56 results on '"E. Klinker"'
Search Results
2. Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors
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E. Klinker, Yair Reisner, Florian Oyen, Ana Marcu, Camelia-Maria Monoranu, Matthias Wölfl, Johanna Lager, Nico Trautwein, Lisa M. Henkel, J. Krauss, Anne Keupp, Pascal Johann, Andreas Schlosser, Martin Ebinger, Martin U. Schuhmann, Thorsten Pietsch, Juliane S. Walz, Paul-Gerhardt Schlegel, Hans-Georg Rammensee, Ulrich-W. Thomale, and Matthias Eyrich
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Male ,Cancer Research ,medicine.medical_treatment ,Peptide ,Genome ,Mass Spectrometry ,Epitope ,Central Nervous System Neoplasms ,antigens ,HLA Antigens ,Human proteome project ,Immunology and Allergy ,Child ,RC254-282 ,chemistry.chemical_classification ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunohistochemistry ,Oncology ,Child, Preschool ,Molecular Medicine ,Female ,Immunotherapy ,pediatrics ,Adolescent ,Immunology ,Human leukocyte antigen ,Biology ,Peptides, Cyclic ,Immune system ,Antigen ,medicine ,Humans ,ddc:610 ,Rhabdoid Tumor ,Pharmacology ,Rhabdoid tumors ,Basic Tumor Immunology ,Oncogenes ,medicine.disease ,vaccination ,epitope mapping ,Epitope mapping ,chemistry ,Cancer research ,Peptides ,neoplasm ,CD8 ,Glioblastoma - Abstract
BackgroundAtypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells.MethodsHere, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM.ResultsComparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8+T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors.ConclusionsThese findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.
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- 2021
3. A Comprehensive Analysis of Primary Acute Myeloid Leukemia Identifies Biomarkers Predicting Susceptibility to Human Allogeneic Vγ9Vδ2 T Cells
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Martin Wilhelm, S Gundermann, Brigitte Kimmel, E Klinker, U Flierl, Hermann Einsele, and Kunzmann
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Adult ,Cytotoxicity, Immunologic ,Male ,Cancer Research ,Myeloid ,T-Lymphocytes ,T cell ,medicine.medical_treatment ,Immunology ,Graft vs Leukemia Effect ,GPI-Linked Proteins ,Immunotherapy, Adoptive ,Cancer immunotherapy ,Antigen ,HLA Antigens ,Predictive Value of Tests ,hemic and lymphatic diseases ,medicine ,Humans ,Transplantation, Homologous ,Immunology and Allergy ,neoplasms ,Cells, Cultured ,Aged ,Aged, 80 and over ,Pharmacology ,business.industry ,Intracellular Signaling Peptides and Proteins ,Myeloid leukemia ,Receptors, Antigen, T-Cell, gamma-delta ,Immunotherapy ,Middle Aged ,Prognosis ,medicine.disease ,Transplantation ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Histocompatibility ,Female ,business - Abstract
Allogeneic innate lymphocytes such as Vγ9Vδ2 T cells are attractive candidates for cancer immunotherapy as they provide MHC-unrestricted antitumor activity without clinical evidence for inducing graft-versus-host disease (GvHD). However, current cellular immunotherapy approaches lack predictive biomarkers identifying patient cohorts most susceptible to immune attack. For this purpose we performed a comprehensive analysis of clinical, genetic, metabolic, and immunophenotypic features of 19 primary acute myeloid leukemia (AML) samples and correlated these factors with AML blast recognition by allogeneic Vγ9Vδ2 T cells. We show that 36% of primary AML samples were intrinsically susceptible to allogeneic Vγ9Vδ2 T cells. Among several evaluated features, only UL-16 binding protein 1 (ULBP1) expression (P
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- 2014
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4. THE EUROPEAN-CENTER-FOR-MEDIUM-RANGE-WEATHER-FORECASTS (ECMWF) PROGRAM ON EXTENDED-RANGE PREDICTION
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Ulrich Cubasch, Tim Palmer, Anthony Hollingsworth, Čedo Branković, Franco Molteni, E. Klinker, Laura Ferranti, and Stefano Tibaldi
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Global Forecast System ,Atmospheric Science ,Ensemble forecasting ,Meteorology ,extended-range forecast ,systematic errors ,tropical/extratropical interaction ,ensemble forecasting ,Forecast skill ,Numerical weather prediction ,Climatology ,Quantitative precipitation forecast ,Environmental science ,Probabilistic forecasting ,Tropical cyclone forecast model ,North American Mesoscale Model ,Physics::Atmospheric and Oceanic Physics - Abstract
Results from 3 ½-yr experimental program of extended-range integrations of the ECMWF numerical weather prediction model are summarized. The topics discussed include: 1) The evolution of extended-range systematic errors and skill in forecasting large-scale weather regime transitions ; 2) The dependence of extended-range systematic error and skill on model horizontal resolution ; 3) Monthly mean forecast of tropical rainfall ; 4) Tropical/extratropical interaction, and the influence of tropical low-frequency variability on extratropical forecast skill ; 5) Ensemble forecasting, including the impact of ensemble averaging on forecast skill, and ensemble dispersion as a measure of forecast reliability ; and 6) Probabilistic forecasting using phase-space cluster analysis. Our results are broadly consistent with those from other major centers evaluating the feasibility of dynamical extended-range prediction. We believe that operational extende-range forecasting using the ECMWF model may be viable to day 20 – and possibly beyond – following further research on techniques for Monte Carlo forecasting, and when model systematic error in the tropics has been reduced significantly.
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- 2016
5. ILDS Newsletter No. 24
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Luca Antonioli, Cristina Magnoni, Sara Bassoli, Michel Janier, Luigi Rusciani Scorza, K.A.P. Meeuwis, G. Quéreux, Mazen Kurban, P.C.M. van de Kerkhof, A.D. Cohen, Liping Li, Philippe Bonhomme, Hiroki Fujikawa, E. Klinker, Alain Taïeb, Francesca Giusti, L. Borradori, T. Passeron, B. Dréno, Qiang Ding, M.M. Tang, A. Cozzio, K. Reisenbauer, T. Lombardi, Sébastien Fouéré, V. Failla, Julien Seneschal, Rebeca Bella, F. Rusca, Daniel López Aventín, Stefania Mantarro, Carlo Tomasini, Raffaele Rauso, A.D. Ormerod, Abdul-Ghani Kibbi, Laura Bachini, Demian Manzano López González, Josette Stokkermans, Muhammad Farooq, L.F.A.G. Massuger, Druck Reinhardt Druck Basel, Pascal Del-Giudice, I. Casin, Giovanni Ponti, L. Naldi, A. Brocard, Stefania Seidenari, Yutaka Shimomura, Myriem Zouakh-Agsous, M.M. van Rossum, Esperanza Jordá, Ossama Abbas, Ke Xu, J. Jacques, O. Chosidow, N. Irla, E.B. Bröcker, A.F. Nikkels, Atsushi Fujimoto, A.G.A. Kolios, M. Augustin, S. Benoit, Khaled Ezzedine, J.P. Lacour, José Martín, P. Bahadoran, K.D. Watson, Bingkun Li, Satz Mengensatzproduktion, Inmaculada Gil, P.I. Spuls, C. Castronovo, Carlo Cirinei, C. Baker, Daniela Maria Micci, J.A. de Hullu, Pierre-Luc Dion, M. Schmitt-Egenolf, Olivier Chosidow, L. Peuvrel, L. Boursault, Brigitte Milpied, Christine Labrèze, Chiara Ferrari, Chiara Pisani, H. Beltraminelli, I. Garcia-Doval, Irela Reig, N. Erfan, V. Hofman, J. Stoevesandt, Giuseppe Curinga, L.E. French, Emeline Kubica, M.M. Bornstein, Antonietta Troccola, Carlos Monteagudo, Corrado Blandizzi, Milena Pardini, L.L. Lecluse, Xiang Wang, Antonio Rusciani Scorza, Marinella Rubinelli, P.A. Müller, Ramon M. Pujol, F. Desruelles, T.N. Dam, Marco Tuccori, M. Saint-Jean, Stefania Borsari, A.A. Navarini, Matteo Fornai, Zujun Fang, J.P. Ortonne, and Rasha Mohammad Moustafa
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Enthusiasm ,geography ,medicine.medical_specialty ,Evening ,Summit ,geography.geographical_feature_category ,media_common.quotation_subject ,Library science ,Dermatology ,Executive committee ,Political science ,medicine ,media_common - Abstract
On the occasion of the 70th annual meeting of the American Academy of Dermatology in San Diego the ILDS Executive Committee hosted a cocktail reception in the evening of 18 March. The reception, held at the Marriott Hotel on an evening of several competing attractions, was well attended by friends of the ILDS, who stopped by for a drink and a chat. Jean Bolognia and Chris Griffiths acted as official ILDS meeters and greeters for the guests. Our president, Wolfram Sterry gave a short speech of welcome and provided an update for those present on the recent achievements of and plans for the ILDS. The announcement of the Berlin summit was particularly well received by our member societies. Jerry Shapiro then took the floor to apprise us of the arrangements for the Vancouver World Congress, these too were greeted with enthusiasm...
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- 2012
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6. Successful adjuvant treatment of severe bullous pemphigoid by tryptophan immunoadsorption
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J. E. Herrero‐González, Cassian Sitaru, Detlef Zillikens, E. Klinker, and Eva-B. Bröcker
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Male ,medicine.drug_class ,medicine.medical_treatment ,Dermatology ,Autoantigens ,Antigen ,Adrenal Cortex Hormones ,Pemphigoid, Bullous ,medicine ,Humans ,Immunoadsorption ,Immunosorbent Techniques ,Aged ,Autoantibodies ,Aged, 80 and over ,Autoimmune disease ,integumentary system ,biology ,business.industry ,Tryptophan ,Autoantibody ,Middle Aged ,Non-Fibrillar Collagens ,medicine.disease ,Combined Modality Therapy ,Treatment Outcome ,Immunology ,biology.protein ,Corticosteroid ,Female ,Bullous pemphigoid ,Antibody ,business ,Adjuvant - Abstract
Bullous pemphigoid (BP) is an autoimmune blistering skin disease associated with circulating autoantibodies to the hemidesmosomal antigens BP180 and BP230. We report two cases of therapy-refractory BP adjuvantly treated by tryptophan immunoadsorption. In both patients, this treatment was associated with rapid clinical improvement and reduction in the required corticosteroid dosage. In addition, levels of circulating anti-BP180 autoantibodies decreased markedly. Antibodies that were eluted from the tryptophan matrix bound to BP180 and induced dermal-epidermal separation in cryosections of human skin. Our observations suggest that immunoadsorption may be a helpful adjuvant treatment in severe BP.
