Neisseria meningitidis is a human pathogen responsible for life-threatening inflammatory diseases. Meningococcal penicillin-binding proteins (PBPs) and particularly PBP2 are involved in bacterial ...resistance to β-lactams. Here we describe a novel function for PBP2 that activates human and mouse dendritic cells (DC) in a time and dose-dependent manner. PBP2 induces MHC II (LOGEC50 = 4.7 µg/ml ± 0.1), CD80 (LOGEC50 = 4.88 µg/ml ± 0.15) and CD86 (LOGEC50 = 5.36 µg/ml ± 0.1). This effect was abolished when DCs were co-treated with anti-PBP2 antibodies. PBP2-treated DCs displayed enhanced immunogenic properties in vitro and in vivo. Furthermore, proteins co-purified with PBP2 showed no effect on DC maturation. We show through different in vivo and in vitro approaches that this effect is not due to endotoxin contamination. At the mechanistic level, PBP2 induces nuclear localization of p65 NF-kB of 70.7 ± 5.1% cells versus 12 ± 2.6% in untreated DCs and needs TLR4 expression to mature DCs. Immunoprecipitation and blocking experiments showed thatPBP2 binds TLR4. In conclusion, we describe a novel function of meningococcal PBP2 as a pathogen associated molecular pattern (PAMP) at the host-pathogen interface that could be recognized by the immune system as a danger signal, promoting the development of immune responses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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Background: Mantle cell lymphoma (MCL) is characterized by a poor prognosis. Starting in 2004, the European MCL Network has performed the double randomized MCL Elderly trial for first-line ...treatment of patients with MCL, Ann-Arbor stage II-IV, aged 60 years or older and not suitable for autologous stem cell transplantation (Kluin-Nelemans et al., NEJM 2012). Median age of the 560 patients included was 70 years (range, 60-87). The first randomization compared 8xR-CHOP with 6xR-FC induction, the second randomization compared rituximab (R) maintenance with interferon-alpha (IFN) maintenance, both given in remission until progression. The primary evaluation of the induction part showed that R-FC could not improve complete remission rates compared with R-CHOP, while overall survival (OS) with R-FC was substantially shortened compared to R-CHOP. The primary evaluation of the maintenance part showed a prolonged progression-free survival (PFS) in remission with R compared to IFN. After R-CHOP induction, PFS and OS were substantially prolonged by R vs. IFN. We report here the long-term follow-up of the time-to-event endpoints with robust 5-year estimates after a median follow-up of 6.7 years.
Methods: While the primary maintenance question was evaluated per protocol adjusting for interim analyses, the other analyses were according to the intention to treat without adjustment. 95% confidence intervals for Kaplan-Meier estimates were calculated by using Greenwood's variance and the log-log transformation. Using competing risk methods, we additionally estimated cumulative incidences of treatment failure (stable or progressive disease) and of death without treatment failure.
Results: Failure-free survival after start of R-FC or R-CHOP induction was overlapping with 5-year probabilities of 31% (95% CI 25%-37%) in both groups. While R-FC showed lower 5-year cumulative incidence of treatment failure compared with R-CHOP (51% vs. 60%, p=0.083), the cumulative incidence of death without treatment failure was higher with R-FC (19% vs. 9% with R-CHOP, p=0.0032). OS was substantially shorter after R-FC with 5-year probabilities of 42% (36%-49%) compared with 58% (51%-64%) after R-CHOP (p=0.0012). This observation was related to the higher cumulative incidence of death without treatment failure after R-FC and a shorter OS after first treatment failure (R-FC: median 1.0 vs. R-CHOP: 2.3 years).
