Gallbladder carcinoma (GBC) is an aggressive malignancy characterized by late-stage presentation, poor prognosis, and limited therapeutic options. Gallstones (GS) represent a major risk factor and are implicated in the majority of GBC cases; however, the molecular distinctions between GS-associated GBC (GBCGS) and GS-independent/de novo GBC (dnGBC) remain poorly defined. To date, no GBC subtype-specific molecular biomarkers have been established. In this study, we employed an integrative transcriptomic and systems biology framework to delineate coding and non-coding RNA signatures underlying GBC pathogenesis. Transcriptomic profiling was performed on tumor tissues representing dnGBC and GBCGS subtypes, followed by comprehensive computational analyses including differential expression analysis, protein-protein interaction (PPI) networks construction, lncRNA-mRNA correlation networks, and competing endogenous RNA (ceRNA) network integration to identify key regulatory nodes. Systems-level analysis revealed distinct pathway enrichments between the two subtypes, indicating molecular heterogeneity in their pathobiology. In dnGBC, lncRNA DIO3OS and a novel transcript MSTRG.16633.1 were identified as highly connected candidate regulatory lncRNAs associated with genes involved in cell adhesion molecule (CAM) pathways. In contrast, GBCGS was characterized by lncRNA LINC00852 and novel transcript MSTRG.53675.1, which were associated with hub mRNAs enriched in the oncogenic signaling pathway. Expression of candidate mRNAs and lncRNAs identified from network analyses were validated by quantitative RT-PCR. This pilot study highlights the complex molecular heterogeneity within the two GBC subtypes and identifies potential RNA signatures involved in dnGBC and GBCGS pathogenesis that may contribute to improved understanding of molecular stratification and targeted therapeutic development.
BACKGROUND: Epidemiological studies link long-term air pollution to an increased risk of hepatocellular carcinoma (HCC), but the underlying toxicological targets remain poorly understood. We used an integrative computational framework to identify and prioritize candidate molecular mediators potentially linking pollutant-associated gene signatures with hepatocarcinogenesis. METHODS: We retrieved pollutant-responsive genes associated with seven toxicants from the Comparative Toxicogenomics Database and intersected them with HCC-associated genes. We used protein-protein interaction (PPI) network analysis to identify hub nodes. An optimized machine learning pipeline (glmBoost and Ridge regression) was trained on GSE36376 and validated in three independent cohorts. We mapped gene program activity within the tumor microenvironment using single-cell RNA sequencing (scRNA-seq) and modeled perturbations with scTenifoldKnk. Finally, we assessed structural compatibility between pollutants and protein targets. RESULTS: We identified 240 genes at the intersection of pollutant and HCC sets. Enrichment analysis highlighted innate immune signaling and chronic inflammation, specifically the IL-17, TNF, and NF-κB pathways. Hub nodes included IL6, TNF, MMP9, and AKT1. The machine learning model prioritized five candidate transcriptomic markers: FOS (AUC = 0.944), PARP1 (AUC = 0.929), MMP9 (AUC = 0.813), CCL5 (AUC = 0.747), and JUN (AUC = 0.733), all validated across cohorts. scRNA-seq module scoring showed the highest activity in T cells, monocytes, and macrophages. However, these data lack individual-level pollutant exposure documentation. In silico MMP9 knockout perturbed genes involved in angiogenesis and the extracellular matrix. Molecular docking suggested preliminary structural compatibility between toluene and MMP9 (-5.2 kcal/mol). CONCLUSION: This analysis outlines a potential "pollutant-immune/inflammation-HCC" framework and identifies five transcriptomic signatures for further validation. These findings support a hypothesis that air pollutant-associated molecular programs may be linked to HCC pathobiology and warrant experimental validation.
Journal of ovarian researchFeiling Huang, Hongyan Chen, Song Mei, Huadan Xue, Qin Wang, Zhaohui Lu, Peng Zhang, Rong Chen
BACKGROUND: Ovarian steroid cell tumors-not otherwise specified (SCT-NOS) is a rare category of sex cord-stromal tumor, however, its pathophysiology is unclear. A comprehensive cellular atlas of ovarian SCT-NOS remains lacking. METHODS: We reported a case of a 41-year-old woman with hyperandrogenism for whom histopathological analysis confirmed the presence of ovarian SCT-NOS. This study utilized single-cell RNA sequencing in a case of ovarian SCT-NOS. RESULTS: Seven cell types, including four keratin 19 (KRT19)⁺ steroidogenic cell subtypes, were identified in the tumor microenvironment. We detected aberrant gene expression across various cell types in ovarian SCT-NOS. KRT19⁺ steroidogenic cells were enriched in genes involved in ovarian steroidogenesis and steroid biosynthesis pathways, which was consistent with the pathobiology of hyperandrogenism. Moreover, we revealed distinct immune cell types in the tumor microenvironment. Five immune cell types within the tumor microenvironment were identified, among which tumor-associated macrophage (TAM) and dendritic cell (DC) were the predominant immune cells. CONCLUSIONS: This transcriptomic analysis revealed distinct cell types and key genes within the tumor microenvironment, offering insights into the cellular heterogeneity and molecular mechanisms of ovarian SCT-NOS, thereby enhancing the understanding and encouraging further investigations into ovarian SCT-NOS.
