Refine
Year of publication
Document Type
- Preprint (668)
- Article (410)
- Book (1)
- Conference Proceeding (1)
Has Fulltext
- yes (1080)
Is part of the Bibliography
- no (1080)
Keywords
- Heavy Ion Experiments (20)
- Hadron-Hadron Scattering (11)
- Hadron-Hadron scattering (experiments) (11)
- LHC (9)
- Heavy-ion collision (6)
- ALICE experiment (4)
- Collective Flow (4)
- Jets (4)
- Quark-Gluon Plasma (4)
- ALICE (3)
- Heavy Ions (3)
- Jets and Jet Substructure (3)
- cochlear implant (3)
- pp collisions (3)
- Beauty production (2)
- Charm physics (2)
- Experimental nuclear physics (2)
- Experimental particle physics (2)
- Heavy Quark Production (2)
- Lepton-Nucleon Scattering (experiments) (2)
- Particle Correlations and Fluctuations (2)
- Particle and resonance production (2)
- Particle correlations and fluctuations (2)
- Pb–Pb collisions (2)
- QCD (2)
- Single electrons (2)
- clinically important restrictions and symptoms (2)
- composite structures (2)
- development (2)
- observational study (2)
- rare disease (2)
- 900 GeV (1)
- ABC transporters (1)
- ALICE detector (1)
- ATPases (1)
- Anti-nuclei (1)
- Artificial Intelligence (1)
- Baryonic resonances (1)
- Biodiversity Data (1)
- Biological sciences (1)
- Biomonitoring (1)
- Boosted Jets (1)
- Botanical Collections (1)
- Burns (1)
- CAD/CAM (1)
- CD3/CD19 depletion (1)
- CIK cells (1)
- CTLA-4 (1)
- Calcium gluconate (1)
- Centrality Class (1)
- Centrality Selection (1)
- Clinical presentation (1)
- Collective Flow, (1)
- Comparison with QCD (1)
- Conservation (1)
- Data sharing (1)
- Di-hadron correlations (1)
- Diagnostic markers (1)
- Digital subtraction angiography (1)
- Digitization (1)
- Edentulous jaw (1)
- Electron-pion identification (1)
- Electroweak interaction (1)
- Elliptic flow (1)
- Epilepsy (1)
- Femtoscopy (1)
- Fibre/foam sandwich radiator (1)
- Freezeout (1)
- Genetics research (1)
- Guided waves (1)
- HBT (1)
- Hadron production (1)
- Hadron-Hadron Scattering Heavy (1)
- Hadron-hadron interactions (1)
- Hard Scattering (1)
- Heavy Ion Experiment (1)
- Heavy flavor production (1)
- Heavy flavour production (1)
- Heavy ions (1)
- Heavy-flavour decay muons (1)
- Heavy-flavour production (1)
- Heavy-ion collisions (1)
- Heavy-ion reactions (1)
- Herbaria (1)
- Hydrofluoric acid (1)
- Hyperammonemic encephalopathy (1)
- Hyperons (1)
- Hypertension (1)
- IL-15 (1)
- IL-21 (1)
- Immunology (1)
- Implant-supported bars (1)
- Inclusive spectra (1)
- Intensity interferometry (1)
- Interference fragmentation function (1)
- Invariant Mass Distribution (1)
- Ionisation energy loss (1)
- Jet Physics (1)
- Jet Substructure (1)
- Material budget (1)
- Mathematical biosciences (1)
- Mid-rapidity (1)
- Minimum Bias (1)
- Monte Carlo (1)
- Multi-Parton Interactions (1)
- Multi-strange baryons (1)
- Multi-wire proportional drift chamber (1)
- NK cells (1)
- Neonatal urea cycle disorders (1)
- Neural network (1)
- Neuroscience (1)
- Nuclear modification factor (1)
- Nucleus (1)
- PD-1 (1)
- PYTHIA (1)
- Parkinson's disease (1)
- Particle and Resonance Production (1)
- Pb–Pb (1)
- Predictive markers (1)
- Production Cross Section (1)
- Profilometry (1)
- Properties of Hadrons (1)
- Proton (1)
- Proton–proton (1)
- Quark Deconfinement (1)
- Quark Gluon Plasma (1)
- Quark Production (1)
- Quark gluon plasma (1)
- Quarkonium (1)
- Radiotherapy (1)
- Rapidity Range (1)
- Relativistic heavy ion physics (1)
- Relativistic heavy-ion collisions (1)
- Research Infrastructure (1)
- Resolution Parameter (1)
- Roughness (1)
- Semantics (1)
- Single muons (1)
- Strangeness (1)
- Surface (1)
- Surgical oncology (1)
- Systematic Uncertainty (1)
- TR (1)
- Taxonomy (1)
- Time Projection Chamber (1)
- Tracking (1)
- Transition radiation detector (1)
- Transverse momentum (1)
- Transversity (1)
- Trigger (1)
- Vasospasm (1)
- Vector Boson Production (1)
- X-ray crystallography (1)
- Xenon-based gas mixture (1)
