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Preclinical Evaluation of CD40-Directed Immunotherapy in B-Cell Lymphoma Using [<sup>18</sup>F]Fluorothymidine-PET

Advances in Molecular Imaging 2015年第2期5卷 17-28页

作者： Nicolas Graf Zhoulei Li k.n Herrmann Michaela Aichler Jolanta Slawsk. Axel Walch Christian Peschel Mark.s Schwaiger andreas k. buck Tobias Dechow Ulrich k.ller III. Medical Department of Hematology and Medical Oncology Technische Universitat München Munich Germany Department of Nuclear Medicine Technische Universitat München Munich Germany Department of Nuclear Medicine Universitat Sklinikum Würzburg Würzburg Germany Institute of Pathology—Analytical Pathology Helmholtz Zentrum München Neuherberg Germany German Cancer Consortium (Dk.k. and German Cancer Research Center (Dk.Z) Heidelberg Germany

Back.round: Inhibition of the lymphoma surface antigen CD40 by the antagonistic CD40 antibody NVP-HCD122 (HCD122) demonstrates activity in various lymphoma subtypes. In this preclinical in vivo study we examined the suitability of positron emission tomography (PET) using the thymidine analogue 3’-deoxy-3’-[18F]fluorothymidine (FLT) for early response assessment upon HCD122 treatment in diffuse large B cell lymphoma (DLBCL). Methods: Immunodeficient mice bearing human DLBCL xenografts (SU-DHL-4) received week.y intraperitoneal injections of HCD122. Tumor growth was followed up until Day 14. Molecular imaging with FLT-PET was performed before (Day 0) and after start of therapy (Day 2 and Day 7). On Day 14 lymphoma xenografts were explanted for immunohistochemical analysis to correlate PET findings with CD40 surface expression on tumor tissue. Results: Treatment with HCD122 significantly delayed tumor growth resulting in a tumor growth inhibition of 45% on Day 14. Significant reduction of tumor-to-back.round ratio (TBR) of FLT-PET was seen in treated animals on Day 7 and preceded change of tumor volume, thus predicting therapy response to HCD122. Immunohistochemical analysis of xenografts revealed significantly higher CD40 expression on treated than on untreated tissue. Moreover, we found a significant correlation between CD40 expression and FLT-PET response for xenograft tumor treated with HCD122. Conclusions: Treatment of DLBCL with the antagonistic CD40 antibody HCD122 can be monitored with FLT-PET as early as seven days after commencement of therapy and seems to increase CD40 expression on tumor tissue.

关键词： CD40 Antibody FLT-PET Lymphoma Therapy Monitoring

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Microglia:a promising therapeutic target in spinal cord injury

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Neural Regeneration Research 2025年第2期20卷 454-463页

作者： Xiaowei Zha Guoli Zheng Thomas Sk.tella k.rl k.ening andreas Unterberg Alexander Younsi Department of Neurosurgery Heidelberg University HospitalHeidelbergGermany Department of Neuroanatomy Institute for Anatomy and Cell BiologyHeidelberg UniversityHeidelbergGermany

Microglia are present throughout the central nervous system and are vital in neural repair,nutrition,phagocytosis,immunological regulation,and maintaining neuronal *** a healthy spinal cord,microglia are accountable for immune surveillance,however,when a spinal cord injury occurs,the microenvironment drastically changes,leading to glial scars and failed axonal *** this context,microglia vary their gene and protein expression during activation,and proliferation in reaction to the injury,influencing injury responses both favorably and unfavorably.A dynamic and multifaceted injury response is mediated by microglia,which interact directly with neurons,astrocytes,oligodendrocytes,and neural stem/progenitor *** a clear understanding of their essential nature and origin,the mechanisms of action and new functions of microglia in spinal cord injury require extensive *** review summarizes current studies on microglial genesis,physiological function,and pathological state,highlights their crucial roles in spinal cord injury,and proposes microglia as a therapeutic target.

关键词： astrocytes cytok.nes functional recovery immune regulation M1/M2 activation macrophages microglia neuroinflammation spinal cord injury therapy

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Determination of particle exchange rates at over-flow weirs in horizontal fluidised beds by particle track.ng velocimetry

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Particuology 2017年第3期15卷 1-9页

作者： k.tja Meyer andreas buck Evangelos Tsotsas Thermal Process Engineering Otto von Guericke University Magdeburg UniversitStsplatz 2 D-39106 Magdeburg Germany

Residence time distributions （RTDs） in horizontal fluidised beds have a huge effect on solid product properties and are infuenced by the internal design of the apparatus, e.g. the separation into different compartments by weirs. Weirs can be passed in or against the overall solid transport direction, with the back.flow resulting in axial dispersion, which is a measure of the spread of the RTD. Therefore, the ratio of exchange rates at weirs under different fluidisation conditions provides information on axial dispersion. In this work. a methodology based on particle track.ng velocimetry is presented to obtain information on the exchange rates of particles at weirs in horizontal fluidised beds. The internal recirculation is studied for over-flow weirs with respect to different fluidisation conditions, providing a first step towards determining the effects of weirs and fluidisation conditions on axial dispersion and RTDs in horizontal fluidised beds.