Journal of the neurological sciencesAlexander H Morrison, Jeffrey A Allen
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated syndrome that causes progressive and relapsing weakness and sensory loss. Evidence-based treatments that have been shown to lessen disability, improve impairment, and prevent relapse include immunoglobulins, corticosteroids, and plasma exchange. While these therapeutics are beneficial to most patients, not all patients respond, residual deficits are common even in responding patients, and each treatment is associated with a unique set of side effects and logistical limitations. The neonatal Fc receptor (FcRn) has emerged as a promising therapeutic target in IgG antibody-mediated diseases. Multiple FcRn inhibitors are now under development for CIDP with one, efgartigimod, now approved for treatment of CIDP. This review summarizes the pathobiology of CIDP, the current treatment landscape, and the rationale for FcRn inhibition in CIDP. It then reviews the data on FcRn inhibitors currently under investigation for CIDP with a focus on applying the clinical trial evidence to clinical practice.
Worldwide implementation of antiretroviral therapy (ART) for pregnant women living with human immunodeficiency virus type-1 (HIV-1) has markedly reduced mother-to-child HIV-1 transmission rate to less than one percent. Despite this benefit, adverse pregnancy outcomes remain a major concern. Placental deficits induced by antiretroviral drugs (ARVs) are increasingly recognized as a potential causative factor. Additionally, comorbid effects of substance use on placenta cannot be overstated. Addictive substances are commonly used by people living with HIV-1 (PLWH). However, globally, nicotine exposure through smoking or tobacco use remains a major comorbidity in PLWH. Yet, to date, whether and how, HIV-1, ARVs, and nicotine together exacerbate adverse effects on placenta and affect birth outcomes is unknown. Due to ethical concerns and impracticality of obtaining placenta tissues at different stages of pregnancy, appropriate experimental models that closely recapitulate in vivo placenta physiology are essential to define how HIV-1, ART, and nicotine independently or collectively affect placental development and functions. Herein, we provide a comprehensive review of the experimental placenta models that have been or are yet to be utilized to study placental comorbid pathobiology induced by HIV-1 infection, ART, and/or nicotine exposure. We emphasize how each model is used (or underused) to interrogate infection biology, pharmacokinetic profile, and toxico-pharmacologic mechanisms. Moreover, key limitations associated with each placenta model and necessary improvements for investigating HIV-1 and associated comorbidity are highlighted. Overall, this review seeks to educate both clinical and basic scientists on advances made, and remaining challenges in understanding comorbid effects of HIV-1-ART-nicotine on pregnancy outcomes using experimental placenta models.
CirculationMarc Humbert, Katarina Zeder, Gabor Kovacs, Jason Weatherald
Pulmonary arterial hypertension (PAH) is a rare, progressive disease of the precapillary pulmonary arteries, characterized by fibroproliferative vascular remodeling, increased pulmonary vascular resistance, right ventricular failure, and premature death. Over the past four decades, substantial advances in understanding PAH pathobiology, epidemiology, diagnosis, and treatment have meaningfully improved patient outcomes. The pathobiology of PAH is multifaceted, involving endothelial dysfunction, smooth muscle cell hyperproliferation, inflammation, and dysregulation of key signaling pathways, including the prostacyclin, nitric oxide, endothelin 1, and bone morphogenetic/TGF-β (transforming growth factor β) axes. Dysregulation of the activin arm of the TGF-β pathway has emerged as a critical driver of vascular remodeling and is the target of sotatercept, the first antiremodeling therapy approved for PAH. Epidemiologically, PAH now more commonly affects older adults with cardiovascular and pulmonary comorbidities compared with historical cohorts. The global burden varies considerably, with methamphetamine-associated PAH rising in North America and schistosomiasis- and HIV-associated PAH prevalent in low- and middle-income countries, where underdiagnosis likely remains substantial. Diagnosis continues to be delayed, with advanced symptoms present at the time of diagnosis for most patients. Right heart catheterization remains essential for definitive diagnosis. Emerging tools, including artificial intelligence applied to electrocardiography, echocardiography, and electronic health records, hold promise for earlier case identification. Management and prognostication of PAH is based on regular risk stratification using validated multiparameter tools. The initial therapy choice is up-front combination therapy with 2 oral medications for most patients, with initial triple therapy that includes a parenteral prostacyclin used in high-risk patients. Add-on therapy with sotatercept is now an option for patients not achieving low risk, a strategy that led to improvements in hemodynamics, right heart function, and reduced the risk of adverse clinical outcomes in recent randomized trials. For patients who remain at higher risk despite maximal therapy, lung transplantation remains an important and life-saving option. Despite remarkable therapy progress, gaps persist in earlier detection, management of comorbid phenotypes, personalized therapy, and novel therapies targeting right ventricular failure. Ongoing clinical trials and translational research continue to advance the field toward the goal of normal survival and quality of life for patients with PAH.