- allogeneic hematological stem cell transplantation (1)
- anti-angiogenic therapy (1)
- antibiotic prophylactic therapy (1)
- asymmetric hearing (1)
- auditory development (1)
- binaural cochlear implants (1)
- biobank (1)
- biogeographic legaciese (1)
- bottom-up (1)
- cell therapy (1)
- children (1)
- common genetic variation (1)
- congenital deafness (1)
- critical periods (1)
- cross-modal plasticity (1)
- cryo-EM (1)
- dE/dx (1)
- deaf white cat (1)
- deafness (1)
- deprivation (1)
- detector (1)
- disease prevalence (1)
- ex vivo expansion (1)
- experimental results (1)
- forest classification (1)
- forest functional similarity (1)
- gastrointestinal stromal tumours (1)
- genetic diversity (1)
- genome-wide association study (1)
- glioblastoma (1)
- global change (1)
- graft-versus host (1)
- habitat destruction (1)
- health-related quality of life (1)
- health-relatedquality of life (1)
- heavy ion experiments (1)
- hospital exemption (1)
- immune checkpoint blockade (1)
- immunotherapy (1)
- infection precaution (1)
- interaural time difference (1)
- land use (1)
- liver metastasis (1)
- macrophage polarization (1)
- membrane proteins (1)
- mesenchymal stromal cell (1)
- molecular machines (1)
- neuroblastoma (1)
- omega stringer (1)
- open guided waves (1)
- phylogenetic community distance (1)
- phylogeny (1)
- plasticity (1)
- predictive coding (1)
- primary active transporters (1)
- quark gluon plasma (1)
- reference damage (1)
- refractory aGvHD (1)
- sarcoma (1)
- scanning laser Doppler vibrometry (1)
- schizophrenia (1)
- sensory deprivation (1)
- sequence alignment (1)
- signal processing (1)
- single subject classification (1)
- single-sided deafness (1)
- spectra (1)
- steroid-resistant aGvHD (1)
- structural biology (1)
- structural health monitoring (1)
- synchronization (1)
- temporal classification (1)
- therapy resistance (1)
- top–down (1)
- transplantation (1)
- treatment resistance (1)
- tropical forests (1)
- tumor angiogenesis (1)
- tyrosine kinase inhibitors (1)
- uveal melanoma (1)
- vaccination (1)
- √sN N = 2.76 TeV (1)
Institute
- Physik (1046)
- Frankfurt Institute for Advanced Studies (FIAS) (959)
- Informatik (921)
- Medizin (25)
- Informatik und Mathematik (5)
- Biodiversität und Klima Forschungszentrum (BiK-F) (2)
- Hochschulrechenzentrum (2)
- Institut für Ökologie, Evolution und Diversität (2)
- Biochemie und Chemie (1)
- Biowissenschaften (1)
- Ernst Strüngmann Institut (1)
- Psychologie (1)
- Senckenbergische Naturforschende Gesellschaft (1)
Epilepsy can have many different causes and its development (epileptogenesis) involves a bewildering complexity of interacting processes. Here, we present a first-of-its-kind computational model to better understand the role of neuroimmune interactions in the development of acquired epilepsy. Our model describes the interactions between neuroinflammation, blood-brain barrier disruption, neuronal loss, circuit remodeling, and seizures. Formulated as a system of nonlinear differential equations, the model is validated using data from animal models that mimic human epileptogenesis caused by infection, status epilepticus, and blood-brain barrier disruption. The mathematical model successfully explains characteristic features of epileptogenesis such as its paradoxically long timescales (up to decades) despite short and transient injuries, or its dependence on the intensity of an injury. Furthermore, stochasticity in the model captures the variability of epileptogenesis outcomes in individuals exposed to identical injury. Notably, in line with the concept of degeneracy, our simulations reveal multiple routes towards epileptogenesis with neuronal loss as a sufficient but non-necessary component. We show that our framework allows for in silico predictions of therapeutic strategies, providing information on injury-specific therapeutic targets and optimal time windows for intervention.
Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.
Purpose: Preoperative (neoadjuvant) chemoradiotherapy (CRT) and total mesorectal excision is the standard treatment for rectal cancer patients (UICC stage II/III). Up to one-third of patients treated with CRT achieve a pathological complete response (pCR). These patients could be spared from surgery and its associated morbidity and mortality, and assigned to a “watch and wait” strategy. However, reliably identifying pCR based on clinical or imaging parameters remains challenging.
Experimental design: We generated gene-expression profiles of 175 patients with locally advanced rectal cancer enrolled in the CAO/ARO/AIO-94 and -04 trials. One hundred and sixty-one samples were used for building, training and validating a predictor of pCR using a machine learning algorithm. The performance of the classifier was validated in three independent cohorts, comprising 76 patients from (i) the CAO/ARO/AIO-94 and -04 trials (n = 14), (ii) a publicly available dataset (n = 38) and (iii) in 24 prospectively collected samples from the TransValid A trial.
Results: A 21-transcript signature yielded the best classification of pCR in 161 patients (Sensitivity: 0.31; AUC: 0.81), when not allowing misclassification of non-complete-responders (False-positive rate = 0). The classifier remained robust when applied to three independent datasets (n = 76).
Conclusion: The classifier can identify >1/3 of rectal cancer patients with a pCR while never classifying patients with an incomplete response as having pCR. Importantly, we could validate this finding in three independent datasets, including a prospectively collected cohort. Therefore, this classifier could help select rectal cancer patients for a “watch and wait” strategy.
Translational relevance: Forgoing surgery with its associated side effects could be an option for rectal cancer patients if the prediction of a pathological complete response (pCR) after preoperative chemoradiotherapy would be possible. Based on gene-expression profiles of 161 patients a classifier was developed and validated in three independent datasets (n = 76), identifying over 1/3 of patients with pCR, while never misclassifying a non-complete-responder. Therefore, the classifier can identify patients suited for “watch and wait”.
Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our “hub-spoke” model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.
Denervation-induced changes in excitatory synaptic strength were studied following entorhinal deafferentation of hippocampal granule cells in mature (≥3 weeks old) mouse organotypic entorhino-hippocampal slice cultures. Whole-cell patch-clamp recordings revealed an increase in excitatory synaptic strength in response to denervation during the first week after denervation. By the end of the second week synaptic strength had returned to baseline. Because these adaptations occurred in response to the loss of excitatory afferents, they appeared to be in line with a homeostatic adjustment of excitatory synaptic strength. To test whether denervation-induced changes in synaptic strength exploit similar mechanisms as homeostatic synaptic scaling following pharmacological activity blockade, we treated denervated cultures at 2 days post lesion for 2 days with tetrodotoxin. In these cultures, the effects of denervation and activity blockade were not additive, suggesting that similar mechanisms are involved. Finally, we investigated whether entorhinal denervation, which removes afferents from the distal dendrites of granule cells while leaving the associational afferents to the proximal dendrites of granule cells intact, results in a global or a local up-scaling of granule cell synapses. By using computational modeling and local electrical stimulations in Strontium (Sr2+)-containing bath solution, we found evidence for a lamina-specific increase in excitatory synaptic strength in the denervated outer molecular layer at 3–4 days post lesion. Taken together, our data show that entorhinal denervation results in homeostatic functional changes of excitatory postsynapses of denervated dentate granule cells in vitro.
We present measurements of exclusive ensuremathπ+,0 and η production in pp reactions at 1.25GeV and 2.2GeV beam kinetic energy in hadron and dielectron channels. In the case of π+ and π0 , high-statistics invariant-mass and angular distributions are obtained within the HADES acceptance as well as acceptance-corrected distributions, which are compared to a resonance model. The sensitivity of the data to the yield and production angular distribution of Δ (1232) and higher-lying baryon resonances is shown, and an improved parameterization is proposed. The extracted cross-sections are of special interest in the case of pp → pp η , since controversial data exist at 2.0GeV; we find \ensuremathσ=0.142±0.022 mb. Using the dielectron channels, the π0 and η Dalitz decay signals are reconstructed with yields fully consistent with the hadronic channels. The electron invariant masses and acceptance-corrected helicity angle distributions are found in good agreement with model predictions.
