1-20 von 3154 Publikationen

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      The patient above all else: Introducing JCSM Clinical Reports A legitimate crown princess, daughter of the Journal of Cachexia, Sarcopenia and Muscle 

      Trippel, Tobias Daniel; Ebner, Nicole; Haehling, Stephan von
      Journal of Cachexia, Sarcopenia and Muscle ‐ Clinical Reports 207; 1(1): Art. e00015
      not available
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      Immunological Properties of Murine Parthenogenetic Stem Cell-Derived Cardiomyocytes and Engineered Heart Muscle. 

      Didié, Michael; Galla, Satish; Muppala, Vijayakumar; Dressel, Ralf; Zimmermann, Wolfram-Hubertus
      Frontiers in immunology 2017; 8 p.955-955
      Pluripotent parthenogenetic stem cells (pSCs) can be derived by pharmacological activation of unfertilized oocytes. Homozygosity of the major histocompatibility complex (MHC) in pSCs makes them an attractive cell source for applications in allogeneic tissue repair. This was recently demonstrated for pSC-based tissue-engineered heart repair. A detailed analysis of immunological properties of pSC-derived cardiomyocytes and engineered heart muscle (EHM) thereof is, however, lacking. The aim of this study was to determine baseline and cytokine-inducible MHC class I and MHC class II as well as programmed death ligand-1 (PDL-1) and co-stimulatory protein (CD40, CD80, CD86) expression in pSC-derived cardiomyocytes and pSC-EHM in vitro and in vivo. Cardiomyocytes from an MHC-homologous (H2(d/d)) pSC-line were enriched to ~90% by making use of a recently developed cardiomyocyte-specific genetic selection protocol. MHC class I and MHC class II expression in cardiomyocytes could only be observed after stimulation with interferon gamma (IFN-γ). PDL-1 was markedly upregulated under IFN-γ. CD40, CD80, and CD86 were expressed at low levels and not upregulated by IFN-γ. EHM constructed from H2(d/d) cardiomyocytes expressed similarly low levels of MHC class I, MHC class II, and costimulatory molecules under basal conditions. However, in EHM only MHC class I, but not MHC class II, molecules were upregulated after IFN-γ-stimulation. We next employed a cocultivation system with MHC-matched and MHC-mismatched splenocytes and T-cells to analyze the immune stimulatory properties of EHMs. Despite MHC-mismatched conditions, EHM did not induce splenocyte or T-cell proliferation in vitro. To evaluate the immunogenicity of pSC-derived cardiomyocytes in vivo, we implanted pSC-derived embryoid bodies after elimination of non-cardiomyocytes (cardiac bodies) under the kidney capsules of MHC-matched and -mismatched mice. Spontaneous beating of cardiac bodies could be observed for 28 days in the matched and for 7 days in the mismatched conditions. Teratomas formed after 28 days only in the MHC-matched conditions. Immunohistochemistry revealed single clusters of CD3-positive cells in the border zone of the implant in the mismatched conditions with few CD3-positive cells infiltrating the implant. Taken together, MHC-matched pSC-cardiomyocyte allografts show little immune cell activation, offering an explanation for the observed long-term retention of pSC-EHM allografts in the absence of immunosuppression.
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      Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Show Different but Partially Overlapping Profile Compared to Vascular Dementia 

      Llorens, Franc; Schmitz, Matthias; Knipper, Tobias; Schmidt, Christian; Lange, Peter; Fischer, Andre; Hermann, Peter; Zerr, Inga
      Frontiers in Aging Neuroscience 2017; 9: Art. 289
      Vascular factors increase the risks of developing Alzheimer’s disease (AD) and they contribute to AD pathology. Since amyloid beta (Ab) deposits can be observed in both diseases, there is an overlap which impedes a clear discrimination and difficult clinical diagnosis. In the present study, we compared cerebrospinal fluid (CSF) profiles of neurodegenerative and inflammatory biomarkers in a patient cohort of controls (n = 50), AD (n = 65) and vascular dementia (VaD) (n = 31) cases. Main results were validated in a second cohort composed of AD (n = 26), rapidly progressive AD (rpAD) (n = 15), VaD (n = 21), and cognitively unimpaired patients with vascular encephalopathy (VE) (n = 25) cases. In the study, cohort significant differences were detected in tau, p-tau, and Ab1-42 (Ab42) levels between AD and VaD patients, but not for the neuron-specific enolase (NSE), S100B protein, 14-3-3 and YKL-40. Differential tau, p-tau, and Ab42 levels between AD and VaD were confirmed in the validation cohort, which additionally showed no differences between AD and rpAD, nor between VaD and VE. The evaluation of the biomarker performance in discrimination between AD and VaD patients revealed that the best diagnostic accuracy could be obtained when tau, p-tau, and Ab42 were combined in form of Ab42/p-tau (AUC 0.84–0.90, sensitivity 77–81%, specificity 80–93%) and (tau × p-tau)/Ab42 ratio (AUC 0.83–0.87, sensitivity 73–81%, specificity 78–87%). Altogether, our studies provided neurodegenerative biomarker profiles in two cohorts of AD and VaD patients favoring the combination of CSF biomarker to differentiate between diseases.
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      Lymphadenopathy in Autoimmune Thyroiditis: Paratracheal Lymph Nodes are Indeed Crucial 

