Search Results (11)

Background/Objectives: Acute myeloid leukemia (AML) is a rare hematological malignancy with a poor prognosis. Activating c-Kit (CD117) mutations occur in 5% of de novo AML and 30% of core-binding factor (CBF) AML, leading to worse clinical outcomes. Posttranslational modifications, particularly with myristic and palmitic acid, are crucial for various cellular processes, including membrane organization, signal transduction, and apoptosis regulation. However, most research has focused on solid tumors, with limited understanding of these mechanisms in AML. Fatty acid synthase (FASN), a key palmitoyl-acyltransferase, regulates the subcellular localization, trafficking, and degradation of target proteins, such as H-Ras, N-Ras, and FLT3-ITDmut receptors in AML. Methods: In this study, we investigated the role of FASN in two c-Kit-N822K-mutated AML cell lines using FASN knockdown via shRNA and the FASN inhibitor TVB-3166. Functional implications, including cell proliferation, were assessed through Western blotting, mass spectrometry, and PamGene. Results: FASN inhibition led to an increased phosphorylation of c-Kit (p-c-Kit), Lyn kinase (pLyn), MAP kinase (pMAPK), and S6 kinase (pS6). Furthermore, we observed sustained high expression of Gli1 in Kasumi1 cells following FASN inhibition, which is well known to be mediated by the upregulation of pS6. Conclusions: The combination of TVB-3166 and the Gli inhibitor GANT61 resulted in a significant reduction in the survival of Kasumi1 cells. Full article

Aqueous sources like salt lake brines and seawater are the most abundant source for lithium ions and might contribute to the growing demand for lithium for energy storage. By coupling with the increasingly relevant reverse osmosis systems, nanofiltration can provide a promising process alternative to conventional methods such as water evaporation and salt precipitation from ores or brines for this purpose. One possible model for nanofiltration is the solution-diffusion-electromigration model (SDEM). First, the model was parametrized by determining the permeances from simple electrolyte mixtures containing two salts. Then, the SDEM was used to predict the rejections of complex multi-electrolyte solutions that mimic seawater and reverse osmosis brine, without fitting additional parameters to experimental data of this complex mixture. This allowed predicting ion rejections satisfactorily. Negative rejections due to spontaneously generated electric fields in the membrane could also be qualitatively described. In summary, this SDEM modeling can provide an important contribution to the purification of Li⁺ from aqueous sources. Full article

Nanofiltration is well suited to separate monovalent ions from multivalent ions, such as the separation of Li⁺ and Mg²⁺ from seawater, a potential lithium source for the production of lithium-ion batteries. To the best of our knowledge, there is no existing work on the optimization of a multi-stage membrane plant that differentiates between different ions and that is based on a validated transport model. This study presents a method for modeling predefined membrane interconnections using discretization along the membrane length and across the membrane thickness. The solution-diffusion–electromigration model was used as the transport model in a fundamental membrane flowsheet, and the model was employed to optimize a given flowsheet with a flexible objective function. The methodology was evaluated for three distinct separation tasks, and optimized operating points were found. These show that permeances and feed concentrations might cause negative rejections and positive rejections (especially for bivalent ions) depending on the ions’ properties and fluxes, thereby allowing for a favorable separation between the ions of different valence at optimized conditions. In an application-based case study for the separation of Li⁺ and Mg²⁺ from seawater, the method showed that under optimal conditions, the mol-based ratio of Mg²⁺/Li⁺ can be reduced from 2383 to 2.8 in three membrane stages. Full article

A great challenge in the use of standardized cancer registry data is deriving reliable, evidence-based results from large amounts of data. A solution could be its mapping to a common data model such as OMOP, which represents knowledge in a unified semantic base, enabling decentralized analysis. The recently released Episode Domain of the OMOP CDM allows episodic modelling of a patient’ disease and treatment phases. In this study, we mapped oncology registry data to the Episode Domain. A total of 184,718 Episodes could be implemented, with the Concept of Cancer Drug Treatment most frequently. Additionally, source data were mapped to new terminologies as part of the release. It was possible to map ≈ 73.8% of the source data to the respective OMOP standard. Best mapping was achieved in the Procedure Domain with 98.7%. To evaluate the implementation, the survival probabilities of the CDM and source system were calculated (n = 2756/2902, median OAS = 82.2/91.1 months, 95% Cl = 77.4–89.5/84.4–100.9). In conclusion, the new release of the CDM increased its applicability, especially in observational cancer research. Regarding the mapping, a higher score could be achieved if terminologies which are frequently used in Europe are included in the Standardized Vocabulary Metadata Repository. Full article