The efficacy of R maintenance was confirmed with a significantly prolonged PFS from end of induction (primary evaluation, p=0.0109, hazard ratio 0.48, 5-year PFS, R: 53%, 44%-61% vs. IFN: 23%, 15%-31%); OS was also prolonged (p=0.008). After response to R-CHOP, the 5-year PFS with R vs. IFN was 51% (40%-62%) vs. 22% (14%-32%, Figure 1A, p<0.0001) in comparison to 52% (39%-63%) vs. 32% (20%-45%) after R-FC (p=0.032, interaction p=0.19). With R-maintenance after R-FC, the 5-year cumulative incidence of death without progression was as high as the cumulative incidence of progression (24% and 23%, respectively). After R-CHOP, OS was prolonged by R vs. IFN with 5-year OS of 79% (67%-86%) vs. 59% (48%-69%, p=0.0026, Figure 1B), in contrast to R-FC with 5-year OS of 57% (44%-68%) vs. 54% (39%-66%, p=0.60, interaction p=0.096).
Conclusions: After long-term follow-up we confirm the substantially prolonged PFS and OS with R-maintenance after R-CHOP induction in first-line treatment of older MCL patients who are no candidates for autologous stem cell transplantation. Despite indications for anti-lymphoma activity, induction with six cycles of R-FC was associated with severe treatment complications leading to a higher cumulative incidence of death without treatment failure and shorter survival compared with 8 cycles of R-CHOP.
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Hoster:Roche: Other: Travel support, Research Funding. Hermine:INatherys: Equity Ownership, Research Funding; AB Science: Equity Ownership, Honoraria, Patents & Royalties, Research Funding; Celgene: Research Funding; Novartis: Research Funding; Hybrigenics: Research Funding. Walewski:Roche: Consultancy, Honoraria, Other: travel costs, Research Funding; Takeda: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Servier: Consultancy; GSK/Novartis: Research Funding. Trneny:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Geisler:Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy, Research Funding. Stilgenbauer:Genzyme: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Thieblemont:Bayer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vehling-Kaiser:Lilly: Consultancy; AbbVie: Consultancy; Amgen: Consultancy; F. Hoffmann-LaRoche: Consultancy; MSD: Consultancy; Gilead: Consultancy. Doorduijn:Celgene: Honoraria; Roche: Honoraria. Karlin:Janssen: Honoraria, Other: Travel expenses. Tilly:Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria; Immunogen: Honoraria. Ribrag:Gilead: Honoraria; Roche: Honoraria; BMS: Honoraria; Nanostring: Honoraria; ArgenX: Research Funding; Infinity: Honoraria; MSD: Honoraria; Servier: Consultancy, Honoraria; Epizyme: Honoraria. Andre:Takeda: Honoraria, Other: Advisory board, Research Funding. Hiddemann:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Janssen: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sandoz: Consultancy; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; MorphoSys AG: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau.
Abstract 3567
Autologous transplantation significantly improves the progression free survival (PFS) and overall survival (OS) of patients with relapsed or resistant follicular (rFL) lymphoma compared ...with chemotherapy alone (Schouten H, et al. J Clin Oncol 2003;21:3918–27). Small phase II trials suggest, that rituximab (R) given peritransplant further improves survival outcome. Whilst the role of maintenance R post chemotherapy in FL is established, the benefit and safety of maintenance R following autologous transplant is unknown. In this randomised prospective study the efficacy and safety of R as in vivo purging pretransplant and as maintenance treatment immediately post transplant was assessed. From Oct 1999 to Apr 2006, 280 of a planned 420 R naïve patients with rFL in first (n=16), second (n= 222) or third remission (n=41) who achieved either a complete remission (n=83) or a very good partial remission (n=196) to induction chemotherapy, with limited bone marrow infiltration (<25% B-lymphocytes) underwent a single randomisation in a 2 × 2 design to R purging 375 mg/m2 weekly × 4 (RP) before high-dose therapy with BEAM conditioning (HDC) and