TY  - JOUR
A1  - Boltze, Johannes
A1  - Kleinschnitz, Christoph
A1  - Reymann, Klaus G.
A1  - Reiser, Georg
A1  - Wagner, Daniel-Christoph
A1  - Kranz, Alexander
A1  - Michalski, Dominik
T1  - Neurovascular pathophysiology in cerebral ischemia, dementia and the ageing brain – current trends in basic, translational and clinical research
JF  - Experimental & Translational Stroke Medicine
N2  - The 7th International Symposium on Neuroprotection and Neurorepair was held from May 2nd to May 5th, 2012 in Potsdam, Germany. The symposium, which directly continues the successful Magdeburg meeting series, attracted over 330 colleagues from 29 countries to discuss recent findings and advances in the field. The focus of the 2012 symposium was widened from stroke and traumatic brain injury to neurodegenerative diseases, notably dementia, and more generally the ageing brain. Thereby, emphasis was given on neurovascular aspects of neurodegeneration and stroke including the blood–brain barrier, recent findings regarding the pathomechanism of Alzheimer’s disease, and brain imaging approaches. In addition, neurobiochemical aspects of neuroprotection, the role of astrogliosis, the clinical progress of cell-based approaches as well as translational hurdles and opportunities were discussed in-depth. This review summarizes some of the most stimulating discussions and reports from the meeting.
KW  - translational research
KW  - small vessel disease
KW  - Alzheimer’s disease
KW  - cerebral ischemia
KW  - neurorepair
KW  - neuroprotection
KW  - vascular dementia
KW  - mitochondria
KW  - astrogliosis
KW  - in vivo imaging
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126679
VL  - 4
IS  - 14
ER  - 
TY  - JOUR
A1  - Gruschwitz, Philipp
A1  - Hartung, Viktor
A1  - Kleefeldt, Florian
A1  - Ergün, Süleyman
A1  - Lichthardt, Sven
A1  - Huflage, Henner
A1  - Hendel, Robin
A1  - Kunz, Andreas Steven
A1  - Pannenbecker, Pauline
A1  - Kuhl, Philipp Josef
A1  - Augustin, Anne Marie
A1  - Bley, Thorsten Alexander
A1  - Petritsch, Bernhard
A1  - Grunz, Jan-Peter
T1  - Standardized assessment of vascular reconstruction kernels in photon-counting CT angiographies of the leg using a continuous extracorporeal perfusion model
JF  - Scientific Reports
N2  - This study evaluated the influence of different vascular reconstruction kernels on the image quality of CT angiographies of the lower extremity runoff using a 1st-generation photon-counting-detector CT (PCD-CT) compared with dose-matched examinations on a 3rd-generation energy-integrating-detector CT (EID-CT). Inducing continuous extracorporeal perfusion in a human cadaveric model, we performed CT angiographies of eight upper leg arterial runoffs with radiation dose-equivalent 120 kVp acquisition protocols (CTDIvol 5 mGy). Reconstructions were executed with different vascular kernels, matching the individual modulation transfer functions between scanners. Signal-to-noise-ratios (SNR) and contrast-to-noise-ratios (CNR) were computed to assess objective image quality. Six radiologists evaluated image quality subjectively using a forced-choice pairwise comparison tool. Interrater agreement was determined by calculating Kendall’s concordance coefficient (W). The intraluminal attenuation of PCD-CT images was significantly higher than of EID-CT (414.7 ± 27.3 HU vs. 329.3 ± 24.5 HU; p < 0.001). Using comparable kernels, image noise with PCD-CT was significantly lower than with EID-CT (p ≤ 0.044). Correspondingly, SNR and CNR were approximately twofold higher for PCD-CT (p < 0.001). Increasing the spatial frequency for PCD-CT reconstructions by one level resulted in similar metrics compared to EID-CT (CNRfat; EID-CT Bv49: 21.7 ± 3.7 versus PCD-CT Bv60: 21.4 ± 3.5). Overall image quality of PCD-CTA achieved ratings superior to EID-CTA irrespective of the used reconstruction kernels (best: PCD-CT Bv60; worst: EID-CT Bv40; p < 0.001). Interrater agreement was good (W = 0.78). Concluding, PCD-CT offers superior intraluminal attenuation, SNR, and CNR compared to EID-CT in angiographies of the upper leg arterial runoff. Combined with improved subjective image quality, PCD-CT facilitates the use of sharper convolution kernels and ultimately bears the potential of improved vascular structure assessability.