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- 2005
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7. Reanalysis and reforecast of three major European storms of the twentieth century using the ECMWF forecasting system. Part II: Ensemble forecasts
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S. Uppala, E. Klinker, and Thomas Jung
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Atmospheric Science ,Meteorology ,Ensemble prediction ,Climatology ,Early warning system ,Environmental science ,Storm ,Predictability ,Loss of life - Abstract
In Part II of this study the ECMWF Ensemble Prediction System (EPS) is used to study the probabilistic predictability of three major European storms of the twentieth century. The storms considered are the Dutch storm of 1 February 1953, the Hamburg storm of 17 February 1962, and the British/French storm of October 1987 (Great October storm). Common to all these storms is their severity that caused large loss of life and widespread damage. In Part I of this study it has been found that deterministic predictability of the Dutch and Hamburg storms amount to 48 and 84 hours, respectively. Here, it is shown that the ensemble forecasts supplement the deterministic forecasts. The large number of members in the 48 and 84 hour ensemble forecasts of the Dutch and Hamburg storms, respectively, suggest that at this forecast range and for these storms the sensitivity of the forecasts to analysis and model uncertainties is rather small. From these results, therefore, it is argued that reliable warnings (i.e. low probability for the occurrence of a forecast failure) for the Dutch and Hamburg storms could have been issued 48 and 84 hours, respectively, in advance, had the current ECMWF EPS been available. For the Great October storm it has been found in Part I of this study that short-range and medium-range forecasts of the intensity and track of the storm were very skilful with a high-resolution model of the ECWMF model. The actual timing of the storm, however, was difficult to predict. Here, it is shown that the EPS is capable of predicting large forecast uncertainties associated with the timing of the Great October storm up to 4 days in advance. It is argued that reliable warnings could have been issued at least 96 hours in advance had the ECMWF EPS been available. From the results presented in this study it is concluded that an Ensemble Prediction System is an important component of every early warning system for it allows an a priori quantification of the probability of the occurrence of severe wind storms. Copyright © 2005 Royal Meteorological Society
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- 2005
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8. Reanalysis and reforecast of three major European storms of the twentieth century using the ECMWF forecasting system. Part I: Analyses and deterministic forecasts
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Thomas Jung, S. Uppala, and E. Klinker
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Horizontal resolution ,Atmospheric Science ,Meteorology ,Climatology ,Environmental science ,Storm surge ,Storm ,Predictability ,Loss of life - Abstract
In Part I of this study recent versions of the ECWMF Integrated Forecasting System (IFS) are used together with historical observational data to carry out reanalyses and deterministic reforecasts of three major north-west European wind storms of the twentieth century. The storms considered are the Dutch storm of 1 February 1953, the Hamburg storm of 17 February 1962, and the British October storm of 1987 (Great October Storm). Common to all these storms is their severity, which caused large loss of life and widespread damage. Reanalysis of the storms is based on a 3D-Var and 4D-Var assimilation scheme at a horizontal resolution of TL159(≈ 125 km) and TL511(≈ 50 km), respectively. Similarly, two different horizontal resolutions (TL159 and TL511) are used to investigate the deterministic predictability of these storms. The lower-resolution system is exactly that used in the ERA-40 reanalysis project. The high-resolution system is a more recent version of the ECMWF IFS. It is shown that the basic characteristics of the Dutch and Hamburg storms that gave rise to the storm surge are well predicted by the single deterministic forecasts up to about 48 and 84 hours, respectively, in advance. Our capability to predict the Great October Storm is more difficult to assess. On the one hand, even recent versions of the ECMWF IFS underestimate the severity of the storm in the very short-range (12–24-hour forecasts started at 12 UTC 15 October 1987). On the other hand, the high-resolution version of the ECMWF IFS provides excellent deterministic forecasts of the track and intensity of the storm up to 96 hours in advance. However, there are errors in the timing of the storm (12 hours for the 96 hour forecast). From the results presented in this study it is concluded – bearing in mind the limited number of cases considered – that with the current ECMWF forecasting system reliable deterministic predictions of some European wind storms are possible several days in advance. Copyright © 2004 Royal Meteorological Society.
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- 2004
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9. Protein A immunoadsorption: a novel and effective adjuvant treatment of severe pemphigus
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Andreas Opitz, Cassian Sitaru, E‐B. Bröcker, Maria-Elisabeth Goebeler, B. Mansouri Taleghoni, Enno Schmidt, Detlef Zillikens, E. Klinker, and Herzog S
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Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Enzyme-Linked Immunosorbent Assay ,Dermatology ,Desmoglein ,Adjuvants, Immunologic ,medicine ,Adjuvant therapy ,Humans ,Child ,Fluorescent Antibody Technique, Indirect ,Staphylococcal Protein A ,Immunoadsorption ,Aged ,integumentary system ,business.industry ,Pemphigus vulgaris ,Autoantibody ,Middle Aged ,medicine.disease ,Pemphigus ,Methylprednisolone ,Chronic Disease ,Female ,Plasmapheresis ,business ,medicine.drug - Abstract
SummaryBackground Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are autoimmune blistering skin diseases usually treated with high-dose systemic corticosteroids and other immunosuppressants that may cause severe side-effects. Plasmapheresis also has been demonstrated to be of benefit in the treatment of pemphigus. In contrast to plasmapheresis, staphylococcal protein A immunoadsorption (PA–IA) specifically removes immunoglobulin from the circulation, allows treatment of larger plasma volumes, and does not require the substitution of plasma components. Objectives To determine the effectiveness and side-effects of PA–IA in patients with severe pemphigus. Methods Five patients with severe pemphigus (PV, n = 4; PF, n = 1) were treated by PA–IA. Three of these patients had been refractory to various treatment regimens. In addition to PA–IA, methylprednisolone, 0·5 mg kg−1 body weight day−1 was given initially and subsequently tapered. Results In all patients, a dramatic clinical improvement was seen within 2 weeks after initiation of therapy. Patients were free of lesions after 3, 4, 4, 10 and 21 weeks of treatment, respectively. Concurrently, autoantibody levels decreased rapidly. Conclusions PA–IA is a rational, effective, and safe adjuvant therapy for severe pemphigus and warrants wider use for this indication. A controlled study should compare side-effects and effectiveness of PA–IA with other treatment options for pemphigus.
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- 2003
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10. Diagnosis of systematic forecast errors dependent on flow pattern
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Laura Ferranti, Brian J. Hoskins, E. Klinker, and Anthony Hollingsworth
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Atmospheric Science ,Jet (fluid) ,Meteorology ,North Atlantic oscillation ,Western europe ,Climatology ,Anomaly (natural sciences) ,Flow (psychology) ,Mode (statistics) ,Geopotential height ,Magnitude (mathematics) ,Geology - Abstract
Singular-value decomposition (SVD) analysis is employed to study flow-dependent forecast errors. The results presented are based on ECMWF operational forecasts and verifying analysis of 500 hPa heights for the most recent seven winter periods. Beyond forecast day 3 the flow-dependent errors are mainly localized over the Atlantic sector and are associated with the North Atlantic Oscillation- (NAO)-like circulation anomalies. The forecasts systematically underestimate the intensity of pressure anomalies centred over Iceland with the effect of reducing the anomalous westerly/easterly flow over the eastern north Atlantic/western Europe. The flowdependent component of the errors explains about 10% of the total forecast-error variance. However, since it is associated with the NAO mode that dominates the variability of the European weather on longer time-scales, it is essential to identify the model limitations in predicting this flow anomaly in order to guide future work on improving forecasts over Europe. The relationship between forecast-error variability and NAO fluctuations is effectively described by an SVD analysis performed on fields of forecast-error magnitude and analyses. Regions with large (small) forecast-error anomalies are located over the maximum of the anomalous westerly (easterly) jet, while on the flanks of the jet the error anomaly is expected to be minimum/maximum. Copyright © 2002 Royal Meteorological Society.
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- 2002
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11. The ecmwf operational implementation of four-dimensional variational assimilation. III: Experimental results and diagnostics with operational configuration
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Jean-François Mahfouf, Florence Rabier, Graeme Kelly, and E. Klinker
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Set (abstract data type) ,Operational system ,Atmospheric Science ,Data assimilation ,Meteorology ,Baroclinity ,Middle latitudes ,Forecast skill ,Minification ,Numerical weather prediction - Abstract
The first two papers of this series describe the development of the operational four-dimensional variational assimilation (4D-Var) configuration implemented at the European Centre for Medium-Range Weather Forecasts (ECMWF). The basic features are a 6-hour incremental 4D-Var set-up with two minimization steps, using very simplified physics in the first minimization and a more complete set of linear physics in the second. This paper describes the validation of this configuration. Prior to implementation, 12 weeks of experimentation showed a consistent improvement relative to 3D-Var. After an additional 6 weeks of encouraging parallel operation with the then current operational suite, 4D-Var with physics was introduced in operations at ECMWF in November 1997. The difference in scores is statistically significant, and the fast-growing components of the 4D-Var analysis errors are shown to be smaller than their 3D-Var counterparts. The performance of this new operational assimilation system is studied for the month of January 1998, for which the 4D-Var analyses exhibit more realistic baroclinic waves than the 3D-Var, especially in the Pacific area. A case-study illustrates the improvement one can expect in forecast terms in the mid latitudes. The 4D-Var system improved the forecast skill in the Tropics in general. Observing-system experiments show that the current 4D-Var operational system benefits from the assimilation both of satellite data and conventional observations.
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- 2000
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12. Estimation of key analysis errors using the adjoint technique
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Ronald Gelaro, E. Klinker, and Florence Rabier
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Atmospheric Science ,Forecast error ,Baroclinity ,Weather forecasting ,computer.software_genre ,Numerical weather prediction ,Enstrophy ,Model integration ,Statistics ,Minification ,Algorithm ,computer ,Physics::Atmospheric and Oceanic Physics ,Non-sampling error ,Mathematics - Abstract
An iteration procedure minimizing the short-range forecast error leads, after some iterations, to so-called key analysis errors. These are estimates of the part of analysis errors that is largely responsible for the short-range forecast errors. The first step of the minimization procedure provides a scaled gradient of the two-day forecast errors for which the ‘energy’ inner-product provides an efficient way of identifying the analysis errors at scales that are relevant for forecast error growth. By using an ‘enstrophy’ like inner-product as an alternative to ‘energy’ the sensitivity gradient obtains an unrealistically large scale. Performing a few more steps in the minimization provides better estimates of the analysis error in the directions spanned by the leading singular vectors of the tangent-linear model. On a case study it is shown that three steps provide key analysis increments which, when added to the analysis, both significantly improve the fit to the available data, and substantially improve the subsequent model integration. It does not appear to be beneficial to do more steps of the minimization because of the uncertainty in the definition of the short-range forecast error, and of approximations in the tangent-linear model. Key analysis errors represent an improved estimate of analysis errors compared to the scaled gradient of day-2 forecast errors. In particular the geographical distribution shows the stability dependence of the scaled gradient. The projection of the gradient on the fastest growing errors limits maximum sensitivity to the major baroclinic zones. The close correspondence of evolved key analysis errors and forecast errors shows that key analysis errors are more realistically projecting on to full analysis errors. The close link between the stability of the flow and the gradient of the forecast errors implies an unreasonably strong seasonal variation of analysis errors estimates. In contrast, key analysis errors are nearly seasonally independent, which means that their detrimental effect on forecast errors in absolute terms in summer and winter is comparable.
