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The Influence of Sulfation Degree of Glycosaminoglycan-Functionalized 3D Collagen I Networks on Cytokine Profiles of In Vitro Macrophage–Fibroblast Cocultures
No full textCell–cell interactions between fibroblasts and immune cells, like macrophages, are influenced by interaction with the surrounding extracellular matrix during wound healing. In vitro hydrogel models that mimic and modulate these interactions, especially of soluble mediators like cytokines, may allow for a more detailed investigation of immunomodulatory processes. In the present study, a biomimetic extracellular matrix model based on fibrillar 3D collagen I networks with a functionalization with heparin or 6-ON-desulfated heparin, as mimics of naturally occurring heparan sulfate, was developed to modulate cytokine binding effects with the hydrogel matrix. The constitution and microstructure of the collagen I network were found to be stable throughout the 7-day culture period. A coculture study of primary human fibroblasts/myofibroblasts and M-CSF-stimulated macrophages was used to show its applicability to simulate processes of progressed wound healing. The quantification of secreted cytokines (IL-8, IL-10, IL-6, FGF-2) in the cell culture supernatant demonstrated the differential impact of glycosaminoglycan functionalization of the collagen I network. Most prominently, IL-6 and FGF-2 were shown to be regulated by the cell culture condition and network constitution, indicating changes in paracrine and autocrine cell–cell communication of the fibroblast–macrophage coculture. From this perspective, we consider our newly established in vitro hydrogel model suitable for mechanistic coculture analyses of primary human cells to unravel the role of extracellular matrix factors in key events of tissue regeneration and beyond
Costly Causes of Funeral Dissatisfaction and Satisfaction: Responses to an All-Japan Survey
No full textBackground: Previous research shows that grief causes medical and psychological problems for a substantial minority of the bereaved, which places stress on modern medical and social welfare systems. Other research demonstrates that funeral dissatisfaction correlates with medical and psychological problems, but does not address what aspects of funerals cause greatest satisfaction or dissatisfaction. We examined anonymized survey responses describing aspects of funerals causing the greatest anxiety or relief to bereaved Japanese individuals—and in turn affecting medical/welfare costs for the entire society. Method: A research team centered at Kyoto University collected over 1400 questionnaires from recently bereaved Japanese, of whom more than 300 volunteered anonymous comments about their funeral experiences. This article categorizes and analyses these qualitative data. Results: We classified their comments into 10 themes: Hospital Interaction; Pre-arrangement; Timing good-byes; Attendance; Friends/relations; Rituals; Crematorium; Ceremonial meals; Costs; Follow-up. Conclusions: The greatest disappointment appeared in attendance, connection to friends and relations and rituals. When lacking, insufficient, or ill-handled, these leave long-standing bad memories and dissatisfaction that aggravate mourners’ psychological and physical ailments. Our research highlights the psychological effects of cremation, and the value of itemization and explanation of funeral costs. Funeral directors can significantly reduce dissatisfaction by awareness of and sensitivity to these issues, thus contributing to national health and welfare
Construction of Knowledge Graphs: Current State and Challenges
No full textWith Knowledge Graphs (KGs) at the center of numerous applications such as recommender systems and question-answering, the need for generalized pipelines to construct and continuously update such KGs is increasing. While the individual steps that are necessary to create KGs from unstructured sources (e.g., text) and structured data sources (e.g., databases) are mostly well researched for their one-shot execution, their adoption for incremental KG updates and the interplay of the individual steps have hardly been investigated in a systematic manner so far. In this work, we first discuss the main graph models for KGs and introduce the major requirements for future KG construction pipelines. Next, we provide an overview of the necessary steps to build high-quality KGs, including cross-cutting topics such as metadata management, ontology development, and quality assurance. We then evaluate the state of the art of KG construction with respect to the introduced requirements for specific popular KGs, as well as some recent tools and strategies for KG construction. Finally, we identify areas in need of further research and improvement