NOP56, a core nucleolar component involved in small nucleolar ribonucleoprotein assembly, has been genetically implicated in spinocerebellar ataxia type 36. However, the role of NOP56 in mammalian neurodevelopment and disease remains poorly defined. We investigated NOP56 pathobiology using both in vitro induced pluripotent stem cell-derived neurons and in vivo NOP56 knockout mouse models. NOP56 expression significantly decreased both in the spinocerebellar ataxia type 36 patients induced pluripotent cells and induced pluripotent cell-derived neurons, which suggests the possibility that the NOP56 loss of function is involved in the spinocerebellar ataxia type 36 phenotype. Therefore, we generated and validated the NOP56 knockout mouse phenotype. Homozygous NOP56 deletion resulted in total embryonic lethality; no NOP56-/- progeny was viable at birth. Heterozygous knockouts showed clasping at 8 months of age and had a larger body size with aging, although there was no significant difference in survival between heterozygous and wild type. Heterozygous knockout mice showed deterioration in rotarod performance and a decrease in exploration behavior. Immunohistochemical analysis of the heterozygous knockouts revealed widespread, significant central nervous system abnormalities, particularly cerebellar degeneration, accompanied by motor cortex and spinal cord disturbances. Widespread ubiquitin-positive inclusions were detected in the cerebellum, motor cortex, and anterior spinal cord of the heterozygous knockout mice at the 12-month age, and it was positive from the 6-month age in the cerebellum. Colocalizations of TDP-43 and ubiquitin were observed in the motor cortex, spinal cord, and cerebellum. Along with findings from previous reports showing early downregulation of NOP56 in SOD1 G93A transgenic mice, this finding indicates that NOP56 might be involved in a wide range of motor neuron diseases. The pathological characteristics of the NOP56 heterozygous knockouts are like those of a patient with spinocerebellar ataxia type 36. Results reveal that NOP56 is indispensable for mammalian embryogenesis and central nervous system maintenance, and that its reduction contributes to molecular pathology in spinocerebellar ataxia type 36. These findings uncover a convergent neurodegenerative mechanism and identify NOP56 as a potential therapeutic target.Clinical trial registrationThis study was registered with the Japan Clinical Trials Registry (http//umin.ac.jp/ctr/index/htm), under the number UMIN000047097.
