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  • 2005-2009  (55)
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  • 2005-2009  (55)
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  • 1
    In: International Journal of Oncology, Spandidos Publications, ( 2006-04-01)
    Type of Medium: Online Resource
    ISSN: 1019-6439 , 1791-2423
    RVK:
    Language: Unknown
    Publisher: Spandidos Publications
    Publication Date: 2006
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    detail.hit.zdb_id: 1154403-X
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  • 2
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2911-2911
    Abstract: We have demonstrated immunological responses and positive clinical effects of a peptide vaccination for patients with AML, MDS, MM and CLL with a limited tumor load or a minimal residual disease over-expressing RHAMM using 300 μg RHAMM-R3 peptide (Schmitt et al., Blood 2008; Giannopoulos et al., abstract submitted). To date, 26 patients were enrolled in this clinical peptide vaccination trial. Here, we report on the second cohort of nine patients with AML, MDS and MM vaccinated with a higher peptide dose (1000 μg RHAMM-R3 peptide). The vaccine was given four times at a biweekly interval and GM-CSF was added for five days each vaccination. Similar to the patients vaccinated with 300 μg peptide only mild drug-related adverse events were observed such as erythema and induration of the skin. Immunomonitoring was performed using ELISpot assays for Interferon gamma and Granzyme B, tetramer-based flow cytometry and chromium release assays. Moreover, the frequency of regulatory T cells was quantified at different time points of vaccination. In this second cohort of patients treated with 1,000 μg peptide we detected specific immune responses in a lower frequency (4/9 patients) in contrast to patients in the 300 μg cohort (7/10 patients). In these patients with immune responses we found an increase of CD8+/HLA-A2/RHAMM-R3 tetramer+/CD45RA+/CCR7−/CD27−/CD28− effector T cells in flow cytometry in accordance with an increase of R3-specific CD8+ T cells in ELISpot assays. Two patients with positive immune responses showed a significant decrease of regulatory T cells. One patient without positive immune and clinical effects showed an increase of the frequency of regulatory T cells (5.03% to 15.9%). Three out of nine patients treated with 1,000 μg showed positive clinical effects: One patient with MDS RAEB-2 showed a reduction of leukemic blasts in the bone morrow to lower than 5%, one MDS patient achieved a normalization of the peripheral blood counts and one patient with multiple myeloma experienced a reduction of light chain in serum. The patients in the 300 μg cohort showed also a higher frequency of positive clinical effects (5 out of 10 patients). Taken together, RHAMM-R3 peptide vaccination induced both immunological and clinical responses. Therefore, RHAMM constitutes a promising structure for further targeted immunotherapies in patients with different hematological malignancies. However, higher doses of peptide do not improve the frequency and intensity of immune responses in this clinical trial.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 3
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2052-2052
    Abstract: B-cell chronic lymphocytic leukemia (B-CLL) is a very attractive disease to be targeted by immunotherapy due to its rather low progression and due to the availability of cancer cells in the peripheral blood. Dendritic cells (DCs) are the most professional antigen presenting cells, but are deficient in B-CLL. Therefore administration of ex vivo generated DCs might improve the anti-leukemic T cell response in patients with B-CLL. Our group reported the first clinical trial with allogeneic DCs stimulated with leukemic cells lysates in B-CLL patients. To answer the question whether autologous DCs might cause a similar immunotherapeutical effect we conducted the present study assessing the safety and feasibility as well as the clinical and immunological responses to autologous monocyte-derived DC immunotherapy in B-CLL patients. Precursor cells for DC generation were obtained using two methods: by plastic adherence of PBMC from leukapheresis or CD14 positive separation through magnetic beads of PBMC from 150mL of peripheral blood. Twelve patients at clinical stage 0 and 2 according to Rai were vaccinated intradermally up to eight times with a mean number of 7.4×106 DCs pulsed with B-CLL cell lysates. Specific CD8+ T cell responses