maintenance R 375 mg/m2 every 3 months for 2 years (RM). The primary endpoint of the study was PFS. All analysis is by intention to treat. The median age was 51 years (range: 26–70), and baseline characteristics were well balanced between groups. On average patients were 44.1 (range 3.4–463.8) months from diagnosis with 79.3% having 2 lines of therapy and 15% three lines of prior therapy. Patients were equally distributed between low, intermediate and high FLIPI scores. Pretransplant 70% of patients were in PR and 30% in CR. Fifty seven patients failed to mobilise peripheral blood stem cells. Nineteen patients withdrew, 5 due to toxicity, 9 were ineligible. In the 196 (70%) patients transplanted, neutrophil engraftment > 0.5 × 109 /L was prompt, median 14.3 days (range 10–115) and platelets > 50 × 109/L,median 25.1 days (range 9–190). Time to engraftment and early or late toxicities did not differ significantly between the groups apart from a lower neutrophil count at 3 months in patients on maintenance. No graft failures or late neutropenia was reported. Transplant related mortality was 0.5%. Only 3 infection related deaths have been reported post 100 days. Two hundred and seventeen patients are alive on continued follow-up. Median follow-up is 6.4 years. PFS at 5 years was 62.9% for patients receiving RP + RM versus 37.6 % for patients receiving no R (logrank PFS; p=0.004; HR 0.76, 95%CI: 0.66 – 0.93). OS at 5 years was 79.5% % versus 78.4 % for patient receiving RP + RM versus no R (logrank PFS; p>0.1). Multivariate analysis was not able to define a high or low risk patient group. R in vivo purging and maintenance results in superior PFS compared to no R. R does not adversely affect peripheral blood stem cell harvesting or engraftment and maintenance R post transplant is safe. The impressive OS suggests that relapsed FL patients can be effectively salvaged post R purging and maintenance.
R Purging + R MaintenanceR MaintenanceR PurgingNo RPt number69697270Median PFSNR@ 6.4 y7.23 y4.03 y3.34 y5y PFS62.9 %56 %46 %37.6 %5y OS79.5 %80.5 %84.8 %78.4 %
Pettengell:Roche: Honoraria. Schmitz:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gisselbrecht:Roche: Research Funding. Walewski:Roche: Honoraria, Research Funding. Geisler:Roche: Research Funding. Kimby:Roche: Honoraria, Research Funding. Goldstone:Roche: Honoraria, Speakers Bureau.
The paper deals with the importance of historicism in modern social science. The social history of cities should clarify the complex interplay between global structural changes and everyday social ...life. In a way, it is a quintessence of social history. Urban historians are, therefore, encouraged to address the grand problems of social change and to trace the interaction between large-scale shifts in economic organization and urban geography, and changes in the quality of social life. In the paper some of the interactions are listed and briefly analyzed and special attention is paid to the analysis of urban migration. The paper is a transcription of a lecture given by the author in 1991.
To analyse factors that differentiate patients who attend follow-up assessments versus those who do not, and to identify predictors for drop-out within the context of the European Day Hospital ...Evaluation Study (EDEN-Study).
The EDEN-Study, a multi-center RCT comparing acute psychiatric day care with inpatient care, required re-assessment of patients at discharge, 3 and 12 months after discharge. Follow-up rates varied between 54.0% and 99.5%. Socio-demographic and clinical characteristics of patients who did and did not attend follow-up were analysed using uni- and multivariate statistical methods.
Univariate analyses showed differences between patients regarding study site, treatment setting, living situation, employment, age, psychopathological symptoms and treatment satisfaction. They were not confirmed in multivariate analyses thus meaningful predictors of drop-out could not be identified.
Results emphasize the general need to compare patients re-assessed and not re-assessed in terms of their most relevant socio-demographic and clinical variables to assess the generalizability of results.