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- 1998
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13. Organized convective systems in the tropical western pacific as a process in general circulation models: A toga coare case-study
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Mitchell W. Moncrieff and E. Klinker
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Convection ,Atmospheric Science ,Mesoscale convective system ,Data assimilation ,Meteorology ,Supercluster ,Climatology ,Thunderstorm ,Mesoscale meteorology ,Convective momentum transport ,Parametrization ,Physics::Atmospheric and Oceanic Physics ,Geology - Abstract
We examine the large-scale effects of organized convective systems in the tropical western Pacific observed during the Tropical-Ocean Global-Atmosphere Coupled Ocean-Atmosphere Response Experiment (TOGA COARE). In a case-study approach, we examine realizations of a supercluster, associated with the onset of the December 1992 westerly wind burst, in the T213 operational medium-range weather forecasting model of the European Centre for Medium-Range Weather Forecasts (ECMWF). We idealize a supercluster as a hierarchy of three interacting scales, namely organized cumulonimbus C 1 , mesoscale convective systems C 2 , and the supercluster component C 3 . It is shown that the ECMWF model represents this hierarchy as a C 3 -like surrogate whose influence dominates the effect of parametrized convection. This causes over-prediction of the model tendencies which, in the case of zonal momentum, is explained in elementary terms. The structure of the resolved-scale momentum flux is explained by Moncrieff's (1992) archetypal theory of organized convection which has been verified against observations and cloud-resolving model data-sets. The parametrization of subgrid-scale convective momentum-flux in the ECMWF model, based on a momentum mixing concept, produces subgrid-scale tendencies that are physically different from transports associated with cumulonimbus convection in a shear flow. We outline a strategy for parametrizing the momentum flux by the C 1 component based on the archetypal model. The C 2 component, which is part-resolved and part-parametrized, is at odds with the assumptions of scale separation underpinning parametrization. It is argued that this component should be represented as part of the prognostic treatment of convectively generated cirrus. Finally, we suggest cloud-resolving modelling studies to further quantify the structure and large-scale impact of superclusters in a westerly-wind-burst environment, ranging from idealized models to models having data assimilation capability.
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- 1997
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14. Sensitivity of forecast errors to initial conditions
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Philippe Courtier, Florence Rabier, Anthony Hollingsworth, and E. Klinker
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Troposphere ,Atmospheric Science ,Quality (physics) ,Forecast error ,Statistics ,General pattern ,Initial value problem ,Fraction (mathematics) ,Sensitivity (control systems) ,Physics::Atmospheric and Oceanic Physics ,Energy (signal processing) ,Mathematics - Abstract
The adjoint method has been used to calculate the sensitivity of short-range forecast errors to the initial conditions. The gradient of the energy of the day 2 forecast error with respect to the initial conditions can be interpreted as a sum of rapidly growing components of the analysis error. An analysis modified by subtracting an appropriately scaled vector, proportional to the gradient, provides initial conditions for a ‘sensitivity integration’ that can be used to diagnose the effect of initial-data errors on forecast errors. Statistics of sensitivity calculations for the month of April 1994 characterize the sensitivity patterns as small-scale, middle or lower tropospheric structures which are tilted in the vertical. The general pattern of these structures is known to be associated with the fastest possible growth of forecast error. When used as initial perturbations, they evolve rapidly into synoptic-scale structures, propagating both downstream and to higher atmospheric levels. On average, the sensitivity integration corrects for about a tenth of the day 2 forecast error, which indicates that indeed not all of the error is in the fastest-amplifying modes. But the fraction of the error corrected at day 2 is important for an improvement in the medium-range, as this fraction continues to grow substantially in the non-linear regime. These results have proved that there is still scope for great improvement in the medium-range forecast, particularly over Europe, by a better description of the initial conditions. The sensitivity experimentation suggests that many cases of major forecast-errors may be explained by defects in the analysis. A small but well-chosen change in the analysis can frequently improve the forecast quality.
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- 1996
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15. Relation between Mean Boundary-Layer Structure and Cloudiness at theR/VValdiviaduring ASTEX
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Christopher S. Bretherton, E. Klinker, and Alan K. Betts
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Atmospheric Science ,Boundary layer ,Daytime ,Planetary boundary layer ,Cloud cover ,Climatology ,Diurnal temperature variation ,Late afternoon ,Saturation (chemistry) ,Atmospheric sciences ,Geology - Abstract
The relationship between boundary-layer thermodynamic structure and cloud fields and their diurnal variation are explored using seven days of data from dw R/V Valdivia during the Atlantic Stratocumulus Transition Experiment. Cloudiness is at a maximum before dawn, when the boundary layer (BL) has the thermodynamic structure of a partially mixed, conditionally unstable stratocumulus layer, which is close to mean saturation below the inversion. Cloudiness falls during the daytime, and in the late afternoon the BL has two distinct layers: a warmer, drier cloud layer (characteristic of trade cumulus) above a more well-mixed subcloud layer. The observed mean profiles are consistent with an earlier suggestion that there is a cloud-cover transition once the BL mixing-line slope exceeds half that of the moist adiabat. In contrast, the BL structure in the ECMWF model for the same week has a much drier, warmer, more stable “cloud” layer than the observations.
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- 1995
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16. Comparison of Ceilometer, Satellite, and Synoptic Measurements of Boundary-Layer Cloudiness and the ECMWF Diagnostic Cloud Parameterization Scheme during ASTEX
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E. Klinker, Alan K. Betts, Christopher S. Bretherton, and James A. Coakley
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Atmospheric Science ,Boundary layer ,Diurnal cycle ,Planetary boundary layer ,Cloud cover ,Climatology ,Cloud fraction ,Radiative transfer ,Environmental science ,Inversion (meteorology) ,Atmospheric sciences ,Ceilometer - Abstract
Cloud fraction is a widely used parameter for estimating the effects of boundary-layer cloud on radiative transfer. During the Atlantic Stratocumulus Transition Experiment (ASTEX) during June 1992, ceilometer and satellite-based measurements of boundary-layer cloud fraction were made in the subtropical North Atlantic, a region typified by a 1–2 km deep marine boundary layer with cumulus clouds rising into a broken stratocumulus layer underneath an inversion. Both the diurnal cycle and day-to-day variations in low-cloud fraction are examined. It is shown that ECMWF low cloudiness analyses do not correlate with the observed variations in cloudiness and substantially underestimate the mean low cloudiness. In these analyses, the parameterization of low cloud fraction is primarily based on the inversion strength. A comparison of ECMWF analyses and ASTEX soundings (most of which were assimilated into the analyses) shows that the thermodynamic structure of the boundary layer and the inversion strength a...
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- 1995
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17. Adjuvant treatment of recalcitrant bullous pemphigoid with immunoadsorption
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J. Stoevesandt, E. Klinker, Eva-B. Bröcker, P.A. Müller, and S. Benoit
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medicine.medical_specialty ,Dystonin ,medicine.medical_treatment ,Prednisolone ,Azathioprine ,Nerve Tissue Proteins ,Dermatology ,Dapsone ,Autoantigens ,Severity of Illness Index ,Adjuvants, Immunologic ,Pemphigoid, Bullous ,medicine ,Humans ,ddc:610 ,Immunoadsorption ,Staphylococcal Protein A ,Immunosorbent Techniques ,Autoantibodies ,Membrane Glycoproteins ,integumentary system ,business.industry ,Middle Aged ,Mycophenolic Acid ,Non-Fibrillar Collagens ,medicine.disease ,Discontinuation ,Pemphigus ,Cytoskeletal Proteins ,Treatment Outcome ,Drug Therapy, Combination ,Female ,Sorption Detoxification ,Bullous pemphigoid ,Dermatologic Agents ,business ,Carrier Proteins ,Adjuvant ,medicine.drug - Abstract
Elimination of pathogenic autoantibodies by immunoadsorption (IA) has been described as an effective adjuvant treatment in severe bullous autoimmune diseases, especially in pemphigus. There is much less experience in the treatment of bullous pemphigoid (BP). BP was diagnosed in a 62-year-old Caucasian woman presenting a pruritic rash with multiple tense blisters. Standard treatments with topical and oral corticosteroids, steroid-sparing agents including dapsone, azathioprine, mycophenolate mofetil (MMF) and intravenous immunoglobulins were ineffective or had to be discontinued due to adverse events. An immediate clinical response could be achieved by two treatment cycles of adjuvant protein A immunoadsorption (PA-IA) in addition to continued treatment with MMF (2 g/day) and prednisolone (1 mg/kg/day). Tolerance was excellent. Clinical improvement remained stable after discontinuation of IA and went along with sustained reduction of circulating autoantibodies. Our data demonstrate that PA-IA might be a safe and effective adjuvant treatment in severe and recalcitrant BP.
- Published
- 2012
18. Applications of satellite radiance data in the medium range forecasting environment at ECMWF
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William A. Heckley, Jean-Jaques Morcrette, and E. Klinker
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Atmospheric Science ,Meteorology ,Diabatic ,Weather forecasting ,Aerospace Engineering ,Initialization ,Astronomy and Astrophysics ,computer.software_genre ,Geophysics ,Space and Planetary Science ,Weather Research and Forecasting Model ,Medium range ,Radiance ,General Earth and Planetary Sciences ,Environmental science ,Tropical cyclone forecast model ,computer ,Remote sensing - Abstract
Some applications of satellite radiance data in the medium range weather forecasting environment are described. In the first, data is used as a proxy for rainfall rates, which may be used for diabatic initialization of the model. The second uses the data to study the behaviour of the parametrized radiation scheme within the forecast model. Finally there is an example of a verification of the integrity of the analyses by a comparison of observed and inferred radiances.