Inflammation research : official journal of the European Histamine Research Society ... [et al.]Lingfeng Liu, Mingjun Jiang, Muzi Lei, Kun Du, Xiangyang Ye, Dafei Wei, Xiaowu Tan, Zhuang Mi, Yao Tang, Ruiting Sun, Sha Liu
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation, chronic airway inflammation, and epithelial remodeling. Although oxidative stress and lipid peroxidation are increasingly recognized as important contributors to COPD pathobiology, the epithelial biomarkers and regulatory pathways linking cigarette-smoke exposure to ferroptosis-related injury remain incompletely defined. OBJECTIVE: This study aimed to identify COPD-associated biomarkers and pathways by integrating bulk transcriptomics, single-cell RNA sequencing, machine-learning analysis, and experimental validation, with a particular focus on the potential association between CYP1B1 and ferroptosis-related epithelial stress. METHODS: Public transcriptomic cohorts, including GSE47460, GSE76925, and GSE37768, were analyzed using differential expression analysis, weighted gene co-expression network analysis, functional enrichment analysis, and machine-learning-based feature prioritization. Single-cell RNA-seq datasets, including GSE196341 and GSE135893, were used to explore cell-type localization of candidate genes. A cigarette-smoke-exposed mouse model and cigarette-smoke extract-treated 16HBE cells were used for experimental validation, and small-scale proteomic data were incorporated as orthogonal supporting evidence. Molecular docking was performed as an exploratory analysis to predict putative interactions between CYP1B1 and candidate compounds. RESULTS: Twenty-four candidate genes were identified by intersecting COPD-associated co-expression modules with differentially expressed genes. Machine-learning analysis prioritized BHLHE22, DPP6, DHRS9, and CYP1B1 as candidate diagnostic biomarkers. The combined model showed high discrimination in the training cohort, with reduced but retained performance in an external validation cohort. Single-gene ROC analysis in an independent dataset suggested moderate discriminatory performance, with CYP1B1 showing relatively consistent performance across analyses. Single-cell analysis indicated that CYP1B1 expression was enriched in airway secretory cell-related populations, and CYP1B1-high airway secretory cells were associated with ferroptosis-related pathway signatures. In cigarette-smoke-exposed mice and CSE-treated 16HBE cells, CYP1B1 expression was increased, accompanied by inflammatory and epithelial injury-related changes. Knockdown of CYP1B1 attenuated CSE-induced alterations in ferroptosis-related markers, including GPX4, MDA, 4-HNE, and GSH/GSSG. Exploratory molecular docking identified several compounds with predicted CYP1B1-binding potential, although experimental validation is required. CONCLUSIONS: Integrative multi-omics and experimental analyses identified CYP1B1 as a candidate COPD-associated epithelial stress biomarker linked to ferroptosis-related signatures in airway secretory cell populations. The findings suggest a potential association between cigarette-smoke-induced CYP1B1 upregulation, lipid peroxidation-related epithelial injury, and epithelial remodeling in COPD. However, CYP1B1 should be considered an exploratory biomarker and putative mechanistic node rather than a validated diagnostic tool or therapeutic target at this stage. Further studies using larger clinically annotated cohorts, smoking-adjusted analyses, cell-type-specific perturbation, ferroptosis rescue experiments, and pharmacological validation are needed.
International journal of molecular medicineRuhui Yang, Haimin Zeng, Qi Xiao, Yining Xie, Yi Long, Xiang Chen
Osteoarthritis (OA) is a chronic degenerative joint disease closely associated with aging and metabolic dysfunction, characterized by cartilage degeneration, synovial inflammation, aberrant subchondral bone remodeling, pain and progressive functional impairment. Beyond mechanical loading, accumulating evidence indicates that OA is increasingly recognized as a whole‑joint disorder shaped by the interplay between local tissue damage and systemic endocrine‑metabolic imbalance. Endocrine factors, including sex hormones, thyroid hormone, melatonin, parathyroid hormone and vitamin D, together with metabolic disturbances, such as obesity, insulin resistance, dysregulated glucose and lipid metabolism and gut microbiota imbalances, can cooperatively remodel the joint microenvironment. Mechanistically, these alterations converge on immuno‑inflammatory amplification, mitochondrial dysfunction, oxidative stress, cellular senescence, metabolic reprogramming and regulated cell death, thereby promoting extracellular matrix degradation, persistent synovitis and uncoupled bone‑cartilage remodeling. The present review systematically summarizes the molecular basis of endocrine‑metabolic crosstalk in OA and discusses emerging therapeutic opportunities targeting hormonal signaling, metabolic pathways, circadian regulation, nutritional support and lifestyle interventions. Nevertheless, the reciprocal interactions among endocrine signals, systemic metabolic abnormalities and local joint pathology remain incompletely understood, and their translation into mechanism‑based clinical stratification remains at an early stage. Thus, targeting endocrine‑metabolic crosstalk may support mechanism‑based phenotyping and subtype‑informed precision therapy for OA, provided that candidate biomarkers and interventions are validated in prospective clinical studies.
