Refine
Year of publication
Document Type
- Article (109)
- Preprint (12)
- Conference Proceeding (5)
- Book (3)
Has Fulltext
- yes (129)
Is part of the Bibliography
- no (129)
Keywords
- Mammakarzinom (12)
- breast cancer (12)
- Behandlung (8)
- Metastasen (8)
- CDK4/6 (6)
- PD1/PDL1 (6)
- Prävention (6)
- Studien (6)
- prevention (6)
- treatment (6)
- metastases (5)
- Risiko (4)
- risk (4)
- trials (4)
- metastatic (3)
- Alpelisib (2)
- Atezolizumab (2)
- Biomarkers (2)
- CV9202 (2)
- Diagnostik (2)
- Früherkennung (2)
- Healthy adults (2)
- Katherine (2)
- Lokalrezidiv (2)
- NMR spectroscopy (2)
- Nachsorge (2)
- Non-small cell lung cancer (2)
- PARP (2)
- PD1/ PDL1 (2)
- PD‑L1 (2)
- PI3K (2)
- Phylogeographie (2)
- Prognosefaktoren (2)
- Prädiktivfaktoren (2)
- Richtlinie (2)
- Supportivtherapie (2)
- T‑DM1 (2)
- adjuvant therapy (2)
- adjuvante Therapie (2)
- advanced (2)
- alpelisib (2)
- atezolizumab (2)
- diagnosis (2)
- early breast cancer (2)
- follow‑up (2)
- fortgeschritten (2)
- frühes Mammakarzinom (2)
- guideline (2)
- kidney (2)
- local recurrence (2)
- neoadjuvant therapy (2)
- neoadjuvante Therapie (2)
- phylogeography (2)
- predictive factors (2)
- prognostic factors (2)
- screening (2)
- studies (2)
- supportive therapy (2)
- survival (2)
- treatment/therapy (2)
- 1,2-Dimesitoylbenzene (1)
- ADAMTS-13 (1)
- AM1 Calculations (1)
- AML (1)
- Advanced breast cancer (1)
- Alzheimer’s dementia (1)
- Amyloid-beta 42 (1)
- Animal models (1)
- Aniridia (1)
- Anti-kaon–nucleon physics (1)
- Antihormone therapy (1)
- Aphakia (1)
- Artificial iris (1)
- Automata theory (1)
- BCOR (1)
- BCORL1 (1)
- BI1361849 (1)
- Baryonic resonances (1)
- Benthos (1)
- Biodiversität (1)
- Biotin (1)
- Blocked occlusion (1)
- Body sway (1)
- CAI-1 (1)
- CRISPR/Cas (1)
- Carrier-bound fibrin sealant (1)
- Causality assessment (1)
- Clinical Trials and Observations (1)
- Clinical trial (1)
- Cohort studies (1)
- Collagen hemostat (1)
- Council for International Organizations of Medical Sciences (1)
- Crystal Structure (1)
- Crystal structure (1)
- Cyanine Distortion (1)
- Dehydrogenase Cofactors (1)
- Direct carbon (1)
- Diversity (1)
- Duganella (1)
- EP300 (1)
- ESR Spectra (1)
- EWSR1 (1)
- Effective half-life (1)
- Electron Transfer (1)
- Electron-pion identification (1)
- Electronic Structure (1)
- Entomology (1)
- Esters (1)
- Eukaryota (1)
- Expedition Brochure (1)
- Expeditionsbericht (1)
- FAPI PET (1)
- FOXO1 (1)
- Fibre/foam sandwich radiator (1)
- Freezeout (1)
- Fusarium graminearum (1)
- G-protein-coupled receptor (1)
- Gene fusion (1)
- Genome editing (1)
- Graves’ disease (1)
- HER2 c-erbB2 (1)
- HER2/neu (1)
- Heavy ion storage ring (1)
- Heavy-ion reactions (1)
- Hemostatics (1)
- Herb induced liver injury (1)
- Herbs (1)
- Heregulin (1)
- High-pressure (1)
- Hippocampal volume (1)
- Hyperconjugation (1)
- Hypofractionated radiotherapy (1)
- IOL scleral Fixation (1)
- Immunomonitoring (1)
- Infinite games with perfect information (1)
- Internal ribosome entry site (1)
- Ionisation energy loss (1)
- Isolierung (1)
- Janthinobacterium (1)
- Kaonic nuclei (1)
- Labordiagnose (1)
- Lebensgemeinschaft (1)
- Liver resection (1)
- Low energy QCD (1)
- Luciferase (1)
- MM-121 (1)
- MNDO Calculations (1)
- Meersseman test (1)
- Meloneta alpica (1)
- Metastatic (1)
- Mild cognitive impairment (1)
- Molecular Conformation (1)
- Molecular diagnostic testing (1)
- Multi-wire proportional drift chamber (1)
- Multianvil (1)
- Myeloid Neoplasia (1)
- Neural network (1)
- Neuroepithelial tumor (1)
- Ocular trauma (1)
- Orbital electron capture (1)
- Organosilicon Compounds (1)
- Orthopaedics (1)
- Oxidation States (1)
- Oxo-and Alkylamino-Substituted p-Benzoquinone Derivatives (1)
