Search Results (153)

Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, with its highly heterogeneous tumor microenvironment posing substantial challenges for precision diagnosis and therapy. To address this, we aim to construct a novel prognostic framework based on tumor-immune interactions. Through integrative analysis of single-cell RNA sequencing data from 30 TNBC samples (106,132 cells), we identify key tumor expression metaprograms and uncover their interaction with an immunosuppressive dendritic-cell subset, a process associated with the NECTIN1–NECTIN4 axis. Leveraging these interactions, we developed and validated two immunological prognostic models using multi-cohort transcriptomic data, including the stress response tumor cell and pDC_CLEC4C prognostic model (SPSM) and the immune response tumor cell and pDC_CLEC4C prognostic model (IPSM). These models effectively stratified TNBC patients into distinct risk groups, with the low-risk group characterized by an immunologically active microenvironment and elevated expression of immune checkpoint genes, suggesting a potential responsiveness to immunotherapy. Furthermore, we identified several potential therapeutic agents, including imatinib and bortezomib. Collectively, our dual-model framework provides a tool for risk stratification, offers translational insights for precision treatment, and presents new directions for understanding TNBC heterogeneity and therapeutic development. Full article

Background: Tumor-associated neutrophils (TANs) exhibit remarkable functional plasticity within tumor microenvironment (TME), with N1-like subtypes promoting anti-tumor immunity and N2-like subtypes facilitating tumor progression. Despite their critical role in cancer immunology, strategies to selectively modulate TAN polarization remain limited. Methods: We integrated transcriptomic analyses of TAN subtypes to identify potential hub molecules. Molecular docking and experimental assays were used to evaluate DHA’s effect on neutrophil-like cell polarization. Results: Hub genes (TNF, IL1B, PTGS2, BCL2A1, MSR1, ACOD1, CXCL16, CLEC10A, and SOCS3) were identified, with TNF serving as a potential core regulator. Molecular docking indicated that DHA forms stable interactions hub proteins. Experimentally, DHA treatment of neutrophil-like dNB4 cells promoted N1 polarization, evidenced by upregulation of TNF, IL1B, PTGS2, BCL2A1, MSR1, ACOD1, CXCL16, and N1 markers PD-L1 and NOX2, and downregulation of N2 marker CEACAM8 and hub genes CLEC10A and SOCS3. Functional assays demonstrated that DHA-treated cells exhibited increased secretion of TNF, IL1β, ROS, and PD-L1, accompanied by enhanced cytotoxic activity against hepatocellular carcinoma cells in a co-culture system. Conclusions: These findings reveal the molecular mechanisms underlying TAN polarization, and establish DHA as a potent immunomodulatory agent capable of reshaping TANs toward an anti-tumor phenotype. Full article

We evaluated whether macrophage-targeted glyco-modulation can improve day-to-day function in aging companion animals. In a multicenter, randomized, double-blind, placebo-controlled trial, 60 client-owned geriatric dogs (≥10 years) received subcutaneous EF-M2 (0.1 μg/kg, every 72 h for 4 weeks; protocolized, blinded step-up to every 48 h at day 14 for partial responders) or matched placebo, followed by 4 weeks off-treatment. Two prespecified co-primary endpoints were tested hierarchically: change in accelerometer-measured active minutes/day at week 1 and change in a day-28 vitality composite (z-score of inverted CBPI-PSS, HRQL-vitality, and appetite VAS). EF-M2 was superior to placebo on both: +23.05 min/day at week 1 (95% CI, 18.16–27.94; p < 0.001) and +2.01 z-units at day 28 (95% CI, 1.52–2.50; p < 0.001). Key secondaries favored EF-M2, including greater week-4 activity (+33.00 min/day, 26.83–39.18; p < 0.001), lower BAER auditory threshold (−5.28 dB, −7.53 to −3.04; p < 0.001), and reduced transepidermal water loss (−1.35 g/m²·h, −2.45 to −0.25; p = 0.02); multiplicity was controlled with Holm–Bonferroni procedures. Owner-reported global improvement was more frequent with EF-M2 at day 28 (93.3% vs. 10.0%) and remained higher at day 56 off-treatment (50.0% vs. 16.7%). Prespecified pharmacodynamic markers shifted in directions consistent with M2-skewing (ARG1:iNOS ratio and IL-10 increased; TNF-α decreased) by day 7. Adverse events were infrequent, mild, and similar to placebo; no treatment-related withdrawals or serious events occurred. These findings support macrophage-targeted glyco-modulation as a promising approach to rapidly improve real-world activity and multidomain vitality in older dogs, with short-term signals persisting off-treatment; longer, adequately powered trials are warranted to define durability, structural outcomes, and phenotype-specific benefits. Full article

