Pathophysiology : the official journal of the International Society for Pathophysiology最新文献

{"title":"NG2 Glia and Cellular Crosstalk in Health and Disease: Focus on Spinal Cord Injury.","authors":"Ilyas Kabdesh, Aizilya Bilalova, Yana Mukhamedshina, Yuri Chelyshev","doi":"10.3390/pathophysiology33020038","DOIUrl":"10.3390/pathophysiology33020038","url":null,"abstract":"<p><p>NG2 glia, also known as oligodendrocyte progenitor cells, represent a unique population of glial cells characterized by dynamic morphology and the ability to extend branched processes that actively contact neurons and other cellular elements. These structural and functional interactions enable NG2 glia to contribute to the regulation of axonal excitability, electrical activity, and axonal architecture. Unlike most other glial cells, NG2 glia receive direct synaptic input from neurons and can generate action potentials, defining their distinctive physiological status. A particularly important feature of this cell population is the expression of the chondroitin sulfate proteoglycan NG2/CSPG4, which serves as a key molecular marker and plays an essential role in intercellular interactions. Following spinal cord injury (SCI), NG2 glia rapidly become activated, undergo phenotypic changes, and engage in extensive interactions with neurons, astrocytes, microglia, and endothelial cells. These interactions form a complex regulatory network that influences both the severity of secondary injury and the effectiveness of remodeling and repair processes. Mechanisms of particular importance include the secretion of chondroitin sulfate proteoglycans and alterations in extracellular matrix properties. Finally, this review highlights potential therapeutic approaches aimed at modulating NG2 glial activity and their intercellular interactions. The focus is on strategies designed to reduce the inhibitory effects of proteoglycans while enhancing the remyelinating and neuroprotective potential of these cells, thereby opening new perspectives for regenerative therapies after SCI.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13304641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148321496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intracellular Ionic Remodeling During Fetal Development of Hereditary Cardiomyopathy of the Hamster.","authors":"Ghassan Bkaily, Alexandre Normand, Ashley Jazzar, Houssein Najibeddine, Danielle Jacques","doi":"10.3390/pathophysiology33020037","DOIUrl":"10.3390/pathophysiology33020037","url":null,"abstract":"<p><strong>Background/objectives: </strong>The development of hereditary cardiomyopathy associated with early death was known to take place during the patients' lifetime. Previous work showed that remodeling of heart cells in hereditary cardiomyopathy of hamsters (HCMH) took place as early as during postnatal development. The present work tested the hypothesis that cardiomyocyte remodeling in HCMH occurred early in fetal development.</p><p><strong>Methods and results: </strong>Using quantitative 3D confocal microscopy associated with ionic and immunofluorescence, our results showed that, as in the adult heart, cardiomyocytes isolated from 15-day-old fetal HCMH hearts showed an increase in intracellular calcium, sodium, ROS, and sodium-hydrogen exchanger 1 (NHE-1) when compared to age-matched cardiomyocytes of a normal hamster (NH).</p><p><strong>Conclusions: </strong>These results demonstrated that hereditary cardiomyopathy occurred during fetal heart development, and that early treatment with an NHE-1 blocker might have prevented the development of hereditary cardiomyopathy and heart failure that occur during the hamsters' lifetime.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13304898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148321367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Glycocalyx Shedding to Microvascular Collapse in Sepsis: Endothelial Pathophysiology, Organ Dysfunction, and Mechanistic Biomarkers.","authors":"Jhan S Saavedra-Torres, Lady Viviana Acosta Castillo, Alexandra Montoya Rendon, Daniel Esteban Castro Valencia, Diego A Lucero Guanga, Manuela Garzon Ovalle, Fabián Darío Arias Rodríguez, Andrés López-Cortés, Juan S Izquierdo-Condoy","doi":"10.3390/pathophysiology33020036","DOIUrl":"10.3390/pathophysiology33020036","url":null,"abstract":"<p><p>Sepsis is a systemic disorder in which infection-induced inflammation progressively disrupts vascular homeostasis and drives organ dysfunction. This review reframes septic pathophysiology as a sequential and self-amplifying process centered on endothelial failure. Early activation of innate immune pathways by pathogen- and damage-associated molecular patterns promotes cytokine release, oxidative stress, and enzymatic degradation of the endothelial glycocalyx. Loss of this protective surface layer exposes endothelial cells to unbuffered inflammatory and mechanical injury, impairing mechanotransduction, increasing leukocyte and platelet adhesion, and destabilizing vascular