- PAGE (1)
- PCR (1)
- PLAGL1 (1)
- Partial wave analysis (1)
- Phospho-tau (1)
- Phosphorylation (1)
- Phylogenetik (1)
- Phylogenomics (1)
- Pityogenes (1)
- Population genetics (1)
- Prediction (1)
- Protein translation (1)
- RNA (1)
- RNActive (1)
- Radical Anion Sodium Salt (1)
- Radioiodine therapy (1)
- Radioiodine uptake test (1)
- Randomized controlled trial (1)
- Rare-earth borate (1)
- Re-exposure (1)
- Registries (1)
- Ruthenium Complexes (1)
- SSCP (1)
- Scolytidae (1)
- Scolytinae (1)
- Seribantumab (1)
- Single Crystal Structures (1)
- Single particle decay spectroscopy (1)
- Substituent Effects (1)
- Supratentorial (1)
- Symmetrical blocked occlusion (1)
- T-DM1 (1)
- TLR2/6 (1)
- TR (1)
- Tau (1)
- Terbium (1)
- Thyroid (1)
- Tracking (1)
- Transition radiation detector (1)
- Translation initiation (1)
- Translational research (1)
- Trigger (1)
- Two body weak decay (1)
- Upper body posture (1)
- VARGADO (1)
- Videorasterstereography (1)
- Water balance (1)
- Weight distribution (1)
- Xenon-based gas mixture (1)
- Yamane (1)
- Zellkultur (1)
- Zooplankton (1)
- acute myeloid leukemia (1)
- advanced breast cancer (1)
- algorithms (1)
- allocation (1)
- angio-immunogenic switch (1)
- antihormone therapy (1)
- available water capacity (1)
- bacterium-fungus interaction (1)
- benthic communities (1)
- biodiversity (1)
- biogenic amine (1)
- bleeding (1)
- blood flow recovery (1)
- bortezomib (1)
- cell culture (1)
- cellular signaling (1)
- chemical vapour deposition (1)
- chemotherapy (1)
- child (1)
- collateral growth (1)
- combinatorics (1)
- dE/dx (1)
- data structures (1)
- denervation (1)
- detection (1)
- docetaxel (1)
- dopamine (1)
- drought-stress (1)
- dwarf-shrub heath (1)
- femoral artery ligation (1)
- fibrosis imaging (1)
- field-effect transistor (1)
- forest (1)
- forest site classification (1)
- fourth (1)
- graft (1)
- habitat boundary (1)
- hierarchies and reducibilities (1)
- induction chemotherapy (1)
- induction regimen (1)
- insect (1)
- interleukin-6 (1)
- intracranial hemorrhage (1)
- isolation (1)
- laboratory diagnosis (1)
- lapatinib (1)
- lenalidomide (1)
- local radiotherapy (1)
- logic (1)
- loss (1)
- loss-of-function (1)
- mRNA active cancer immunotherapy (1)
- mRNA vaccine (1)
- metastasis (1)
- mitochondrial DNA (1)
- mitochondriale DNA (1)
- mtDNA (1)
- multiple myeloma (1)
- nintedanib (1)
- non-small cell lung cancer (1)
- non-small-cell lung cancer (1)
- nuclear cardiology (1)
- oligosilanes (1)
- pertuzumab (1)
- phylogenetics (1)
- platelet substitution (1)
- ppK − (1)
- proteomics (1)
- pulmonary hypertension (1)
- quorum sensing (1)
- radiation (1)
- radiation-induced nanostructures (1)
- re-transplantation (1)
- reactive systems (1)
- renal failure (1)
- repeated (1)
- respiratorische Infektion (1)
- respiratory infection (1)
- risk stratification (1)
- salivary gland (1)
- silicon nanowires (1)
- site classification system (1)
- small proteins (1)
- specification and verification (1)
- structural biology (1)
- structure–activity relationships (1)
- third (1)
- thrombotic microangiopathy (1)
- thrombotic thrombocytopenic purpura (1)
- trastuzumab (1)
- tumor microenvironment (1)
- vapor–liquid–solid mechanism (1)
- vascular surgery (1)
- verification (1)
- violacein (1)
- von Willebrand factor (1)
- zooplankton (1)
- α-Iminoketones (1)
Institute
Background: Leukocyte progenitors derived from clonal hematopoiesis of undetermined potential (CHIP) are associated with increased cardiovascular events. However, the prevalence and functional relevance of CHIP in coronary artery disease (CAD) are unclear, and cells affected by CHIP have not been detected in human atherosclerotic plaques.