Background: Sarcoidosis is a systemic granulomatous disease of unknown etiology. Pulmonary sarcoidosis with extrapulmonary lesions (EPL) confers poor prognoses. The transcriptomic features of peripheral blood mononuclear cells (PBMCs) could be crucial in sarcoidosis pathogenesis. However, the gene expression characteristics associated with EPL development remain unknown. Methods: Bulk PBMCs were collected from 26 healthy controls and 14 patients with pulmonary sarcoidosis stratified into those with (n = 9) or without (n = 5) EPL. None of the participants were receiving immunosuppressive agents. PBMC transcriptomic analysis was conducted using RNA sequencing. Results: Principal component analysis (PCA) revealed a clear distinction between pulmonary sarcoidosis and healthy control groups, with 227 differentially expressed genes (88 upregulated, 139 downregulated), including upregulated (CLEC7A, GBP5, JAK2, IL15, IL1B, CXCL8, and CXCL10) and downregulated (TNFRSF13C, CD40LG, CD28, and ID3) genes in pulmonary sarcoidosis group. Enrichment analysis revealed upregulated immunological pathways related to granuloma formation in pulmonary sarcoidosis PBMCs, including T helper 17 and tumor necrosis factor-alpha signaling pathways, IL-1B, IL-6, and IL-17 production, and response to external stimuli. Furthermore, patients with and without EPL showed 206 differentially expressed genes (131 upregulated, 75 downregulated), including upregulated (IFNG and IFNLR1) and downregulated (SOCS3, MMP9, and CXCL10) genes. Gene ontology (GO) analysis revealed that interleukin 6 (IL-6) and IL-23 production were upregulated in patients with EPL. Conclusions: These findings elucidate the mechanisms underlying granuloma formation in sarcoidosis and demonstrate the differential transcriptomic features of PBMCs in patients with and without EPL. The upregulation of IFNG and IFNLR1 may be related to EPL development and could serve as potential therapeutic targets for sarcoidosis. Full article

Human intraperitoneal omental adipose tissue, part of the visceral adipose depots, surrounds the abdominal organs and has functions distinct from the subcutaneous adipose depots. In the clinical setting, it is observed that the omentum is beneficial to combat internal sources of inflammation, oxidative stress, and injury-related stress. However, the molecular mechanisms involved in these functions are not fully understood. We previously demonstrated that adipose stem cells derived from human omental adipose tissue (om-hASCs) secrete exosomes (exos). We and others have extensively evaluated the subcutaneous adipose depot-derived exosomes; however, the role of adipose stem cells derived from the human omental depot (om-hASCs) remains less known. In this study, we postulated that exosomes from om-hASCs (om-hASCexos) drive the repair ability of the omentum to heal organs after internal injury and insults. First, we characterized the om-hASCexos using a proteomic analysis which identified the distinct cargo. Using in vitro injury models, we show that om-hASCexos significantly improve cell migration and proliferation, while decreasing oxidative stress and inflammation. To study acute in vivo healing, a rat wound model was evaluated. Om-hASCexos significantly improved the healing rate of injuries. RNAseq revealed that om-hASCexo treatment acts upon pathways associated with lipid and fatty acid metabolism, apoptosis, immune response, and cell differentiation. The pathway analysis indicated that om-hASCexos significantly regulate the expression of Clec5a and Trem1 in the immune response pathway. Overall, we demonstrate the singular properties of om-hASCexos that are distinct from other sources of hASC. Thus, this study provides an understanding of the unique ability of the omental adipose depot to combat internal injuries. Full article