barrier function. Subsequent disruption of intercellular junctions promotes capillary leakage, tissue edema, and impaired oxygen diffusion, while mitochondrial dysfunction and redox imbalance reduce endothelial repair capacity. In parallel, complement activation, neutrophil extracellular trap formation, platelet-leukocyte interactions, and loss of anticoagulant signaling shift the microvasculature toward a prothrombotic and proinflammatory state. These interconnected mechanisms culminate in microvascular incoherence, characterized by heterogeneous capillary flow, regional hypoxia, impaired oxygen extraction, and progressive organ failure despite apparent restoration of systemic hemodynamics. Within this framework, biomarkers such as syndecan-1, soluble thrombomodulin, angiopoietin-2, von Willebrand factor, and plasminogen activator inhibitor-1 are best interpreted as mechanistic readouts of glycocalyx shedding, endothelial injury, permeability imbalance, and thromboinflammatory activation. Understanding sepsis as an evolving endothelial pathophysiological process provides a coherent framework for integrating inflammation, vascular leakage, hypoxia, coagulation, and organ dysfunction while identifying mechanistic biomarkers that reflect distinct stages of microvascular collapse.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13305657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148321385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Insights into the Role of Artificial Intelligence and Machine Learning in the Diagnosis and Management of Multiple Sclerosis.","authors":"Alireza Minagar, Mohammadali Sahraian","doi":"10.3390/pathophysiology33020035","DOIUrl":"10.3390/pathophysiology33020035","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system whose heterogeneous clinical, radiological, and biological course has long resisted precise individual-level prediction. The recent convergence of large longitudinal datasets, advanced computational methods, and increasingly informative biomarkers has created conditions in which artificial intelligence (AI) and machine learning (ML) can begin to address that problem substantively. This review surveys the current evidence for AI/ML applications across the MS care continuum, with particular focus on the literature from 2022 through early 2026. Nine domains are examined: automated MRI lesion segmentation and quantification, fluid biomarker interpretation, unsupervised disease subtyping, disability progression prediction, treatment response stratification, drug repurposing and molecular discovery, digital biomarker monitoring, mechanistic interpretability, and integrated clinical management protocols. Notable recent contributions include the SuStaIn-based identification of two biologically distinct MS trajectories distinguished by early versus late serum neurofilament light chain elevation, the MindGlide deep learning platform enabling longitudinal analysis of archived routine clinical MRI data, the T-cell morphological classifier predicting natalizumab treatment response before drug initiation, and the fenebrutinib Phase III program that produced the first Bruton's tyrosine kinase inhibitor results meeting primary endpoints in both relapsing and primary progressive MS. A proposed AI-Enhanced Management Protocol (AMP-26) reflecting 2026 clinical standards is included as an appendix. Throughout, emphasis is placed on mechanistic interpretability: the distinction between models that correlate features with outcomes and models whose decision logic reflects established MS pathobiology is considered a prerequisite for clinical credibility and regulatory readiness.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13306067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148321546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nasal Cytology as a Local Biomarker of Airway Inflammation: A Paradigm Shift in Precision Medicine.","authors":"Matteo Gelardi","doi":"10.3390/pathophysiology33020034","DOIUrl":"10.3390/pathophysiology33020034","url":null,"abstract":"<p><p>Biomarker-driven approaches have markedly improved the stratification and management of airway inflammatory diseases. However, in everyday clinical practice, these strategies still rely mainly on systemic indicators, which often provide only an indirect view of the inflammatory processes occurring within the airway mucosa. This limitation becomes particularly evident in chronic conditions such as chronic rhinosinusitis with nasal polyps (CRSwNP), where local inflammatory patterns may not relate to circulating biomarkers. Nasal cytology represents a simple, non-invasive, and reproducible technique that allows direct evaluation of the cellular components of the nasal mucosa. By identifying distinct inflammatory patterns, it offers a real-time snapshot of the local inflammatory microenvironment, bringing the clinician closer to the site of disease. In this hypothesis, we propose that airway inflammation is primarily driven by local