关键词： Particle track.ng velocimetry Horizontal fluidised bedAxial dispersion Granulation Drying

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Estimation of particle dynamics in 2-D fluidized beds using particle track.ng velocimetry

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Particuology 2015年第5期13卷 39-51页

作者： Thomas Hagemeier Christoph Roloff andreas buck Evangelos Tsotsas NaWiTec Thermal Process EngineeringOtto-von-Guericke University MagdeburgUniversitaetsplatz 239106 MagdeburgGermany Fluid Dynamics and Technical Flow Otto-von-Guericke University MagdeburgUniversitaetsplatz 239106 MagdeburgGermany

The experimental characterization of particle dynamics in fluidized beds is of great importance in fostering an understanding of solid phase motion and its effect on particle properties in granulation processes, Commonly used techniques such as particle image velocimetry rely on the cross-correlation of illumination intensity and averaging procedures. It is not possible to obtain single particle velocities with such techniques. Moreover, the estimated velocities may not accurately represent the local particle velocities in regions with high velocity gradients. Consequently, there is a need for devices and methods that are capable of acquiring individual particle velocities. This paper describes how particle track.ng velocimetry can be adapted to dense particulate flows. The approach presented in this paper couples high-speed imaging with an innovative segmentation algorithm for particle detection, and employs the Voronoi method to solve the assignment problem usually encountered in densely seeded fows. Lagrangian particle track. are obtained as primary information, and these serve as the basis for calculating sophisticated quantities such as the solid-phase flow field, granular temperature, and solid volume fraction. We show that the consistency of individual trajectories is sufficient to recognize collision events.

关键词： Particle dynamics Particle track.ng velocimetry Pseudo-2D Fluidized bed

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No evidence for female discrimination against male house mice carrying a selfish genetic element

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Current Zoology 2016年第6期62卷 675-685页

作者： andreas SUTTER Anna k. LINDHOLM Institute of Evolutionary Biology and Environmental Studies University of Zurich Winterthurerstrasse 190 Zurich 8057 Switzerland

Meiotic drivers distort transmission to the next generation in their favor, with detrimental effects on the fitness of their homologues and the rest of the genome. Male carriers of meiotic drivers commonly inflict costs on their mates through genetic incompatibility, reduced fecundity, or biased brood sex ratios. Given these costs, evidence for female discrimination against male carriers is surprisingly rare. One of few examples is the t haplotype in house mice, a meiotic driver that shows strong transmission distortion in males and is typically homozygote lethal. As a consequence, mating between 2 t heterozygous （＋/t） mice leads to high embryo mortality. Previous experiments showing that＋/t females avoid this incompatibility cost by preferring ＋/＋ versus ＋/t males have inferred preference based on olfactory cues or brief social interactions. Evidence from mating contexts in laboratory settings and semi-natural populations has been inconclusive. Here, we investigated female choice from a large number of no-choice mating trials. We found no evidence for discrimination against＋/t males based on mating, remating, and copulatory behavior. Further, we found no evidence for avoidance of incompatibility through selective interactions between game- tes. The lik.lihood of mating showed significant effects of female weight and genotype, suggesting that our test paradigm enabled females to exhibit mate choice. We discuss the strengths and limitations of our approach. By explicitly considering selection at both the individual and gene level, we argue why precopulatory female discrimination by＋/t females may be less evolutionarily stable than discrimination by all females based on postcopulatory mechanisms.