Spray applications enable a uniform distribution of substances on surfaces in a highly efficient manner, and thus can be found at workplaces as well as in consumer environments. A systematic literature review on modelling exposure by spraying activities has been conducted and status and further needs have been discussed with experts at a symposium. This review summarizes the current knowledge about models and their level of conservatism and accuracy. We found that extraction of relevant information on model performance for spraying from published studies and interpretation of model accuracy proved to be challenging, as the studies often accounted for only a small part of potential spray applications. To achieve a better quality of exposure estimates in the future, more systematic evaluation of models is beneficial, taking into account a representative variety of spray equipment and application patterns. Model predictions could be improved by more accurate consideration of variation in spray equipment. Inter-model harmonization with regard to spray input parameters and appropriate grouping of spray exposure situations is recommended. From a user perspective, a platform or database with information on different spraying equipment and techniques and agreed standard parameters for specific spraying scenarios from different regulations may be useful. Full article

Retinoblastoma and other eye tumors in childhood are rare diseases. Many eye tumors are the first signs of a genetic tumor predisposition syndrome and the affected children carry a higher risk of developing other cancers later in life. Clinical and genetic data of all children with eye tumors diagnosed between 2013–2018 in Germany and Austria were collected in a multicenter prospective observational study. In five years, 300 children were recruited into the study: 287 with retinoblastoma, 7 uveal melanoma, 3 ciliary body medulloepithelioma, 2 retinal astrocytoma, 1 meningioma of the optic nerve extending into the eye. Heritable retinoblastoma was diagnosed in 44% of children with retinoblastoma. One child with meningioma of the optic nerve extending into the eye was diagnosed with neurofibromatosis 2. No pathogenic constitutional variant in DICER1 was detected in a child with medulloepithelioma while two children did not receive genetic analysis. Because of the known association with tumor predisposition syndromes, genetic counseling should be offered to all children with eye tumors. Children with a genetic predisposition to cancer should receive a tailored surveillance including detailed history, physical examinations and, if indicated, imaging to screen for other cancer. Early detection of cancers may reduce mortality. Full article

Despite the increased risk of subsequent primary tumors (SPTs) external beam radiation (EBRT) may be the only therapeutic option to preserve a retinoblastoma eye. Due to their physical properties, proton beam therapy (PBT) offers the possibility to use the effectiveness of EBRT in tumor treatment and to decisively reduce the treatment-related morbidity. We report our experiences of PBT as rescue therapy in a retrospectively studied cohort of 15 advanced retinoblastoma eyes as final option for eye-preserving therapy. The average age at the initiation of PBT was 35 (14–97) months, mean follow-up was 22 (2–46) months. Prior to PBT, all eyes were treated with systemic chemotherapy and a mean number of 7.1 additional treatments. Indication for PBT was non-feasibility of intra-arterial chemotherapy (IAC) in 10 eyes, tumor recurrence after IAC in another 3 eyes and diffuse infiltrating retinoblastoma in 2 eyes. Six eyes (40%) were enucleated after a mean time interval of 4.8 (1–8) months. Cataract formation was the most common complication affecting 44.4% of the preserved eyes, yet 77.8% achieved a visual acuity of >20/200. Two of the 15 children treated developed metastatic disease during follow-up, resulting in a 13.3% metastasis rate. PBT is a useful treatment modality as a rescue therapy in retinoblastoma eyes with an eye-preserving rate of 60%. As patients are at lifetime risk of SPTs consistent monitoring is mandatory. Full article