The European Larynx Organ Preservation Study [MK-3475-C44]
No full textThe European Larynx Organ Preservation Study (ELOS; NCT06137378) is a prospective, randomized, open-label, two-armed parallel group controlled, phase II multicenter larynx organ preservation (LOP) trial in locoregionally advanced (LA) stage III, IVA/B head and neck squamous cell carcinoma of the larynx or hypopharynx (LHSCC) amenable for total laryngectomy (TL) with PD-L1 expression within tumor tissue biopsy, calculated as CPS ≥ 1. Induction chemotherapy (IC) with docetaxel and cisplatin (TP) followed by radiation will be compared to TP plus PD-1 inhibition by pembrolizumab (MK-3475; 200 mg i.v. starting day 1 q3w for 17 cycles). After a short induction early response evaluation (ERE) 21 ± 3 days after the first cycle of IC (IC-1), responders achieving endoscopic estimated tumor surface shrinkage (ETSS) ≥30% will get an additional two cycles of IC followed by intensity-modulated radiotherapy 70–72 Gy (EQD2/α/β = 10) aiming at LOP. Nonresponders (ETSS < 30% or progressing disease) will receive TL and bilateral neck dissection followed by postoperative radiation or chemoradiation as recommended by the clinic’s multidisciplinary tumor board. Pembrolizumab treatment will be continued in the intervention arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent of subsequent decisions on adjuvant therapy after TL
Mineralocorticoid Receptor Signaling in Peripheral Blood Cells in Patients with Multiple Sclerosis
No full textPrognostic Role of Human Leukocyte Antigen Alleles and Cytokine Single-Nucleotide Polymorphisms in Patients with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitor Drugs
No full textTyrosine kinase inhibitor (TKI) drugs have significantly improved chronic myeloid leukemia (CML) outcomes. Neopeptides from CML cells may induce specific immune responses, which are crucial for deep molecular (DMR) and treatment-free remission (TFR). In this study of Ethiopian patients with CML (n = 162), the HLA alleles and single-nucleotide polymorphisms of five cytokines revealed significant associations with clinical outcomes. Clinically unfavorable outcomes correlated with HLA alleles A*03:01/02, A*23:17:01, B*57:01/02/03, and HLA-DRB4*01:01 (p-value = 0.0347, p-value = 0.0285, p-value = 0.037, and p-value = 0.0127, respectively), while HLA-DRB4*01:03:01 was associated with favorable outcomes (p-value = 0.0058). After assigning values for the ‘low’, ‘intermediate’, and ‘high’ gene expression of the SNPs’ respective cytokine genes, Kaplan–Meier estimates for relapse-free survival, adjusted for age, treatment duration, and relapse risk among patients after the administration of TKIs, indicated that a gene expression ratio above the overall median of TNF-α, IL-6, and the combination of TGF-β1/IL-10, IFNγ, and IL-6/IL-10 TGF-β1 was correlated with a higher likelihood of treatment failure ((RR: 3.01; 95% CI: 1.1–8.3; p-value = 0.0261) and (RR: 2.4; 95% CI: 1.1–5.2; p-value = 0.022), respectively). Multi-SNPs, surpassing single-SNPs, and HLA allele polymorphisms showed promise in predicting outcomes of patients with CML during TKI treatment, prompting further exploration into their potential utility
A Flow Cytometry-Based Examination of the Mouse White Blood Cell Differential in the Context of Age and Sex
No full textAnalysis of the white blood cell differential as part of a flow cytometry-based approach is a common routine diagnostic tool used in clinics and research. For human blood, the methodological approach, suitable markers, and gating strategies are well-established. However, there is a lack of information regarding the mouse blood count. In this article, we deliver a fast and easy protocol for reprocessing mouse blood for the purpose of flow cytometric analysis, as well as suitable markers and gating strategies. We also present two possible applications: for the analysis of the whole blood count, with blood from a cardiac puncture, and for the analysis of a certain leukocyte subset at multiple time points in the framework of a mouse experiment, using blood from the facial vein. Additionally, we provide orientation values by applying the method to 3-month-old and 24-month-old male and female C57BL/6J mice. Our analyses demonstrate differences in the leukocyte fractions depending on age and sex. We discuss the influencing factors and limitations that can affect the results and that, therefore, need to be considered when applying this method. The present study fills the gap in the knowledge related to the rare information on flow cytometric analysis of mouse blood and, thus, lays the foundation for further investigations in this area