关键词： cryptic female choice female preference indirect benefits mate choice segregation distortion t haplotype

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Experimental study and modeling of particle drying in a continuously-operated horizontal fluidized bed

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Particuology 2017年第5期15卷 134-146页

作者： k.icheng Chen Philipp Bachmann andreas buck Michael Jacob Evangelos Tsotsas Thermal Process Engineering Otto-von-Guericke-University Universityatsplatz 239106 MagdeburgGermany Glatt Ingenieurtechnik.GmbH Nordstrasse 12 99427 Weimar Germany

Multistage fluidized beds are frequently used for product drying in industry. One advantage of these fluidized beds is that they can achieve a high throughput, when operated continuously. In this study, γ- A1203 particles were dried in a pilot-scale horizontal fluidized bed, without considering any comminution effects. For each experiment, the particle moisture content distribution and residence time distribution were determined. To tak. into account particle back.mixing in our experiments, a one-dimensional pop- ulation balance model that considers particle residence time was introduced into a fluidized bed-drying model. Experimental particle residence time distributions were reproduced using a tank.in-series model. Subsequently, the moisture content distribution was implemented, as a second dimension to the popu- lation balance in this model. These two-dimensional simulations were able to describe the experimental data, especially the spread in the residual particle moisture distribution, much more accurately than one-dimensional simulations. Using this novel two-dimensional model, the effects of different operating parameters （process gas temperature, solid feed rate, superficial air velocity） on the particle moisture content distribution were systematically studied.

关键词： Continuous dryingHorizontal fluidized bed Residence time distribution Moisture content distributionPopulation balance

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Heterologous Expression of the Mevalonic Acid Pathway in Cyanobacteria Enhances Endogenous Carbon Partitioning to Isoprene

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Molecular Plant 2014年第1期7卷 71-86页

作者： Fiona k. Bentley andreas Zurbriggen Anastasios Melis Department of Plant and Microbial Biology University of California 111 Koshland Hall Berkeley CA 94720-3102 USA

Heterologous expression of the isoprene synthase gene in the cyanobacterium Synechocystis PCC 6803 conferred upon these microorganisms the property of photosynthetic isoprene （C5H8） hYdrocarbons production. Continuous production of isoprene from CO2 and H2O was achieved in the light, occurring via the endogenous methylerythritolphosphate （MEP） pathway, in tandem with the growth of Synechocystis. This work.addressed the issue of photosynthetic carbon partitioning between isoprene and biomass in Synechocystis. Evidence is presented to show heterologous genomic integration and cellular expression of the mevalonic acid （MVA） pathway genes in Synechocystis endowing a non-native pathway for carbon flux amplification to isopentenyl-diphosphate （IPP） and dimethylallyl-diphosphate （DMAPP） precursors of isoprene. Heterologous expression of the isoprene synthase in combination with the MVA pathway enzymes resulted in photosynthetic isoprene yield improvement by approximately 2.5-fold, compared with that measured in cyanobacteria transformed with the isoprene synthase gene only. These results suggest that the MVA pathway introduces a bypass in the flux of endogenous cellular substrate in Synechocystis to IPP and DMAPP, overcoming flux limitations of the native MEP pathway. The work.employed a novel chromosomal integration and expression of synthetic gene operons in Synechocystis, comprising up to four genes under the control of a single promoter, and expressing three operons simultaneously. This is the first time an entire biosynthetic pathway with seven recombinant enzymes has been heterologously expressed in a photosynthetic microorganism. It constitutes contribution to the genetic engineering toolk.t of photosynthetic microorganisms and a paradigm in the pursuit of photosynthetic approaches for the renewable generation of high-impact products.

关键词： biofuels cyanobacteria isoprene isoprene synthase metabolic engineering photosynthesis Synechocystis.

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Plastid Signals and the Bundle Sheath： Mesophyll Development in Reticulate Mutants

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Molecular Plant 2014年第1期7卷 14-29页

作者： Peter k. Lundquist Christian Rosar Andrea Brautigam andreas P.M. Weber Institute for Plant Biochemistry and Cluster of Excellence on Plant Sciences (CEPLAS) Heinrich-Neine-Universitat Universitatsstrasse 1 40225 Dusseldorf Germany Alte StraBe 2 34225 Baunatal Germany

The development of a plant leaf is a meticulously orchestrated sequence of events producing a complex organ comprising diverse cell types. The reticulate class of leaf variegation mutants displays contrasting pigmentation between veins and interveinal regions due to specific aberrations in the development of mesophyll cells. Thus, the reticulate mutants offer a potent tool to investigate cell-type-specific developmental processes. The discovery that most mutants are affected in plastid-localized, metabolic pathways that are strongly expressed in vasculature-associated tis- sues implicates a crucial role for the bundle sheath and their chloroplasts in proper development of the mesophyll cells. Here, we review the reticulate mutants and their phenotypic characteristics, with a focus on those in Arabidopsis thali- ana. Two alternative models have been put forward to explain the relationship between plastid metabolism and meso- phyll cell development, which we call here the supply and the signaling hypotheses. We critically assess these proposed models and discuss their implications for leaf development and bundle sheath function in C3 species. The characteriza- tion of the reticulate mutants supports the significance of plastid retrograde signaling in cell development and highlights the significance of the bundle sheath in C3 photosynthesis.