cytological patterns. In particular, we suggest that the interaction between eosinophils and mast cells constitutes a key pathogenic axis underlying disease activity, severity, and progression. From a pathophysiological perspective, eosinophils may reflect a more chronic component of inflammation, whereas mast cells are more closely associated with active and dynamic phases of the disease. Their coexistence may therefore identify a state of amplified inflammatory activity, often associated with more severe clinical phenotypes. We further propose that integrating cytological findings into clinical-cytological grading (CCG) systems could improve patient stratification and support more personalized therapeutic strategies. This model is readily testable in current clinical and research settings and may contribute to a progressive shift toward the use of local biomarkers in precision medicine.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13305861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148321547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is There a Unified Etiology of Hypoplastic Left Heart Syndrome? Evaluating Genetic, Structural, and Hemodynamic Models of Disease Initiation.","authors":"Reese Leonhard, Zachary Beau Phillips, Jamie Wilson, Zaid Abu-Mowis, John DiGiorgi, Epiphany N Wilson, Zane Borenstein, Laura Wilson, Richard Tang, Elizabeth H Stephens, Adrian Crucean, Michael S Shillingford, Giles J Peek, Mark Steven Bleiweis, J Steven Alexander, Jeffrey Phillip Jacobs","doi":"10.3390/pathophysiology33020033","DOIUrl":"10.3390/pathophysiology33020033","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;b&gt;Background&lt;/b&gt;: Hypoplastic left heart syndrome (HLHS) is defined as \"a spectrum of congenital cardiovascular malformations with normally aligned great arteries without a common atrioventricular junction, characterized by underdevelopment of the left heart with significant hypoplasia of the left ventricle including atresia, stenosis, or hypoplasia of the aortic or mitral valve, or both valves, and hypoplasia of the ascending aorta and aortic arch\". Without treatment, HLHS is usually lethal in the neonate. Many hypotheses have been advanced to explain the etiology of HLHS; however, no single theory appears to fully explain the phenotypic variability seen in HLHS. Furthermore, many of these theories offer no explanations regarding the &lt;b&gt;&lt;i&gt;precipitating events&lt;/i&gt;&lt;/b&gt; which lead to the development of HLHS. &lt;b&gt;Objective&lt;/b&gt;: This review considers and critically evaluates the strengths and weaknesses of the leading theories proposed to explain the pathogenesis of HLHS-including &lt;b&gt;&lt;i&gt;hemodynamic disturbances&lt;/i&gt;&lt;/b&gt;, &lt;b&gt;&lt;i&gt;primary myocardial structural defects&lt;/i&gt;&lt;/b&gt;, &lt;b&gt;&lt;i&gt;valvar malformations&lt;/i&gt;&lt;/b&gt;, and &lt;b&gt;&lt;i&gt;genetic or epigenetic alterations that may provoke developmental and anatomic abnormalities&lt;/i&gt;&lt;/b&gt;. After presenting each model, we propose a novel, comprehensive, and data-driven framework which may assist researchers in developing models for the pathogenesis of the various subtypes of HLHS. &lt;b&gt;Methods&lt;/b&gt;: Key findings from human fetal imaging, histopathology, genetic studies, and animal models were considered, as well as the hypothetical contribution of each in observed HLHS phenotypes. The rationales for these findings as causal factors initiating individual HLHS patterns, as well as how they might contribute to HLHS in general, were critically analyzed. &lt;b&gt;Results&lt;/b&gt;: The &lt;b&gt;&lt;i&gt;flow theory&lt;/i&gt;&lt;/b&gt; is strongly supported by animal models and in utero interventions that demonstrate the impact of altered hemodynamics on cardiac morphogenesis. However, the flow theory fails to identify initial causes of disturbed flow or related histological features of HLHS like endocardial fibroelastosis. The &lt;b&gt;&lt;i&gt;myocardial and valve-first models&lt;/i&gt;&lt;/b&gt; suggest an important role in developmental defects, but do not necessarily have a strong experimental basis that provides explanations for how they mediate HLHS. &lt;b&gt;&lt;i&gt;Genetic studies&lt;/i&gt;&lt;/b&gt; in patients with HLHS have identified several candidate causal mutations. However, such genetic causes of HLHS exhibit incomplete phenotypic penetrance and clinical impact. A &lt;b&gt;&lt;i&gt;multifactorial framework&lt;/i&gt;&lt;/b&gt; attempts to integrate these diverse mechanisms and may provide the most coherent explanation that can accommodate the heterogeneity and variable presentation of HLHS. Such a framework may identify multiple forces that drive disease but does not provide useful pathways for future research about HLHS. &lt;b&gt;Conclusions&lt;/b&gt;: No single hypothesis has fully explained how HLHS is initiated, progresses,","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13214730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148039272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pantothenic