TY - JOUR A1 - Pillai, Deepu R. A1 - Heidemann, Robin M. A1 - Kumar, Praveen A1 - Shanbhag, Nagesh A1 - Lanz, Titus A1 - Dittmar, Michael S. A1 - Sandner, Beatrice A1 - Beier, Christoph P. A1 - Weidner, Norbert A1 - Greenlee, Mark W. A1 - Schuierer, Gerhard A1 - Bogdahn, Ulrich A1 - Schlachetzki, Felix T1 - Comprehensive Small Animal Imaging Strategies on a Clinical 3 T Dedicated Head MR-Scanner; Adapted Methods and Sequence Protocols in CNS Pathologies JF - PLoS ONE N2 - Background: Small animal models of human diseases are an indispensable aspect of pre-clinical research. Being dynamic, most pathologies demand extensive longitudinal monitoring to understand disease mechanisms, drug efficacy and side effects. These considerations often demand the concomitant development of monitoring systems with sufficient temporal and spatial resolution. Methodology and Results: This study attempts to configure and optimize a clinical 3 Tesla magnetic resonance scanner to facilitate imaging of small animal central nervous system pathologies. The hardware of the scanner was complemented by a custom-built, 4-channel phased array coil system. Extensive modification of standard sequence protocols was carried out based on tissue relaxometric calculations. Proton density differences between the gray and white matter of the rodent spinal cord along with transverse relaxation due to magnetic susceptibility differences at the cortex and striatum of both rats and mice demonstrated statistically significant differences. The employed parallel imaging reconstruction algorithms had distinct properties dependent on the sequence type and in the presence of the contrast agent. The attempt to morphologically phenotype a normal healthy rat brain in multiple planes delineated a number of anatomical regions, and all the clinically relevant sequels following acute cerebral ischemia could be adequately characterized. Changes in blood-brain-barrier permeability following ischemia-reperfusion were also apparent at a later time. Typical characteristics of intracerebral haemorrhage at acute and chronic stages were also visualized up to one month. Two models of rodent spinal cord injury were adequately characterized and closely mimicked the results of histological studies. In the employed rodent animal handling system a mouse model of glioblastoma was also studied with unequivocal results. Conclusions: The implemented customizations including extensive sequence protocol modifications resulted in images of high diagnostic quality. These results prove that lack of dedicated animal scanners shouldn't discourage conventional small animal imaging studies. KW - Rat spinal-cord KW - Middle cerebral-artery KW - Blood-brain-barrier KW - Experimental intracerebral hemorrhage KW - Partially parallel acquisitions KW - Magnetic-resonance microscopy KW - IN-VIVO KW - Mouse-brain KW - Edema formation KW - White-matter Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134193 VL - 6 IS - 2 ER - TY - JOUR A1 - von Bueren, André O. A1 - Oehler, Christoph A1 - Shalaby, Tarek A1 - von Hoff, Katja A1 - Pruschy, Martin A1 - Seifert, Burkhardt A1 - Gerber, Nicolas U. A1 - Warmuth-Metz, Monika A1 - Stearns, Duncan A1 - Eberhart, Charles G. A1 - Kortmann, Rolf D. A1 - Rutkowski, Stefan A1 - Grotzer, Michael A. T1 - c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients JF - BMC Cancer N2 - Background: To study whether and how c-MYC expression determines response to radio-and chemotherapy in childhood medulloblastoma (MB). Methods: We used DAOY and UW228 human MB cells engineered to stably express different levels of c-MYC, and tested whether c-MYC expression has an effect on radio-and chemosensitivity using the colorimetric 3-(4,5-dimethylthiazol- 2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay, clonogenic survival, apoptosis assays, cell cycle analysis, and western blot assessment. In an effort to validate our results, we analyzed c-MYC mRNA expression in formalin-fixed paraffin-embedded tumor samples from well-documented patients