Sarcomas are rare cancers with high heterogeneity in terms of type, location, and treatment. The health-related quality of life (HRQoL) of sarcoma patients has rarely been investigated and is the subject of this analysis. Adult sarcoma patients and survivors were assessed between September 2017 and February 2019 in 39 study centers in Germany using standardized, validated questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)). Associated factors were analyzed exploratively using multivariable linear regressions. Among 1113 patients, clinically important limitations and symptoms were most pronounced in emotional (63%, 95% CI 60–66%), physical (60%, 95% CI 57–62%), role functioning (51%, 95% CI 48–54%), and pain (56%, 95% CI 53–59%) and fatigue (51%, 95% CI 48–54%). HRQoL differed between tumor locations with lower extremities performing the worst and sarcoma types with bone sarcoma types being most affected. Additionally, female gender, higher age, lower socioeconomic status, recurrent disease, not being in retirement, comorbidities, and being in treatment were associated with lower HRQoL. Sarcoma patients are severely restricted in their HRQoL, especially in functioning scales. The heterogeneity of sarcomas with regard to type and location is reflected in HRQoL outcomes. During treatment and follow-up, close attention has to be paid to the reintegration of the patients into daily life as well as to their physical abilities and emotional distress.
Background: Due to their increased precision, CAD/CAM generated bars (Computer-Aided Design/ Computer-Aided Manufacturing) are increasingly utilized in implant prosthodontics. For optimal clinical results, surface morphology should promote the integration of soft tissue while minimizing plaque and bacterial retention.
Objective: Despite their clinical use, only limited information on the biological and clinical surface quality of CAD/CAM milled bars is available. The aim of the study was therefore to characterize the surface topography of bars of different manufacturers based on the profilometric analysis and the need for manual post-processing in the laboratory.
Methods: A custom mandibular edentulous cast with four anterior implants was used as a reference cast and reproduced eight times. On each reproduction cast, corresponding scan flags were positioned and digitized. Acrylic 3D printed bar frameworks were produced and sent to the respective production center along with the digital files of the CAD bars for milling. In the course of profilometric analysis, all bars were examined in three critical Regions of Interest (ROI): Transmucosal, labial, basal. Sa and Ra values of each construction were determined. To evaluate the necessary refinishing time eight dental technicians macroscopically evaluated the bars by performing a subjective visual inspection. Kruskal-Wallis H-tests and Tukey and Kramer's post hoc tests were applied to detect differences between the samples.
Results: After profilometric examination, three specimens (Dentsply Sirona: ZDC; Straumann: ZST; CAMLOG: ZCC) demonstrated surface roughness values in the biological acceptable range (Sa 0.2-0.4 μm) in the transmucosal region and provided optimal conditions for a reliable soft tissue adaptation. The Ra measurements revealed values beyond the acceptable threshold in the transmucosal region for three bars (Straumann: ZST; Dentsply Sirona: ZDC; Amann Girrbach: LAC). Four bars (LAC: Amann Girrbach; ZBC: BEGO; Datron: LDC & LDT; Zirkonzahn: ZZC) needed undesirable extensive manual rework. The evaluation of quality and time for manual post-processing by dental technicians confirmed the measurement-based ranking of the bars.
Conclusion: It is desirable to define a clear roughness threshold for the clinical acceptance of transmucosal CAD/CAM generated surfaces. Clinical studies with profilometric data could help to further improve the surface quality of CAD/CAM milled bars and reduce the need for manual reworking time and effort.
Pattern recognition approaches to the analysis of neuroimaging data have brought new applications such as the classification of patients and healthy controls within reach. In our view, the reliance on expensive neuroimaging techniques which are not well tolerated by many patient groups and the inability of most current biomarker algorithms to accommodate information about prior class frequencies (such as a disorder's prevalence in the general population) are key factors limiting practical application. To overcome both limitations, we propose a probabilistic pattern recognition approach based on cheap and easy-to-use multi-channel near-infrared spectroscopy (fNIRS) measurements. We show the validity of our method by applying it to data from healthy controls (n = 14) enabling differentiation between the conditions of a visual checkerboard task. Second, we show that high-accuracy single subject classification of patients with schizophrenia (n = 40) and healthy controls (n = 40) is possible based on temporal patterns of fNIRS data measured during a working memory task. For classification, we integrate spatial and temporal information at each channel to estimate overall classification accuracy. This yields an overall accuracy of 76% which is comparable to the highest ever achieved in biomarker-based classification of patients with schizophrenia. In summary, the proposed algorithm in combination with fNIRS measurements enables the analysis of sub-second, multivariate temporal patterns of BOLD responses and high-accuracy predictions based on low-cost, easy-to-use fNIRS patterns. In addition, our approach can easily compensate for variable class priors, which is highly advantageous in making predictions in a wide range of clinical neuroimaging applications. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.