KW  - experimental models of disease
KW  - preclinical research
KW  - translational research
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357912
VL  - 13
ER  - 
TY  - JOUR
A1  - Kress, Sebastian
A1  - Baur, Johannes
A1  - Otto, Christoph
A1  - Burkard, Natalie
A1  - Braspenning, Joris
A1  - Walles, Heike
A1  - Nickel, Joachim
A1  - Metzger, Marco
T1  - Evaluation of a miniaturized biologically vascularized scaffold in vitro and in vivo
JF  - Scientific Reports
N2  - In tissue engineering, the generation and functional maintenance of dense voluminous tissues is mainly restricted due to insufficient nutrient supply. Larger three-dimensional constructs, which exceed the nutrient diffusion limit become necrotic and/or apoptotic in long-term culture if not provided with an appropriate vascularization. Here, we established protocols for the generation of a pre-vascularized biological scaffold with intact arterio-venous capillary loops from rat intestine, which is decellularized under preservation of the feeding and draining vascular tree. Vessel integrity was proven by marker expression, media/blood reflow and endothelial LDL uptake. In vitro maintenance persisted up to 7 weeks in a bioreactor system allowing a stepwise reconstruction of fully vascularized human tissues and successful in vivo implantation for up to 4 weeks, although with time-dependent decrease of cell viability. The vascularization of the construct lead to a 1.5× increase in cellular drug release compared to a conventional static culture in vitro. For the first time, we performed proof-of-concept studies demonstrating that 3D tissues can be maintained within a miniaturized vascularized scaffold in vitro and successfully implanted after re-anastomosis to the intrinsic blood circulation in vivo. We hypothesize that this technology could serve as a powerful platform technology in tissue engineering and regenerative medicine.
KW  - biological models
KW  - translational research
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176343
VL  - 8
IS  - 4719
ER  - 
TY  - JOUR
A1  - Munawar, Umair
A1  - Zhou, Xiang
A1  - Prommersberger, Sabrina
A1  - Nerreter, Silvia
A1  - Vogt, Cornelia
A1  - Steinhardt, Maximilian J.
A1  - Truger, Marietta
A1  - Mersi, Julia
A1  - Teufel, Eva
A1  - Han, Seungbin
A1  - Haertle, Larissa
A1  - Banholzer, Nicole
A1  - Eiring, Patrick
A1  - Danhof, Sophia
A1  - Navarro-Aguadero, Miguel Angel
A1  - Fernandez-Martin, Adrian
A1  - Ortiz-Ruiz, Alejandra
A1  - Barrio, Santiago
A1  - Gallardo, Miguel
A1  - Valeri, Antonio
A1  - Castellano, Eva
A1  - Raab, Peter
A1  - Rudert, Maximilian
A1  - Haferlach, Claudia
A1  - Sauer, Markus
A1  - Hudecek, Michael
A1  - Martinez-Lopez, J.
A1  - Waldschmidt, Johannes
A1  - Einsele, Hermann
A1  - Rasche, Leo
A1  - Kortüm, K. Martin
T1  - Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma
JF  - Communications Biology
N2  - The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.
KW  - immunotherapy
KW  - translational research
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357609
VL  - 6
ER  - 
TY  - JOUR
A1  - Schreiber, Laura M.
A1  - Lohr, David
A1  - Baltes, Steffen
A1  - Vogel, Ulrich
A1  - Elabyad, Ibrahim A.