- Published
- 1992
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19. The Diagnosis of Mechanical Dissipation in the Atmosphere from Large-Scale Balance Requirements
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E. Klinker and Prashant D. Sardeshmukh
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Troposphere ,Momentum ,Atmospheric Science ,Boundary layer ,Meteorology ,Drag ,Advection ,Rossby wave ,Environmental science ,Enstrophy ,Atmospheric sciences ,Stratosphere ,Physics::Atmospheric and Oceanic Physics - Abstract
The momentum budget for January 1987 is evaluated with global observations analyzed at the European Centre for Medium-Range Weather Forecasts (ECMWF). The dissipation term is diagnosed from the budget as a balance requirement, that is, as that required to balance the sum of the advection, Coriolis, pressure gradient, and local tendency terms. This is then compared with the parameterized subgrid-scale effects in the ECMWF model's momentum equation, with a view of identifying possible errors in those parameterizations. The balance requirement does not support the high parameterized values of orographically induced gravity-wave drag in the lower stratosphere. A deeper analysis also does not suggest a major role for turbulent vertical transports above the boundary layer. On the other hand, our budget does indicate that more effort be spent on a better representation of the potential enstrophy cascade associated with Rossby wave breaking in the upper troposphere. These statements are qualified by the ...
- Published
- 1992
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20. Investigation of systematic errors by relaxation experiments
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E. Klinker
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Systematic error ,Current (stream) ,Atmospheric Science ,Propagation of uncertainty ,Momentum (technical analysis) ,Eddy ,Meteorology ,Baroclinity ,Storm track ,Relaxation (approximation) ,Physics::Atmospheric and Oceanic Physics ,Geology ,Physics::Geophysics - Abstract
The systematic errors of the ECMWF forecast model have been investigated by relaxing forecasts towards analyses in selected regions. This method proved to be a useful tool to study the initial error growth in a certain region and the subsequent error propagation. The forecast fields in the tropics were relaxed towards the analysis by adding a contribution proportional to the current forecast error to the tendencies of temperature and momentum. From the comparison of control forecasts with tropically relaxed forecasts it was possible to separate large errors generated in the extra-tropics from comparatively small errors penetrating from the tropics into the extra-tropics. Relaxation in the major mountain regions showed different results for the Rocky Mountains and the Himalayas. the errors originating from the Rocky Mountains are substantial contributors to errors of both transient eddies and stationary eddies. the baroclinic waves in the Atlantic storm track are weakened and the stationary eddies develop a wave-train-like error pattern which is typical for many operational forecasts in the winter season. The errors in the Pacific are much less dependent on errors from the mountainous region. the error structure of the transient and stationary eddies, as revealed from experiments in which the Asian mountains are excluded or included from the relaxation, shows little similarity to operational forecast errors.
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- 1990
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21. Überraschender Morbus haemolyticus bei unerkannter Rhesus-Immunisierung
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Ö Anvari, D d'Alquen, D Singer, E Klinker, and B Wiewrodt
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Maternity and Midwifery ,Pediatrics, Perinatology and Child Health ,Obstetrics and Gynecology ,Neurology (clinical) ,General Medicine - Published
- 2006
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22. Improved protocol for treatment of pemphigus vulgaris with protein A immunoadsorption
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E. Klinker, Andreas Opitz, Eva-B. Bröcker, Maria-Elisabeth Goebeler, Enno Schmidt, Detlef Zillikens, Herzog S, and Iakov Shimanovich
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Male ,medicine.medical_specialty ,Azathioprine ,Dermatology ,Methylprednisolone ,Severity of Illness Index ,Clinical Protocols ,medicine ,Humans ,Immunoadsorption ,Staphylococcal Protein A ,Immunosorbent Techniques ,Aged ,Autoantibodies ,Autoimmune disease ,integumentary system ,Desmoglein 3 ,business.industry ,Pemphigus vulgaris ,Remission Induction ,Autoantibody ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Pemphigus ,Regimen ,Treatment Outcome ,Female ,Sorption Detoxification ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Summary Background. Pemphigus vulgaris is a life-threatening autoimmune blistering skin disease, usually treated with high-dose corticosteroids in combination with other immunosuppressants. However, this regimen may prove inadequate in severe cases and can cause dangerous side-effects. We have recently reported protein A immunoadsorption (PAIA) to be an effective adjuvant treatment for induction of remission in severe pemphigus. However, in a significant number of cases, the disease rapidly recurred once PAIA and immunosuppressive medication were tapered. Aims. The aim of the present study was to develop a PAIA-based therapeutic regimen that would result in a more prolonged remission of pemphigus. Methods. Nine patients with pemphigus vulgaris were treated with a modified protocol characterized by a combination of PAIA with a higher initial dose of systemic methylprednisolone (2 mg/kg). In addition, azathioprine or mycophenolate mofetil was administered as a steroid-sparing agent. Results. In all nine patients treated with this regimen, we observed a sharp decline of circulating autoantibody levels and dramatic improvement of cutaneous and mucosal lesions within 4 weeks of therapy. The patients remained free of clinical disease for up to 26 months after PAIA treatment was discontinued. Conclusion. The improved treatment protocol appears to combine highly effective induction of clinical remission in severe or treatment-resistant pemphigus with a prolonged subsequent symptom-free interval.
- Published
- 2006
23. The transformation of earth-system observations into information of socio-economic value in GEOSS
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Christian Pfrang, S. Uppala, Ad de Roo, David M. Burridge, E. Klinker, Jeanette Onvlee, Frederic Vitart, Anthony Hollingsworth, and J. W. de Vries
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Sustainable development ,System of systems ,Atmospheric Science ,geography ,Summit ,geography.geographical_feature_category ,Warning system ,Meteorology ,business.industry ,Environmental resource management ,Earth system science ,Global Earth Observation System of Systems ,Natural hazard ,business ,Group on Earth Observations - Abstract
The Group on Earth Observations System of Systems, GEOSS, is a co-ordinated initiative by many nations to address the needs for earth-system information expressed by the 2002 World Summit on Sustainable Development. We discuss the role of earth-system modelling and data assimilation in transforming earth-system observations into the predictive and status-assessment products required by GEOSS, across many areas of socio-economic interest. First we review recent gains in the predictive skill of operational global earth-system models, on time-scales of days to several seasons. We then discuss recent work to develop from the global predictions a diverse set of end-user applications which can meet GEOSS requirements for information of socio-economic benefit; examples include forecasts of coastal storm surges, floods in large river basins, seasonal crop yield forecasts and seasonal lead-time alerts for malaria epidemics. We note ongoing efforts to extend operational earth-system modelling and assimilation capabilities to atmospheric composition, in support of improved services for air-quality forecasts and for treaty assessment. We next sketch likely GEOSS observational requirements in the coming decades. In concluding, we reflect on the cost of earth observations relative to the modest cost of transforming the observations into information of socio-economic value.
- Published
- 2005
24. Hydrological verification of ECMWF and Limited Area Model simulations for the November 1966 catastrophic floods in Italy (Florence and Eastern Alps)
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Grossi G., B. Bacchi, R. Ranzi, R. Buizza, S. Uppala, E. Klinker, A. Buzzi, and P. Malguzzi
- Published
- 2003
25. Evaluation of the Spatio-Temporal Variability of Tropical Convection in GCMs by Using Geostationary Satellite Data
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E. Klinker, J.-Ph. Duvel, and J. J. Morcrette
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Meteorology ,Infrared window ,Climatology ,Cloud fraction ,Radiance ,Tropical wave ,Geostationary orbit ,International Satellite Cloud Climatology Project ,Environmental science ,Radiative forcing ,Physics::Atmospheric and Oceanic Physics ,Convection cell - Abstract
The temporal variability of convection at short time-scales (from diurnal to intra-seasonal) is an important characteristic outlining the response of the tropical atmosphere to astronomical forcing and its interaction with dynamical forcing. The spatial organisation of the convective cells into larger clusters of different sizes also is a strong characteristic of tropical convection. This paper presents analyses that can be used to evaluate the spatio-temporal variability in GCMs from measurements of geostationary meteorological satellites. The aim is not only to evaluate the description of the convective activity but also to trace the source of the cloud radiative forcing obtained in GCMs. These analyses make use of the modelled radiance in the infrared window and are compared to satellite data in a “model-to-satellite”approach. As an illustration, we present some preliminary results obtained from a comparison between the ECMWF model and Meteosat data over Africa and the Atlantic Ocean. Three model time series are used based either on “first guess” or on two runs without assimilation. The aim of the “first guess” time series is to validate the response of the cloud parameterization to realistic (i.e. close to the analysis) dynamical and thermodynamical fields. Two runs of three months without assimilation, identical except for the cloud scheme, are also analysed.
- Published
- 1996
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26. L'avenir de la prévision d'ensemble
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T. N. Palmer, D. Richardson, Jan Barkmeijer, R. Buizza, and E. Klinker
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EnglishIn this paper, ensemble prediction is shown to be more suitable for predicting severe weather events than standard deterministic forecasting. Moreover, as ensemble prediction leads to a probabilistic formulation of weather forecasts, it is a valuable decision-making tool for weather-sensitive economic or social activities. Although computationally demanding, this weather forecasting technique could therefore become a useful quantitative tool for meteorological risk management. francaisDans cet article, on montre que la prevision d'ensemble est plus apte a prevoir les phenomenes meteorologiques dangereux que la prevision deterministe classique. De plus, la possibilite de formuler les previsions du temps de facon probabiliste fait de la prevision d'ensemble un outil d'aide a la decision bien adapte aux activites economiques ou sociales sensibles aux conditions meteorologiques. Bien que gourmande en calcul, cette technique de prevision du temps pourrait donc devenir un excellent outil de gestion du risque meteorologique.
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- 2002
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27. Une nouvelle technique d'assimilation des données d'observation au CEPMMT : L'assimilation variationnelle quadridimensionnelle
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E. Klinker, Florence Rabier, and Jean-François Mahfouf
- Abstract
EnglishECMWF made a major step by switching its operational data assimilation method to four-dimensional data assimilation (4D-VAR). 4D-VAR uses all the tools from the previous operational system, 3D-VAR (same 6-hour assimilation window, same observations and same background term). The new ingredient is the temporal dimension. Over the 6-hour data assimilation window, 4D-VAR seeks the atmospheric model trajectory best fitting the observations and the background while satisfying an approximate geostrophic balance constraint. This allows to make a better use of the observations, in a way consistent with the dynamics, leading to better forecasts at all ranges in mid-latitudes. More over, a set of sub-grid scale physical processes has been introduced in the linearised versions of the forecast model used to solve the 4D-VAR variational problem. These physical processes describe deep moist convection, large-scale precipitation, vertical diffusion, longwave radiation and sub-grid-scale orographic effects. Because of the cost, these physical processes have been introduced in only a fraction of the variational processes. Nevertheless, their impact is significant for the humidity field in the Tropics, with a better performance of forecast quality in this region. 4D-VAR has been tested in parallel with the previous 3D-VAR for several months. A significant improvement of the forecast quality has been observed in both hemispheres. francaisLe Centre europeen pour les previsions meteorologiques a moyen terme (CEPMMT) a franchi le 25 novembre 1997 une etape majeure en adoptant l'assimilation variationnelle quadridimensionnelle (4D-VAR) en tant que methode d'assimilation de donnees pour la prevision numerique du temps. L'assimilation 4D-VAR emploie tous les ingredients du systeme precedent, le 3D-VAR (meme fenetre temporelle de six heures, memes observations et meme terme d'ecart a l'ebauche), auxquels elle ajoute la dimension temporelle. Sur la fenetre temporelle de six heures, le 4D-VAR recherche la trajectoire du modele atmospherique qui passe « au plus pres » des observations et de l'ebauche, tout en satisfaisant une contrainte d'equilibre geostrophique approche. Cela permet de mieux prendre en compte les observations, de facon coherente avec la dynamique. D'ou des previsions ameliorees a toutes les echeances aux latitudes temperees. De plus, un ensemble de processus physiques d'echelle sous-maille a ete introduit dans les versions linearisees du modele de prevision qui servent a resoudre le probleme variationnel que traite le 4D-VAR. Ces processus physiques representent les effets de la convection profonde, des precipitations stratiformes, de la diffusion turbulente, des processus radiatifs de grande longueur d'onde et de la partie du relief non resolue par les modeles. Pour des raisons de cout, ces processus physiques n'ont ete introduits que dans une partie du traitement variationnel. Ils ont cependant un effet significatif sur la description du champ d'humidite en zone tropicale, avec pour consequence une amelioration de la qualite des previsions dans ces regions. La technique 4D-VAR a ete testee en parallele avec l'ancienne methode 3D-VAR pendant plusieurs mois. On a observe une amelioration notable des performances de la prevision dans les deux hemispheres.