Methods: CHIP mutations in blood and tissues were identified by targeted deep-DNA-sequencing (DNAseq: coverage >3,000) and whole-genome-sequencing (WGS: coverage >35). CHIP-mutated leukocytes were visualized in human atherosclerotic plaques by mutaFISHTM. Functional relevance of CHIP mutations was studied by RNAseq.
Results: DNAseq of whole blood from 540 deceased CAD patients of the Munich cardIovaScular StudIes biObaNk (MISSION) identified 253 (46.9%) CHIP mutation carriers (mean age 78.3 years). DNAseq on myocardium, atherosclerotic coronary and carotid arteries detected identical CHIP mutations in 18 out of 25 mutation carriers in tissue DNA. MutaFISHTM visualized individual macrophages carrying DNMT3A CHIP mutations in human atherosclerotic plaques. Studying monocyte-derived macrophages from Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET; n=941) by WGS revealed CHIP mutations in 14.2% (mean age 67.1 years). RNAseq of these macrophages revealed that expression patterns in CHIP mutation carriers differed substantially from those of non-carriers. Moreover, patterns were different depending on the underlying mutations, e.g. those carrying TET2 mutations predominantly displayed upregulated inflammatory signaling whereas ASXL1 mutations showed stronger effects on metabolic pathways.
Conclusions: Deep-DNA-sequencing reveals a high prevalence of CHIP mutations in whole blood of CAD patients. CHIP-affected leukocytes invade plaques in human coronary arteries. RNAseq data obtained from macrophages of CHIP-affected patients suggest that pro-atherosclerotic signaling differs depending on the underlying mutations. Further studies are necessary to understand whether specific pathways affected by CHIP mutations may be targeted for personalized treatment.
Coordination of substitutionally inert [Ru(bpy)2]2+ fragments (bpy: 2,2′-bipyridine) to the a-iminoketone chelate ligands pyrazine-2-dimethylcarboxamide (4) and 4,7-phenanthroline-5,6-dione (5) yields the complexes [(N,O-4)Ru(bpy)2]2⊕, [(O,O′-5⊖)Ru(bpy)2]⊕ and {(N,O; N′,O′-5)[Ru(bpy)2]2}4⊕ which exhibit a rich electrochemistry. The distinctly different electronic structures of the complexes are evident from the ESR behaviour of paramagnetic intermediates: N.O-coordinated complexes have the unpaired electron residing in the ligand n system upon reduction, albeit with g<2 for the binuclear complex of 5. The paramagnetic O,O′-coordinated mononuclear complex with 5 has its redox potentials shifted positively relative to that of the binuclear system. These results are particularly noteworthy because 4 and 5 can be regarded as model compounds for the flavin and methoxatin dehydrogenase cofactors.
Crista junctions (CJs) are important for mitochondrial organization and function, but the molecular basis of their formation and architecture is obscure. We have identified and characterized a mitochondrial membrane protein in yeast, Fcj1 (formation of CJ protein 1), which is specifically enriched in CJs. Cells lacking Fcj1 lack CJs, exhibit concentric stacks of inner membrane in the mitochondrial matrix, and show increased levels of F1FO–ATP synthase (F1FO) supercomplexes. Overexpression of Fcj1 leads to increased CJ formation, branching of cristae, enlargement of CJ diameter, and reduced levels of F1FO supercomplexes. Impairment of F1FO oligomer formation by deletion of its subunits e/g (Su e/g) causes CJ diameter enlargement and reduction of cristae tip numbers and promotes cristae branching. Fcj1 and Su e/g genetically interact. We propose a model in which the antagonism between Fcj1 and Su e/g locally modulates the F1FO oligomeric state, thereby controlling membrane curvature of cristae to generate CJs and cristae tips.
Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.
Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
Objective: The objective of this study was to describe and analyze the effects of depression on health care utilization and costs in a sample of multimorbid elderly patients.
Method: This cross-sectional analysis used data of a prospective cohort study, consisting of 1,050 randomly selected multimorbid primary care patients aged 65 to 85 years. Depression was defined as a score of six points or more on the Geriatric Depression Scale (GDS-15). Subjects passed a geriatric assessment, including a questionnaire for health care utilization. The impact of depression on health care costs was analyzed using multiple linear regression models. A societal perspective was adopted.
Results: Prevalence of depression was 10.7%. Mean total costs per six-month period were €8,144 (95% CI: €6,199-€10,090) in patients with depression as compared to €3,137 (95% CI: €2,735-€3,538; p<0.001) in patients without depression. The positive association between depression and total costs persisted after controlling for socio-economic variables, functional status and level of multimorbidity. In particular, multiple regression analyses showed a significant positive association between depression and pharmaceutical costs.
Conclusion: Among multimorbid elderly patients, depression was associated with significantly higher health care utilization and costs. The effect of depression on costs was even greater than reported by previous studies conducted in less morbid patients.
Die Flechte Cladonia stygia (Fr.) Ruoss wurde anlässlich einer Bestandsaufnahme der Rentierflechten 2009 erstmals aus Hessen gemeldet. Da die Unterscheidung von der ähnlichen C. rangiferina (L.) F. H. Wigg. anhand morphologischer Merkmale oft unsicher ist, wurden molekulargenetische Daten zur Identifizierung der hessischen Belege der Art herangezogen. Phylogenetische Stammbäume auf der Grundlage von sechs mitochondrialen und nuklearen Genloci untermauern die Abgrenzung beider Arten. Nur zwei von sieben gemeldeten hessischen Vorkommen gehören nach diesen Ergebnissen zu C. stygia, die übrigen zu C. rangiferina. Eine gezielte Suche nach C. stygia und eine durch molekulargenetische Daten untermauerte Bestimmung der Belege erscheint notwendig, um den Status der Art in Hessen zuverlässig beurteilen zu können.
This paper reports on Monte Carlo simulation results for future measurements of the moduli of time-like proton electromagnetic form factors, |GE | and |GM|, using the ¯pp → μ+μ− reaction at PANDA (FAIR). The electromagnetic form factors are fundamental quantities parameterizing the electric and magnetic structure of hadrons. This work estimates the statistical and total accuracy with which the form factors can be measured at PANDA, using an analysis of simulated data within the PandaRoot software framework. The most crucial background channel is ¯pp → π+π−,due to the very similar behavior of muons and pions in the detector. The suppression factors are evaluated for this and all other relevant background channels at different values of antiproton beam momentum. The signal/background separation is based on a multivariate analysis, using the Boosted Decision Trees method. An expected background subtraction is included in this study, based on realistic angular distribuations of the background contribution. Systematic uncertainties are considered and the relative total uncertainties of the form factor measurements are presented.
In Eurotransplant kidney allocation system (ETKAS), candidates can be considered unlimitedly for repeated re‐transplantation. Data on outcome and benefit are indeterminate. We performed a retrospective 15‐year patient and graft outcome data analysis from 1464 recipients of a third or fourth or higher sequential deceased donor renal transplantation (DDRT) from 42 transplant centers. Repeated re‐DDRT recipients were younger (mean 43.0 vs. 50.2 years) compared to first DDRT recipients. They received grafts with more favorable HLA matches (89.0% vs. 84.5%) but thereby no statistically significant improvement of patient and graft outcome was found as comparatively demonstrated in 1st DDRT. In the multivariate modeling accounting for confounding factors, mortality and graft loss after 3rd and ≥4th DDRT (P < 0.001 each) and death with functioning graft (DwFG) after 3rd DDRT (P = 0.001) were higher as compared to 1st DDRT. The incidence of primary nonfunction (PNF) was also significantly higher in re‐DDRT (12.7%) than in 1st DDRT (7.1%; P < 0.001). Facing organ shortage, increasing waiting time, and considerable mortality on dialysis, we question the current policy of repeated re‐DDRT. The data from this survey propose better HLA matching in first DDRT and second DDRT and careful selection of candidates, especially for ≥4th DDRT.