      Brosche, S.; Sahlmann, C. O.; Meller, J.; Bouter, C.
      Open Access Journal of Endocrinology 2017; 1(2)
      Cervical lymphadenopathy is common in patients with autoimmune thyroiditis and supposed to be pathognomic for the disease if found in the paratracheal compartment (Robbins level VI). The aim of this prospective study is the extensive characterization of all cervical lymph node compartments in order to determine the significance of sonographic visible cervical lymphnodes in autoimmune thyroiditis. The study comprises 32 consecutive autoimmune thyroiditis patients and 32 controls without any thyroid pathologies. All patients underwent high resolution ultrasound and all visible lymph nodes were evaluated in all cervical levels by size, volume, S/L-ratio, appearance, vascularity and structural changes. In total, 84 lymph nodes in Robbins level VI were detected in the group of patients with autoimmune thyroiditis whereas the control group showed 2 positive lymph nodes. Lymph nodes in Robbins level VI were significantly smaller compared to lymph nodes in other cervical compartments with 54% of lymph nodes <5mm. Robbins level I-IV did not show any significant differences in the number of enlarged lymph nodes. S/L-ratio, vascularity and appearance was comparable in both groups in all cervical levels. In this prospective setting Robbins level VI could be identified as crucial lymph node level specific for autoimmune thyroiditis being pathognomic for the disease.
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      Increased Mitochondrial Mass and Cytosolic Redox Imbalance in Hippocampal Astrocytes of a Mouse Model of Rett Syndrome: Subcellular Changes Revealed by Ratiometric Imaging of JC-1 and roGFP1 Fluorescence 

      Bebensee, Dörthe F.; Can, Karolina; Müller, Michael
      Oxidative Medicine and Cellular Longevity 2017; 2017 p.1-15
      Rett syndrome (RTT) is a neurodevelopmental disorder with mutations in the MECP2 gene. Mostly girls are affected, and an apparently normal development is followed by cognitive impairment, motor dysfunction, epilepsy, and irregular breathing. Various indications suggest mitochondrial dysfunction. In Rett mice, brain ATP levels are reduced, mitochondria are leaking protons, and respiratory complexes are dysregulated. Furthermore, we found in MeCP2-deficient mouse (Mecp2−/y) hippocampus an intensified mitochondrial metabolism and ROS generation. We now used emission ratiometric 2-photon imaging to assess mitochondrial morphology, mass, and membrane potential (ΔΨm) in Mecp2−/y hippocampal astrocytes. Cultured astrocytes were labeled with the ΔΨm marker JC-1, and semiautomated analyses yielded the number of mitochondria per cell, their morphology, and ΔΨm. Mecp2−/y astrocytes contained more mitochondria than wild-type (WT) cells and were more oxidized. Mitochondrial size, ΔΨm, and vulnerability to pharmacological challenge did not differ. The antioxidant Trolox opposed the oxidative burden and decreased the mitochondrial mass, thereby dampening the differences among WT and Mecp2−/y astrocytes; mitochondrial size and ΔΨm were not markedly affected. In conclusion, mitochondrial alterations and redox imbalance in RTT also involve astrocytes. Mitochondria are more numerous in Mecp2−/y than in WT astrocytes. As this genotypic difference is abolished by Trolox, it seems linked to the oxidative stress in RTT.
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      Generation of a KLF15 homozygous knockout human embryonic stem cell line using paired CRISPR/Cas9n, and human cardiomyocytes derivation 