- Published
- 2000
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28. Sensibilité des erreurs de prévision aux conditions initiales
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Anthony Hollingsworth, E. Klinker, Philippe Courtier, and Florence Rabier
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Geography ,Forecast error ,Forestry ,Variational assimilation ,Cartography - Abstract
EnglishThe adjoint model, which is used in four-dimensional variational assimilation of meteorological data, can also tielp to investigate the sensitivity of forecast error to initial conditions in a diagnostic manner. Results obtained by this method over the month of April 1994 show that many cases of relatively poor model performance can be explained by weaknesses in the analysis. A slight modification of the analysis can be sufficient for improving substantially the quality of the forecast. francaisLe modele adjoint, qui est utilise pour mettre en oeuvre l'assimilation variationnelle quadridimensionnelle de donnees meteorologiques, peut egalement servir a evaluer la sensibilite de l'erreur de prevision aux conditions initiales. Les resultats obtenus par cette methode sur le mois d'avril 1994 montrent que de nombreux cas d'echecs relatifs de la prevision peuvent etre expliques par des faiblesses de l'analyse. Une modification mineure de cette derniere est souvent suffisante pour ameliorer notablement la qualite de la prevision.
- Published
- 1995
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29. Systematic errors of the ECMWF operational forecasting model in mid-latitudes
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K. Arpe and E. Klinker
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Atmospheric Science ,Jet (fluid) ,Meteorology ,Baroclinity ,Physics::Geophysics ,Troposphere ,Middle latitudes ,Climatology ,Cyclogenesis ,Kondratiev wave ,Tropopause ,Stratosphere ,Physics::Atmospheric and Oceanic Physics ,Geology - Abstract
The systematic errors of the ECMWF spectral operational model (April 1983 to April 1985) in midlatitudes are described. The main errors are: * a zonalization of the time-mean flow with considerably reduced diffluent flow at the jet exits; * a wavenumber-2 pattern in the mean height error field with forecast heights too low over Europe and the Bering Strait, and too high over Canada and Siberia; * an upward shift of the subtropical jet and the tropopause; * a cooling of the stratosphere; * a cooling of the middle troposphere which decreases the static stability in the lower troposphere; * an increase of the horizontal and vertical tilts of baroclinic waves; * changes in the geographical distributions of baroclinic waves and cyclones, with enhanced activity near jet exits and reduced activity near areas of cyclogenesis; * a drop of eddy kinetic energy during the 10-day forecasts, first in the baroclinic waves and later in the long waves. The errors in both hemispheres have similar characteristics. The relations between the different errors and possible causes are discussed and comparisons with the errors of the former ECMWF operational grid point model are made. The introduction of the spectral model has led to significant improvements in the speed of baroclinic waves, which are now predicted more accurately up to day 3.
- Published
- 1986
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30. The structure and characteristics of African easterly wave disturbances as determined from the ECMWF operational analysis/forecast system
- Author
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E. Klinker, A. Hollingsworth, and R. J. Reed
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Atmospheric Science ,Wavelength ,Baroclinity ,Atmospheric wave ,Climatology ,Tropical wave ,Storm ,Storm track ,Zonal and meridional ,Atmospheric sciences ,African easterly jet ,Geology - Abstract
Gridded data from the ECMWF archives are analyzed spectrally in order to determine the structure and characteristics of the African wave disturbances observed during August–September 1985. Major findings are: (1) The most prominent peaks in the 850 mb meridional wind spectra occurred at periods of 3–5 days. Co-spectrum analysis revealed that the 3–5-day oscillations were produced by waves of approximately 2500 km wavelength that travelled westward at speeds of about 8 m s−1. (2) Patterns of vorticity variance in the 3–5-day frequency band indicated that the waves originated primarily in two regions, one centered near 10°E and 22°N and the other centered near 10°E and 12°N, and that the storm tracks emanating from these regions merged into a single track, located between 15° and 20°N, over the Atlantic. (3) The energetics of the waves, inferred from covariance patterns of temperature, vertical velocity and meridional and zonal winds, indicated that the waves formed as a result of the joint baroclinic/barotropic instability of the African Easterly Jet. There was evidence that wave-CISK enhanced the growth of the waves that followed the southerly storm track.
- Published
- 1988
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31. Randy E. Reffitt, trumpet and Student Brass Quintet
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Reffitt, Randy E.; Klinker, Susan; Ball State University. Student Brass Quintet; Egolf, Cindy; Murphy, Jonathan; Dittrich, Adele; Plettner, Frank; Cook, Andrew; Rideout, Jeffrey J., Ball State University. School of Music, Reffitt, Randy E.; Klinker, Susan; Ball State University. Student Brass Quintet; Egolf, Cindy; Murphy, Jonathan; Dittrich, Adele; Plettner, Frank; Cook, Andrew; Rideout, Jeffrey J., and Ball State University. School of Music
- Abstract
Student Brass Quintet: Cindy Egolf, trumpet, Jon Murphy, trumpet, Adele Dittrich, horn, Frank Plettner, trombone, Andy Cook, tuba.; Randy E. Reffitt is assisted by Susan Klinker, piano.; The Brass Quintet is under the musical supervision of Jeffrey Rideout., Series XXXVI, Number 101., This archival material has been provided for educational purposes. Ball State University Libraries recognizes that some historic items may include offensive content. Our statement regarding objectionable content is available at: https://dmr.bsu.edu/digital/about
- Published
- 1982
32. Tropical-extratropical interaction associated with the 30-60 day oscillation and its impact on medium and extended range prediction
- Author
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Franco Molteni, Tim Palmer, E. Klinker, and Laura Ferranti
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Atmospheric Science ,North Atlantic oscillation ,Oscillation ,Climatology ,Mode (statistics) ,Extratropical cyclone ,Geopotential height ,Environmental science ,Outgoing longwave radiation ,Empirical orthogonal functions ,Teleconnection - Abstract
An observational and modeling study is made of tropical-extratropical interactions on time scales relevant to medium and extended range forecasting. First, an empirical orthogonal function (EOF) analysis is made of outgoing longwave radiation (OLR) in the tropics over seven winters. Having removed the seasonal cycle and interannual variability, the two leading EOFs describe the 30–60 day oscillation. A composite of extratropical 500 mb geopotential height correlated simultaneously with this mode of tropical variability is constructed. In its two phase-quadrature components, this composite has significant projection onto the Pacific/North American teleconnection pattern and onto the North Atlantic oscillation pattern, respectively. The 500 mb height composite is compared with the Simmons, Wallace and Branstator (SWB) mode of barotropic instability, which has similar periodicity and similar spatial structure in both its phase-quadrature components. A simple theoretical analysis shows that the SWB m...
33. The ECMWF operational implementation of four-dimensional variational assimilation. I: Experimental results with simplified physics
- Author
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Florence Rabier, Heikki Järvinen, Adrian Simmons, E. Klinker, and Jean-François Mahfouf
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Atmospheric Science ,Data assimilation ,Meteorology ,Dissipative system ,Trajectory ,Applied mathematics ,Classification of discontinuities ,Diffusion (business) ,Parametrization ,Physics::Atmospheric and Oceanic Physics ,Mathematics ,Term (time) ,Orographic lift - Abstract
A comprehensive set of physical parametrizations has been linearized for use in the European Centre for Medium-Range Weather Forecasts (ECMWF's) incremental four-dimensional variational (4D-Var) system described in Part I. The following processes are represented: vertical diffusion, subgrid-scale orographic effects, large-scale precipitation, deep moist convection and long-wave radiation. The tangent-linear approximation is examined for finite-size perturbations. Significant improvements are illustrated for surface wind and specific humidity with respect to a simplified vertical diffusion scheme. Singular vectors computed over 6 hours (compatible with the 4D-Var assimilation window) have lower amplification rates when the improved physical package is included, due to a more realistic description of dissipative processes, even though latent-heat release contributes to amplify the potential energy of perturbations in rainy areas. A direct consequence is a larger value of the observation term of the cost-function at the end of the minimization process when improved physics is included in 4D-Var. However, the larger departure of the analysis state from observations in the lower-resolution inner-loop is in better agreement with the behaviour of the full nonlinear model at high resolution. More precisely, the improved physics produces smaller discontinuities in the value of the cost-function when going from low to high resolution. In order to reduce the computational cost of the linear physics, a new configuration of the incremental 4D-Var system using two outer-loops is defined. In a first outer-loop, a minimization is performed at low resolution with simplified physics (50 iterations), while in the second loop a second minimization is performed with improved physics (20 iterations) after an update of the model trajectory at high resolution. In this configuration the extra cost of the physics is only 25%, and results from a 2-week assimilation period show positive impacts in terms of quality of the forecasts in the Tropics (reduced spin-down of precipitation, lower root-mean-square errors in wind scores). This 4D-Var configuration with improved physics and two outer-loops was implemented operationally at ECMWF in November 1997.