An experiment addressing electron capture (EC) decay of hydrogen-like 142Pm60+ions has been conducted at the experimental storage ring (ESR) at GSI. The decay appears to be purely exponential and no modulations were observed. Decay times for about 9000 individual EC decays have been measured by applying the single-ion decay spectroscopy method. Both visually and automatically analysed data can be described by a single exponential decay with decay constants of 0.0126(7)s−1 for automatic analysis and 0.0141(7)s−1 for manual analysis. If a modulation superimposed on the exponential decay curve is assumed, the best fit gives a modulation amplitude of merely 0.019(15), which is compatible with zero and by 4.9 standard deviations smaller than in the original observation which had an amplitude of 0.23(4).
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
Herein, the high-pressure/high-temperature synthesis (11 GPa, 650 °C) of Tb3B10O17(OH)5 in a modified Walker-type multianvil device is presented. The structure of this rare-earth borate was determined by single-crystal X-ray diffraction methods and was found to crystallize orthorhombically in the space group Pmn21 (no. 31) with the unit cell parameters a = 16.2527(4), b = 4.4373(1), and c = 8.8174(2) Å. The new compound was further characterized using infrared spectroscopy, energy-dispersive X-ray spectroscopy, second harmonic generation (SHG) measurements, and temperature-dependent X-ray powder diffraction. Tb3B10O17(OH)5 decomposes to β-Tb(BO2)3 at temperatures higher than 460 °C. With increasing temperatures, the formation of μ-TbBO3 was observed, which transforms to π-TbBO3 upon cooling.
Janthinobacteria commonly form biofilms on eukaryotic hosts and are known to synthesize antibacterial and antifungal compounds. Janthinobacterium sp. HH01 was recently isolated from an aquatic environment and its genome sequence was established. The genome consists of a single chromosome and reveals a size of 7.10 Mb, being the largest janthinobacterial genome so far known. Approximately 80% of the 5,980 coding sequences (CDSs) present in the HH01 genome could be assigned putative functions. The genome encodes a wealth of secretory functions and several large clusters for polyketide biosynthesis. HH01 also encodes a remarkable number of proteins involved in resistance to drugs or heavy metals. Interestingly, the genome of HH01 apparently lacks the N-acylhomoserine lactone (AHL)-dependent signaling system and the AI-2-dependent quorum sensing regulatory circuit. Instead it encodes a homologue of the Legionella- and Vibrio-like autoinducer (lqsA/cqsA) synthase gene which we designated jqsA. The jqsA gene is linked to a cognate sensor kinase (jqsS) which is flanked by the response regulator jqsR. Here we show that a jqsA deletion has strong impact on the violacein biosynthesis in Janthinobacterium sp. HH01 and that a jqsA deletion mutant can be functionally complemented with the V. cholerae cqsA and the L. pneumophila lqsA genes.
During winter 2015/2016, the Arctic stratosphere was characterized by extraordinarily low temperatures in connection with a very strong polar vortex and with the occurrence of extensive polar stratospheric clouds. From mid-December 2015 until mid-March 2016, the German research aircraft HALO (High Altitude and Long-Range Research Aircraft) was deployed to probe the lowermost stratosphere in the Arctic region within the POLSTRACC (Polar Stratosphere in a Changing Climate) mission. More than 20 flights have been conducted out of Kiruna, Sweden, and Oberpfaffenhofen, Germany, covering the whole winter period. Besides total reactive nitrogen (NOy), observations of nitrous oxide, nitric acid, ozone, and water were used for this study. Total reactive nitrogen and its partitioning between the gas and particle phases are key parameters for understanding processes controlling the ozone budget in the polar winter stratosphere. The vertical redistribution of total reactive nitrogen was evaluated by using tracer–tracer correlations (NOy–N2O and NOy–O3). The trace gases are well correlated as long as the NOy distribution is controlled by its gas-phase production from N2O. Deviations of the observed NOy from this correlation indicate the influence of heterogeneous processes. In early winter no such deviations have been observed. In January, however, air masses with extensive nitrification were encountered at altitudes between 12 and 15 km. The excess NOy amounted to about 6 ppb. During several flights, along with gas-phase nitrification, indications for extensive occurrence of nitric acid containing particles at flight altitude were found. These observations support the assumption of sedimentation and subsequent evaporation of nitric acid-containing particles, leading to redistribution of total reactive nitrogen at lower altitudes. Remnants of nitrified air masses have been observed until mid-March. Between the end of February and mid-March, denitrified air masses have also been observed in connection with high potential temperatures. This indicates the downward transport of air masses that have been denitrified during the earlier winter phase. Using tracer–tracer correlations, missing total reactive nitrogen was estimated to amount to 6 ppb. Further, indications of transport and mixing of these processed air masses outside the vortex have been found, contributing to the chemical budget of the winter lowermost stratosphere. Observations within POLSTRACC, at the bottom of the vortex, reflect heterogeneous processes from the overlying Arctic winter stratosphere. The comparison of the observations with CLaMS model simulations confirm and complete the picture arising from the present measurements. The simulations confirm that the ensemble of all observations is representative of the vortex-wide vertical NOy redistribution.