Neuroblastoma (NB) is the most common solid extracranial tumor in childhood. Despite therapeutic progress, prognosis in high-risk NB is poor and innovative therapies are urgently needed. Therefore, we addressed the potential cytotoxic capacity of interleukin (IL)-activated natural killer (NK) cells compared to cytokine-induced killer (CIK) cells for the treatment of NB. NK cells were isolated from peripheral blood mononuclear cells (PBMCs) by indirect CD56-enrichment or CD3/CD19-depletion and expanded with different cytokine combinations, such as IL-2, IL-15, and/or IL-21 under feeder-cell free conditions. CIK cells were generated from PBMCs by ex vivo stimulation with interferon-γ, IL-2, OKT-3, and IL-15. Comparative analysis of expansion rate, purity, phenotype and cytotoxicity was performed. CD56-enriched NK cells showed a median expansion rate of 4.3-fold with up to 99% NK cell content. The cell product after CD3/CD19-depletion consisted of a median 43.5% NK cells that expanded significantly faster reaching also 99% of NK cell purity. After 10–12 days of expansion, both NK cell preparations showed a significantly higher median cytotoxic capacity against NB cells relative to CIK cells. Remarkably, these NK cells were also capable of efficiently killing NB spheroidal 3D culture in long-term cytotoxicity assays. Further optimization using a novel NK cell culture medium and a prolonged culturing procedure after CD3/CD19-depletion for up to 15 days enhanced the expansion rate up to 24.4-fold by maintaining the cytotoxic potential. Addition of an IL-21 boost prior to harvesting significantly increased the cytotoxicity. The final cell product consisted for the major part of CD16−, NCR-expressing, poly-functional NK cells with regard to cytokine production, CD107a degranulation and antitumor capacity. In summary, our study revealed that NK cells have a significantly higher cytotoxic potential to combat NB than CIK cell products, especially following the synergistic use of IL-15 and IL-21 for NK cell activation. Therefore, the use of IL-15+IL-21 expanded NK cells generated from CD3/CD19-depleted apheresis products seems to be highly promising as an immunotherapy in combination with haploidentical stem cell transplantation (SCT) for high-risk NB patients.
Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.
Background: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse.
Methods: A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel.
Results: Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion.
Conclusions: This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.
Introduction: We report on successful endovascular treatment of a hydrofluoric acid burn to the hand.
Report: A worker complained of severe pain in the fingers D II to D V after injury with 60% hydrofluoric acid. A digital subtraction angiography showed vasospasm of the common palmar digital artery. We selectively applied 20% calcium gluconate intra-arterially.
After treatment all arteries were perfused. Alprostadil, acetylsalicylic acid and clopidogrel were administered in conjunction. Pain symptoms improved and sensory and motor functions were restored.
Discussion: Immediate angiography and intra-arterial application of calcium gluconate are recommended to treat hydrofluoric acid burn to a limb.
The electrical and computational properties of neurons in our brains are determined by a rich repertoire of membrane-spanning ion channels and elaborate dendritic trees. However, the precise reason for this inherent complexity remains unknown. Here, we generated large stochastic populations of biophysically realistic hippocampal granule cell models comparing those with all 15 ion channels to their reduced but functional counterparts containing only 5 ion channels. Strikingly, valid parameter combinations in the full models were more frequent and more stable in the face of perturbations to channel expression levels. Scaling up the numbers of ion channels artificially in the reduced models recovered these advantages confirming the key contribution of the actual number of ion channel types. We conclude that the diversity of ion channels gives a neuron greater flexibility and robustness to achieve target excitability.
Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.
n this paper we report on the investigation of baryonic resonance production in proton-proton collisions at the kinetic energies of 1.25 GeV and 3.5 GeV, based on data measured with HADES. Exclusive channels npπ+ and ppπ0 as well as ppe+e− were studied simultaneously in the framework of a one-boson exchange model. The resonance cross sections were determined from the one-pion channels for Δ(1232) and N(1440) (1.25 GeV) as well as further Δ and N* resonances up to 2 GeV/c2 for the 3.5 GeV data. The data at 1.25 GeV energy were also analysed within the framework of the partial wave analysis together with the set of several other measurements at lower energies. The obtained solutions provided the evolution of resonance production with the beam energy, showing a sizeable non-resonant contribution but with still dominating contribution of Δ(1232)P33. In the case of 3.5 GeV data, the study of the ppe+e− channel gave the insight on the Dalitz decays of the baryon resonances and, in particular, on the electromagnetic transition form-factors in the time-like region. We show that the assumption of a constant electromagnetic transition form-factors leads to underestimation of the yield in the dielectron invariant mass spectrum below the vector mesons pole. On the other hand, a comparison with various transport models shows the important role of intermediate ρ production, though with a large model dependency. The exclusive channels analysis done by the HADES collaboration provides new stringent restrictions on the parameterizations used in the models.
