43 research outputs found
Effect of MOR202, a human CD38 antibody, in combination with lenalidomide and bortezomib, on bone lysis and tumor load in a physiologic model of myeloma.
A comprehensive overview of daratumumab and carfilzomib and the recently approved daratumumab, carfilzomib and dexamethasone regimen in relapsed/refractory multiple myeloma
Element budgets in an Arctic mesocosm CO2 perturbation study
Recent studies on the impacts of ocean acidification on pelagic communities demonstrated changes in carbon
to nutrient dynamics with related shifts in elemental stoichiometry. In principle mesocosm experiments provide
the opportunity of determining the temporal dynamics of all relevant carbon and nutrient pools and performing
elemental budgets. In practice, attempts to budget mesocosm enclosures are often hampered by uncertainties in
some of the measured pools and fluxes, in particular due to air/sea exchange, particle sinking, and wall growth. In
an Arctic mesocosm study on ocean acidification using KOSMOS (Kiel Off-Shore Mesocosm facility for future
Ocean Simulation) all relevant element pools and fluxes of carbon, nitrogen and phosphorus were measured, using
an improved experimental design intended to narrow down some of those uncertainties. Water column concentrations
of particulate and dissolved organic and inorganic constituents were determined daily. New approaches
for quantitative estimates of material sinking to the bottom of the msocosms and gas exchange in 48 h temporal
resolution, as well as estimates of wall growth were obtained to close the gaps in element budgets. Element pools,
fluxes and their stoichiometry at selected days of the experiment will be presented and critically examined with
regard to achieving closed budgets
Extreme Levels of Ocean Acidification Restructure the Plankton Community and Biogeochemistry of a Temperate Coastal Ecosystem : A Mesocosm Study
The oceans’ uptake of anthropogenic carbon dioxide (CO2) decreases seawater pH and alters the inorganic carbon speciation – summarized in the term ocean acidification (OA). Already today, coastal regions experience episodic pH events during which surface layer pH drops below values projected for the surface ocean at the end of the century. Future OA is expected to further enhance the intensity of these coastal extreme pH events. To evaluate the influence of such episodic OA events in coastal regions, we deployed eight pelagic mesocosms for 53 days in Raunefjord, Norway, and enclosed 56–61 m3 of local seawater containing a natural plankton community under nutrient limited post-bloom conditions. Four mesocosms were enriched with CO2 to simulate extreme pCO2 levels of 1978 – 2069 μatm while the other four served as untreated controls. Here, we present results from multivariate analyses on OA-induced changes in the phyto-, micro-, and mesozooplankton community structure. Pronounced differences in the plankton community emerged early in the experiment, and were amplified by enhanced top-down control throughout the study period. The plankton groups responding most profoundly to high CO2 conditions were cyanobacteria (negative), chlorophyceae (negative), auto- and heterotrophic microzooplankton (negative), and a variety of mesozooplanktonic taxa, including copepoda (mixed), appendicularia (positive), hydrozoa (positive), fish larvae (positive), and gastropoda (negative). The restructuring of the community coincided with significant changes in the concentration and elemental stoichiometry of particulate organic matter. Results imply that extreme CO2 events can lead to a substantial reorganization of the planktonic food web, affecting multiple trophic levels from phytoplankton to primary and secondary consumers.publishe
Implications of elevated CO2 on pelagic carbon fluxes in an Arctic mesocosm study – an elemental mass balance approach
Recent studies on the impacts of ocean acidification on pelagic communities have identified changes in carbon to nutrient dynamics with related shifts in elemental stoichiometry. In principle, mesocosm experiments provide the opportunity of determining temporal dynamics of all relevant
carbon and nutrient pools and, thus, calculating elemental budgets. In practice, attempts to budget mesocosm enclosures are often hampered by uncertainties in some of the measured pools and fluxes, in particular due to uncertainties in constraining air–sea gas exchange, particle sinking, and wall growth. In an Arctic mesocosm study on ocean acidification applying KOSMOS (Kiel Off-Shore Mesocosms for future Ocean Simulation), all relevant element pools and fluxes of carbon, nitrogen and phosphorus were measured, using an improved experimental design intended to narrow down the mentioned uncertainties. Water-column concentrations of particulate and dissolved organic and inorganic matter were determined daily. New approaches for quantitative estimates of material sinking to the bottom of the mesocosms and gas exchange in 48 h temporal resolution as well as estimates of wall growth were developed to close the gaps in element budgets. However, losses elements from the budgets into a sum of insufficiently determined pools were detected, and are principally unavoidable in mesocosm investigation. The comparison of variability patterns of all single measured datasets revealed analytic precision to be the main issue in determination of budgets. Uncertainties in dissolved organic carbon (DOC), nitrogen (DON) and particulate organic phosphorus (POP) were much higher than the summed error in
determination of the same elements in all other pools. With estimates provided for all other major elemental pools, mass balance calculations could be used to infer the temporal development of DOC, DON and POP pools. Future elevated pCO2 was found to enhance net autotrophic community carbon uptake in two of the three experimental phases but did not significantly affect particle elemental composition. Enhanced carbon consumption appears to result in accumulation of dissolved organic carbon under nutrient-recycling summer conditions. This carbon overconsumption effect becomes evident from mass balance calculations, but was too small to be resolved by direct measurements
of dissolved organic matter. Faster nutrient uptake by comparatively small algae at high CO2 after nutrient addition resulted in reduced production rates under future ocean CO2 conditions at the end of the experiment. This CO2 mediated shift towards smaller phytoplankton and enhanced cycling of dissolved matter restricted the development of larger phytoplankton, thus pushing the system towards a retention type food chain with overall negative effects on export potential
Die Alpha-Emitter Radioimmuntherapie des multiplen Myeloms mit 213Bi-CHX-A“-DTPA-anti-CD38 Immunkonjugaten zeigt eine hohe Effizienz im präklinischen Xenograft-Modell
Trotz jüngster Fortschritte in der Behandlung des multiplen Myeloms mit Bortezomib oder Lenalidomid ist diese Tumorerkrankung unheilbar. Ein Zielmolekül für einen neuen Therapieansatz ist das Glykoprotein CD38, das von Myelomzellen meist überexprimiert wird. Es wurden die therapeutische Effizienz von 213Bi-anti-CD38 Immunkonjugaten im Mausmodell und die zugrundeliegenden molekularen Mechanismen untersucht.JRC.E.5-Nuclear chemistr
Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway
α-Radioimmunotherapy with 213Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma.