      Noack, Claudia; Haupt, Luis Peter; Zimmermann, Wolfram-Hubertus; Streckfuss-Bömeke, Katrin; Zelarayán, Laura Cecilia
      Stem Cell Research 2017; 23 p.127-131
      Krueppel-like factor 15 (KLF15) is abundantly expressed in liver, kidney, and muscle, including myocardium. In the adult heart KLF15 is important to maintain homeostasis and to repress hypertrophic remodeling. We generated a homozygous hESC KLF15 knockout (KO) line using paired CRISPR/Cas9n. KLF15-KO cells maintained full pluripotency and differentiation potential as well as genomic integrity. We demonstrated that KLF15-KO cells can be differentiated into morphologically normal cardiomyocytes turning them into a valuable tool for studying human KLF15-mediated mechanisms resulting in human cardiac dysfunction.
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      Radiological imaging characteristics of intramammary hematological malignancies: results from a german multicenter study. 

      Wienbeck, Susanne; Meyer, Hans Jonas; Uhlig, Johannes; Herzog, Aimee; Nemat, Sogand; Teifke, Andrea; Heindel, Walter; Schäfer, Fritz; Kinner, Sonja; Surov, Alexey
      Scientific reports 2017-08-07; 7(1): Art. 7435
      To assess radiological procedures and imaging characteristics in patients with intramammary hematological malignancies (IHM). Radiological imaging studies of histopathological proven IHM cases from ten German University affiliated breast imaging centers from 1997-2012 were retrospectively evaluated. Imaging modalities included ultrasound (US), mammography and magnetic resonance imaging (MRI). Two radiologists blinded to the histopathological diagnoses independently assessed all imaging studies. Imaging studies of 101 patients with 204 intramammary lesions were included. Most patients were women (95%) with a median age of 64 years. IHM were classified as Non Hodgkin lymphoma (77.2%), plasmacytoma (11.9%), leukemia (9.9%), and Hodgkin lymphoma (1%). The mean lesion size was 15.8 ± 10.1 mm. Most IHM presented in mammography as lesions with comparable density to the surrounding tissue, and a round or irregular shape with indistinct margins. On US, most lesions were of irregular shape with complex echo pattern and indistinct margins. MRI shows lesions with irregular or spiculated margins and miscellaneous enhancement patterns. Using US or MRI, IHM were more frequently classified as BI-RADS 4 or 5 than using mammography (96.2% and 89.3% versus 75.3%). IHM can present with miscellaneous radiological patterns. Sensitivity for detection of IHM lesions was higher in US and MRI than in mammography.
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      Robotic versus thoracoscopic lung resection: A systematic review and meta-analysis. 

      Emmert, Alexander; Straube, Carmen; Buentzel, Judith; Roever, Christian
      Medicine 2017-09; 96(35): Art. e7633
      BACKGROUND: Robotic video-assisted surgery (RVATS) has been reported to be equally effective to video-assisted surgery (VATS) in lung resection (pneumonectomy, lobectomy, and segmentectomy). Operation time, mortality, drainage duration, and length of hospitalization of patients undergoing either RVATS or VATS are compared in this meta-analysis. METHODS: A systematic research for articles meeting our inclusion criteria was performed using the PubMed database. Articles published from January 2011 to January 2016 were included. We used results of reported mortality, operation time, drainage duration, and hospitalization length for performing this meta-analysis. Mean difference and logarithmic odds ratio were used as summary statistics. RESULTS: Ten studies eligible were included into this analysis (5 studies for operation time, 3 studies for chest in tube days, 4 studies for length of hospitalization, and 6 studies for mortality). We were able to include 3375 subjects for RVATS and 58,683 subjects for VATS. Patients were mainly treated for lung cancer, metastatic foci, and benign lesions. We could not detect any difference between operation time; however, we found 2 trends showing that drainage duration and length of hospitalization are shorter for following RVATS than for following VATS. Mortality also is lower in patients undergoing RVATS. CONCLUSIONS: Therefore, we conclude that RVATS is a suitable minimal-invasive procedure for lung resection and suitable alternative to VATS. RVATS is as time-efficient as VATS and shows a trend to reduced hospital stay and drainage duration. More and better studies are required to provide reliable, unbiased evidence regarding the relative benefits of both methods.
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      Novel Drug Delivery Systems Tailored for Improved Administration of Glucocorticoids. 