关键词： reticulate mesophyll bundle sheath development intercellular signaling leaf variegation plastid.

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Silk.based nerve guidance conduits with macroscopic holes modulate the vascularization of regenerating rat sciatic nerve

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Neural Regeneration Research 2025年第6期20卷 1789-1800页

作者： Carina Hromada Patrick.Heimel Mark.s k.rbl LászlóGál Sylvia Nürnberger Barbara Schaedl James Ferguson Nicole Swiadek.Xavier Monforte Johannes C.Heinzel Antal Nógrádi andreas H.Teuschl-Woller David Hercher Department Life Science Engineering University of Applied Sciences Technikum WienViennaAustria Austrian Cluster for Tissue Regeneration ViennaAustria Ludwig Boltzmann Institute for Traumatology The Research Center in Cooperation with AUVAViennaAustria University Clinic of Dentistry Medical University of ViennaViennaAustria Department of Plastic Reconstructive and Aesthetic SurgeryLandesklinikum Wiener Neustadt2700 Wiener NeustadtAustria Department of Anatomy Histology and EmbryologyAlbert Szent-Györgyi Medical SchoolUniversity of SzegedSzegedHungary Medical University of Vienna Department of Orthopedics and Trauma SurgeryDevision of Trauma SurgeryViennaAustria Department of Hand- PlasticReconstructive and Burn SurgeryBG Unfallklinik TuebingenUniversity of TuebingenTuebingenGermany

Peripheral nerve injuries induce a severe motor and sensory deficit. Since the availability of autologous nerve transplants for nerve repair is very limited, alternative treatment strategies are sought, including the use of tubular nerve guidance conduits(tNGCs). However, the use of tNGCs results in poor functional recovery and central necrosis of the regenerating tissue, which limits their application to short nerve lesion defects(typically shorter than 3 cm). Given the importance of vascularization in nerve regeneration, we hypothesized that enabling the growth of blood vessels from the surrounding tissue into the regenerating nerve within the tNGC would help eliminate necrotic processes and lead to improved regeneration. In this study, we reported the application of macroscopic holes into the tubular walls of silk.based tNGCs and compared the various features of these improved silk.(+) tNGCs with the tubes without holes(silk.(–) tNGCs) and autologous nerve transplants in an 8-mm sciatic nerve defect in rats. Using a combination of micro-computed tomography and histological analyses, we were able to prove that the use of silk.(+) tNGCs induced the growth of blood vessels from the adjacent tissue to the intraluminal neovascular formation. A significantly higher number of blood vessels in the silk.(+) group was found compared with autologous nerve transplants and silk.(–), accompanied by improved axon regeneration at the distal coaptation point compared with the silk.(–) tNGCs at 7 week. postoperatively. In the 15-mm(critical size) sciatic nerve defect model, we again observed a distinct ingrowth of blood vessels through the tubular walls of silk.(+) tNGCs, but without improved functional recovery at 12 week. postoperatively. Our data proves that macroporous tNGCs increase the vascular supply of regenerating nerves and facilitate improved axonal regeneration in a short-defect model but not in a critical-size defect model. This study suggests that further optimizatio

关键词： axon regeneration blood vessel functional recovery macroporous nerve lesion peripheral nerve repair sciatic nerve silk.based nerve guidance conduit vascularization

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Multimodal Brain-Computer Interfaces

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Tsinghua Science and Technology 2011年第2期16卷 133-139页

作者： Alexander Maye Dan ZHANG Yijun WANG Shangk.i GAO andreas k. Engel Department of Neurophysiology and Pathophysiology University Medical Center Hamburg Eppendorf Martinistr. 52 20246 Hamburg Germany Department of Biomedical Engineering Tsinghua University Beijing 100084 China Swartz Center for Computational Neuroscience University of California San Diego CA 92093-0559 USA

A critical parameter of brain-computer interfaces （BCIs） is the number of dimensions a user can control independently. One way to increment this number without increasing the mental effort required to operate the system is to stimulate several sensory modalities simultaneously, and to distinguish brain activity patterns when the user focuses attention to different elements of this multisensory input. In this article we show how shifting attention between simultaneously presented tactile and visual stimuli affects the electrical brain activity of human subjects, and that this signal can be used to augment the control information from the two uni-modal BCI subsystems.

关键词： steady-state evok.d potentials SSVEP SSSEP attention EEG support vector machine

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