BACKGROUND: Aplastic anemia (AA) is an immune-mediated bone marrow failure syndrome marked by pancytopenia and a hypocellular, fatty bone marrow. Growing evidence indicates that intrinsic abnormalities in bone marrow-derived mesenchymal stem cells (BM-MSCs), including inadequate hematopoietic support, cellular senescence, chronic inflammation, and enhanced adipogenic differentiation, contribute to disease pathophysiology. However, the epigenetic mechanisms underlying these abnormalities remain poorly understood. This work aims to define the epigenetic landscape of AA BM-MSCs and investigate key epigenetic regulators associated with niche failure. METHODS AND RESULTS: RNA sequencing data from AA patients and healthy controls were analyzed using bioinformatics methods, including differential gene expression analysis, Gene Ontology (GO) analysis, and Reactome pathway enrichment analysis. Principal component analysis revealed a clear separation between AA and control samples. Differential expression analysis identified 713 disrupted epigenetic regulators in AA BM-MSCs. Functional enrichment analysis indicated significant changes in pathways including chromatin remodelling, stem cell maintenance, DNA damage response, cellular senescence, inflammation, and lineage commitment. Quantitative real-time PCR validation confirmed overexpression of SETD1A, MLL1, EZH2, KDM3A, and PRMT1, and downregulation of DNMT3A, KDM2B, EHMT1, and KDM5C, consistent with the transcriptomic results. CONCLUSIONS: Our data show that AA BM-MSCs exhibit broad epigenetic dysregulation, which may contribute to bone marrow niche failure, chronic inflammation, senescence-associated changes, and reduced hematopoietic support. These findings provide novel insights into the epigenetic basis of AA pathobiology and suggest potential treatment targets to restore the function of the bone marrow microenvironment.
bioRxiv : the preprint server for biologyKiyoshi Uemasu, Kazuya Tanimura, Atsushi Miyamoto, Koichi Hasegawa, Zachary Lane, Reika Nyunoya, Haruka Uemasu, Brett A Kaufman, Corrine R Kliment, Divay Chand…
Single-cell transcriptomic profiling of chronic obstructive pulmonary disease (COPD) lungs identified QKI, an RNA-binding protein, as a candidate emphysema-associated gene, but its epithelial role in COPD pathobiology remains unclear. We show that QKI expression is reduced in human COPD lungs and that alveolar type 2 epithelial (AT2) cell QKI protein levels correlate strongly with spirometric indices and diffusing capacity (DL CO ). Lung epithelium-specific QKI knockout mice (QKI Δ/Δ ) developed spontaneous airspace enlargement with emphysema-like mechanics, and QKI-deficient AT2 cells showed impaired spheroid colony formation and increased apoptosis. Integrated transcriptomic and proteomic analyses of primary AT2 cells revealed a selective reduction in functional mitochondrial (respiratory-chain and metabolic) protein abundance despite relatively preserved transcript levels, consistent with mitochondrial transcriptome-proteome discordance. QKI loss increased mtDNA abundance and TOMM20 staining but decreased ATP5A, indicating accumulation of structurally increased but functionally dysfunctional mitochondria. In human epithelial cells, CRISPR-mediated QKI deficiency reduced oxidative respiration, increased glycolytic reliance, elevated mitochondrial ROS and membrane potential, and increased apoptosis; these phenotypes were partially rescued by QKI re-expression. These findings identify epithelial QKI as a regulator of mitochondrial integrity and stress tolerance in COPD.
PloS oneEbrar Altınalan, Aleksandra Panina, Robert Fredriksson, Ayse Arzu Şakul, Helgi B Schiöth
Vestibular schwannoma (VS) is a benign Schwann cell-derived tumor that frequently causes progressive hearing loss and vestibulocochlear dysfunction, substantially impacting quality of life. The molecular mechanisms underlying VS pathobiology remain poorly defined, and reliable biomarkers or targeted therapies are lacking. This study aimed to delineate the molecular landscape of VS through a transcriptome-wide meta-analysis. We performed a genome-wide random-effects meta-analysis of four independent Affymetrix microarray datasets from the Gene Expression Omnibus (GEO) database. Differential expression analyses were conducted with and without covariate adjustment. Gene Ontology enrichment and DrugBank-based drug-gene interaction analyses were subsequently applied to characterize biological pathways and assess translational potential. Across the meta-analysis, more than 3,200 differentially expressed genes were identified in the covariate-free model. After applying a more stringent threshold (|metaLFC| > 1 and FDR < 0.05), 1,095 genes remained differentially expressed, with high concordance between the covariate-free and covariate-adjusted models. Downregulated genes included extracellular matrix and stromal components (MFAP5, FABP4, DCN), and sensory- and synapse-related transcripts (SLC22A3, LGI1). Upregulated genes included immune- and inflammation-associated genes (TREM2, CCL3, CCL4, L1CAM) and proliferative regulators (CCND1, RAB31, MOXD1). Functional enrichment highlighted extracellular matrix remodeling, immune modulation, sensory signaling, and cell cycle pathways. Notably, many of the most strongly dysregulated genes have not previously been associated with VS. Drug-gene interaction analysis identified multiple dysregulated genes with known pharmacological targets, suggesting potential translational relevance. This transcriptome-wide meta-analysis provides a comprehensive overview of gene expression patterns in VS, highlighting alterations related to extracellular matrix organization, sensory and synaptic processes, immune-associated signaling, and cell cycle-related pathways. The study highlights novel disease-associated genes and pathways and may help prioritize candidates for further investigation, including those with potential relevance for therapeutic targeting.
