bravar, Alessandro ; Brzychczyk, Janusz ; Bunyatov, S. A. ; Busygina, O. ; Cherif, H. ; Ćirković, M. ; Czopowicz, T. ; Damyanova, A. ; Davis, N. ; Dembinski, H. ; Deveaux, Michael ; Dominik, W. ; Dorosz, Piotr ; Dumarchez, J. ; Engel, Ralph ; Ereditato, A. ; Faas, S. ; Feofilov, Grigori A. ; Fodor, Zoltán ; Francois, C. ; Garrido, X. ; Garibov, A. ; Gaździcki, Marek ; Golubeva, Marina ; Grebieszkow, Katarzyna ; Guber, Fedor ; Haesler, A. ; Hervé, A. E. ; Hylen, J. ; Igolkin, Sergey N. ; Ivashkin, Alexander ; Johnson, S. R. ; Kadija, Krešo ; Kaptur, E. ; Kiełbowicz, Mirosław ; Kireyeu, Viktar A. ; Klochkov, Viktor ; Kolesnikov, Vadim I. ; Kolev, D. ; Korzenev, A. ; Kovalenko, V. N. ; Kowalik, K. ; Kowalski, S. ; Koziel, Michal ; Krasnoperov, A. ; Kucewicz, Wojciech ; Kuich, M. ; Kurepin, Alexander ; Larsen, Dag Toppe ; László, A. ; Lazareva, Tatiana V. ; Lewicki, M. ; Lundberg, B. ; Łysakowski, B. ; Lyubushkin, V. V. ; Mariş, I. C. ; Maćkowiak-Pawłowska, Maja ; Maksiak, B. ; Malakhov, Aleksandr I. ; Manić, D. ; Marchionni, A. ; Marcinek, A. ; Marino, A. D. ; Marton, K. ; Mathes, H. -J. ; Matulewicz, Tomasz ; Matveev, V. ; Melkumov, Georgy L. ; Merzlaya, Anastasia O. ; Messerly, B. ; Mik, Łukasz ; Mills, G. B. ; Morozov, Sergey ; Mrówczyński, Stanislaw ; Nagai, Y. ; Naskręt, Michał ; Ozvenchuk, Vitalii ; Paolone, V. ; Pavin, M. ; Petukhov, Oleg ; Pistillo, C. ; Płaneta, Roman ; Podlaski, P. ; Popov, B. A. ; Posiadała, M. ; Puławski, S. ; Puzović, Jovan ; Rameika, R. ; Rauch, Wolfgang Hans ; Ravonel, M. ; Renfordt, Rainer Arno Ernst ; Richter-Wąs, E. ; Röhrich, Dieter ; Rondio, E. ; Roth, M. ; Rumberger, Brant T. ; Ruprecht, M. ; Rustamov, Anar ; Rybczyński, Maciej ; Rybicki, Andrzej ; Sadovsky, Alexander ; Schmidt, K. ; Selyuzhenkov, Ilya ; Seryakov, A. Yu. ; Seyboth, Peter ; Słodkowski, M. ; Snoch, Aleksandra ; Staszel, P. ; Stefanek, Grzegorz ; Stepaniak, J. ; Strichanov, Michail Nikolaevič ; Ströbele, Herbert ; Šuša, Tatjana ; Szuba, M. ; Taranenko, Arkadiy ; Tefelska, A. ; Tefelski, Dariusz ; Tereshchenko, V. ; Toia, Alberica ; Tsenov, R. ; Turko, L. ; Ulrich, R. ; Unger, M. ; Valiev, F. F. ; Veberič, Darko ; Vechernin, V. V. ; Walewski, M. ; Wickremasinghe, A. ; Wilkinson, C. ; Włodarczyk, Zbigniew ; Wojtaszek-Szwarc, Agnieszka ; Wyszyński, Oskar ; Zambelli, L. ; Zimmerman, E. D. ; Zwaska, Robert
We present measurements of ρ0, ω and K∗0 spectra in π−+ C production interactions at 158 GeV / c and ρ0 spectra at 350 GeV / c using the NA61/SHINE spectrometer at the CERN SPS. Spectra are presented as a function of the Feynman’s variable xF in the range 0<xF<1 and 0<xF<0.5 for 158 and 350 GeV / c respectively. Furthermore, we show comparisons with previous measurements and predictions of several hadronic interaction models. These measurements are essential for a better understanding of hadronic shower development and for improving the modeling of cosmic ray air showers.
Alix/AIP1 is an adaptor protein involved in regulating the function of receptor and cytoskeleton-associated tyrosine kinases. Here, we investigated its interaction with and regulation by Src. Tyr319 of Alix bound the isolated Src homology-2 (SH2) domain and was necessary for interaction with intact Src. A proline-rich region in the C terminus of Alix bound the Src SH3 domain, but this interaction was dependent on the release of the Src SH2 domain from its Src internal ligand either by interaction with Alix Tyr319 or by mutation of Src Tyr527. Src phosphorylated Alix at a C-terminal region rich in tyrosines, an activity that was stimulated by the presence of the Alix binding partner SETA/CIN85. Phosphorylation of Alix by Src caused it to translocate from the membrane and cytoskeleton to the cytoplasm and reduced its interaction with binding partners SETA/CIN85, epidermal growth factor receptor, and Pyk2. As a consequence of this, Src antagonized the negative regulation of receptor tyrosine kinase internalization and cell adhesion by Alix. We propose a model whereby Src antagonizes the effects of Alix by phosphorylation of its C terminus, leading to the disruption of interactions with target proteins.