his contribution aims to give a basic overview of the latest results regarding the production of resonances in different collision systems. The results were extracted from experimental data collected with HADES that is a multipurpose detector located at the GSI Helmholtzzentrum, Darmstadt. The main points discussed here are: the properties of the strange resonances Λ(1405) and Σ(1385), the role of Δ’s as a source of pions in the final state, the production dynamics reflected in form of differential cross sections, and the role of the ϕ meson as a source for K− particles.
The development of epilepsy (epileptogenesis) involves a complex interplay of neuronal and immune processes. Here, we present a first-of-its-kind mathematical model to better understand the relationships among these processes. Our model describes the interaction between neuroinflammation, blood-brain barrier disruption, neuronal loss, circuit remodeling, and seizures. Formulated as a system of nonlinear differential equations, the model reproduces the available data from three animal models. The model successfully describes characteristic features of epileptogenesis such as its paradoxically long timescales (up to decades) despite short and transient injuries or the existence of qualitatively different outcomes for varying injury intensity. In line with the concept of degeneracy, our simulations reveal multiple routes toward epilepsy with neuronal loss as a sufficient but non-necessary component. Finally, we show that our model allows for in silico predictions of therapeutic strategies, revealing injury-specific therapeutic targets and optimal time windows for intervention.
Members of the ATP‐binding cassette (ABC) transporter superfamily translocate a broad spectrum of chemically diverse substrates. While their eponymous ATP‐binding cassette in the nucleotide‐binding domains (NBDs) is highly conserved, their transmembrane domains (TMDs) forming the translocation pathway exhibit distinct folds and topologies, suggesting that during evolution the ancient motor domains were combined with different transmembrane mechanical systems to orchestrate a variety of cellular processes. In recent years, it has become increasingly evident that the distinct TMD folds are best suited to categorize the multitude of ABC transporters. We therefore propose a new ABC transporter classification that is based on structural homology in the TMDs:
Background. Arterial ex situ back-table perfusion (BP) reportedly reduces ischemic-type biliary lesion after liver transplantation. We aimed to verify these findings in a prospective investigation.
Methods. Our prospective, randomized, controlled, multicenter study involved livers retrieved from patients in 2 German regions, and compared the outcomes of standard aortic perfusion to those of aortic perfusion combined with arterial ex situ BP. The primary endpoint was the incidence of ischemic-type biliary lesions over a follow-up of 2 years after liver transplantation, whereas secondary endpoints included 2-year graft survival, initial graft damage as reflected by transaminase levels, and functional biliary parameters at 6 months after transplantation.
Results. A total of 75 livers preserved via standard aortic perfusion and 75 preserved via standard aortic perfusion plus arterial BP were treated using a standardized protocol. The incidence of clinically apparent biliary lesions after liver transplantation (n = 9 for both groups; P = 0.947), the 2-year graft survival rate (standard aortic perfusion, 74%; standard aortic perfusion plus arterial BP, 68%; P = 0.34), and incidence of initial graft injury did not differ between the 2 perfusion modes. Although 33 of the 77 patients with cholangiography workups exhibited injured bile ducts, only 10 had clinical symptoms.
Conclusions. Contrary to previous findings, the present study indicated that additional ex situ BP did not prevent ischemic-type biliary lesions or ischemia-reperfusion injury after liver transplantation. Moreover, there was considerable discrepancy between cholangiography findings regarding bile duct changes and clinically apparent cholangiopathy after transplantation, which should be considered when assessing ischemic-type biliary lesions.