Das erstmals Ende 2002 im Süden Chinas aufgetretene schwere akute respiratorische Syndrom (SARS) führte bis zum August 2003 zu insgesamt über 8000 Erkrankungen und über 700 Todesfällen. Eine von der Weltgesundheitsorganisation (WHO) ins Leben gerufene Kooperation verschiedener Laboratorien weltweit ermöglichte innerhalb von nur vier Wochen die Identifizierung des kausalen Agens, eines bislang unbekannten Coronavirus (vorläufig bezeichnet als SARS-assoziiertes Coronavirus oder SARS-CoV), welches die Koch’schen Postulate erfüllt. Der Erreger lässt sich (unter Hochsicherheitsbedingungen) gut in Zellkulturen vermehren, was weitere Studien zur Stabilität sowie die Entwicklung von antiviral wirksamen Substanzen und Impfstoffen erleichtert.
Obwohl schon rasch diagnostische Labortests, insbesondere zum Nachweis der viralen Nukleinsäure und virusspezifischer Antikörper, zur Verfügung standen, basiert die Falldefinition von SARS weiterhin auf klinisch-epidemiologischen Kriterien. In Hinblick auf die Gefahr eines (saisonalen) Wiederauftretens der Infektion müssen die verfügbaren Labormethoden dringend überprüft und weiter verbessert werden.
SARS ist ein gutes Beispiel dafür, wie schnell sich eine Infektionskrankheit über den internationalen Reiseverkehr ausbreiten kann, aber auch dafür, wie wichtig in einem solchen Falle eine gut koordinierte internationale Kooperation ist; durch Einsatz neuester, aber auch bewährter konventioneller Labormethoden und ständigen Austausch aktueller (Zwischen-)Ergebnisse sowie von Patientenproben und Reagenzien führte eine bisher einmalige Zusammenarbeit schnell zu einem Durchbruch. Dies lässt auf ähnliche Fortschritte beim Kampf gegen weitere neuartige Infektionserreger hoffen.
Background and Objectives: Proteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity.
Methods: Patients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded.
Results: Of 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5–8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1–4.8, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3–15.25 vs n = 41, median 4 ng/mL, and IQR 2–7; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels.
Discussion: D-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS.
Classification of Evidence: This study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
DGK and DZHK position paper on genome editing: basic science applications and future perspective
(2021)
For a long time, gene editing had been a scientific concept, which was limited to a few applications. With recent developments, following the discovery of TALEN zinc-finger endonucleases and in particular the CRISPR/Cas system, gene editing has become a technique applicable in most laboratories. The current gain- and loss-of function models in basic science are revolutionary as they allow unbiased screens of unprecedented depth and complexity and rapid development of transgenic animals. Modifications of CRISPR/Cas have been developed to precisely interrogate epigenetic regulation or to visualize DNA complexes. Moreover, gene editing as a clinical treatment option is rapidly developing with first trials on the way. This article reviews the most recent progress in the field, covering expert opinions gathered during joint conferences on genome editing of the German Cardiac Society (DGK) and the German Center for Cardiovascular Research (DZHK). Particularly focusing on the translational aspect and the combination of cellular and animal applications, the authors aim to provide direction for the development of the field and the most frequent applications with their problems.