The utilization of CO₂-containing steel-mill gases for synthesis of methanol was investigated. Four different scenarios with syngas derived from steel-mill gases were considered. A process model for an industrial methanol production including gas recirculation was applied to provide realistic conditions for catalyst performance tests. A long-term test series was performed in a close-to-practice setup to demonstrate the stability of the catalyst. In addition, the experimental results were used to discuss the quality of the simulation results. Kinetic parameters of the reactor model were fitted. A comparison of two different kinetic approaches and the experimental results revealed which approach better fits CO-rich or CO₂-rich steel-mill gases. Full article

The Karlsruhe Tritium Neutrino (KATRIN) experiment aims at measuring the effective electron neutrino mass with a sensitivity of 0.2 eV/c², i.e., improving on previous measurements by an order of magnitude. Neutrino mass data taking with KATRIN commenced in early 2019, and after only a few weeks of data recording, analysis of these data showed the success of KATRIN, improving on the known neutrino mass limit by a factor of about two. This success very much could be ascribed to the fact that most of the system components met, or even surpassed, the required specifications during long-term operation. Here, we report on the performance of the laser Raman (LARA) monitoring system which provides continuous high-precision information on the gas composition injected into the experiment’s windowless gaseous tritium source (WGTS), specifically on its isotopic purity of tritium—one of the key parameters required in the derivation of the electron neutrino mass. The concentrations c_x for all six hydrogen isotopologues were monitored simultaneously, with a measurement precision for individual components of the order 10⁻³ or better throughout the complete KATRIN data taking campaigns to date. From these, the tritium purity, ε_T, is derived with precision of <10⁻³ and trueness of <3 × 10⁻³, being within and surpassing the actual requirements for KATRIN, respectively. Full article

The next generation of satellite-based augmentation systems (SBAS) will support aviation receivers that take advantage of the ionosphere-free dual-frequency combination. By combining signals of the L1 and L5 bands, about 99% of the ionospheric refraction effects on the GNSS (Global Navigation Satellite Systems) signals can be removed in the user receivers without additional SBAS corrections. Nevertheless, even if most of the negative impacts on GNSS signals are removed by the ionospheric-free combination, some residuals remain and have to be taken into account by overbounding models in the integrity computation conducted by safety-of-live (SoL) receivers in airplanes. Such models have to overbound residuals as well, which result from the most rare extreme ionospheric events, e.g., such as the famous “Halloween Storm”, and should thus include the tails of the error distribution. Their application shall lead to safe error bounds on the user position and allow the computation of protection levels for the horizontal and vertical position errors. Here, we propose and justify such an overbounding model for residual ionospheric delays that remain after the application of the ionospheric-free linear combination. The model takes into account second- and third-order ionospheric refraction effects, excess path due to ray bending, and increased ionospheric total electron content (TEC) along the signal path due to ray bending. Full article

Almost all protease families have been associated with plant development, particularly senescence, which is the final developmental stage of every organ before cell death. Proteolysis remobilizes and recycles nitrogen from senescent organs that is required, for example, seed development. Senescence-associated expression of proteases has recently been characterized using large-scale gene expression analysis seeking to identify and characterize senescence-related genes. Increasing activities of proteolytic enzymes, particularly cysteine proteases, are observed during the senescence of legume nodules, in which a symbiotic relationship between the host plant and bacteria (Rhizobia) facilitate the fixation of atmospheric nitrogen. It is generally considered that cysteine proteases are compartmentalized to prevent uncontrolled proteolysis in nitrogen-fixing nodules. In addition, the activities of cysteine proteases are regulated by endogenous cysteine protease inhibitors called cystatins. These small proteins form reversible complexes with cysteine proteases, leading to inactivation. However, very little is currently known about how the cysteine protease-cysteine protease inhibitor (cystatin) system is regulated during nodule development. Moreover, our current understanding of the expression and functions of proteases and protease inhibitors in nodules is fragmented. To address this issue, we have summarized the current knowledge and techniques used for studying proteases and their inhibitors including the application of “omics” tools, with a particular focus on changes in the cysteine protease-cystatin system during nodule development. Full article