      Lühder, Fred; Reichardt, Holger M.
      International journal of molecular sciences 2017-08-24; 18(9)
      Glucocorticoids (GC) are one of the most popular and versatile classes of drugs available to treat chronic inflammation and cancer, but side effects and resistance constrain their use. To overcome these hurdles, which are often related to the uniform tissue distribution of free GC and their short half-life in biological fluids, new delivery vehicles have been developed including PEGylated liposomes, polymeric micelles, polymer-drug conjugates, inorganic scaffolds, and hybrid nanoparticles. While each of these nanoformulations has individual drawbacks, they are often superior to free GC in many aspects including therapeutic efficacy when tested in cell culture or animal models. Successful application of nanomedicines has been demonstrated in various models of neuroinflammatory diseases, cancer, rheumatoid arthritis, and several other disorders. Moreover, investigations using human cells and first clinical trials raise the hope that the new delivery vehicles may have the potential to make GC therapies more tolerable, specific and efficient in the future.
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      The FER rs4957796 TT genotype is associated with unfavorable 90-day survival in Caucasian patients with severe ARDS due to pneumonia. 

      Hinz, José; Büttner, Benedikt; Kriesel, Fabian; Steinau, Maximilian; Frederik Popov, Aron; Ghadimi, Michael; Beissbarth, Tim; Tzvetkov, Mladen; Bergmann, Ingo; Mansur, Ashham
      Scientific reports 2017-08-29; 7(1): Art. 9887
      A recent genome-wide association study showed that a genetic variant within the FER gene is associated with survival in patients with sepsis due to pneumonia. Because severe pneumonia is the main cause of acute respiratory distress syndrome (ARDS), we aimed to investigate the effect of the FER polymorphism rs4957796 on the 90-day survival in patients with ARDS due to pneumonia. An assessment of a prospectively collected cohort of 441 patients with ARDS admitted to three intensive care units at the University Medical Centre identified 274 patients with ARDS due to pneumonia. The 90-day mortality risk was recorded as the primary outcome parameter. Sepsis-related organ failure assessment (SOFA) scores and organ support-free days were used as the secondary variables. FER rs4957796 TT-homozygous patients were compared with C-allele carriers. The survival analysis revealed a higher 90-day mortality risk among T homozygotes than among C-allele carriers (p = 0.0144) exclusively in patients with severe ARDS due to pneumonia. The FER rs4957796 TT genotype remained a significant covariate for the 90-day mortality risk in the multivariate analysis (hazard ratio, 4.62; 95% CI, 1.58-13.50; p = 0.0050). In conclusion, FER rs4957796 might act as a prognostic variable for survival in patients with severe ARDS due to pneumonia.
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      Considering technique of assessment and method for normalizing skeletal muscle mass. 

      Saitoh, Masakazu; Ishida, Junichi; Springer, Jochen
      Journal of cachexia, sarcopenia and muscle
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      The Functioning of a Cortex without Layers. 

      Guy, Julien; Staiger, Jochen F
      Frontiers in neuroanatomy 2017; 11: Art. 54
      A major hallmark of cortical organization is the existence of a variable number of layers, i.e., sheets of neurons stacked on top of each other, in which neurons have certain commonalities. However, even for the neocortex, variable numbers of layers have been described and it is just a convention to distinguish six layers from each other. Whether cortical layers are a structural epiphenomenon caused by developmental dynamics or represent a functionally important modularization of cortical computation is still unknown. Here we present our insights from the reeler mutant mouse, a model for a developmental, "molecular lesion"-induced loss of cortical layering that could serve as ground truth of what an intact layering adds to the cortex in terms of functionality. We could demonstrate that the reeler neocortex shows no inversion of cortical layers but rather a severe disorganization that in the primary somatosensory cortex leads to the complete loss of layers. Nevertheless, the somatosensory system is well organized. When exploring an enriched environment with specific sets of whiskers, activity-dependent gene expression takes place in the corresponding modules. Precise whisker stimuli lead to the functional activation of somatotopically organized barrel columns as visualized by intrinsic signal optical imaging. Similar results were obtained in the reeler visual system. When analyzing pathways that could be responsible for preservation of tactile perception, lemniscal thalamic projections were found to be largely intact, despite the smearing of target neurons across the cortical mantle. However, with optogenetic experiments we found evidence for a mild dispersion of thalamic synapse targeting on layer IV-spiny stellate cells, together with a general weakening in thalamocortical input strength. This weakening of thalamic inputs was compensated by intracortical mechanisms involving increased recurrent excitation and/or reduced feedforward inhibition. In conclusion, a layer loss so far only led to the detection of subtle defects in sensory processing by reeler mice. This argues in favor of a view in which cortical layers are not an essential component for basic perception and cognition. A view also supported by recent studies in birds, which can have remarkable cognitive capacities despite the lack of a neocortex with multiple cortical layers. In conclusion, we suggest that future studies directed toward understanding cortical functions should rather focus on circuits specified by functional cell type composition than mere laminar location.
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      Divergent co-transcriptomes of different host cells infected with Toxoplasma gondii reveal cell type-specific host-parasite interactions. 