In spite of development of molecular therapeutics, multiple myeloma (MM) is fatal in most cases. CD38 is a promising target for selective treatment of MM. We tested radioimmunoconjugates consisting of the α-emitter 213Bi coupled to an anti-CD38 MAb in preclinical treatment of MM. Efficacy of 213Bi-anti-CD38-MAb was assayed towards different MM cell lines with regard to induction of DNA double-strand breaks, induction of apoptosis and initiation of cell cycle arrest. Moreover, mice bearing luciferase-expressing MM xenografts were treated with 213Bi-anti-CD38-MAb. Therapeutic efficacy was monitored by bioluminescence imaging, overall survival and histology. 213Bi-anti-CD38-MAb treatment induced DNA damage which did not result in activation of the G2 DNA-damage-response checkpoint, but instead in mitotic arrest and subsequent mitotic catastrophe. The anti-tumor effect of 213Bi-anti-CD38-MAb correlated with the expression level of CD38 in each MM cell line. In myeloma xenografts, treatment with 213Bi-anti-CD38-MAb suppressed tumor growth via induction of apoptosis in tumor tissue and significantly prolonged survival compared to controls. The major organ systems did not show any signs of 213Bi-induced toxicity. Preclinical treatment of MM with 213Bi-anti-CD38-MAb turned out as an effective therapeutic option
α-Radioimmunotherapy with 213Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma
In spite of development of molecular therapeutics, multiple myeloma (MM) is fatal in most cases. CD38 is a promising target for selective treatment of MM. We tested radioimmunoconjugates consisting of the α-emitter 213Bi coupled to an anti-CD38 MAb in preclinical treatment of MM. Efficacy of 213Bi-anti-CD38-MAb was assayed towards different MM cell lines with regard to induction of DNA double-strand breaks,
induction of apoptosis and initiation of cell cycle arrest. Moreover, mice bearing luciferase-expressing MM xenografts were treated with 213Bi-anti-CD38-MAb. Therapeutic efficacy was monitored by bioluminescence imaging, overall survival and histology. 213Bi-anti-CD38-MAb treatment induced DNA damage which did not result in activation of the G2 DNA-damage-response checkpoint, but instead in mitotic arrest and subsequent mitotic catastrophe. The anti-tumor effect of 213Bi-anti-CD38- MAb correlated with the expression level of CD38 in each MM cell line. In myeloma xenografts, treatment with 213Bi-anti-CD38-MAb suppressed tumor growth via induction of apoptosis in tumor tissue and significantly prolonged survival compared to controls. The major organ systems did not show any signs of 213Bi-induced toxicity.
Preclinical treatment of MM with 213Bi-anti-CD38-MAb turned out as an effective therapeutic option.JRC.E.5-Nuclear chemistr
Reactions of nitroxide radicals in aqueous solutions exposed to non-thermal plasma : limitations of spin trapping of the plasma induced species
Low temperature (‘cold’) atmospheric pressure plasmas have gained much attention in recent years due to their biomedical effects achieved through the interactions of plasma induced species with the biological substrate. Monitoring of the radical species in an aqueous biological milieu is usually performed via electron paramagnetic resonance (EPR) spectroscopy using various nitrone spin traps, which form persistent radical adducts with the short-lived radicals. However, the stability of these nitroxide radical adducts in the plasma-specific environment is not well known. In this work, chemical transformations of nitroxide radicals in aqueous solutions using a model nitroxide 4-oxo-TEMPO were studied using EPR and LC-MS. The kinetics of the nitroxide decay when the solution was exposed to plasma were assessed, and the reactive pathways proposed. The use of different scavengers enabled identification of the types of reactive species which cause the decay, indicating the predominant nitroxide group reduction in oxygen-free plasmas. The 2H adduct of the PBN spin trap (PBN-D) was shown to decay similarly to the model molecule 4-oxo-TEMPO. The decay of the spin adducts in plasma-treated solutions must be considered to avoid rendering the spin trapping results unreliable. In particular, the selectivity of the decay indicated the limitations of the PTIO/PTI nitroxide system in the detection of nitric oxide