with postoperative residual tumor and compared c-MYC mRNA expression with response to radio-and chemotherapy as examined by neuroradiological imaging. Results: In DAOY -and to a lesser extent in UW228 -cells expressing high levels of c-MYC, the cytotoxicity of cisplatin, and etoposide was significantly higher when compared with DAOY/UW228 cells expressing low levels of c-MYC. Irradiation-and chemotherapy-induced apoptotic cell death was enhanced in DAOY cells expressing high levels of c-MYC. The response of 62 of 66 residual tumors was evaluable and response to postoperative radio-(14 responders (CR, PR) vs. 5 non-responders (SD, PD)) or chemotherapy (23 CR/PR vs. 20 SD/PD) was assessed. c-MYC mRNA expression was similar in primary MB samples of responders and non-responders (Mann-Whitney U test, p = 0.50, ratio 0.49, 95% CI 0.008-30.0 and p = 0.67, ratio 1.8, 95% CI 0.14-23.5, respectively). Conclusions: c-MYC sensitizes MB cells to some anti-cancer treatments in vitro. As we failed to show evidence for such an effect on postoperative residual tumors when analyzed by imaging, additional investigations in xenografts and larger MB cohorts may help to define the exact function of c-MYC in modulating response to treatment. KW - Induced apoptosis KW - Down-regulation KW - Childhood medulloblastoma KW - Melanoma-cells KW - Cisplatin KW - Lines KW - Gene KW - Radiotherapy KW - Fibroblasts KW - Activation Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134185 VL - 11 IS - 74 ER - TY - JOUR A1 - Endesfelder, Ulrike A1 - Malkusch, Sebastian A1 - Flottmann, Benjamin A1 - Mondry, Justine A1 - Liguzinski, Piotr A1 - Verveer, Peter J. A1 - Heilemann, Mike T1 - Chemically Induced Photoswitching of Fluorescent Probes - A General Concept for Super-Resolution Microscopy JF - Molecules N2 - We review fluorescent probes that can be photoswitched or photoactivated and are suited for single-molecule localization based super-resolution microscopy. We exploit the underlying photochemical mechanisms that allow photoswitching of many synthetic organic fluorophores in the presence of reducing agents, and study the impact of these on the photoswitching properties of various photoactivatable or photoconvertible fluorescent proteins. We have identified mEos2 as a fluorescent protein that exhibits reversible photoswitching under various imaging buffer conditions and present strategies to characterize reversible photoswitching. Finally, we discuss opportunities to combine fluorescent proteins with organic fluorophores for dual-color photoswitching microscopy. KW - Photoactivated localization microscopy KW - Fusion proteins KW - Molecules KW - Patterns KW - Switch KW - Limit KW - Time KW - photoswitchable organic fluorophores KW - fluorescent proteins KW - super-resolution KW - PALM KW - dSTORM Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134080 VL - 16 IS - 4 ER - TY - JOUR A1 - Ondrusch, Nicolai A1 - Kreft, Jürgen T1 - Blue and Red Light Modulates SigB-Dependent Gene Transcription, Swimming Motility and Invasiveness in \(Listeria\) \(monocytogenes\) JF - PLoS ONE N2 - Background: In a number of gram-positive bacteria, including Listeria, the general stress response is regulated by the alternative sigma factor B (SigB). Common stressors which lead to the activation of SigB and the SigB-dependent regulon are high osmolarity, acid and several more. Recently is has been shown that also blue and red light activates SigB in Bacillus subtilis. Methodology/Principal Findings: By qRT-PCR we analyzed the transcriptional response of the pathogen L. monocytogenes to blue and red light in wild type bacteria and in isogenic deletion mutants for the putative blue-light receptor Lmo0799 and the stress sigma factor SigB. It was found that both blue (455 nm) and red (625 nm) light induced the transcription of sigB and SigB-dependent genes, this induction was completely abolished in the SigB mutant. The blue-light effect was largely dependent on Lmo0799, proving that this protein is a genuine blue-light receptor. The deletion