BACKGROUND: Various explicit screening tools, developed mostly in central Europe and the USA, assist clinicians in optimizing medication use for older adults. The Turkish Inappropriate Medication use in oldEr adults (TIME) criteria set, primarily based on the STOPP/START criteria set, is a current explicit tool originally developed for Eastern Europe and subsequently validated for broader use in Central European settings. Reviewed every three months to align with the latest scientific literature, it is one of the most up-to-date tools available. The tool is accessible via a free mobile app and website platforms, ensuring convenience for clinicians and timely integration of updates as needed. Healthcare providers often prefer to use their native language in medical practice, highlighting the need for prescribing tools to be translated and adapted into multiple languages to promote optimal medication practices. OBJECTIVE: To describe the protocol for cross-cultural and language validation of the TIME criteria in various commonly used languages and to outline its protocol for clinical validation across different healthcare settings. METHODS: The TIME International Study Group comprised 24 geriatric pharmacotherapy experts from 12 countries. In selecting the framework for the study, we reviewed the steps and outcomes from previous research on cross-cultural adaptations and clinical validations of explicit tools. Assessment tools were selected based on both their validity in accurately addressing the relevant issues and their feasibility for practical implementation. The drafted methodology paper was circulated among the study group members for feedback and revisions leading to a final consensus. RESULTS: The research methodology consists of two phases. Cross-cultural adaptation/language validation phase follows the 8-step approach recommended by World Health Organization. This phase allows regions or countries to make modifications to existing criteria or introduce new adjustments based on local prescribing practices and available medications, as long as these adjustments are supported by current scientific evidence. The second phase involves the clinical validation, where participants will be randomized into two groups. The control group will receive standard care, while the intervention group will have their treatment evaluated by clinicians who will review the TIME criteria and consider its recommendations. A variety of patient outcomes (i.e., number of hospital admissions, quality of life, number of regular medications [including over the counter medications], geriatric syndromes and mortality) in different healthcare settings will be investigated. CONCLUSION: The outputs of this methodological report are expected to promote broader adoption of the TIME criteria. Studies building on this work are anticipated to enhance the identification and management of inappropriate medication use and contribute to improved patient outcomes.
BACKGROUND: The treatment of non-small cell lung cancer (NSCLC) patients is correlated with the efficacy of immune checkpoint blockade therapy (ICB) targeting programmed cell death ligand 1 (PD-L1) or its cognate receptor (PD-1) on cancer cells or infiltrating immune cells. Analysis of PD-L1/PD-1 expression in tumor tissue represents a crucial step before PD-L1/PD-1 blocker usage. METHODS: We used directed evolution of protein variants derived from a 13 kDa Myomedin loop-type combinatorial library with 12 randomized amino acid residues to select high-affinity binders of human PD-L1 (hPD-L1). After the ribosome display, individual clones were screened by ELISA. Detailed analysis of binding affinity and kinetics was performed using LigandTracer. The specificity of Myomedins was assessed using fluorescent microscopy on HEK293T-transfected cells and cultured cancer cells in vitro, formalin-fixed paraffin-embedded (FFPE) sections of human tonsils, and FFPE tumor samples of NSCLC patients. RESULTS: Seven identified PD-L1 binders, called MLE, showed positive staining for hPD-L1 on transfected HEK293T cells and cultured MCF-7 cells. MLE031, MLE105, MLE249, and MLE309 exhibited high affinity to both human and mouse PD-L1-transfected HEK293T cells measured with LigandTracer. The diagnostic potential of MLE variants was tested on human tonsillitis tissue and compared with diagnostic anti-PD-L1 antibody DAKO 28-8 and PD-L1 IHC 22C3 pharmDx antibody. MLE249 and MLE309 exhibited an excellent overlap with diagnostic DAKO 28-8 (Pearson ́s coefficient (r) = 0.836 and 0.731, respectively) on human tonsils on which MLE309 exhibited also excellent overlap with diagnostic 22C3 antibody (r = 0.876). Using three NSCLC tissues, MLE249 staining overlaps with 28-8 antibody (r = 0.455-0.883), and MLE309 exhibited overlap with 22C3 antibody (r = 0.534-0.619). Three MLE proteins fused with Fc fragments of rabbit IgG, MLE249-rFc, MLE309-rFc and MLE031-rFc, exhibited very good overlap with anti-PD-L1 antibody 28-8 on tonsil tissue (r = 0.691, 0.610, and 0.667, respectively). Finally, MLE249-rFc, MLE309-rFc and MLE031-rFc exhibited higher sensitivity in comparison to IHC 22C3 antibody using routine immunohistochemistry staining system Ventana, which is one of gold standards for PD-L1 diagnosis. CONCLUSIONS: We demonstrated the development of MLE Myomedins specifically recognizing hPD-L1 that may serve as a refinement tool for clinical PD-L1 detection.