Acid Derivatives Modulate Oxidative Stress and Hepatic Fibrosis in Bile Duct Ligation-Induced Cholestatic Liver Injury.","authors":"Dmitry S Semenovich, Polina A Abramicheva, Ljubava D Zorova, Andrey V Elchaninov, Maria A Kozlova, David A Areshidze, Nadezda V Andrianova, Nina P Kanunnikova, Andrey G Moiseenok, Irina B Pevzner, Egor Y Plotnikov, Dmitry B Zorov","doi":"10.3390/pathophysiology33020032","DOIUrl":"10.3390/pathophysiology33020032","url":null,"abstract":"<p><strong>Background/objectives: </strong>Inflammation and oxidative stress are key factors contributing to the initiation and progression of liver fibrosis in chronic obstructive cholestasis. Pantothenic acid (PA) and some of its derivatives have been reported to exhibit moderate anti-inflammatory, antioxidant, and regenerative effects. This study aimed to evaluate the redox-modulating effects of PA derivatives-panthenol (PL), pantethine (PT), and hopantenic acid (HPA) in a rat model of chronic obstructive cholestasis induced by common bile duct ligation (BDL).</p><p><strong>Methods: </strong>Macroscopic, histological, and ultrastructural alterations in the liver were assessed, along with molecular markers of oxidative stress, inflammation, and parameters of the glutathione (GSH) system.</p><p><strong>Results: </strong>BDL-induced liver injury was associated with enhanced lipid peroxidation, mitochondrial structural alterations, depletion of GSH, increased levels of protein S-glutathionylation (PSSG), and elevated thiobarbituric acid-reactive substances in mitochondria. Treatment with PL and, to a lesser extent, PT was associated with attenuation of hepatocellular ultrastructural damage, reduced bile duct hyperplasia, decreased inflammatory and necrotic changes, and moderate improvement in fibrosis-related parameters. In contrast, HPA (a PA antagonist) did not demonstrate hepatoprotective effects and it was associated with more pronounced liver injury.</p><p><strong>Conclusions: </strong>Chronic BDL is accompanied by suppression of glutathione redox capacity and enhanced oxidative stress. PL and PT, but not HPA, were associated with reduced levels of protein S-glutathionylation and partial restoration of redox balance. The protective effects of PL and PT may contribute to their antifibrotic activity, potentially through direct antioxidant capacity or redox-modulating mechanisms associated with the GSH system.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13214685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148039285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Syndrome Is Associated with Increased Plasma Fibroblast Growth Factor 21 (FGF21) in Postmenopausal Breast Cancer Survivors: Implications for Therapy and Diagnosis.","authors":"Pedro Céspedes, Cristina Buigues, María Dolores Torregrosa, Francisco M Martínez-Arnau, Omar Cauli, Isabel Trapero","doi":"10.3390/pathophysiology33020031","DOIUrl":"10.3390/pathophysiology33020031","url":null,"abstract":"<p><strong>Background: </strong>Fibroblast growth factor 21 (FGF21) is a peptide hormone that is synthesized by several organs and regulates energy homeostasis, including reducing fat mass and lowering hyperglycemia, insulin resistance and dyslipidemia. It also increased metabolic syndrome (MS) and cardiovascular risk in breast cancer (BC) survivors treated with aromatase inhibitors (AIs) aimed at reducing cancer recurrence. We evaluated whether blood FGF21 concentration is associated with MS and its five criteria in postmenopausal women treated with AIs, and whether this persists after multimodal interventions that reduce MS.</p><p><strong>Methods: </strong>A quasi-experimental longitudinal study in 31 postmenopausal women with localized BC on Ais, assessed via a 12-week multimodal program. Their MS was evaluated per the NCEP-ATP III guidelines (waist circumference, blood pressure, fasting glucose, triglycerides, HDL-cholesterol). Plasma FGF21 was measured pre/post-intervention via fasting blood samples, centrifugation, and ELISA assay.</p><p><strong>Results: </strong>Pre-intervention FGF21 median: 377.62 pg/mL (38.40-1616.42). Plasma FGF21 concentrations positively correlated with MS criteria number pre- and post-intervention (all <i>p</i> < 0.05). Linear regression confirmed pre-intervention MS criteria (β = 127.262, <i>p</i> = 0.006) and antihypertensive drugs as predictors of post-FGF21 levels. Analysis of individual MS criteria revealed significant associations with blood pressure (<i>p</i> = 0.028 and <i>p</i> = 0.022 for systolic and diastolic pressure, respectively) and fasting glucose changes (<i>p</i> = 0.008).</p><p><strong>Conclusions: </strong>Plasma FGF21 may act as a biomarker for monitoring exercise-based interventions which reduce MSs, particularly hypertension and hyperglycemia, in AI-treated BC survivors.