International journal of molecular sciencesKaren Flores, Karem Arriaza, Eduardo Pena, Isaac Cortes, Maite Villalobos, Samia El Alam
Exposure to high altitudes for hours or days is defined as acute hypobaric hypoxia (AHH) condition, which rapidly engages adjustments such as signaling pathways involving inflammation, immune modulation and oxidative stress, whose dysregulation has been described as contributing to the pathophysiology of high-altitude illnesses, due to insufficient acclimatization, such as developing acute mountain sickness (AMS). Given its traditional high-altitude use and bioactive properties, Senecio nutans (S. nutans) extract, or chachacoma (CH), has emerged as a potential therapeutic strategy to mitigate high-altitude related pathobiology. The aim of this study was to evaluate the effects of S. nutans on acclimatization, regarding the status of oxidative stress, inflammation, immune and symptoms associated with AMS in an animal model exposed to AHH. Twenty-eight female Wistar rats (≈3 months old) were randomly allocated into four experimental groups (n = 7 each): normobaric normoxia (NX), normobaric normoxia plus S. nutans administration (NX+CH), acute hypobaric hypoxia (AHH; 48 h exposure), and acute hypobaric hypoxia plus S. nutans administration (AHH+CH). S. nutans was administered subcutaneously at a dose of 80 mg/kg, one hour prior to hypoxic exposure. Outcomes included body weight, food intake, hematological parameters, lung histopathology, pulmonary mRNA expression of HIF-1α, NF-κB, TNF-α, IL-1β, IL-6, and VEGF, and lipid peroxidation in lung tissue assessed by malondialdehyde (MDA) levels. After 48 h of AHH, animals exhibited a decrease in body weight and food intake, increase in hematocrit level and total leukocytes, as well as lung injury characterized by thickening of alveolar walls and inflammatory infiltrates. In addition, AHH induced an increase in pulmonary IL-6 and IL-1β mRNA expression. In contrast, S. nutans administration partially attenuated hypoxia-induced body weight loss, mitigated the rise in hematocrit levels, and reduced lung damage, while returning total leukocyte counts to control levels. Notably, S. nutans also decreased the hypoxia-induced overexpression of IL-6 and IL-1β. Regarding lipid peroxidation, no significant differences were observed among groups. These findings suggest that S. nutans exerts a protective effect against acute hypobaric hypoxia by attenuating inflammatory responses and preserving pulmonary structure, thereby supporting its potential as a preventive strategy to mitigate early pathophysiological alterations associated with high-altitude exposure.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease characterized by aberrant epithelial repair, oxidative stress, and chronic inflammatory activation. Although local pulmonary mechanisms have been extensively investigated, systemic molecular alterations in untreated patients remain incompletely understood. This study aimed to explore circulating inflammatory, redox, apoptosis-related, and repair-associated alterations in drug-naive IPF. In this prospective exploratory case-control study, 35 drug-naive IPF patients and 40 healthy controls were enrolled. IPF diagnosis was established according to multidisciplinary evaluation and current international diagnostic guidelines. Serum levels of IL-6, IL-1β, and IL-18 were measured by ELISA. Oxidative stress parameters, including total oxidant status (TOS), total antioxidant status (TAS), and superoxide dismutase (SOD), were evaluated using colorimetric assays. Expression levels of p53, EGFR, VEGF, BAX, BCL-2, and FGF were analyzed by quantitative real-time PCR. Statistical analyses were performed using the Mann-Whitney U test. Drug-naive IPF patients exhibited significantly elevated circulating IL-6, IL-1β, and IL-18 levels compared with healthy controls (all p < 0.05), indicating systemic inflammatory activation. Oxidative stress analysis demonstrated significantly increased TOS levels together with reduced TAS and SOD activity (all p < 0.05), consistent with systemic redox imbalance. Gene expression analysis revealed significantly increased p53 and VEGF expression, whereas EGFR expression was significantly decreased in the IPF group (p < 0.05). No significant differences were observed for BAX, BCL-2, or FGF expression. Collectively, these findings suggest the presence of coordinated inflammatory, oxidative, and stress-response alterations in untreated IPF. Drug-naive IPF was associated with detectable systemic inflammatory, redox, and apoptosis-related alterations in peripheral blood samples. These findings support the concept that circulating biomarker changes may accompany early IPF pathobiology beyond the local lung environment. However, given the exploratory and peripheral blood-based design of the study, further tissue-level and longitudinal investigations are required to clarify the mechanistic and clinical significance of these observations.
