@article{GoeringSchumannMuelleretal.2022,
  author    = {G{\"o}ring, Lukas and Schumann, Sarah and M{\"u}ller, Jessica and Buck, Andreas K. and Port, Matthias and Lassmann, Michael and Scherthan, Harry and Eberlein, Uta},
  title     = {Repair of a-particle-induced DNA damage in peripheral blood mononuclear cells after internal ex vivo irradiation with \(^{223}\)Ra},
  series = {European Journal of Nuclear Medicine and Molecular Imaging},
  volume    = {49},
  journal   = {European Journal of Nuclear Medicine and Molecular Imaging},
  number    = {12},
  doi       = {10.1007/s00259-022-05860-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324557},
  pages     = {3981-3988},
  year      = {2022},
  abstract  = {Purpose As α-emitters for radiopharmaceutical therapies are administered systemically by intravenous injection, blood will be irradiated by α-particles that induce clustered DNA double-strand breaks (DSBs). Here, we investigated the induction and repair of DSB damage in peripheral blood mononuclear cells (PBMCs) as a function of the absorbed dose to the blood following internal ex vivo irradiation with [\(^{223}\)Ra]RaCl2. Methods Blood samples of ten volunteers were irradiated by adding [\(^{223}\)Ra]RaCl2 solution with different activity concentrations resulting in absorbed doses to the blood of 3 mGy, 25 mGy, 50 mGy and 100 mGy. PBMCs were isolated, divided in three parts and either fixed directly (d-samples) or after 4 h or 24 h culture. After immunostaining, the induced γ-H2AX α-tracks were counted. The time-dependent decrease in α-track frequency was described with a model assuming a repair rate R and a fraction of non-repairable damage Q. Results For 25 mGy, 50 mGy and 100 mGy, the numbers of α-tracks were significantly increased compared to baseline at all time points. Compared to the corresponding d-samples, the α-track frequency decreased significantly after 4 h and after 24 h. The repair rates R were (0.24 ± 0.05) h-1 for 25 mGy, (0.16 ± 0.04) h-1 for 50 mGy and (0.13 ± 0.02) h-1 for 100 mGy, suggesting faster repair at lower absorbed doses, while Q-values were similar. Conclusion The results obtained suggest that induction and repair of the DSB damage depend on the absorbed dose to the blood. Repair rates were similar to what has been observed for irradiation with low linear energy transfer.},
  language  = {en}
}
@article{MuellerMuellerRiederer2021,
  author    = {M{\"u}ller, Thomas and Mueller, Bernhard Klaus and Riederer, Peter},
  title     = {Perspective: Treatment for disease modification in chronic neurodegeneration},
  series = {Cells},
  volume    = {10},
  journal   = {Cells},
  number    = {4},
  issn      = {2073-4409},
  doi       = {10.3390/cells10040873},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236644},
  year      = {2021},
  abstract  = {Symptomatic treatments are available for Parkinson's disease and Alzheimer's disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms for disease modification with antibodies against pathological protein enrichment, such as α-synuclein, amyloid or tau, based on post mortem findings. Instead a more uniform regenerative and reparative therapeutic approach for chronic neurodegenerative disease entities is proposed with stimulation of an endogenously existing repair system, which acts independent of specific disease mechanisms. The repulsive guidance molecule A pathway is involved in the regulation of peripheral and central neuronal restoration. Therapeutic antagonism of repulsive guidance molecule A reverses neurodegeneration according to experimental outcomes in numerous disease models in rodents and monkeys. Antibodies against repulsive guidance molecule A exist. First clinical studies in neurological conditions with an acute onset are under way. Future clinical trials with these antibodies should initially focus on well characterized uniform cohorts of patients. The efficiency of repulsive guidance molecule A antagonism and associated stimulation of neurogenesis should be demonstrated with objective assessment tools to counteract dilution of therapeutic effects by subjectivity and heterogeneity of chronic disease entities. Such a research concept will hopefully enhance clinical test strategies and improve the future therapeutic armamentarium for chronic neurodegeneration.},