The present study investigates the hemispheric contributions of neuronal reorganization following early single-sided hearing (unilateral deafness). The experiments were performed on ten cats from our colony of deaf white cats. Two were identified in early hearing screening as unilaterally congenitally deaf. The remaining eight were bilaterally congenitally deaf, unilaterally implanted at different ages with a cochlear implant. Implanted animals were chronically stimulated using a single-channel portable signal processor for two to five months. Microelectrode recordings were performed at the primary auditory cortex under stimulation at the hearing and deaf ear with bilateral cochlear implants. Local field potentials (LFPs) were compared at the cortex ipsilateral and contralateral to the hearing ear. The focus of the study was on the morphology and the onset latency of the LFPs. With respect to morphology of LFPs, pronounced hemisphere-specific effects were observed. Morphology of amplitude-normalized LFPs for stimulation of the deaf and the hearing ear was similar for responses recorded at the same hemisphere. However, when comparisons were performed between the hemispheres, the morphology was more dissimilar even though the same ear was stimulated. This demonstrates hemispheric specificity of some cortical adaptations irrespective of the ear stimulated. The results suggest a specific adaptation process at the hemisphere ipsilateral to the hearing ear, involving specific (down-regulated inhibitory) mechanisms not found in the contralateral hemisphere. Finally, onset latencies revealed that the sensitive period for the cortex ipsilateral to the hearing ear is shorter than that for the contralateral cortex. Unilateral hearing experience leads to a functionally-asymmetric brain with different neuronal reorganizations and different sensitive periods involved.
The function of the cerebral cortex essentially depends on the ability to form functional assemblies across different cortical areas serving different functions. Here we investigated how developmental hearing experience affects functional and effective interareal connectivity in the auditory cortex in an animal model with years-long and complete auditory deprivation (deafness) from birth, the congenitally deaf cat (CDC). Using intracortical multielectrode arrays, neuronal activity of adult hearing controls and CDCs was registered in the primary auditory cortex and the secondary posterior auditory field (PAF). Ongoing activity as well as responses to acoustic stimulation (in adult hearing controls) and electric stimulation applied via cochlear implants (in adult hearing controls and CDCs) were analyzed. As functional connectivity measures pairwise phase consistency and Granger causality were used. While the number of coupled sites was nearly identical between controls and CDCs, a reduced coupling strength between the primary and the higher order field was found in CDCs under auditory stimulation. Such stimulus-related decoupling was particularly pronounced in the alpha band and in top–down direction. Ongoing connectivity did not show such a decoupling. These findings suggest that developmental experience is essential for functional interareal interactions during sensory processing. The outcomes demonstrate that corticocortical couplings, particularly top-down connectivity, are compromised following congenital sensory deprivation.
Cortical development extensively depends on sensory experience. Effects of congenital monaural and binaural deafness on cortical aural dominance and representation of binaural cues were investigated in the present study. We used an animal model that precisely mimics the clinical scenario of unilateral cochlear implantation in an individual with single-sided congenital deafness. Multiunit responses in cortical field A1 to cochlear implant stimulation were studied in normal-hearing cats, bilaterally congenitally deaf cats (CDCs), and unilaterally deaf cats (uCDCs). Binaural deafness reduced cortical responsiveness and decreased response thresholds and dynamic range. In contrast to CDCs, in uCDCs, cortical responsiveness was not reduced, but hemispheric-specific reorganization of aural dominance and binaural interactions were observed. Deafness led to a substantial drop in binaural facilitation in CDCs and uCDCs, demonstrating the inevitable role of experience for a binaural benefit. Sensitivity to interaural time differences was more reduced in uCDCs than in CDCs, particularly at the hemisphere ipsilateral to the hearing ear. Compared with binaural deafness, unilateral hearing prevented nonspecific reduction in cortical responsiveness, but extensively reorganized aural dominance and binaural responses. The deaf ear remained coupled with the cortex in uCDCs, demonstrating a significant difference to deprivation amblyopia in the visual system.
There is a need for diagnostic biomarkers of epilepsy and status epilepticus to support clinical examination, electroencephalography and neuroimaging. Extracellular microRNAs may be potentially ideal biomarkers since some are expressed uniquely within specific brain regions and cell types. Cerebrospinal fluid offers a source of microRNA biomarkers with the advantage of being in close contact with the target tissue and sites of pathology. Here we profiled microRNA levels in cerebrospinal fluid from patients with temporal lobe epilepsy or status epilepticus, and compared findings to matched controls. Differential expression of 20 microRNAs was detected between patient groups and controls. A validation phase included an expanded cohort and samples from patients with other neurological diseases. This identified lower levels of miR-19b in temporal lobe epilepsy compared to controls, status epilepticus and other neurological diseases. Levels of miR-451a were higher in status epilepticus compared to other groups whereas miR-21-5p differed in status epilepticus compared to temporal lobe epilepsy but not to other neurological diseases. Targets of these microRNAs include proteins regulating neuronal death, tissue remodelling, gliosis and inflammation. The present study indicates cerebrospinal fluid contains microRNAs that can support differential diagnosis of temporal lobe epilepsy and status epilepticus from other neurological and non-neurological diseases.
Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region-specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern-hemisphere forests.
The production of Σ0 baryons in the nuclear reaction p (3.5 GeV) + Nb (corresponding to sNN=3.18 GeV) is studied with the detector set-up HADES at GSI, Darmstadt. Σ0s were identified via the decay Σ0→Λγ with subsequent decays Λ→pπ− in coincidence with a e+e− pair from either external (γ→e+e−) or internal (Dalitz decay γ⁎→e+e−) gamma conversions. The differential Σ0 cross section integrated over the detector acceptance, i.e. the rapidity interval 0.5<y<1.1, has been extracted as ΔσΣ0=2.3±(0.2)stat±(−0.6+0.6)sys±(0.2)norm mb, yielding the inclusive production cross section in full phase space σΣ0total=5.8±(0.5)stat±(−1.4+1.4)sys±(0.6)norm±(1.7)extrapol mb by averaging over different extrapolation methods. The Λall/Σ0 ratio within the HADES acceptance is equal to 2.3±(0.2)stat±(−0.6+0.6)sys. The obtained rapidity and momentum distributions are compared to transport model calculations. The Σ0 yield agrees with the statistical model of particle production in nuclear reactions. Keywords: Hyperons, Strangeness, Proton, Nucleus.
The third dataset dedicated to the Open Guided Waves platform aims at carbon fiber composite plates with an additional omega stringer at constant temperature conditions. The two structures used in this work are representative for real aircraft components. Comprehensive measurements were recorded in order to study (I) the impact of the omega stringer on guided wave propagation, and (II) elliptical reference damages of different sizes located at three separate positions on the structure. Measurements were recorded for narrowband excitation (5-cycle toneburst with varying carrier frequencies) and broadband excitation (using chirp waveforms). The paper presents the results of a technical validation including numerical modelling, and enables further research, for example related to probability of detection (POD) analysis.
Vimentin is currently used to differentiate between malignant renal carcinomas and benign oncocytomas. Recent reports showing Vimentin positive oncocytomas seriously question the validity of this present diagnostic approach. Vimentin 3 is a spliced variant and ends with a unique C-terminal ending after exon 7 which differentiates it from the full length version that has 9 exons. Therefore, the protein size is different; the full length Vimentin version has a protein size of ~57 kDa and the truncated version of ~47 kDa. We designed an antibody, called Vim3, against the unique C-terminal ending of the Vimentin 3 variant. Using immune histology, immune fluorescence, Western blot, and qRT-PCR analysis, a Vim3 overexpression was detectable exclusively in oncocytoma, making the detection of Vim3 a potential specific marker for benign kidney tumors. This antibody is the first to clearly differentiate benign oncocytoma and the mimicking eosinophilic variants of the RCCs. This differentiation between malignant and benign RCCs is essential for operative planning, follow-up therapy, and patients' survival. In the future the usage of Vimentin antibodies in routine pathology has to be applied with care. Consideration must be given to Vimentin specific binding epitopes otherwise a misdiagnosis of the patients' tumor samples may result.
Ultrasonic guided waves have been used successfully in structural health monitoring systems to detect damage in isotropic and composite materials with simple and complex geometry. A limitation of current research is given by a lack of freely available benchmark measurements to comparatively evaluate existing methods. This article introduces the extendable online platform Open Guided Waves (http://www.open-guided-waves.de) where high-quality and well-documented datasets for guided wave-based inspections are provided. In this article, we describe quasi-isotropic carbon-fiber-reinforced polymer plates with embedded piezoelectric transducers as a first benchmark structure. Intentionally, this is a structure of medium complexity to enable many researchers to apply their methods. In a first step, ultrasound and X-ray measurements were acquired to verify pristine conditions. Next, mechanical testing was done to determine the stiffness tensor and sample density based on standard test procedures. Guided wave measurements were divided into two parts: first, acoustic wave fields were acquired for a broad range of frequencies by three-dimensional scanning laser Doppler vibrometry. Second, structural health monitoring measurements in the carbon-fiber-reinforced polymer plate were collected at constant temperature using a distributed transducer network and a surface-mounted reversible defect model. Initial results serving as validation are presented and discussed.