      Swierzy, Izabela J.; Händel, Ulrike; Kaever, Alexander; Jarek, Michael; Scharfe, Maren; Schlüter, Dirk; Lüder, Carsten G. K.
      Scientific reports 2017-08-03; 7(1): Art. 7229
      The apicomplexan parasite Toxoplasma gondii infects various cell types in avian and mammalian hosts including humans. Infection of immunocompetent hosts is mostly asymptomatic or benign, but leads to development of largely dormant bradyzoites that persist predominantly within neurons and muscle cells. Here we have analyzed the impact of the host cell type on the co-transcriptomes of host and parasite using high-throughput RNA sequencing. Murine cortical neurons and astrocytes, skeletal muscle cells (SkMCs) and fibroblasts differed by more than 16,200 differentially expressed genes (DEGs) before and after infection with T. gondii. However, only a few hundred of them were regulated by infection and these largely diverged in neurons, SkMCs, astrocytes and fibroblasts indicating host cell type-specific transcriptional responses after infection. The heterogeneous transcriptomes of host cells before and during infection coincided with ~5,400 DEGs in T. gondii residing in different cell types. Finally, we identified gene clusters in both T. gondii and its host, which correlated with the predominant parasite persistence in neurons or SkMCs as compared to astrocytes or fibroblasts. Thus, heterogeneous expression profiles of different host cell types and the parasites' ability to adapting to them may govern the parasite-host cell interaction during toxoplasmosis.
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      Essential Function of the Serine Hydroxymethyl Transferase (SHMT) Gene During Rapid Syncytial Cell Cycles in Drosophila. 

      Winkler, Franziska; Kriebel, Maria; Clever, Michaela; Gröning, Stephanie; Großhans, Jörg
      G3 (Bethesda, Md.) 2017-07-05; 7(7) p.2305-2314
      Many metabolic enzymes are evolutionarily highly conserved and serve a central function in the catabolism and anabolism of cells. The serine hydroxymethyl transferase (SHMT) catalyzing the conversion of serine and glycine and vice versa feeds into tetrahydrofolate (THF)-mediated C1 metabolism. We identified a Drosophila mutation in SHMT (CG3011) in a screen for blastoderm mutants. Embryos from SHMT mutant germline clones specifically arrest the cell cycle in interphase 13 at the time of the midblastula transition (MBT) and prior to cellularization. The phenotype is due to a loss of enzymatic activity as it cannot be rescued by an allele with a point mutation in the catalytic center but by an allele based on the SHMT coding sequence from Escherichia coli The onset of zygotic gene expression and degradation of maternal RNAs in SHMT mutant embryos are largely similar to that in wild-type embryos. The specific timing of the defects in SHMT mutants indicates that at least one of the SHMT-dependent metabolites becomes limiting in interphase 13, if it is not produced by the embryo. Our data suggest that mutant eggs contain maternally-provided and SHMT-dependent metabolites in amounts that suffice for early development until interphase 13.
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      Robotic versus thoracoscopic lung resection: A systematic review and meta-analysis. 