Aim: The study aimed to investigate the level of postpartum anxiety in the research sample of women after childbirth and factors related to increased level of postpartum anxiety. The goal was also to establish the basic psychometric properties of the Postpartum Specific Anxiety Scale (PSAS-SK) in the Slovak language, and explore selected sociodemographic, perinatal, and anamnestic factors related to increased level of postpartum anxiety in a Slovak research sample. Design: Quantitative cross-sectional research study. Methods: The study involved 122 postpartum women (four-eight weeks postpartum, age 29.5; ± 4.8; 19-42). Data were collected using the standardized PSAS-SK questionnaire alongside sociodemographic and anamnestic data. Statistical analyses included nonparametric tests (Kruskal-Wallis test and Mann-Whitney U test) and confirmatory factor analysis (CFA) to assess the results. Results: Clinically significant levels of postpartum anxiety occurred in 25% of research participants. We found a significant relationship between perception of childbirth as traumatic and increased levels of postpartum anxiety. However, no significant relationship was confirmed between level of postpartum anxiety and education parity, type of childbirth, complications during pregnancy, perinatal loss, skin-to-skin contact, or health complications in the child. The PSAS-SK had high internal consistency in a Slovak research sample (Cronbach's alpha 0.96). Results of the CFA focusing on confirmation of the four-factor structure of the PSAS-SK indicated the following results: χ2(df = 405) = 2188.0, p < 0.001, CFI = 0.07, RMSEA = 0.008. Conclusion: The Postpartum Specific Anxiety Scale is a valuable tool for the early detection of postpartum anxiety symptoms and for supporting interventions to manage heightened anxiety during the postpartum period, including recommendation of specialized mental health care when appropriate.
- MeSH
- Adult MeSH
- Mental Health statistics & numerical data MeSH
- Factor Analysis, Statistical MeSH
- Obstetrics and Gynecology Department, Hospital MeSH
- Humans MeSH
- Statistics, Nonparametric MeSH
- Depression, Postpartum * diagnosis epidemiology psychology MeSH
- Psychometrics * methods MeSH
- Statistics as Topic MeSH
- Anxiety diagnosis epidemiology psychology MeSH
- Self Report MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Validation Study MeSH
- Geographicals
- Slovakia MeSH
PURPOSE: Fuchs endothelial corneal dystrophy (FECD) is a common, age-related cause of visual impairment. This systematic review synthesizes evidence from the literature on artificial intelligence (AI) models developed for the diagnosis and management of FECD. METHODS: We conducted a systematic literature search in MEDLINE, PubMed, Web of Science, and Scopus from January 1, 2000, to June 31, 2024. Full-text studies utilizing AI for various clinical contexts of FECD management were included. Data extraction covered model development, predicted outcomes, validation, and model performance metrics. We graded the included studies using the Quality Assessment of Diagnostic Accuracies Studies 2 tool. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. RESULTS: Nineteen studies were analyzed. Primary AI algorithms applied in FECD diagnosis and management included neural network architectures specialized for computer vision, utilized on confocal or specular microscopy images, or anterior segment optical coherence tomography images. AI was employed in diverse clinical contexts, such as assessing corneal endothelium and edema and predicting post-corneal transplantation graft detachment and survival. Despite many studies reporting promising model performance, a notable limitation was that only three studies performed external validation. Bias introduced by patient selection processes and experimental designs was evident in the included studies. CONCLUSIONS: Despite the potential of AI algorithms to enhance FECD diagnosis and prognostication, further work is required to evaluate their real-world applicability and clinical utility. TRANSLATIONAL RELEVANCE: This review offers critical insights for researchers, clinicians, and policymakers, aiding their understanding of existing AI research in FECD management and guiding future health service strategies.
