Abstract
To date, more than 263 million people have been infected with SARS-CoV-2 during the COVID-19 pandemic. In many countries, the global spread occurred in multiple pandemic waves characterized ...by the emergence of new SARS-CoV-2 variants. Here we report a sequence and structural-bioinformatics analysis to estimate the effects of amino acid substitutions on the affinity of the SARS-CoV-2 spike receptor binding domain (RBD) to the human receptor hACE2. This is done through qualitative electrostatics and hydrophobicity analysis as well as molecular dynamics simulations used to develop a high-precision empirical scoring function (ESF) closely related to the linear interaction energy method and calibrated on a large set of experimental binding energies. For the latest variant of concern (VOC), B.1.1.529 Omicron, our Halo difference point cloud studies reveal the largest impact on the RBD binding interface compared to all other VOC. Moreover, according to our ESF model, Omicron achieves a much higher ACE2 binding affinity than the wild type and, in particular, the highest among all VOCs except Alpha and thus requires special attention and monitoring.
Miconidin (2-methoxy-6-pentyl-1,4-dihydroxybenzene) and the allergen primin (2-methoxy-6-pentyl-1,4-benzoquinone) have been isolated from fresh unchopped plant material (leaves, stems and flowers ...together) of Primula obconica. Miconidin and primin were obtained in approximately equal amounts and their structures determined by NMR and GC-MS. Miconidin, which is biogenetically related to primin, has not previously been isolated from Primula species, and the possibility that miconidin is an allergen in P. obconica is discussed.
In this study, a 96‐well exposure system for safety assessment of nanomaterials is developed and characterized using an air–liquid interface lung epithelial model. This system is designed for ...sequential nebulization. Distribution studies verify the reproducible distribution over all 96 wells, with lower insert‐to‐insert variability compared to non‐sequential application. With a first set of chemicals (TritonX), drugs (Bortezomib), and nanomaterials (silver nanoparticles and (non‐)fluorescent crystalline nanocellulose), sequential exposure studies are performed with human lung epithelial cells followed by quantification of the deposited mass and of cell viability. The developed exposure system offers for the first time the possibility of exposing an air–liquid interface model in a 96‐well format, resulting in high‐throughput rates, combined with the feature for sequential dosing. This exposure system allows the possibility of creating dose‐response curves resulting in the generation of more reliable cell‐based assay data for many types of applications, such as safety analysis. In addition to chemicals and drugs, nanomaterials with spherical shapes, but also morphologically more complex nanostructures can be exposed sequentially with high efficiency. This allows new perspectives on in vivo‐like and animal‐free approaches for chemical and pharmaceutical safety assessment, in line with the 3R principle of replacing and reducing animal experiments.
In this study, a 96‐well exposure system for safety assessment of nanomaterials is developed and characterized using an air–liquid interface lung epithelial model. In addition to chemicals and drugs, nanomaterials can be exposed sequentially with high efficiency. This allows new perspectives on in vivo‐like and animal‐free approaches for chemical and pharmaceutical safety assessment, in line with the 3R principle.
Metastatic pancreatic cancer (PDAC) has a poor clinical outcome with a 5-year survival rate below 3%. Recent transcriptome profiling of PDAC biopsies has identified 2 clinically distinct subtypes - ...the "basal-like" (BL) subtype with poor prognosis and therapy resistance compared with the less aggressive and drug-susceptible "classical" (CLA) subtype. However, the mechanistic events and environmental factors that promote the BL subtype identity are not very clear. Using preclinical models, patient-derived xenografts, and FACS-sorted PDAC patient biopsies, we report here that the axon guidance receptor, roundabout guidance receptor 3 (ROBO3), promotes the BL metastatic program via a potentially unique AXL/IL-6/phosphorylated STAT3 (p-STAT3) regulatory axis. RNA-Seq identified a ROBO3-mediated BL-specific gene program, while tyrosine kinase profiling revealed AXL as the key mediator of the p-STAT3 activation. CRISPR/dCas9-based ROBO3 silencing disrupted the AXL/p-STAT3 signaling axis, thereby halting metastasis and enhancing therapy sensitivity. Transcriptome analysis of resected patient tumors revealed that AXLhi neoplastic cells associated with the inflammatory stromal program. Combining AXL inhibitor and chemotherapy substantially restored a CLA phenotypic state and reduced disease aggressiveness. Thus, we conclude that a ROBO3-driven hierarchical network determines the inflammatory and prometastatic programs in a specific PDAC subtype.
Purpose
Second opinions in oncology are becoming increasingly important in an era of more complex treatments and a growing demand for information by patients. Therefore, we analyzed their effects and ...influencing factors like patients’ motives, subjective extent of information and satisfaction with communications.
Methods
This prospective study evaluated second opinions for patients with breast cancer or gynecological malignancy. The patients received a questionnaire before and two months after, which inquired expectations, reasons, and satisfaction with the second opinion and the attending physicians.
Results
A total of 164 patients were included and the majority had breast cancer (75.0%). Receiving the second opinion made 89.7% feel better informed, their need for information decreased (from 75.3% to 39.2%,
P
< 0.0001), and satisfaction with doctor–patient communications increased (from 61.9 to 91.8%,
P
= 0.0002). There were various reasons for requesting a second opinion, e.g., the extremely stressful situation of a cancer diagnosis, hope for change in the treatment recommendation or dissatisfaction with the initial physicians.
Conclusions
Second opinions can lead to significantly greater patient satisfaction, meeting the need for information and leading to better management of patients in the extremely stressful situation of a cancer diagnosis. Doctor–patient communications play a key role.
Kulturen des Reparierens Stefan Krebs, Gabriele Schabacher, Heike Weber / Stefan Krebs, Gabriele Schabacher, Heike Weber
2018
eBook
Reparieren und Instandhalten sind ökonomisch wie kulturell zentrale Praktiken im »Leben« technischer Dinge und Infrastrukturen.Der Band rückt diese bislang wenig untersuchten Tätigkeiten in den ...Vordergrund und fragt nach den Wissensformen der unterschiedlichen Kulturen des Reparierens. Die Expertisen und politischen Ambitionen menschlicher Akteure finden dabei ebenso Berücksichtigung wie die Eigendynamik der Dinge. Die Beiträge untersuchen Praktiken wie die Uhr- oder Computerreparatur sowie Räume wie die Wohnung und das Krankenhaus, das Repair Café und die Stadt des Globalen Südens. Nicht zuletzt geht es um die Frage, inwiefern Reparieren und reparaturfreundliches Design zu mehr Nachhaltigkeit beitragen können.
Introduction: Oncological second opinions are becoming increasingly important in the era of complex treatments and established certified cancer centers. Oncological guidelines with the highest levels ...of evidence are available, but these can only be effective to the extent that they are implemented. Therefore, we analyzed the effects of second opinions with regard to their agreement with first opinions and conformity with guidelines. Methods: In 164 patients with a diagnosis of breast cancer or gynecological malignancy who requested a second opinion, the first and second opinions, established at the interdisciplinary tumor conference, and conformity with the guidelines were evaluated. Results: The first opinion was not in agreement with the guidelines in 34.8% (15.2% diagnosis, 12.8% surgical therapy, 13.4% systemic therapy, and 5.5% radiotherapy), and the recommendations were optimized in the second opinion in 56.7% (28.7% diagnosis, 15.9% surgical therapy, 30.5% systemic therapy, and 8.5% radiotherapy). Conclusions: Oncological second opinions showed significant effects and one-third of first opinions were not in conformity with the guidelines. In a significant proportion of cases, the existing treatment plan was changed or supplemented to allow modern and individualized treatment approaches.
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