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13214933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148039290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytoma-Specific Prognostic Associations of Amyloid-Related Biological Processes.","authors":"Felix Y Narvaez Irizarry, Tyrel R Porter, Neisha Ramirez Serrano, Lilia Y Kucheryavykh","doi":"10.3390/pathophysiology33020030","DOIUrl":"10.3390/pathophysiology33020030","url":null,"abstract":"<p><p><b>Background:</b> Amyloid-related pathways are well studied in neurodegenerative diseases but remain poorly characterized in gliomas. Amyloid-related transcriptional programs in low-grade gliomas (astrocytoma grade II-III) and oligodendrogliomas, and their association with patient survival, were analyzed in this study. <b>Methods</b>: Transcriptomic data from 193 grade II-III astrocytomas and 191 oligodendrogliomas were analyzed to evaluate histology-specific expression patterns and prognostic significance. Differential and single-sample gene set enrichment analyses (ssGSEA) were used to calculate per-sample enrichment scores for 30 amyloid-related Gene Ontology biological process gene sets across the combined cohort. These scores were used to compare pathway activity between grade II-III astrocytoma and oligodendroglioma samples. Pathway-level survival analyses were performed for each tumor type using ssGSEA enrichment scores to evaluate associations with overall survival. <b>Results</b>: Distinct amyloid-related transcriptional programs were identified between glioma subtypes. Grade II-III astrocytomas showed enrichment of pathways related to amyloid precursor protein (APP) processing and amyloid-β clearance, whereas oligodendrogliomas were enriched in lipid transport and negative regulation of amyloid formation. Survival analyses revealed that higher activity of the positive regulation of APP biosynthetic process and amyloid-β clearance by transcytosis was significantly associated with worse overall survival in grade II-III astrocytoma, but not in oligodendroglioma. Gene-level analyses in astrocytoma demonstrated consistent survival associations across multiple genes within these pathways, supporting coordinated pathway-level effects rather than isolated single-gene prognostic markers. <b>Conclusions</b>: Amyloid-related transcriptional programs differ substantially between diffuse glioma subtypes. Increased APP biosynthesis and amyloid-β transcytosis pathways are associated with poorer survival specifically in grade II-III astrocytoma, suggesting a potential role for amyloid metabolism in tumor progression. These findings identify APP-related pathways as candidates for further mechanistic investigation and potential therapeutic targeting in grade II-III astrocytoma.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13214923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148039266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High uPAR and Low miR-221 Expression Predict Poor Disease-Free Survival in Triple-Negative Breast Cancer.","authors":"Weiwei Gong, Yueyang Liu, Natalie Falkenberg, Marion Kiechle, Holger Bronger, Julia Dorn, Viktor Magdolen, Tobias Dreyer","doi":"10.3390/pathophysiology33020029","DOIUrl":"10.3390/pathophysiology33020029","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is associated with poor prognosis and limited targeted treatment options. The urokinase plasminogen activator receptor (uPAR) contributes to tumor aggressiveness and may be regulated by microRNAs such as miR-221. This study aimed to evaluate the prognostic relevance of uPAR mRNA and miR-221 expression in TNBC.</p><p><strong>Methods: </strong>uPAR mRNA and miR-221 expression levels were quantified by real-time PCR in tumor tissues from 101 patients with TNBC. Associations with clinicopathological parameters and disease-free survival (DFS) were analyzed using univariate and multivariable Cox regression models. In silico analyses of publicly available datasets were performed for validation and, in addition, for further miR-221 target prediction.</p><p><strong>Results: </strong>In both univariate and multivariable analyses, high uPAR mRNA expression was associated with shorter DFS, whereas, in contrast, elevated miR-221 expression correlated with improved DFS. No inverse correlation between uPAR and miR-221 expression was observed, making a direct regulatory miR-221/uPAR axis in TNBC unlikely. Still, combined analysis revealed a pronounced additive prognostic effect, with high uPAR and low miR-221 expression identifying patients with the poorest DFS. These findings were supported by in silico analysis with publicly available patient data. Finally, other potential miR-221 targets were identified by applying in silico target prediction.</p><p><strong>Conclusions: </strong>uPAR and miR-221 represent independent prognostic markers in TNBC. Their combined expression provides additional prognostic value for disease-free survival and supports their potential relevance as biomarkers and therapeutic targets in TNBC.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147795749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}