to RHAMM and fibromodulin - recently described as tumor specific antigens (TAA) in B-CLL were evaluated by multi-parametric tetramer-based flow cytometry and ELISPOT assays. Furthermore, the percentage of CD4+CD25hiFoxP3+ T regulatory cells in the peripheral blood over the time of vaccination was assessed. We observed a decrease of peripheral blood leukocytes and B CD19+/CD5+ leukemic cells in five patients, three patients showed a stable disease and four patients progressed despite DC vaccination. The best clinical response was observed in the patients treated with DCs generated from adherent fraction of PBMC obtained by leukapheresis. No severe toxicities were noted. After the end of therapy the in vitro proliferation of autologous T cells stimulated by DC pulsed with lysates, as well as by lysates alone increased significantly comparing to the values before treatment (1391±2170, p & lt;0.001; 3280±4842, p & lt;0.001). A significant increase of specific cytotoxic CD8+ T lymphocytes against leukemia-associated antigens (RHAMM/CD168 and fibromodulin), was detected after DC vaccination. In patients with a clinical response, an increase of interleukin 12 (IL-12) serum levels (12±9 pg/ml vs. 6±7 pg/ml; p=0.02,) was noted. In patients with the most favorable clinical response we observed a substantial decrease of CD4+/CD25+ cells (14.3±11.3% vs. 28.6±12.5%) and an increase of CD8+/CD25+ cells percentage after DC therapy (49.3±55.7% vs. 8.9±1.9%), as well as a decrease of the frequency of CD4+CD25hiFOXP3+ T regulatory cells. Taken together, the study demonstrated that vaccination with autologous DC in CLL patients is feasible and safe. Immunological and to some extend hematological responses could be noted, justifying further investigation on this immunotherapeutical approach.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 4
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3671-3671
    Abstract: Abstract 3671 Poster Board III-607 For effective elimination of malignant cells by specific T cells a co-activation of CD4- and CD8-positive T cells might be important. We performed two RHAMM-R3 peptide vaccination trials using 300μg and 1000μg for patients with AML, MDS and multiple myeloma overexpressing RHAMM. Similar mild toxicity of both cohorts was found, only mild drug-related adverse events were observed such as erythema and induration of the skin. In the 300μg cohort we detected in 7/10 (70 %) patients specific immune responses and also positive clinical effects in 5/10 (50 %) patients. In the high dose peptide vaccination trial (1000μg peptide) 4/9 (44 %) patients showed positive immune responses. These patients showed an increase of CD8+RHAMM-R3 tetramer+/CD45RA+/CCR7-/CD27-/CD28- effector T cells and an increase of R3-specific CD8+ T cells. In the higher peptide dose cohort three patients showed positive clinical effects. However, higher doses of peptide do not improve the frequency and intensity of immune responses in this clinical trial and might induce immune tolerance. In this work, we investigated the co-existence of serological immune responses against RHAMM detected by a RHAMM-specific ELISA of patients with AML, MDS and multiple myeloma treated in these two peptide vaccination trials. We correlated these results to specific T cell responses of CD8-positive T cells measured by ELISpot assays for interferon gamma and Granzyme B, tetramer staining and chromium release assays. Moreover, these results were compared to the frequency of regulatory T cells. 4/19 patients have a positive serological immune response in ELISA assay, all of these patients developed also strong specific CD8-positive T cell responses during peptide vaccination detected by ELISpot assays and tetramer staining. As expected, peptide vaccination did not result in the induction of humoral immune responses. In further ELISA assays we measured IL-2 and IL-10 levels in the sera of the patients before and three weeks after four vaccinations. While IL-10 levels remained at a rather low level over the time of vaccination, we detected an increase of IL-2 up to the five-fold of the initial levels in four of ten patients. Moreover, we performed a proteome array to detect cytokine and chemokine regulation in sera of patients vaccinated in these two trials during and after RHAMM-R3 peptide vaccination. 36 cytokines, chemokines and acute phase proteins were measured and both cohorts vaccinated with different peptide doses were compared. Taken together, RHAMM-R3 peptide vaccination induced both immunological and clinical responses. Co-existence of immune responses of CD4-positive T cells against the target RHAMM seems to be important for an induction of strong immune responses of CD8-positive T cells. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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    detail.hit.zdb_id: 80069-7