Kowanetz, Katarzyna ; Crosetto, Nicola ; Haglund, Kaisa ; Schmidt, Mirko Hans Heinrich ; Heldin, Carl-Henrik ; Đikić, Ivan
The ubiquitin (Ub) ligase Cbl plays a critical role in attenuation of receptor tyrosine kinase (RTK) signaling by inducing ubiquitination of RTKs and promoting their sorting for endosomal degradation. Herein, we describe the identification of two novel Cbl-interacting proteins, p70 and Clip4 (recently assigned the names Sts-1 and Sts-2, respectively), that inhibit endocytosis of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor. Sts-1 and Sts-2 contain SH3 domains that interacted with Cbl, Ub-associated domains, which bound directly to mono-Ub or to the EGFR/Ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of Sts-1/2. Ligand-induced recruitment of Sts-1/Sts-2 into activated EGFR complexes led to inhibition of receptor internalization, reduction in the number of EGFR-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways. On the other hand, interference with Sts-1/Sts-2 functions diminished ligand-induced receptor degradation, cell proliferation, and oncogenic transformation in cultured fibroblasts. We suggest that Sts-1 and Sts-2 represent a novel class of Ub-binding proteins that regulate RTK endocytosis and control growth factor-induced cellular functions.
The association of Schlen k’s hydrocarbon was studied by means of osmometric and magnetic measurements. The mixed chain-ring-association can be explained satisfactorily assuming that two different dimers and four monomer species participate in the equilibria, including a monomeric diamagnetic ring. The equilibria existing between the different species are discussed. For the equilibria between the monomer and dimer species, which can be detected in solutions of normal viscosity by means of ESR-measurements, the unexpected values of ΔH=0 for the enthalpie of association and ΔS= +19.7 e. u. for the entropie of association were found.
The cis-trans-isomerism of the WITTIG hydrocarbon was investigated in solid state and solution by means of fluorescence spectroscopy. The fluorescence behavior of both isomers in 2-methyltetrahydrofurane was determined as a function of concentration, temperature, and wavelength of exciting radiation. Furthermore, irradiation experiments were undertaken with light of various wavelengths.
The results obtained are in agreement with the assumption that the WITTIG hydrocarbon behaves with regard to the cis-trans-isomerism like a 1,3-butadien derivative, i.e. a thermal but no photochemical cis-trans-isomerisation can be detected. The enthalpy difference between the two isomers was estimated to ΔΗ = 250 ± 50 cal/mole. It could be shown that the fluorescence of the cis-isomer is quenched by the trans-isomer. This quenching occurs probably according to the resonance energy transfer mechanism.
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)
On the observation of mesospheric air inside the arctic stratospheric polar vortex in early 2003
(2005)
Engel, Andreas ; Möbius, Tanja ; Haase, Hans-Peter ; Bönisch, Harald ; Wetter, Thomas ; Schmidt, Ulrich ; Levin, Ingeborg ; Reddmann, Thomas ; Oelhaf, Hermann ; Wetzel, Gerald ; Grunow, Katja ; Huret, Nathalie ; Pirre, Michel
During several balloon flights inside the Arctic polar vortex in early 2003, unusual trace gas distributions were observed, which indicate a strong influence of mesospheric air in the stratosphere. The tuneable diode laser (TDL) instrument SPIRALE (Spectroscopie InFrarouge par Absorption de Lasers Embarqués) measured unusually high CO values (up to 600 ppb) on 27 January at about 30 km altitude. The cryosampler BONBON sampled air masses with very high molecular Hydrogen, extremely low SF6 and enhanced CO values on 6 March at about 25 km altitude. Finally, the MIPAS (Michelson Interferometer for Passive Atmospheric Sounding) Fourier Transform Infra-Red (FTIR) spectrometer showed NOy values which are significantly higher than NOy* (the NOy derived from a correlation between N2O and NOy under undisturbed conditions), on 21 and 22 March in a layer centred at 22 km altitude. Thus, the mesospheric air seems to have been present in a layer descending from about 30 km in late January to 25 km altitude in early March and about 22 km altitude on 20 March. We present corroborating evidence from a model study using the KASIMA (KArlsruhe Simulation model of the Middle Atmosphere) model that also shows a layer of mesospheric air, which descended into the stratosphere in November and early December 2002, before the minor warming which occurred in late December 2002 lead to a descent of upper stratospheric air, cutting of a layer in which mesospheric air is present. This layer then descended inside the vortex over the course of the winter. The same feature is found in trajectory calculations, based on a large number of trajectories started in the vicinity of the observations on 6 March. Based on the difference between the mean age derived from SF6 (which has an irreversible mesospheric loss) and from CO2 (whose mesospheric loss is much smaller and reversible) we estimate that the fraction of mesospheric air in the layer observed on 6 March, must have been somewhere between 35% and 100%.