of lmo0799 enhanced the red-light effect, the underlying mechanism as well as that of SigB activation by red light remains unknown. Blue light led to an increased transcription of the internalin A/B genes and of bacterial invasiveness for Caco-2 enterocytes. Exposure to blue light also strongly inhibited swimming motility of the bacteria in a Lmo0799- and SigB-dependent manner, red light had no effect there. Conclusions/Significance: Our data established that visible, in particular blue light is an important environmental signal with an impact on gene expression and physiology of the non-phototrophic bacterium L. monocytogenes. In natural environments these effects will result in sometimes random but potentially also cyclic fluctuations of gene activity, depending on the light conditions prevailing in the respective habitat. KW - Gram-positive bacteria KW - Sigma(B)-dependent stress-response KW - Non-phototrophic bacteria KW - Prfa-mediated virulence KW - NTP-binding-properties KW - Bacillus-subtilis KW - Receptor ytva KW - Lov domain KW - Factor sigma(B) Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134050 VL - 6 IS - 1 ER - TY - JOUR A1 - Gerlach, Manfred A1 - Maetzler, Walter A1 - Broich, Karl A1 - Hampel, Harald A1 - Rems, Lucas A1 - Reum, Torsten A1 - Riederer, Peter A1 - Stöffler, Albrecht A1 - Streffer, Johannes A1 - Berg, Daniela T1 - Biomarker candidates of neurodegeneration in Parkinson’s disease for the evaluation of disease-modifying therapeutics JF - Journal of Neural Transmission N2 - Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson’s disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies. KW - Parkinson’s disease KW - Disease-modifying therapies KW - Neuroprotection KW - Biomarkers KW - Surrogate endpoints KW - Drug development KW - Disease progression Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133856 VL - 119 IS - 1 ER - TY - JOUR A1 - Eberlein, Uta A1 - Bröer, Jörn Hendrik A1 - Vandevoorde, Charlot A1 - Santos, Paula A1 - Bardiès, Manuel A1 - Bacher, Klaus A1 - Nosske, Dietmar A1 - Lassmann, Michael T1 - Biokinetics and dosimetry of commonly used radiopharmaceuticals in diagnostic nuclear medicine – a review JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - Purpose The impact on patients’ health of radiopharmaceuticals in nuclear medicine diagnostics has not until now been evaluated systematically in a European context. Therefore, as part of the EU-funded Project PEDDOSE.NET (www.​peddose.​net), we review and summarize the current knowledge on biokinetics and dosimetry of commonly used diagnostic radiopharmaceuticals. Methods A detailed literature search on published biokinetic and dosimetric data was performed mostly via PubMed (www.​ncbi.​nlm.​nih.​gov/​pubmed). In principle the criteria for inclusion of data followed the EANM Dosimetry Committee guidance document on good clinical reporting. Results Data on dosimetry and biokinetics can be difficult to find, are scattered in various journals and, especially in paediatric nuclear medicine, are very scarce. The data collection and calculation methods vary with respect to the time-points, bladder voiding, dose assessment after the last data point and the way the effective dose was calculated. In many studies the number of subjects included for obtaining biokinetic and dosimetry data was fewer than ten, and some of the biokinetic data were acquired more than 20 years ago. Conclusion It would be of interest to generate new data on biokinetics and dosimetry in diagnostic nuclear medicine using state-of-the-art equipment and more uniform dosimetry protocols. For easier public access to dosimetry data for diagnostic radiopharmaceuticals, a database containing these data should be created and maintained. KW - Dosimetry KW - Biokinetics KW - Diagnostic radiopharmaceuticals KW - Effective dose Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133846 VL - 38 IS - 12 ER - TY - JOUR A1 - Schmitt, Jana A1 - Keller, Andreas A1 - Nourkami-Tutdibi, Nasenien A1 - Heisel, Sabrina A1 - Habel, Nunja