Neisseria meningitidis is a human pathogen responsible for life-threatening inflammatory diseases. Meningococcal penicillin-binding proteins (PBPs) and particularly PBP2 are involved in bacterial ...resistance to beta-lactams. Here we describe a novel function for PBP2 that activates human and mouse dendritic cells (DC) in a time and dose-dependent manner. PBP2 induces MHC II (LOGEC50=4.7 mu g/ml +/- 0.1), CD80 (LOGEC50=4.88 mu g/ml +/- 0.15) and CD86 (LOGEC50=5.36 mu g/ml +/- 0.1). This effect was abolished when DCs were co-treated with anti-PBP2 antibodies. PBP2-treated DCs displayed enhanced immunogenic properties in vitro and in vivo. Furthermore, proteins co-purified with PBP2 showed no effect on DC maturation. We show through different in vivo and in vitro approaches that this effect is not due to endotoxin contamination. At the mechanistic level, PBP2 induces nuclear localization of p65 NF-kB of 70.7 +/- 5.1% cells versus 12 +/- 2.6% in untreated DCs and needs TLR4 expression to mature DCs. Immunoprecipitation and blocking experiments showed that PBP2 binds TLR4. In conclusion, we describe a novel function of meningococcal PBP2 as a pathogen associated molecular pattern (PAMP) at the host-pathogen interface that could be recognized by the immune system as a danger signal, promoting the development of immune responses.
Neisseria meningitidis is a human pathogen responsible for life-threatening inflammatory diseases. Meningococcal penicillin-binding proteins (PBPs) and particularly PBP2 are involved in bacterial ...resistance to beta-lactams. Here we describe a novel function for PBP2 that activates human and mouse dendritic cells (DC) in a time and dose-dependent manner. PBP2 induces MHC II (LOGEC50=4.7 mu g/ml +/- 0.1), CD80 (LOGEC50=4.88 mu g/ml +/- 0.15) and CD86 (LOGEC50=5.36 mu g/ml +/- 0.1). This effect was abolished when DCs were co-treated with anti-PBP2 antibodies. PBP2-treated DCs displayed enhanced immunogenic properties in vitro and in vivo. Furthermore, proteins co-purified with PBP2 showed no effect on DC maturation. We show through different in vivo and in vitro approaches that this effect is not due to endotoxin contamination. At the mechanistic level, PBP2 induces nuclear localization of p65 NF-kB of 70.7 +/- 5.1% cells versus 12 +/- 2.6% in untreated DCs and needs TLR4 expression to mature DCs. Immunoprecipitation and blocking experiments showed that PBP2 binds TLR4. In conclusion, we describe a novel function of meningococcal PBP2 as a pathogen associated molecular pattern (PAMP) at the host-pathogen interface that could be recognized by the immune system as a danger signal, promoting the development of immune responses.
Neisseria meningitidis is a human pathogen responsible for life-threatening inflammatory diseases. Meningococcal penicillin-binding proteins (PBPs) and particularly PBP2 are involved in bacterial ...resistance to beta-lactams. Here we describe a novel function for PBP2 that activates human and mouse dendritic cells (DC) in a time and dose-dependent manner. PBP2 induces MHC II (LOGEC50=4.7 mu g/ml +/- 0.1), CD80 (LOGEC50=4.88 mu g/ml +/- 0.15) and CD86 (LOGEC50=5.36 mu g/ml +/- 0.1). This effect was abolished when DCs were co-treated with anti-PBP2 antibodies. PBP2-treated DCs displayed enhanced immunogenic properties in vitro and in vivo. Furthermore, proteins co-purified with PBP2 showed no effect on DC maturation. We show through different in vivo and in vitro approaches that this effect is not due to endotoxin contamination. At the mechanistic level, PBP2 induces nuclear localization of p65 NF-kB of 70.7 +/- 5.1% cells versus 12 +/- 2.6% in untreated DCs and needs TLR4 expression to mature DCs. Immunoprecipitation and blocking experiments showed that PBP2 binds TLR4. In conclusion, we describe a novel function of meningococcal PBP2 as a pathogen associated molecular pattern (PAMP) at the host-pathogen interface that could be recognized by the immune system as a danger signal, promoting the development of immune responses.
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