      Emmert, Alexander; Straube, Carmen; Buentzel, Judith; Roever, Christian
      Medicine 2017-09; 96(35): Art. e7633
      BACKGROUND: Robotic video-assisted surgery (RVATS) has been reported to be equally effective to video-assisted surgery (VATS) in lung resection (pneumonectomy, lobectomy, and segmentectomy). Operation time, mortality, drainage duration, and length of hospitalization of patients undergoing either RVATS or VATS are compared in this meta-analysis. METHODS: A systematic research for articles meeting our inclusion criteria was performed using the PubMed database. Articles published from January 2011 to January 2016 were included. We used results of reported mortality, operation time, drainage duration, and hospitalization length for performing this meta-analysis. Mean difference and logarithmic odds ratio were used as summary statistics. RESULTS: Ten studies eligible were included into this analysis (5 studies for operation time, 3 studies for chest in tube days, 4 studies for length of hospitalization, and 6 studies for mortality). We were able to include 3375 subjects for RVATS and 58,683 subjects for VATS. Patients were mainly treated for lung cancer, metastatic foci, and benign lesions. We could not detect any difference between operation time; however, we found 2 trends showing that drainage duration and length of hospitalization are shorter for following RVATS than for following VATS. Mortality also is lower in patients undergoing RVATS. CONCLUSIONS: Therefore, we conclude that RVATS is a suitable minimal-invasive procedure for lung resection and suitable alternative to VATS. RVATS is as time-efficient as VATS and shows a trend to reduced hospital stay and drainage duration. More and better studies are required to provide reliable, unbiased evidence regarding the relative benefits of both methods.
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      Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4- and MYC-dependent manner 

      Mishra, Vivek Kumar; Wegwitz, Florian; Kosinsky, Robyn Laura; Sen, Madhobi; Baumgartner, Roland; Wulff, Tanja; Siveke, Jens T.; Schildhaus, Hans-Ulrich; Najafova, Zeynab; Kari, Vijayalakshmi; et al.
      Kohlhof, HellaHessmann, ElisabethJohnsen, Steven A.
      Nucleic Acids Research 2017; 45(11) p.6334-6349
      Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a particularly dismal prognosis. Histone deacetylases (HDAC) are epigenetic modulators whose activity is frequently deregulated in various cancers including PDAC. In particular, class-I HDACs (HDAC 1, 2, 3 and 8) have been shown to play an important role in PDAC. In this study, we investigated the effects of the class Ispecific HDAC inhibitor (HDACi) 4SC-202 in multiple PDAC cell lines in promoting tumor cell differentiation. We show that 4SC-202 negatively affects TGF signaling and inhibits TGF -induced epithelial-tomesenchymal transition (EMT). Moreover, 4SC-202 markedly induced p21 (CDKN1A) expression and significantly attenuated cell proliferation. Mechanistically, genome-wide studies revealed that 4SC-202- induced genes were enriched for Bromodomaincontaining Protein-4 (BRD4) and MYC occupancy. BRD4, a well-characterized acetyllysine reader, has been shown to play a major role in regulating transcription of selected subsets of genes. Importantly, BRD4 and MYC are essential for the expression of a subgroup of genes induced by class-I HDACi. Taken together, our study uncovers a previously unknown role of BRD4 and MYC in eliciting the HDACimediated induction of a subset of genes and provides molecular insight into the mechanisms of HDACi action in PDAC.
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      Using phase II data for the analysis of phase III studies: An application in rare diseases. 

      Wandel, Simon; Neuenschwander, Beat; Röver, Christian; Friede, Tim
      Clinical trials (London, England) 2017-06; 14(3) p.277-285
      BACKGROUND: Clinical research and drug development in orphan diseases are challenging, since large-scale randomized studies are difficult to conduct. Formally synthesizing the evidence is therefore of great value, yet this is rarely done in the drug-approval process. Phase III designs that make better use of phase II data can facilitate drug development in orphan diseases. METHODS: A Bayesian meta-analytic approach is used to inform the phase III study with phase II data. It is particularly attractive, since uncertainty of between-trial heterogeneity can be dealt with probabilistically, which is critical if the number of studies is small. Furthermore, it allows quantifying and discounting the phase II data through the predictive distribution relevant for phase III. A phase III design is proposed which uses the phase II data and considers approval based on a phase III interim analysis. The design is illustrated with a non-inferiority case study from a Food and Drug Administration approval in herpetic keratitis (an orphan disease). Design operating characteristics are compared to those of a traditional design, which ignores the phase II data. RESULTS: An analysis of the phase II data reveals good but insufficient evidence for non-inferiority, highlighting the need for a phase III study. For the phase III study supported by phase II data, the interim analysis is based on half of the patients. For this design, the meta-analytic interim results are conclusive and would justify approval. In contrast, based on the phase III data only, interim results are inconclusive and require further evidence. CONCLUSION: To accelerate drug development for orphan diseases, innovative study designs and appropriate methodology are needed. Taking advantage of randomized phase II data when analyzing phase III studies looks promising because the evidence from phase II supports informed decision-making. The implementation of the Bayesian design is straightforward with public software such as R.
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      Atrial fibrillation in retinal vascular occlusion disease and non-arteritic anterior ischemic optic neuropathy. 