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  • 5
    In: Transfusion, Wiley, Vol. 47, No. 9 ( 2007-09), p. 1588-1594
    Type of Medium: Online Resource
    ISSN: 0041-1132 , 1537-2995
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2007
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  • 6
    In: European Journal of Pediatrics, Springer Science and Business Media LLC, Vol. 165, No. 9 ( 2006-9), p. 658-659
    Type of Medium: Online Resource
    ISSN: 0340-6199 , 1432-1076
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2006
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  • 7
    Online Resource
    Online Resource
    Cold Spring Harbor Laboratory ; 2007
    In:  RNA Vol. 13, No. 10 ( 2007-10), p. 1648-1655
    In: RNA, Cold Spring Harbor Laboratory, Vol. 13, No. 10 ( 2007-10), p. 1648-1655
    Abstract: Pop6 and Pop7 are protein subunits of Saccharomyces cerevisiae RNase MRP and RNase P. Here we show that bacterially expressed Pop6 and Pop7 form a soluble heterodimer that binds the RNA components of both RNase MRP and RNase P. Footprint analysis of the interaction between the Pop6/7 heterodimer and the RNase MRP RNA, combined with gel mobility assays, demonstrates that the Pop6/7 complex binds to a conserved region of the P3 domain. Binding of these proteins to the MRP RNA leads to local rearrangement in the structure of the P3 loop and suggests that direct interaction of the Pop6/7 complex with the P3 domain of the RNA components of RNases MRP and P may mediate binding of other protein components. These results suggest a role for a key element in the RNase MRP and RNase P RNAs in protein binding, and demonstrate the feasibility of directly studying RNA–protein interactions in the eukaryotic RNases MRP and P complexes.
    Type of Medium: Online Resource
    ISSN: 1355-8382 , 1469-9001
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2007
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    SSG: 12
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  • 8
    In: Autoimmunity, Informa UK Limited, Vol. 42, No. 5 ( 2009-01), p. 467-474
    Type of Medium: Online Resource
    ISSN: 0891-6934 , 1607-842X
    RVK:
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2009
    detail.hit.zdb_id: 2031170-9
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  • 9
    Online Resource
    Online Resource
    Hogrefe Publishing Group ; 2009
    In:  Psychologische Rundschau Vol. 60, No. 1 ( 2009-01), p. 8-22
    In: Psychologische Rundschau, Hogrefe Publishing Group, Vol. 60, No. 1 ( 2009-01), p. 8-22
    Abstract: Zusammenfassung. Menschen unterscheiden sich in ihrer Sensibilität für Ungerechtigkeit. Diese Unterschiede sind stabil und lassen sich über einzelne Fälle von Ungerechtigkeit hinweg generalisieren. Ungerechtigkeitssensibilität gliedert sich in vier Facetten: Opfersensibilität, Beobachtersensibilität, Nutznießersensibilität und Tätersensibilität. Diese Facetten korrelieren systematisch untereinander. Wir stellen Untersuchungen vor, die Zusammenhänge der Facetten mit egoistischen und prosozialen Dispositionen und mit egoistischem und prosozialem Verhalten in experimentellen Spielen sowie mit Zivilcourage aufzeigen. In diesen Untersuchungen lassen sich die Facetten klar differenzieren. Während Beobachter-, Nutznießer- und Tätersensibilität in einem genuinen Bedürfnis nach Gerechtigkeit zu wurzeln scheinen, beinhaltet Opfersensibilität auch eine selbstbezogene Sorge, ausgebeutet zu werden. Vermittelnde Emotionen differenzieren weiterhin zwischen Beobachter- und Nutznießersensibilität: Beobachtersensibilität führt zu verstärkter Empörung, Nutznießersensibilität zu Schuldgefühlen als Reaktion auf Ungerechtigkeit. Erste Befunde lassen vermuten, dass der Einfluss von Ungerechtigkeitssensibilität auf Verhalten durch Prozesse der Informationsverarbeitung vermittelt wird. Zu diesen Prozessen gehören die automatische Aufmerksamkeitslenkung, die Interpretation mehrdeutiger Information und die Erinnerung an relevante Information. Als Ursache für die gefundenen Zusammenhänge zwischen Ungerechtigkeitssensibilität und Informationsverarbeitung wird die bei ungerechtigkeitssensiblen Personen erhöhte Aktivierbarkeit und Elaboriertheit von Gerechtigkeitskonzepten angenommen.