34. The ECMWF implementation of three-dimensional variational assimilation (3D-Var). III: Experimental results
- Author
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Graeme Kelly, Drasko Vasiljevic, M. J. Miller, Erik Andersson, Andreas Lanzinger, Carla Cardinali, Philippe Courtier, Catherine Gaffard, E. Klinker, Anthony Hollingsworth, Čedo Branković, Bernard Strauss, Pedro Viterbo, Adrian Simmons, Peter A. E. M. Janssen, Per Undén, Florence Rabier, Jean-Noël Thépaut, Jan Haseler, and Christian Jakob
- Subjects
Atmospheric Science ,Geopotential ,Meteorology ,Northern Hemisphere ,Weather forecasting ,Scatterometer ,computer.software_genre ,Numerical weather prediction ,Troposphere ,Data assimilation ,Objective analysis ,Climatology ,Environmental science ,Stratosphere ,computer - Abstract
SUMMARY In this third and final paper of a series, we assess the performance of the three-dimensional variational data assimilation scheme, in the light of the results from the extensive pre-operational programme of numerical experimentation. Its performance is compared with that of the previous operational scheme at the European Centre for Medium-Range Weather Forecasts, which was based on Optimal Interpolation. The main features of the new scheme are illustrated, in particular the effects of non-separable structure functions and the improved data usage. TIROS-N Operational Vertical Sounder cloud-cleared radiances, for example, are used directly without a separate retrieval step. Scatterometer data are assimilated in the form of ambiguous winds with the ambiguity removal taking place within the analysis itself. Problems encountered during the tests are discussed and the solutions implemented are explained. The overall impact on forecast accuracy in the troposphere of the northern hemisphere extratropics is neutral for geopotential and positive for wind and temperature. The impact is neutral in the tropics, and significantly positive in the southern hemisphere. Analyses and forecasts for the stratosphere have improved in all regions. Other positive results include a clear improvement in analyses of near-surface winds over oceans, particularly in the vicinity of tropical storms. This is predominantly because of the assimilation of scatterometer wind-data.
35. Profile of the single-use, multiple-pass protein A adsorber column in immunoadsorption.
- Author
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Schossee N, Veit G, Gittel J, Viebahn J, Niklaus M, Klingler P, Üçeyler N, Klinker E, Kobsar A, Boeck M, and Koessler J
- Subjects
- Autoantibodies, Humans, Immunoglobulin G, Receptors, Cholinergic, Myasthenia Gravis therapy, Staphylococcal Protein A
- Abstract
Background and Objectives: Immunoadsorptions (IA) are used to remove autoantibodies from the plasma in autoimmune disorders. In this study, we evaluated the effects of a single-use, recombinant staphylococcal protein A-based immunoadsorber on blood composition of the patient., Materials and Methods: In a cohort of patients with myasthenia gravis or stiff-person syndrome, essential parameters of blood cell count, coagulation, clinical chemistry or plasma proteins and immunoglobulins (Ig) were measured before and after IA (n = 11)., Results: In average, IA reduced the levels of total IgG, IgG1, IgG2 and IgG4 by approximately 60%, the acetylcholine receptor autoantibody levels by more than 70%. IgG3, IgA or IgM were diminished to a lower extent. In contrast to fibrinogen or other coagulation factors, the column markedly removed vitamin K-dependent coagulation factors II, VII, IX and X by approximately 40%-70%. Accordingly, international normalized ratio and activated partial thromboplastin time were increased after IA by 59.1% and 32.7%, respectively. Coagulation tests almost returned to baseline values within 24 h. Blood cell count, electrolytes, total protein or albumin were not essentially affected. No clinical events occurred., Conclusion: The single-use, multiple-pass protein A adsorber column is highly efficient to remove IgG1, IgG2 and IgG4 or specific acetylcholine receptor autoantibodies from the plasma. Coagulation parameters should be monitored, since the column has the capacity to largely reduce vitamin K-dependent factors., (© 2021 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)
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- 2022
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36. Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors.
- Author
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Marcu A, Schlosser A, Keupp A, Trautwein N, Johann P, Wölfl M, Lager J, Monoranu CM, Walz JS, Henkel LM, Krauß J, Ebinger M, Schuhmann M, Thomale UW, Pietsch T, Klinker E, Schlegel PG, Oyen F, Reisner Y, Rammensee HG, and Eyrich M
- Subjects
- Adolescent, Central Nervous System Neoplasms genetics, Central Nervous System Neoplasms metabolism, Central Nervous System Neoplasms therapy, Child, Child, Preschool, Female, HLA Antigens genetics, HLA Antigens immunology, HLA Antigens metabolism, Humans, Immunohistochemistry, Immunotherapy, Male, Mass Spectrometry, Oncogenes, Peptides metabolism, Peptides, Cyclic, Rhabdoid Tumor genetics, Rhabdoid Tumor metabolism, Rhabdoid Tumor therapy, Central Nervous System Neoplasms immunology, Peptides immunology, Rhabdoid Tumor immunology
- Abstract
Background: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells., Methods: Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM., Results: Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8
+ T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors., Conclusions: These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion., Competing Interests: Competing interests: MEy has taken part in pediatric advisory boards of BMS and Atara Biotherapeutics and holds research collaborations with CellSource and Miltenyi Biotec., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2021
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37. Peptide receptor radionuclide therapy as a new tool in treatment-refractory sarcoidosis - initial experience in two patients.
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Lapa C, Kircher M, Hänscheid H, Schirbel A, Grigoleit GU, Klinker E, Böck M, Samnick S, Pelzer T, and Buck AK
- Subjects
- Female, Humans, Middle Aged, Octreotide administration & dosage, Octreotide adverse effects, Octreotide therapeutic use, Radiopharmaceuticals administration & dosage, Radiopharmaceuticals adverse effects, Octreotide analogs & derivatives, Radiopharmaceuticals therapeutic use, Sarcoidosis radiotherapy
- Abstract
Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that can involve virtually all organ systems. Whereas most patients present without symptoms, progressive and disabling organ failure can occur in up to 10% of subjects. Somatostatin receptor (SSTR)-directed peptide receptor radionuclide therapy (PRRT) has recently received market authorization for treatment of SSTR-positive neuroendocrine tumors. Methods: We describe the first case series comprising two patients with refractory multi-organ involvement of sarcoidosis who received 4 cycles of PRRT. Results: PRRT was well-tolerated without any acute adverse effects. No relevant toxicities could be recorded during follow-up. Therapy resulted in partial response accompanied by a pronounced reduction in pain (patient #1) and stable disease regarding morphology as well as disease activity (patient #2), respectively. Conclusion: Peptide receptor radionuclide therapy in sarcoidosis is feasible and might be a new valuable tool in patients with otherwise treatment-refractory disease. Given the long experience with and good tolerability of PRRT, further evaluation of this new treatment option for otherwise treatment-refractory sarcoidosis in larger patient cohorts is warranted., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
- Published
- 2018
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38. Peptide Receptor Radionuclide Therapy for Sarcoidosis.
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Lapa C, Grigoleit GU, Hänscheid H, Klinker E, Jung P, Herrmann K, Schirbel A, Böck M, Buck AK, and Pelzer T
- Subjects
- Female, Humans, Middle Aged, Octreotide therapeutic use, Positron Emission Tomography Computed Tomography, Sarcoidosis diagnostic imaging, Treatment Outcome, Octreotide analogs & derivatives, Organometallic Compounds therapeutic use, Receptors, Peptide therapeutic use, Sarcoidosis radiotherapy
- Published
- 2016
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39. Immunoadsorption versus plasma exchange versus combination for treatment of myasthenic deterioration.
- Author
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Schneider-Gold C, Krenzer M, Klinker E, Mansouri-Thalegani B, Müllges W, Toyka KV, and Gold R
- Abstract
Objectives: The goal of this study was to analyze safety and assess the efficacy of standard plasma exchange (PE) compared with immunoadsorption (IA) alone, or an alternating combination of both in deteriorating myasthenia gravis (MG)., Methods: A total of 72 patients with MG who had received PE procedures for treatment of severe deterioration were retrospectively analyzed. They received either five cycles of PE (1-1.5 plasma volumes), or five cycles of IA in line with plasma separation, or a sequential alternating procedure of one cycle of PE followed by two cycles of IA, which was repeated once or more if needed., Results: A total of 19 patients received PE, 24 patients IA, and 29 the alternating combination therapy. All groups were equally distributed by sex and mean MG score before treatment. The number of treatment cycles and days on therapy did not differ between the groups. Mean MG scores at discharge were 3.0 (PE), 1.8 (IA) and 1.6 (combination) (p = 0.028 for combination versus PE). Inpatient time was 30.7 days (PE), 22.3 days (IA) and 20.0 days in combination therapy (p < 0.05 for combination versus PE). Side effects such as allergic reactions or hypocoagulability were significantly more frequent in the PE group (37% in PE versus 4% in IA and 3.6% in the alternating combination, p < 0.05)., Conclusion: Semiselective IA in combination with PE, and to a lesser extent IA alone, was associated with a shorter hospital stay and more pronounced reduction of the MG score than PE.
- Published
- 2016
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40. Boost and loss of immune responses against tumor-associated antigens in the course of pregnancy as a model for allogeneic immunotherapy.
- Author
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Lutz M, Worschech A, Alb M, Gahn S, Bernhard L, Schwab M, Obermeier S, Einsele H, Kämmerer U, Heuschmann P, Klinker E, Otto C, and Mielke S
- Subjects
- Adult, CD8-Positive T-Lymphocytes immunology, Cross-Sectional Studies, Female, Graft vs Host Disease immunology, HLA-A2 Antigen immunology, Humans, Male, Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, Young Adult, Antigens, Neoplasm immunology, Immunotherapy, Pregnancy immunology
- Abstract
Donor-derived immunity against tumor-associated antigens (TAAs) may exert selective antileukemic activity reprieving the allogeneic recipient from graft-versus-host disease. As TAAs are highly expressed in placental tissues we hypothesized that pregnancy could drive respective immunity in healthy individuals. Thus, we investigated the frequency and level of immune responses against clinically relevant TAAs in 114 blood donors and 44 women during their first pregnancy. Quantitative reverse-transcription polymerase chain reaction was employed to detect low levels of interferon-γ after primary peptide stimulation of CD8(+) T lymphocytes. In blood donors, primary immune responses of low and/or high avidity were found against WT1 (15%), MUC1 (14%), PRAME (7%), and HER2/neu (5%) and exerted killing functions against leukemic cells. Men had higher responses than women, likely due to gonadal cancer-testis-antigen expression. Interestingly, a history of prior delivery was not associated with increased responses, whereas the strongest responses during pregnancy were found in early trimesters to disappear after delivery. This boost and loss of TAA-specific immunity suggests that virtually every donor harbors the potential to mount antileukemic immune responses in a recipient. However, in the absence of the driving target and a permissive environment, they are short-lived and thus require supplemental strategies such as vaccination or immunomodulation to facilitate their persistence., (© 2015 by The American Society of Hematology.)
- Published
- 2015
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41. The effect of immunoadsorption with the Immusorba TR-350 column on coagulation compared to plasma exchange.