American journal of clinical pathologyEdna Garcia, Jenny Diaz, Melissa Kelly, Ryan Soles, Naomi James, Zoë Baker, Amy Spiczka
OBJECTIVES: This study examines the cost of completing laboratory education programs across degree levels and evaluates the availability and use of financial resources for laboratory students. Its findings support advocacy to reduce student debt, inform federal and state policy, and help institutions strengthen recruitment and retention by addressing financial barriers. METHODS: This national cross-sectional study surveyed laboratory professionals, educators, and current or recent students across the United States and its territories. It was conducted in a collaboration among the American Society for Clinical Pathology's (ASCP's) Institute for Science, Technology, and Policy; the ASCP Evaluation, Measurement, and Assessment Department; and the ASCP Board of Certification. RESULTS: The cost of attending a laboratory education program generally falls at or below the lower end of national averages for educational expenses among students and working laboratory professionals. Respondents most often rely on self-funding, federal student loans, and private loans, with financing methods varying by enrollment period. Logistic regression showed that dependence on federal loans and younger age were the strongest predictors of student loan participation among laboratory professionals. CONCLUSIONS: Continued advocacy is essential to ensure that laboratory professionals remain included in federal and state scholarships, grants, and loan forgiveness programs. As policies governing educational funding evolve, it is increasingly important to engage stakeholders in championing financial support for laboratory professionals. Doing so will help reduce the burden of educational costs and strengthen pathways into laboratory careers, ultimately securing recruitment and retention.
American journal of clinical pathologyBusra N Delikkaya, Jaime Eberle-Singh, Joanna Chan, Allison Goldberg
OBJECTIVES: Timely communication of significant surgical pathology results is essential for patient safety, yet quantitative data on how pathologists select result recipients, especially in urgent settings, are limited. We examined real-world communication patterns, focusing on STAT vs routine orders. METHODS: We retrospectively reviewed pathologist-initiated notifications of significant surgical pathology results at a tertiary academic medical center (January to July 2024). In 324 events, we recorded recipient/provider characteristics, care team involvement, urgency status, procedural setting, and turnaround time (TAT). Events were compared by ordering provider (OP) vs alternate provider (AP) contact and by STAT vs routine designation using χ2 tests. RESULTS: Most notifications were sent to OPs (67%), with 33% sent to APs. Alternate provider contact was more frequent for STAT cases, biopsies, and shorter TATs (all P < .05). Contacted OPs were more often subspecialty trained (P < .001) and on the care team (P = .001). Ordering providers were more likely to be contacted directly when they were attending physicians and subspecialty trained; radiology was the predominant AP specialty (62%), while obstetrics and gynecology and gastroenterology were most common among OPs. STAT cases showed faster TATs, outpatient settings, and more frequent notification of nonordering but subspecialty-trained clinicians (all P < .05). Recipient role did not differ by urgency. CONCLUSIONS: Pathologists adjust communication based on urgency, prioritizing rapid notification to qualified clinicians when needed. Flexible recipient selection may support timely clinical action and inform institutional communication policies.
ERJ open researchBrandon Budhram, Léon Genecand, Katarina Zeder, Andrea Baccelli, Aleksandar Bokan, Sarah Cullivan, Da Hee Park, Vasile Foris, Julien Grynblat, Etienne Marie Ju…
#ERSCongress 2025 highlighted key advances in the pathobiology, phenotyping and management of pulmonary vascular diseases, reflecting a shift towards precision medicine in these complex patients https://bit.ly/425cVX6.