    Type of Medium: Online Resource
    ISSN: 0033-3042 , 2190-6238
    RVK:
    Language: German
    Publisher: Hogrefe Publishing Group
    Publication Date: 2009
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    SSG: 5,2
    SSG: 5,21
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  • 10
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 4310-4310
    Abstract: In the era of novel drugs, the role of RIC AT for relapsed Multiple Myeloma (MM) remains to be determined. In this retrospective study we analyzed the results of RIC AT performed in 36 patients with relapsed MM in our institution between June 1999 and August 2007. At diagnostic our population consisted of 27 males and 9 females. Twenty-eight patients had stage III, 4 patients had stage II and 4 patients had stage I DS. B2-micoglobuline was ≤ 3 mg/l in 16 patients and & gt; 3 mg/l in 11 patients. Del 13 was present in 7/18 patients evaluated. Nineteen received at least 2 HDM with autologous stem cell transplantation, 15 received only one and 2 didn’t received HDM as part of frontline treatment. The median age at time of AT was 56 years (range: 44–64). The “pre-AT” treatments consisted in “standard chemotherapy” for 13 patients and targeted treatments, represented by thalidomide or lenalidomide, or bortezomib w or wo dexamethasone in 23 patients. At the time of AT, 29 patients were responder (3 complete response (CR), 6 very good partial response (VGPR) and 20 partial response (PR)), and 7 patients were not responder (6 stable disease (SD) and 1 progressive disease (PD)). RIC regimen consisted of fludarabine associated with busulfan (n=22), treosulfan (n=2), total body irradiation (n=10), idarubicine and cytosine arabinoside (n=1) or melphalan (n=1). In addition, 25 patients received ATG as part of the conditioning. The donor was an HLA-identical sibling in 20 cases or an unrelated donor in 16 cases. GVH Prophylaxis consisted of CSA alone (n=16), CSA with MMF (n=7), or CSA with MTX (n=13). The median delay between AT and the first response evaluation was 3.8 months, 15 patients achieved CR, 3 patients achieved VGPR, 9 patients achieved PR, 2 patients were in SD and 4 in PD. Twenty one patients developed acute GVHD (grade 1–4) and 14 patients developed chronic GVHD. With a med FU of 42 months, 11 patients are alive. The 3-year event free survival (EFS) and overall survival (OS) from AT are 17, 5% (+/−7.2%) and 32% (+/− 8.3%) respectively. The causes of death were transplant-related complications in 11 patients, relapse or progression in 13 patients, and second malignancy in 1 patient. The TRM at Day 100 and Day 365 was 19 % (+/− 6.6 %) and 32 % (+/− 8%) respectively. Among the numerous factors that were evaluated for their prognostic influence, only two were significantly associated with a better OS and EFS (in univariate and multivariate analysis): the achievement of a CR or VGPR after AT (median OS: 31m vs 5; p & lt;0.0001; median EFS: 56m vs 9; p=0.005) and the occurrence of a chronic GVHD (median OS: 31m vs 9; p=0.0003; median EFS: 56m vs 21; p=0.007). The achievement of a CR or a VGPR after the RIC AT was significantly associated with the result achieved before RIC AT. In our small cohort of patients we were unable to identify factor associated with the occurrence of a cGVH. When targeted treatments were used as salvage, the rate of CR+VGPR before and after RIC AT was higher (before:35% vs 7%; after: 61% vs 31%) however, this did not turned in a significant improvement of the OS, the EFS and the TRM. Conclusion: The disease response remains a major goal to improve the results of RIC AT in relapsed Multiple myeloma. The targeted therapies are able to improve the disease response in patients who relapse after HDM and were never treated with such drugs. However we did not document a significant improvement of the overall results of RIC AT following such salvage as compared to chemotherapy salvage.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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