- Author
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Koessler J, Kobsar A, Kuhn S, Koessler A, Yilmaz P, Weinig E, Putz E, Boeck M, and Klinker E
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- Adult, Aged, Aged, 80 and over, Blood Coagulation Factors analysis, Female, Humans, Male, Middle Aged, Blood Coagulation, Plasma Exchange methods, Plasmapheresis methods
- Abstract
Background and Objectives: Plasma exchange (PE) and immunoadsorption with the Immusorba TR-350 column (IA) are used to remove autoantibodies from plasma in acute neurological autoimmune disorders. The impact of IA on coagulation and on low molecular weight heparin (LMWH) levels in comparison with PE was investigated., Patients and Methods: In five patients with neurological autoimmune disorders, coagulation parameters (global tests, coagulation factors) were measured before and after PE or IA (Part A). In five other patients under anticoagulation with LMWH, anti-Xa activity and global tests were measured before and after the treatments (Part B)., Results: After PE, coagulation factors were significantly reduced by 50-70%. After IA, a distinct reduction was observed for fibrinogen, but not for antithrombin and most of the other coagulation factors. Anti-Xa activity was reduced after PE (from 0.57 ± 0·10 to 0.13 ± 0.05 IU/ml) and almost unchanged after IA., Conclusion: It is advisable to discontinue or to reduce LMWH doses and to monitor coagulation parameters and anti-Xa activity after PE or IA to decide about further LMWH dosing., (© 2014 International Society of Blood Transfusion.)
- Published
- 2015
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42. Late-onset myasthenia gravis - CTLA4(low) genotype association and low-for-age thymic output of naïve T cells.
- Author
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Chuang WY, Ströbel P, Bohlender-Willke AL, Rieckmann P, Nix W, Schalke B, Gold R, Opitz A, Klinker E, Inoue M, Müller-Hermelink HK, Saruhan-Direskeneli G, Bugert P, Willcox N, and Marx A
- Subjects
- Aged, Aged, 80 and over, CTLA-4 Antigen genetics, Cell Count, Cell Differentiation, DNA Mutational Analysis, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Immune Tolerance, Male, Middle Aged, Myasthenia Gravis complications, Myasthenia Gravis genetics, Polymorphism, Genetic, Thymoma complications, Thymoma genetics, Thymus Neoplasms complications, Thymus Neoplasms genetics, White People, CTLA-4 Antigen metabolism, Myasthenia Gravis immunology, T-Lymphocytes immunology, Thymocytes immunology, Thymoma immunology, Thymus Gland immunology, Thymus Neoplasms immunology
- Abstract
Late-onset myasthenia gravis (LOMG) has become the largest MG subgroup, but the underlying pathogenetic mechanisms remain mysterious. Among the few etiological clues are the almost unique serologic parallels between LOMG and thymoma-associated MG (TAMG), notably autoantibodies against acetylcholine receptors, titin, ryanodine receptor, type I interferons or IL-12. This is why we checked LOMG patients for two further peculiar features of TAMG - its associations with the CTLA4(high/gain-of-function) +49A/A genotype and with increased thymic export of naïve T cells into the blood, possibly after defective negative selection in AIRE-deficient thymomas. We analyzed genomic DNA from 116 Caucasian LOMG patients for CTLA4 alleles by PCR/restriction fragment length polymorphism, and blood mononuclear cells for recent thymic emigrants by quantitative PCR for T cell receptor excision circles. In sharp contrast with TAMG, we now find that: i) CTLA4(low) +49G(+) genotypes were more frequent (p = 0.0029) among the 69 LOMG patients with age at onset ≥60 years compared with 172 healthy controls; ii) thymic export of naïve T cells from the non-neoplastic thymuses of 36 LOMG patients was lower (p = 0.0058) at diagnosis than in 77 age-matched controls. These new findings are important because they suggest distinct initiating mechanisms in TAMG and LOMG and hint at aberrant immuno-regulation in the periphery in LOMG. We therefore propose alternate defects in central thymic or peripheral tolerance induction in TAMG and LOMG converging on similar final outcomes. In addition, our data support a 60-year-threshold for onset of 'true LOMG' and an LOMG/early-onset MG overlapping group of patients between 40 and 60., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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43. Specific inhibitory effects of the NO donor MAHMA/NONOate on human platelets.
- Author
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Kobsar A, Simonis S, Klinker E, Koessler A, Kuhn S, Boeck M, and Koessler J
- Subjects
- Adenosine Diphosphate pharmacology, Adult, Blood Platelets physiology, Cell Adhesion Molecules metabolism, Collagen pharmacology, Cyclic AMP metabolism, Cyclic GMP metabolism, Humans, Microfilament Proteins metabolism, Middle Aged, Peptide Fragments pharmacology, Phosphoproteins metabolism, Phosphorylation drug effects, Platelet Aggregation drug effects, Signal Transduction drug effects, Young Adult, Blood Platelets drug effects, Hydrazines pharmacology, Nitric Oxide Donors pharmacology
- Abstract
Nitric oxide (NO) is a physiological inhibitor of platelet function and has vaso-dilating effects. Therefore, synthesized NO releasing agents are used e.g. in cardiovascular medicine. The aim of this study was to characterise specific effects of the short living agent MAHMA/NONOate, a NO donor of the diazeniumdiolate class, on human platelets. Whole blood was obtained from healthy volunteers. In washed human platelets, the MAHMA/NONOate induced phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) and cyclic nucleotide production were studied by Western Blot and by enzyme immunoassay kits. Agonist induced aggregation was measured in platelet rich plasma. Paired Student׳s t-test was used for statistical analysis. MAHMA/NONOate significantly stimulated platelet VASP phosphorylation in a concentration dependent manner and increased intracellular cGMP, but not cAMP levels, transiently. ODQ, a specific inhibitor of the soluble guanylyl cyclase, completely prevented VASP phosphorylation induced by low MAHMA/NONOate concentrations (5nM-15nM). The effects of higher concentrations (30-200nM) were only partially inhibited by ODQ. MAHMA/NONOate reduced platelet aggregation induced by low doses of agonists (2µM ADP, 0.5µg/mL collagen, 5µM TRAP-6) in a concentration dependent manner. MAHMA/NONOate leads to a rapid and transient activation of platelet inhibitory systems, accompanied by decreased platelet aggregation induced by low dose agonists. At low MAHMA/NONOate concentrations, the effects are cGMP dependent and at higher concentrations additionally cGMP independent. The substance could be of interest for clinical situations requiring transient and subtotal inhibition of platelet function., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
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44. Increasing susceptibility of nitric oxide-mediated inhibitory platelet signaling during storage of apheresis-derived platelet concentrates.
- Author
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Kobsar A, Klinker E, Kuhn S, Koessler A, Yilmaz P, Boeck M, and Koessler J
- Subjects
- Adult, Blood Platelets metabolism, Female, Fibrinogen metabolism, Flow Cytometry, Humans, Male, Middle Aged, Nitric Oxide metabolism, Platelet Activation drug effects, Platelet Aggregation drug effects, Plateletpheresis, Time Factors, Young Adult, Blood Platelets drug effects, Blood Preservation adverse effects, Nitric Oxide pharmacology
- Abstract
Background: Storage of platelets (PLTs) affects PLT integrity and functionality, a process named the PLT storage lesion. Normal PLT function essentially depends on the balanced interaction of activating and inhibitory signaling pathways. As there are poor data on the alterations of inhibitory signaling during storage of PLT concentrates, this study investigates the modulation capability of the cyclic nucleotide-mediated inhibitory pathways by use of the nitric oxide donor diethylamine diazenium diolate (DEA/NO)., Study Design and Methods: PLTs were obtained from whole blood (WB) and from apheresis-derived PLT concentrates (APCs) stored for 0, 2, and 5 days. Vasodilator-stimulated phosphoprotein (VASP) phosphorylation, cyclic nucleotide concentrations, fibrinogen binding, and agonist-induced aggregation were measured without or after stimulation with DEA/NO., Results: DEA/NO-induced VASP phosphorylation was significantly higher in PLTs from APCs on Days 2 and 5 compared to WB, conditioned by a stronger increase of cyclic guanosine monophosphate (cGMP), but not cyclic adenosine monophosphate (cAMP), in stored PLTs. A quantity of 5 nmol/L DEA/NO neither influenced thrombin receptor activator peptide 6 and collagen-induced aggregation nor fibrinogen binding in freshly collected PLTs, whereas it significantly inhibited both in stored PLTs., Conclusion: Stored PLTs showed an impairment of intracellular cGMP regulation, resulting in exceeding inhibition of agonist-induced aggregation and fibrinogen binding in the course of storage. The observed effects could be an important mechanism contributing to the storage lesion with reduced activating potential of PLTs., (© 2014 AABB.)
- Published
- 2014
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45. A comprehensive analysis of primary acute myeloid leukemia identifies biomarkers predicting susceptibility to human allogeneic Vγ9Vδ2 T cells.
- Author
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Gundermann S, Klinker E, Kimmel B, Flierl U, Wilhelm M, Einsele H, and Kunzmann V
- Subjects
- Adult, Aged, Aged, 80 and over, Cells, Cultured, Cytotoxicity, Immunologic, Female, GPI-Linked Proteins metabolism, Graft vs Leukemia Effect immunology, HLA Antigens immunology, Histocompatibility, Humans, Leukemia, Myeloid, Acute immunology, Male, Middle Aged, Predictive Value of Tests, Prognosis, Receptors, Antigen, T-Cell, gamma-delta metabolism, T-Lymphocytes transplantation, Transplantation, Homologous, Immunotherapy, Adoptive methods, Intracellular Signaling Peptides and Proteins metabolism, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute therapy, T-Lymphocytes immunology
- Abstract
Allogeneic innate lymphocytes such as Vγ9Vδ2 T cells are attractive candidates for cancer immunotherapy as they provide MHC-unrestricted antitumor activity without clinical evidence for inducing graft-versus-host disease (GvHD). However, current cellular immunotherapy approaches lack predictive biomarkers identifying patient cohorts most susceptible to immune attack. For this purpose we performed a comprehensive analysis of clinical, genetic, metabolic, and immunophenotypic features of 19 primary acute myeloid leukemia (AML) samples and correlated these factors with AML blast recognition by allogeneic Vγ9Vδ2 T cells. We show that 36% of primary AML samples were intrinsically susceptible to allogeneic Vγ9Vδ2 T cells. Among several evaluated features, only UL-16 binding protein 1 (ULBP1) expression (P<0.01) determines intrinsic AML susceptibility to allogeneic Vγ9Vδ2 T cells. Within the intrinsically resistant AML samples, pretreatment of AML blasts with nitrogen-containing bisphosphonates (NBP) significantly induced Vγ9Vδ2 T-cell cytotoxicity in 50% of AML samples, whereas 50% of AML samples were consistently refractory to γδ T-cell cytolysis. Activity of the mevalonate pathway (P<0.05) and myelomonocytic differentiation of AML (P<0.05) correlated with sensitivity of primary AML samples toward NBP pretreatment. In conclusion, this study identifies subsets of AML patients most likely to benefit from allogeneic Vγ9Vδ2 T-cell-mediated immunotherapy.