  language  = {en}
}
@article{BangaloreHeilMehringeretal.2020,
  author    = {Bangalore, Disha M. and Heil, Hannah S. and Mehringer, Christian F. and Hirsch, Lisa and Hemmen, Katharina and Heinze, Katrin G. and Tessmer, Ingrid},
  title     = {Automated AFM analysis of DNA bending reveals initial lesion sensing strategies of DNA glycosylases},
  series = {Scientific Reports},
  volume    = {10},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-020-72102-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231338},
  year      = {2020},
  abstract  = {Base excision repair is the dominant DNA repair pathway of chemical modifications such as deamination, oxidation, or alkylation of DNA bases, which endanger genome integrity due to their high mutagenic potential. Detection and excision of these base lesions is achieved by DNA glycosylases. To investigate the remarkably high efficiency in target site search and recognition by these enzymes, we applied single molecule atomic force microscopy (AFM) imaging to a range of glycosylases with structurally different target lesions. Using a novel, automated, unbiased, high-throughput analysis approach, we were able to resolve subtly different conformational states of these glycosylases during DNA lesion search. Our results lend support to a model of enhanced lesion search efficiency through initial lesion detection based on altered mechanical properties at lesions. Furthermore, its enhanced sensitivity and easy applicability also to other systems recommend our novel analysis tool for investigations of diverse, fundamental biological interactions.},
  language  = {en}
}
@article{WeissenbergerWeissenbergerWagenbrenneretal.2020,
  author    = {Weissenberger, Manuel and Weissenberger, Manuela H. and Wagenbrenner, Mike and Heinz, Tizian and Reboredo, Jenny and Holzapfel, Boris M. and Rudert, Maximilian and Groll, J{\"u}rgen and Evans, Christopher H. and Steinert, Andre F.},
  title     = {Different types of cartilage neotissue fabricated from collagen hydrogels and mesenchymal stromal cells via SOX9, TGFB1 or BMP2 gene transfer},
  series = {PLoS One},
  volume    = {15},
  journal   = {PLoS One},
  number    = {8},
  doi       = {10.1371/journal.pone.0237479},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230494},
  year      = {2020},
  abstract  = {Objective As native cartilage consists of different phenotypical zones, this study aims to fabricate different types of neocartilage constructs from collagen hydrogels and human mesenchymal stromal cells (MSCs) genetically modified to express different chondrogenic factors. Design Human MSCs derived from bone-marrow of osteoarthritis (OA) hips were genetically modified using adenoviral vectors encoding sex-determining region Y-type high-mobility-group-box (SOX)9,transforming growth factor beta (TGFB) 1or bone morphogenetic protein (BMP) 2cDNA, placed in type I collagen hydrogels and maintained in serum-free chondrogenic media for three weeks. Control constructs contained unmodified MSCs or MSCs expressing GFP. The respective constructs were analyzed histologically, immunohistochemically, biochemically, and by qRT-PCR for chondrogenesis and hypertrophy. Results Chondrogenesis in MSCs was consistently and strongly induced in collagen I hydrogels by the transgenesSOX9,TGFB1andBMP2as evidenced by positive staining for proteoglycans, chondroitin-4-sulfate (CS4) and collagen (COL) type II, increased levels of glycosaminoglycan (GAG) synthesis, and expression of mRNAs associated with chondrogenesis. The control groups were entirely non-chondrogenic. The levels of hypertrophy, as judged by expression of alkaline phosphatase (ALP) and COL X on both the protein and mRNA levels revealed different stages of hypertrophy within the chondrogenic groups (BMP2>TGFB1>SOX9). Conclusions Different types of neocartilage with varying levels of hypertrophy could be generated from human MSCs in collagen hydrogels by transfer of genes encoding the chondrogenic factorsSOX9,TGFB1andBMP2. This technology may be harnessed for regeneration of specific zones of native cartilage upon damage.},
  language  = {en}
}
@article{EberleinPeperFernandezetal.2015,
  author    = {Eberlein, Uta and Peper, Michel and Fern{\´a}ndez, Maria and Lassmann, Michael and Scherthan, Harry},