A1 - Leidinger, Petra A1 - Ludwig, Nicole A1 - Gessler, Manfred A1 - Graf, Norbert A1 - Berthold, Frank A1 - Lenhof, Hans-Peter A1 - Meese, Eckart T1 - Autoantibody Signature Differentiates Wilms Tumor Patients from Neuroblastoma Patients JF - PLoS ONE N2 - Several studies report autoantibody signatures in cancer. The majority of these studies analyzed adult tumors and compared the seroreactivity pattern of tumor patients with the pattern in healthy controls. Here, we compared the autoimmune response in patients with neuroblastoma and patients with Wilms tumor representing two different childhood tumors. We were able to differentiate untreated neuroblastoma patients from untreated Wilms tumor patients with an accuracy of 86.8%, a sensitivity of 87.0% and a specificity of 86.7%. The separation of treated neuroblastoma patients from treated Wilms tumor patients' yielded comparable results with an accuracy of 83.8%. We furthermore identified the antigens that contribute most to the differentiation between both tumor types. The analysis of these antigens revealed that neuroblastoma was considerably more immunogenic than Wilms tumor. The reported antigens have not been found to be relevant for comparative analyses between other tumors and controls. In summary, neuroblastoma appears as a highly immunogenic tumor as demonstrated by the extended number of antigens that separate this tumor from Wilms tumor. KW - Heparan-sulfate KW - N-Myc KW - Serum autoantibodies KW - Suppressors EXT1 KW - Neuro-blastoma KW - Allelic loss KW - Lung-cancer KW - Children KW - Amplification KW - Therapy Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133794 VL - 6 IS - 12 ER - TY - JOUR A1 - Reinards, THCM A1 - Albers, HM A1 - Brinkman, DMC A1 - Kamphuis, SSM A1 - van Rossum, MAJ A1 - Hoppenreijs, EPAH A1 - Girschick, HJ A1 - Wouters, C A1 - Saurenmann, RK A1 - Houwing-Duistermaat, JJ A1 - Toes, REM A1 - Huizinga, TWJ A1 - ten Cate, R A1 - Schilham, MW T1 - Association of the CD226 (DNAM-1) Gly307Ser polymorphism with juvenile idiopathic arthritis JF - Pediatric Rheumatology N2 - No abstract available. KW - Pädiatrie KW - Rheumatologie Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133773 VL - 9 IS - Suppl. 1 ER - TY - JOUR A1 - Reinards, THCM A1 - Albers, HM A1 - Brinkman, DMC A1 - Kamphuis, SSM A1 - van Rossum, MAJ A1 - Hoppenreijs, EPAH A1 - Girschick, HJ A1 - Wouters, C A1 - Saurenmann, RK A1 - Houwing-Duistermaat, JJ A1 - Toes, REM A1 - Huizinga, TWJ A1 - ten Cate, R A1 - Schilham, MW T1 - Association of the CCR5Δ32 variant with juvenile idiopathic arthritis in a meta-analysis JF - Pediatric Rheumatology N2 - No abstract available. KW - Pädiatrie KW - Rheumatologie Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133763 VL - 9 IS - Suppl. 1 ER - TY - JOUR A1 - Carsten A., Böger A1 - Gorski, Mathias A1 - Li, Man A1 - Hoffmann, Michael M. A1 - Huang, Chunmei A1 - Yang, Qiong A1 - Teumer, Alexander A1 - Krane, Vera A1 - O'Seaghdha, Conall M. A1 - Kutalik, Zoltán A1 - Wichmann, H.-Erich A1 - Haak, Thomas A1 - Boes, Eva A1 - Coassin, Stefan A1 - Coresh, Josef A1 - Kollerits, Barbara A1 - Haun, Margot A1 - Paulweber, Bernhard A1 - Köttgen, Anna A1 - Li, Guo A1 - Shlipak, Michael G. A1 - Powe, Neil A1 - Hwang, Shih-Jen A1 - Dehghan, Abbas A1 - Rivadeneira, Fernando A1 - Uitterlinden, André A1 - Hofman, Albert A1 - Beckmann, Jacques S. A1 - Krämer, Bernhard K. A1 - Witteman, Jacqueline A1 - Bochud, Murielle A1 - Siscovick, David A1 - Rettig, Rainer A1 - Kronenberg, Florian A1 - Wanner, Christoph A1 - Thadhani, Ravi I. A1 - Heid, Iris M. A1 - Fox, Caroline S. A1 - Kao, W.H. T1 - Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD JF - PLoS Genetics N2 - Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression. KW - Chronic Kidney-disease KW - Stage renal-disease KW - Glomerular-filtration-rate KW - Diabetic-nephropathy KW - General-population KW - African-americans KW - Risk KW - Progression KW - Mortality KW - Variants Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133758 VL - 7 IS - 9 ER -