- Published
- 2014
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46. Adjuvant treatment of recalcitrant bullous pemphigoid with immunoadsorption.
- Author
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Müller PA, Bröcker EB, Klinker E, Stoevesandt J, and Benoit S
- Subjects
- Autoantibodies blood, Autoantibodies immunology, Autoantigens immunology, Carrier Proteins, Cytoskeletal Proteins, Dermatologic Agents therapeutic use, Drug Therapy, Combination, Dystonin, Female, Humans, Membrane Glycoproteins immunology, Middle Aged, Mycophenolic Acid analogs & derivatives, Mycophenolic Acid therapeutic use, Nerve Tissue Proteins, Non-Fibrillar Collagens immunology, Pemphigoid, Bullous blood, Pemphigoid, Bullous drug therapy, Pemphigoid, Bullous immunology, Prednisolone therapeutic use, Severity of Illness Index, Staphylococcal Protein A immunology, Treatment Outcome, Collagen Type XVII, Adjuvants, Immunologic therapeutic use, Immunosorbent Techniques, Pemphigoid, Bullous therapy, Sorption Detoxification methods
- Abstract
Elimination of pathogenic autoantibodies by immunoadsorption (IA) has been described as an effective adjuvant treatment in severe bullous autoimmune diseases, especially in pemphigus. There is much less experience in the treatment of bullous pemphigoid (BP). BP was diagnosed in a 62-year-old Caucasian woman presenting a pruritic rash with multiple tense blisters. Standard treatments with topical and oral corticosteroids, steroid-sparing agents including dapsone, azathioprine, mycophenolate mofetil (MMF) and intravenous immunoglobulins were ineffective or had to be discontinued due to adverse events. An immediate clinical response could be achieved by two treatment cycles of adjuvant protein A immunoadsorption (PA-IA) in addition to continued treatment with MMF (2 g/day) and prednisolone (1 mg/kg/day). Tolerance was excellent. Clinical improvement remained stable after discontinuation of IA and went along with sustained reduction of circulating autoantibodies. Our data demonstrate that PA-IA might be a safe and effective adjuvant treatment in severe and recalcitrant BP., (Copyright © 2012 S. Karger AG, Basel.)
- Published
- 2012
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47. The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis.
- Author
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Chuang WY, Ströbel P, Belharazem D, Rieckmann P, Toyka KV, Nix W, Schalke B, Gold R, Kiefer R, Klinker E, Opitz A, Inoue M, Kuo TT, Müller-Hermelink HK, and Marx A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antigens, CD genetics, Antigens, CD immunology, CTLA-4 Antigen, Female, Genetic Predisposition to Disease, Genotype, Humans, Male, Middle Aged, Myasthenia Gravis complications, Myasthenia Gravis genetics, Thymoma complications, Thymoma genetics, Thymus Neoplasms complications, Thymus Neoplasms genetics, White People genetics, Young Adult, Interleukin-2 immunology, Myasthenia Gravis immunology, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 22 immunology, Thymoma immunology, Thymus Neoplasms immunology
- Abstract
Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) inhibits T-cell activation and interleukin-2 (IL-2) production. The PTPN22(gain-of-function)+1858T(+) genotypes predispose to multiple autoimmune diseases, including early-onset (non-thymomatous) myasthenia gravis (MG). The disease association and the requirement of IL-2/IL-2 receptor signaling for intrathymic, negative T-cell selection have suggested that these genotypes may weaken T-cell receptor (TCR) signaling and impair the deletion of autoreactive T cells. Evidence for this hypothesis is missing. Thymoma-associated MG, which depends on intratumorous generation and export of mature autoreactive CD4(+) T cells, is a model of autoimmunity because of central tolerance failure. Here, we analyzed the PTPN22 +1858C/T single nucleotide polymorphism in 426 German Caucasian individuals, including 125 thymoma patients (79 with MG), and investigated intratumorous IL-2 expression levels. Unlike two previous studies on French and Swedish patients, we found strong association of PTPN22 +1858T(+) genotypes not only with early-onset MG (P=0.00034) but also with thymoma-associated MG (P=0.0028). IL-2 expression in thymomas with PTPN22 +1858T(+) genotypes (P=0.028) was lower, implying weaker TCR signaling. We conclude that the PTPN22(gain-of-function) variant biases towards MG in a subgroup of thymoma patients possibly by impeding central tolerance induction.
- Published
- 2009
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48. Five donors-one recipient: modeling a mosaic of granulocytes, natural killer and T cells from cord-blood and third-party donors.
- Author
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Schöttker B, Feuchtinger T, Schumm M, Klinker E, Handgretinger R, Einsele H, and Stuhler G
- Subjects
- Adult, Cord Blood Stem Cell Transplantation, Granulocytes transplantation, Humans, Killer Cells, Natural transplantation, Male, Mosaicism, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, T-Lymphocytes transplantation, Cell Transplantation, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Background: A 21-year-old man was admitted to hospital because of leukocytosis, thrombocytopenia and anemia. The patient had been in good health until a few days earlier, when he developed fever and night sweats and his performance status dramatically declined., Investigations: Laboratory tests, immunophenotyping, cytogenetic analyses, bone-marrow biopsy, minimal residual disease analysis using quantitative real-time polymerase chain reaction, differential chimerism analysis using flow cytometry, mixed chimerism analysis, CT scans, electro-encephalography, cerebral magnetic resonance tomography., Diagnosis: Bcr-abl-positive and Philadelphia-chromosome-positive acute lymphoblastic leukemia, and primary graft failure complicated by invasive fungal infection and cytomegalovirus encephalitis., Management: Double cord-blood rescue transplantation, third-party CD34-positive stem-cell rescue transplantation, third-party cytomegalovirus-specific T lymphocyte transplantation.
- Published
- 2008
- Full Text
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49. Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes.
- Author
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Deleeuw RJ, Zettl A, Klinker E, Haralambieva E, Trottier M, Chari R, Ge Y, Gascoyne RD, Chott A, Müller-Hermelink HK, and Lam WL
- Subjects
- Adult, Aged, Aged, 80 and over, CD56 Antigen genetics, CD56 Antigen metabolism, CD8 Antigens genetics, CD8 Antigens metabolism, Celiac Disease complications, Celiac Disease physiopathology, Chromosome Mapping, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 5 genetics, DNA, Neoplasm genetics, Female, Gene Expression Regulation, Neoplastic, Genotype, HLA-DQ Antigens metabolism, HLA-DQ beta-Chains, Humans, Lymphoma, T-Cell etiology, Male, Middle Aged, Celiac Disease genetics, Genome, Human genetics, HLA-DQ Antigens genetics, Lymphoma, T-Cell classification, Lymphoma, T-Cell genetics
- Abstract
Background & Aims: Enteropathy-type T-cell lymphoma (ETL) is an aggressive extranodal T-cell non-Hodgkin lymphoma assumed to arise in the setting of celiac disease., Methods: To precisely define the genetic alterations underlying the pathogenesis of ETL, 30 ETL samples were profiled for genetic copy number alterations using high-resolution whole-genome tiling path array comparative genomic hybridization. To investigate the potential association of genetic alterations in ETL with celiac disease, HLA-DQB1 genotyping was performed., Results: By array comparative genomic hybridization, 13 novel recurrent minimal regions of chromosomal alteration were identified on multiple chromosome arms. ETL is characterized by frequent complex gains of 9q31.3-qter (70% of cases), or by an almost mutually exclusive 2.5-megabase loss of 16q12.1 (23% of cases). Two distinct groups of ETL could be delineated morphologically and genetically: type 1 ETL is characterized by nonmonomorphic cytomorphology, CD56 negativity, and chromosomal gains of 1q and 5q. Type 1 ETL also appears to be linked pathogenetically to celiac disease, sharing genetic alterations and HLA-DQB1 genotype patterns with (refractory) celiac disease. Type 2 ETL shows monomorphic small- to medium-sized tumor cell morphology, frequently shows CD56 expression, MYC oncogene locus gain, and rare gains of chromosomes 1q and 5q. In contrast to type 1 ETL, type 2 ETL shows a HLA-DQB1 genotype pattern more resembling that of the normal Caucasian population., Conclusions: Contrary to current clinical classification, ETL comprises 2 morphologically, clinically, and genetically distinct lymphoma entities. In addition, type 2 ETL may not be associated with celiac disease.
- Published
- 2007
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50. Improved protocol for treatment of pemphigus vulgaris with protein A immunoadsorption.
- Author
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Shimanovich I, Herzog S, Schmidt E, Opitz A, Klinker E, Bröcker EB, Goebeler M, and Zillikens D
- Subjects
- Aged, Autoantibodies blood, Clinical Protocols, Combined Modality Therapy, Desmoglein 3 immunology, Female, Humans, Immunosorbent Techniques, Immunosuppressive Agents therapeutic use, Male, Methylprednisolone therapeutic use, Middle Aged, Pemphigus drug therapy, Pemphigus immunology, Pemphigus pathology, Remission Induction, Severity of Illness Index, Staphylococcal Protein A, Treatment Outcome, Pemphigus therapy, Sorption Detoxification methods
- Abstract
Background: Pemphigus vulgaris is a life-threatening autoimmune blistering skin disease, usually treated with high-dose corticosteroids in combination with other immunosuppressants. However, this regimen may prove inadequate in severe cases and can cause dangerous side-effects. We have recently reported protein A immunoadsorption (PAIA) to be an effective adjuvant treatment for induction of remission in severe pemphigus. However, in a significant number of cases, the disease rapidly recurred once PAIA and immunosuppressive medication were tapered., Aims: The aim of the present study was to develop a PAIA-based therapeutic regimen that would result in a more prolonged remission of pemphigus., Methods: Nine patients with pemphigus vulgaris were treated with a modified protocol characterized by a combination of PAIA with a higher initial dose of systemic methylprednisolone (2 mg/kg). In addition, azathioprine or mycophenolate mofetil was administered as a steroid-sparing agent., Results: In all nine patients treated with this regimen, we observed a sharp decline of circulating autoantibody levels and dramatic improvement of cutaneous and mucosal lesions within 4 weeks of therapy. The patients remained free of clinical disease for up to 26 months after PAIA treatment was discontinued., Conclusion: The improved treatment protocol appears to combine highly effective induction of clinical remission in severe or treatment-resistant pemphigus with a prolonged subsequent symptom-free interval.
- Published
- 2006
- Full Text
- View/download PDF
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