A1  - Bille, Maya
A1  - Reiter, Theresa
A1  - Kosmala, Aleksander
A1  - Gassenmaier, Tobias
A1  - Stefanescu, Maria R.
A1  - Kollmann, Alena
A1  - Aures, Julia
A1  - Schnitter, Florian
A1  - Pali, Mihaela
A1  - Ueda, Yuichiro
A1  - Williams, Tatiana
A1  - Christa, Martin
A1  - Hofmann, Ulrich
A1  - Bauer, Wolfgang
A1  - Gerull, Brenda
A1  - Zernecke, Alma
A1  - Ergün, Süleyman
A1  - Terekhov, Maxim
T1  - Ultra-high field cardiac MRI in large animals and humans for translational cardiovascular research
JF  - Frontiers in Cardiovascular Medicine
N2  - A key step in translational cardiovascular research is the use of large animal models to better understand normal and abnormal physiology, to test drugs or interventions, or to perform studies which would be considered unethical in human subjects. Ultrahigh field magnetic resonance imaging (UHF-MRI) at 7 T field strength is becoming increasingly available for imaging of the heart and, when compared to clinically established field strengths, promises better image quality and image information content, more precise functional analysis, potentially new image contrasts, and as all in-vivo imaging techniques, a reduction of the number of animals per study because of the possibility to scan every animal repeatedly. We present here a solution to the dual use problem of whole-body UHF-MRI systems, which are typically installed in clinical environments, to both UHF-MRI in large animals and humans. Moreover, we provide evidence that in such a research infrastructure UHF-MRI, and ideally combined with a standard small-bore UHF-MRI system, can contribute to a variety of spatial scales in translational cardiovascular research: from cardiac organoids, Zebra fish and rodent hearts to large animal models such as pigs and humans. We present pilot data from serial CINE, late gadolinium enhancement, and susceptibility weighted UHF-MRI in a myocardial infarction model over eight weeks. In 14 pigs which were delivered from a breeding facility in a national SARS-CoV-2 hotspot, we found no infection in the incoming pigs. Human scanning using CINE and phase contrast flow measurements provided good image quality of the left and right ventricle. Agreement of functional analysis between CINE and phase contrast MRI was excellent. MRI in arrested hearts or excised vascular tissue for MRI-based histologic imaging, structural imaging of myofiber and vascular smooth muscle cell architecture using high-resolution diffusion tensor imaging, and UHF-MRI for monitoring free radicals as a surrogate for MRI of reactive oxygen species in studies of oxidative stress are demonstrated. We conclude that UHF-MRI has the potential to become an important precision imaging modality in translational cardiovascular research.
KW  - ultrahigh-field MRI
KW  - large animal models
KW  - translational research
KW  - research infrastructure
KW  - heart
KW  - organoid
KW  - pig
KW  - cardiovascular MRI
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-317398
SN  - 2297-055X
VL  - 10
ER  - 
TY  - JOUR
A1  - Wu, Hao
A1  - Zhao, Xiufeng
A1  - Hochrein, Sophia M.
A1  - Eckstein, Miriam
A1  - Gubert, Gabriela F.
A1  - Knöpper, Konrad
A1  - Mansilla, Ana Maria
A1  - Öner, Arman
A1  - Doucet-Ladevèze, Remi
A1  - Schmitz, Werner
A1  - Ghesquière, Bart
A1  - Theurich, Sebastian
A1  - Dudek, Jan
A1  - Gasteiger, Georg
A1  - Zernecke, Alma
A1  - Kobold, Sebastian
A1  - Kastenmüller, Wolfgang
A1  - Vaeth, Martin
T1  - Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming
JF  - Nature Communications
N2  - T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.
KW  - cytotoxic T cells
KW  - infection
KW  - lymphocyte differentiation
KW  - translational research
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358052
VL  - 14
ER  -