The Journal of physiologyNadia Haghbin, Michelle S M Kim, Mohammed El-Lakany, David M Richter, Dabasish Kumar Saha, Galina Yu Mironova, David A Steven, Jonathan C Lau, Mel Boulton, Nik…
Constrictor stimuli set arterial tone through coupling processes dependent (electromechanical) and independent (pharmacomechanical) of VM. As the latter receives limited attention, we conducted a focused examination of the cerebral circulation to identify key signalling kinases involved in tone development and their role in regulating blood flow. A multiscale approach was implemented extending from cells to live brain and including myography, western blotting, immunolabelling, two-photon microscopy and modelling. We began by superfusing a G protein-coupled receptor agonist (U46619) onto isolated mouse cerebral arteries to drive a concentration-dependent constriction. Using pharmacology to separate the two processes, electromechanical coupling notably preceded pharmacomechanical, the latter tied to protein kinase C (PKC) activation. PKCδ mediated the pharmacomechanical response, irrespective of whether the agonist was superfused or discretely applied to elicit focal non-electrical constriction. Further analysis revealed (1) the translocation of PKCδ to the membrane, indicating its activation, and (2) the identification of C-kinase-activated protein phosphatase-1 inhibitor of 17 kDa (CPI-17) and heat shock protein 27 (HSP27) as downstream phosphorylation targets of PKCδ involved in regulating tone. Focal non-electrical constriction was observed in vivo along penetrating arterioles, responses dependent on PKCδ. Key findings were confirmed in human cerebral arteries, and modelling demonstrated how focal, non-electrical control sets cerebral blood flow distribution. We conclude pharmacomechanical coupling is robust in cerebral arteries and enabled by PKCδ through phosphorylation of CPI-17 and HSP27. This process allows arteries to focally constrict and presumptively optimize blood flow distribution when discrete stimuli are produced. We discuss how aberrant pharmacomechanical control could underlie focal vascular pathobiology and if PKCδ could be a target for therapeutic control. KEY POINTS: Constrictors set arterial tone through coupling processes dependent (electromechanical) and independent (pharmacomechanical) of membrane potential. The relative contribution of electro- and pharmacomechanical coupling to cerebral arterial tone depends to the concentration and area to which constrictors are applied. Protein kinase Cδ is a key transduction protein within pharmacomechanical coupling that enables a focal segment of cerebral artery to constrict independently of the lengthier vessel. Focal constriction is observed in live cerebral microcirculation and it helps set proper blood flow distribution within the brain.
Proceedings of the National Academy of Sciences of the United States of AmericaAkin Nihat, Parineeta Arora, Christian Schmidt, Melissa L D Rayner, Jacqueline Linehan, Sebastian Brandner, Simon Mead, John Collinge, Parmjit S Jat
Prion diseases represent a unique biological paradigm with mechanistic parallels to other neurodegenerative conditions like Alzheimer's and Parkinson's diseases. However, the study of human prion pathobiology and the development of effective therapeutics has been severely constrained by the inability to propagate human prions in dividing cells-forcing reliance on costly and slow animal bioassays. Here, we report the generation of EKV cells-a humanized cell model which supports the robust, indefinite propagation of sporadic Creutzfeldt-Jakob disease (sCJD) prions. We demonstrate that these cells replicate bona fide human prion infectivity in culture-cell lysates induce lethal neurodegeneration in humanized mice that is clinically and neuropathologically indistinguishable from inoculation with sCJD-infected brain tissue. We use EKV cells to develop the Human Prion Assay (HPA), which quantifies sCJD infectivity with sensitivity comparable to gold-standard mouse bioassay, while reducing the experimental timeline from years to weeks. Furthermore, we demonstrate that established sCJD infection can be cured by an anti-prion protein antibody, validating the system as a high-throughput platform for drug discovery. This model bridges a critical translational gap, offering a renewable alternative to animal bioassays, a paradigm to dissect the biology of human sCJD prion disease and screen for therapeutic agents.
Multiple sclerosis and related disordersOlga Vampertzi, Theofanis Vavilis, Androula Zelilidou, Euthymia Vargiami
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct immune-mediated demyelinating central nervous system disorder, frequently presenting as optic neuritis in children and adolescents. Conversely, aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) is an astrocytopathy characterized by more severe relapses and greater residual visual impairment. This scoping review, conducted according to PRISMA-ScR and JBI methodology, mapped evidence from 23 studies identified across PubMed and Scopus over the last decade. The objective was to examine the epidemiology, clinical presentation, imaging, serological findings, therapeutic strategies, and visual outcomes of these conditions in pediatric populations. Results indicate that pediatric MOGAD-associated optic neuritis often presents with optic disc swelling and bilateral anterior optic nerve involvement with perineural enhancement on MRI, typically resulting in reversible visual loss. The 2023 MOGAD diagnostic criteria show high performance in children. In contrast, AQP4-associated optic neuromyelitis more commonly involves the posterior optic nerve and chiasm, leading to poorer visual outcomes. Regarding treatment, maintenance intravenous immunoglobulin (IVIG) reduces relapse risk in selected MOGAD cases, while B-cell-depleting regimens are primarily used for relapse prevention in AQP4-positive NMOSD. In conclusion, pediatric optic neuritis in MOGAD and AQP4-associated optic neuromyelitis are distinct phenotypes with differing pathobiology and therapeutic requirements. Early serological confirmation and individualized immunotherapy are crucial for preventing relapses and preserving functional vision in pediatric patients.