  title     = {Calibration of the \(\gamma\)-H2AX DNA double strand break focus assay for internal radiation exposure of blood lymphocytes},
  series = {PLoS ONE},
  volume    = {10},
  journal   = {PLoS ONE},
  number    = {4},
  doi       = {10.1371/journal.pone.0123174},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148697},
  pages     = {e0123174},
  year      = {2015},
  abstract  = {DNA double strand break (DSB) formation induced by ionizing radiation exposure is indicated by the DSB biomarkers \(\gamma\)-H2AX and 53BP1. Knowledge about DSB foci formation in-vitro after internal irradiation of whole blood samples with radionuclides in solution will help us to gain detailed insights about dose-response relationships in patients after molecular radiotherapy (MRT). Therefore, we studied the induction of radiation-induced co-localizing \(\gamma\)-H2AX and 53BP1 foci as surrogate markers for DSBs in-vitro, and correlated the obtained foci per cell values with the in-vitro absorbed doses to the blood for the two most frequently used radionuclides in MRT (I-131 and Lu-177). This approach led to an in-vitro calibration curve. Overall, 55 blood samples of three healthy volunteers were analyzed. For each experiment several vials containing a mixture of whole blood and radioactive solutions with different concentrations of isotonic NaCl-diluted radionuclides with known activities were prepared. Leukocytes were recovered by density centrifugation after incubation and constant blending for 1 h at 37°C. After ethanol fixation they were subjected to two-color immunofluorescence staining and the average frequencies of the co-localizing \(\gamma\)-H2AX and 53BP1 foci/nucleus were determined using a fluorescence microscope equipped with a red/green double band pass filter. The exact activity was determined in parallel in each blood sample by calibrated germanium detector measurements. The absorbed dose rates to the blood per nuclear disintegrations occurring in 1 ml of blood were calculated for both isotopes by a Monte Carlo simulation. The measured blood doses in our samples ranged from 6 to 95 mGy. A linear relationship was found between the number of DSB-marking foci/nucleus and the absorbed dose to the blood for both radionuclides studied. There were only minor nuclide-specific intra-and inter-subject deviations.},
  language  = {en}
}
@article{KroeberWengerSchwegleretal.2015,
  author    = {Kroeber, Jana and Wenger, Barbara and Schwegler, Manuela and Daniel, Christoph and Schmidt, Manfred and Djuzenova, Cholpon S and Polat, B{\"u}lent and Flentje, Michael and Fietkau, Rainer and Distel, Luitpold V.},
  title     = {Distinct increased outliers among 136 rectal cancer patients assessed by \(\gamma\)H2AX},
  series = {Radiation Oncology},
  volume    = {10},
  journal   = {Radiation Oncology},
  number    = {36},
  doi       = {10.1186/s13014-015-0344-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144085},
  year      = {2015},
  abstract  = {Background: In recent years attention has focused on \(\gamma\)H2AX as a very sensitive double strand break indicator. It has been suggested that \(\gamma\)H2AX might be able to predict individual radiosensitivity. Our aim was to study the induction and repair of DNA double strand breaks labelled by \(\gamma\)H2AX in a large cohort. Methods: In a prospective study lymphocytes of 136 rectal cancer (RC) patients and 59 healthy individuals were ex vivo irradiated (IR) and initial DNA damage was compared to remaining DNA damage after 2 Gy and 24 hours repair time and preexisting DNA damage in unirradiated lymphocytes. Lymphocytes were immunostained with anti-\(\gamma\)H2AX antibodies and microscopic images with an extended depth of field were acquired. \(\gamma\)H2AX foci counting was performed using a semi-automatic image analysis software. Results: Distinct increased values of preexisting and remaining \(\gamma\)H2AX foci in the group of RC patients were found compared to the healthy individuals. Additionally there are clear differences within the groups and there are outliers in about 12\% of the RC patients after ex vivo IR. Conclusions: The \(\gamma\)H2AX assay has the capability to identify a group of outliers which are most probably patients with increased radiosensitivity having the highest risk of suffering radiotherapy-related late sequelae.},
  language  = {en}
}