- MeSH
- Fuchs' Endothelial Dystrophy * diagnosis therapy MeSH
- Humans MeSH
- Tomography, Optical Coherence methods MeSH
- Artificial Intelligence * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Systematic Review MeSH
Cardiovascular diseases are associated with an altered cardiomyocyte metabolism. Because of a shortage of human heart tissue, experimental studies mostly rely on alternative approaches including animal and cell culture models. Since the use of isolated primary cardiomyocytes is limited, immortalized cardiomyocyte cell lines may represent a useful tool as they closely mimic human cardiomyocytes. This study is focused on the AC16 cell line generated from adult human ventricular cardiomyocytes. Despite an increasing number of studies employing AC16 cells, a comprehensive proteomic, bioenergetic, and oxygen-sensing characterization of proliferating vs. differentiated cells is still lacking. Here, we provide a comparison of these two stages, particularly emphasizing cell metabolism, mitochondrial function, and hypoxic signaling. Label-free quantitative mass spectrometry revealed a decrease in autophagy and cytoplasmic translation in differentiated AC16, confirming their phenotype. Cell differentiation led to global increase in mitochondrial proteins [e.g. oxidative phosphorylation (OXPHOS) proteins, TFAM, VWA8] reflected by elevated mitochondrial respiration. Fatty acid oxidation proteins were increased in differentiated cells, whereas the expression levels of proteins associated with fatty acid synthesis were unchanged and glycolytic proteins were decreased. There was a profound difference between proliferating and differentiated cells in their response to hypoxia and anoxia-reoxygenation. We conclude that AC16 differentiation leads to proteomic and metabolic shifts and altered cell response to oxygen deprivation. This underscores the requirement for proper selection of the particular differentiation state during experimental planning.NEW & NOTEWORTHY Proliferating and differentiated AC16 cell lines exhibit distinct proteomic and metabolic profiles with critical implications for experimental design. Proliferating cells predominantly utilize glycolysis and are highly sensitive to hypoxia, whereas differentiated cells display enhanced mitochondrial biogenesis, oxidative phosphorylation, and resistance to anoxia-reoxygenation. These findings provide novel insights into the metabolic adaptations during differentiation and highlight the necessity of selecting the appropriate cellular stage to ensure accurate experimental outcomes.
- MeSH
- Cell Differentiation * physiology MeSH
- Cell Line MeSH
- Energy Metabolism MeSH
- Cell Hypoxia physiology MeSH
- Myocytes, Cardiac * metabolism MeSH
- Humans MeSH
- Mitochondrial Proteins metabolism MeSH
- Mitochondria * metabolism MeSH
- Oxidative Phosphorylation MeSH
- Cell Proliferation MeSH
- Proteomics methods MeSH
- Signal Transduction * physiology MeSH
- Mitochondria, Heart * metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related deaths worldwide. We recently showed that pharmacologically induced lipotoxicity represents a promising therapeutic strategy for the treatment of HCC. Synthetic LXRα agonists induce the production of toxic saturated fatty acids in tumor cells. When combined with DFG-out Raf inhibitors, which block fatty acid desaturation by inducing proteasomal degradation of stearoyl-CoA desaturase (SCD1), LXRα activation can trigger lipotoxicity-induced cancer cell death. However, the clinical translation of this therapeutic strategy is limited by the lack of specific LXRα agonists for clinical use. Here, we have developed a series of promising maleimide LXR agonists with increased potency for LXRα and enhanced specificity. Our agonist frontrunner 40 shows high selectivity for LXRα and strong therapeutic efficacy in HCC organoids, therefore illustrating a strong potential for advancing this lipotoxic treatment strategy to clinical application.
- MeSH
- Carcinoma, Hepatocellular * drug therapy metabolism pathology MeSH
- Liver X Receptors * agonists metabolism MeSH
- Humans MeSH
- Maleimides * pharmacology chemistry therapeutic use MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Liver Neoplasms * drug therapy metabolism pathology MeSH
- Antineoplastic Agents * pharmacology chemistry therapeutic use chemical synthesis MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's are on the rise and pose significant challenges due to the lack of effective treatments. This review critically examines the neuroprotective effects of various natural products derived from plants, marine organisms, and fungi. Natural products have long been used in traditional medicine and are gaining attention in modern drug discovery for their unique properties. The review explains how these natural products can protect neurons by influencing the key biological pathways involved in neurodegeneration. It discusses mechanisms including antioxidant effects, anti-inflammatory actions, modulation of cellular signalling, and support for mitochondrial function. A systematic literature search was conducted to minimize bias and ensure rigorous study selection. Preclinical studies using animal models and cell cultures show that secondary metabolites like polyphenols, alkaloids, and terpenoids can significantly reduce neuronal damage. Some clinical trials have shown promising results. However, challenges such as bioavailability, standardization, and dosage must be addressed to translate these findings into clinical practice. The review also evaluates the potential synergy of combining natural products with conventional treatments, offering a complementary therapeutic approach. Natural products represent a promising avenue for developing innovative treatments for neurodegenerative diseases. The review highlights key research gaps and proposes future directions. Future studies should focus on overcoming existing challenges and refining these natural products to improve their efficacy and safety in clinical settings. The application of existing knowledge has the potential to significantly enhance the quality of life for individuals affected by neurodegenerative diseases.