      Callizo, Josep; Feltgen, Nicolas; Ammermann, Antje; Ganser, Janina; Bemme, Sebastian; Bertelmann, Thomas; Pfeiffer, Sebastian; Duvinage, Andre; Gröschel, Klaus; Hoerauf, Hans; et al.
      Wachter, Rolf
      PloS one 2017; 12(8): Art. e0181766
      BACKGROUND: Patients with retinal vascular occlusion disease have an increased risk for ischemic stroke and share some risk factors with cerebrovascular disease. The purpose of this study was to analyze the prevalence of atrial fibrillation (AF) in subjects with retinal vascular occlusive disease and anterior ischemic optic neuropathy and to compare these data to an ischemic stroke group. METHODS: Prospective, observational single-center trial. Subjects with retinal artery occlusion (RAO), retinal vein occlusion (RVO) and anterior ischemic optic neuropathy (AION) were included. Patients with ischemic stroke (IS) from a previous observational trial were used as control. Investigation included 7-day Holter ECG, echocardiography, duplex ultrasonography of the carotid arteries, and 24-hour blood pressure monitoring. Further vascular risk factors were documented. RESULTS: During the 1-year study period, 101 patients were recruited. The control group with ischemic stroke consisted of 272 subjects. At inclusion, the prevalence of AF was 12% (RAO), 10.2% (RVO), 11.1% (NAION) and 15.8% (IS). The final prevalence after Holter ECG rose to 16% (RAO), 18.4% (RVO), 14.8% (NAION) and 26.5% (IS). No significant difference was measured between groups. CONCLUSIONS: We detected a similar prevalence of AF in all groups. RVO patients tended to exhibit a higher AF detection rate and lower number needed to screen than RAO and NAION. The detection of AF rose considerably via Holter ECG. As a consequence, we recommend prolonged ECG monitoring in patients with acute ophthalmic vascular diseases.
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      Anodal tDCS Over the Left DLPFC Did Not Affect the Encoding and Retrieval of Verbal Declarative Information 

      Lara, Gabriel A. de; Knechtges, Philipp N.; Paulus, Walter; Antal, Andrea
      Frontiers in Neuroscience 2017; 11: Art. 452
      Several studies imply that anodal transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) can modulate the formation of verbal episodic memories. The aim of this study was to test if tDCS through a multi-electrode Laplacian montage over the left DLPFC could differentially modulate declarative memory performance depending on the application phase. Two groups of healthy participants (n = 2 × 15) received 1mA anodal or sham stimulation for 20min during the encoding or during the recall phase on a delayed cued-recall, using a randomized, double-blinded, repeated-measures experimental design. Memory performance was assessed at two time points: 10min and 24 h after learning. We found no significant difference between anodal and sham stimulation with regard to the memory scores between conditions (stimulation during encoding or recall) or between time points, suggesting that anodal tDCS over the left DLPFC with these stimulation parameters had no effect on the encoding and the consolidation of associative verbal content.
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      Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders 

      Sokpor, Godwin; Xie, Yuanbin; Rosenbusch, Joachim; Tuoc, Tran
      Frontiers in Molecular Neuroscience 2017; 10: Art. 243
      The ATP-dependent BRG1/BRM associated factor (BAF) chromatin remodeling complexes are crucial in regulating gene expression by controlling chromatin dynamics. Over the last decade, it has become increasingly clear that during neural development in mammals, distinct ontogenetic stage-specific BAF complexes derived from combinatorial assembly of their subunits are formed in neural progenitors and post-mitotic neural cells. Proper functioning of the BAF complexes plays critical roles in neural development, including the establishment and maintenance of neural fates and functionality. Indeed, recent human exome sequencing and genome-wide association studies have revealed that mutations in BAF complex subunits are linked to neurodevelopmental disorders such as Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, Kleefstra’s syndrome spectrum, Hirschsprung’s disease, autism spectrum disorder, and schizophrenia. In this review, we focus on the latest insights into the functions of BAF complexes during neural development and the plausible mechanistic basis of how mutations in known BAF subunits are associated with certain neurodevelopmental disorders.
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