- Publication type
- Journal Article MeSH
- Review MeSH
BACKGROUND: Epitranscriptomics, the study of RNA modifications such as N6-methyladenosine (m6A), provides a novel layer of gene expression regulation with implications for numerous biological processes, including cellular adaptation to hypoxia. Hypoxia-inducible factor-1 (HIF-1), a master regulator of the cellular response to low oxygen, plays a critical role in adaptive and pathological processes, including cancer, ischemic heart disease, and metabolic disorders. Recent discoveries accent the dynamic interplay between m6A modifications and HIF-1 signaling, revealing a complex bidirectional regulatory network. While the roles of other RNA modifications in HIF-1 regulation remain largely unexplored, emerging evidence suggests their potential significance. MAIN BODY: This review examines the reciprocal regulation between HIF-1 and epitranscriptomic machinery, including m6A writers, readers, and erasers. HIF-1 modulates the expression of key m6A components, while its own mRNA is regulated by m6A modifications, positioning HIF-1 as both a regulator and a target in this system. This interaction enhances our understanding of cellular hypoxic responses and opens avenues for clinical applications in treating conditions like cancer and ischemic heart disease. Promising progress has been made in developing selective inhibitors targeting the m6A-HIF-1 regulatory axis. However, challenges such as off-target effects and the complexity of RNA modification dynamics remain significant barriers to clinical translation. CONCLUSION: The intricate interplay between m6A and HIF-1 highlights the critical role of epitranscriptomics in hypoxia-driven processes. Further research into these regulatory networks could drive therapeutic innovation in cancer, ischemic heart disease, and other hypoxia-related conditions. Overcoming challenges in specificity and off-target effects will be essential for realizing the potential of these emerging therapies.
- MeSH
- Adenosine analogs & derivatives metabolism MeSH
- Epigenesis, Genetic * MeSH
- Hypoxia-Inducible Factor 1 * metabolism genetics MeSH
- Humans MeSH
- RNA Processing, Post-Transcriptional MeSH
- Gene Expression Regulation MeSH
- Signal Transduction MeSH
- Transcriptome MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG.
- MeSH
- Child MeSH
- Adult MeSH
- Glioma * drug therapy genetics pathology MeSH
- Blood-Brain Barrier metabolism MeSH
- Protein Kinase Inhibitors * pharmacology therapeutic use MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Mutation MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Brain Neoplasms * drug therapy genetics pathology MeSH
- Child, Preschool MeSH
- Antineoplastic Agents * pharmacology therapeutic use MeSH
- Pyrazoles * pharmacology therapeutic use MeSH
- Pyrroles MeSH
- Receptor, Platelet-Derived Growth Factor alpha * genetics antagonists & inhibitors metabolism MeSH
- Neoplasm Grading MeSH
- Triazines MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Mice MeSH
- Child, Preschool MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
We present here the co-expressed protein-protein interactions algorithm. In addition to minimizing correlation-causality imbalance and contextualizing protein-protein interactions to the investigated systems, it combines protein-protein interactions and protein co-expression networks to identify differentially correlated functional modules. To test the algorithm, we processed a set of proteomic profiles from different brain regions of controls and subjects affected by idiopathic Parkinson's disease or carrying a GBA1 mutation. Its robustness was supported by the extraction of functional modules, related to translation and mitochondria, whose involvement in Parkinson's disease pathogenesis is well documented. Furthermore, the selection of hubs and bottlenecks from the weightedprotein-protein interactions networks provided molecular clues consistent with the Parkinson pathophysiology. Of note, like quantification, the algorithm revealed less variations when comparing disease groups than when comparing diseased and controls. However, correlation and quantification results showed low overlap, suggesting the complementarity of these measures. An observation that opens the way to a new investigation strategy that takes into account not only protein expression, but also the level of coordination among proteins that cooperate to perform a given function.
- MeSH
- Algorithms * MeSH
- Glucosylceramidase genetics metabolism MeSH
- Humans MeSH
- Protein Interaction Mapping * methods MeSH
- Protein Interaction Maps MeSH
- Brain metabolism MeSH
- Parkinson Disease * metabolism genetics physiopathology MeSH
- Proteomics methods MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