The treatment of acute myeloid leukemia (AML) remains challenging, largely due to high relapse rates following standard therapies. T-cell engagers (TCEs) offer a promising immunotherapeutic approach by redirecting T cells to recognize and kill AML cells. These therapeutic proteins bind CD3 to T cells and a tumor-associated antigen to AML cells, facilitating targeted immune activation. While CD33 and CD123 are the most commonly targeted AML antigens, others such as CD135, CD38, and CLEC12A/CLL-1 are being evaluated in preclinical and clinical studies. In parallel, various TCE formats—including BiTEs, DuoBodies, DARTs, and DARPin-based constructs—have been developed to optimize pharmacokinetics, stability, and immune engagement. Despite the growing number of TCEs entering clinical evaluation, none have advanced beyond early Phase (I/II) trials, primarily due to the lack of optimal target antigens and challenges in balancing antileukemic activity with the risks of immune-related toxicities such as cytokine release syndrome (CRS). This review aims to summarize the current landscape of TCE development in AML, highlighting key targets, formats, and challenges. Full article

Background: Tetranectin (CLEC3B), a plasminogen-binding protein involved in fibrinolysis and tissue remodeling, has been increasingly studied as a potential diagnostic and prognostic biomarker in cardiovascular disease (CVD). This review synthesizes current evidence on its clinical utility across heart failure (HF), coronary artery disease (CAD), and related conditions. Objectives: To systematically evaluate and synthesize published clinical evidence on the diagnostic and prognostic value of tetranectin in cardiovascular diseases. Methods: A systematic search of PubMed, Google Scholar, and Scopus (January 2010–June 2025) identified original human studies examining associations between tetranectin (CLEC3B) and cardiovascular diseases, including heart failure, coronary artery disease, myocardial infarction, and cardiometabolic conditions. Eligible studies included adult cohorts with observational designs; experimental, in vitro, and pediatric studies were excluded. Two reviewers independently extracted data on study design, population characteristics, biomarker assessment, and outcomes, resolving discrepancies by consensus. Results: Twelve studies were included. Tetranectin levels were consistently lower in patients with CAD, MI, and advanced HF compared to controls. Higher circulating TN levels were associated with reduced risk of HF onset, cardiovascular death, and hospitalization. In two studies, combining tetranectin with NT-proBNP improved diagnostic accuracy over NT-proBNP alone. Mechanistic studies revealed correlations between TN expression and fibrosis-related gene pathways, supporting its biological relevance. Conclusions: Tetranectin shows consistent promise as a diagnostic and prognostic biomarker in cardiovascular disease, particularly in heart failure and coronary artery disease. Its involvement in fibrotic remodeling, plasminogen activation, and vascular homeostasis underlines biological pathways relevance. Combining tetranectin with established biomarkers may improve cardiovascular risk stratification and guide more personalized therapeutic strategies. Further large-scale and longitudinal studies are needed to validate its clinical utility across diverse settings. Full article

Osteoarthritis is a prevalent and disabling condition in companion dogs, yet existing treatments are primarily symptomatic and limited by safety concerns. EF-M2, a defined derivative of vitamin D-binding protein, selectively biases macrophages toward an anti-inflammatory phenotype in vitro. We conducted a randomised, double-blind, placebo-controlled trial (IMPAWS-OA-1) in 60 client-owned dogs with naturally occurring hip or elbow osteoarthritis. Animals were allocated to subcutaneous EF-M2 (0.1 µg/kg) given thrice weekly or twice weekly, or to saline placebo for four weeks, followed by four weeks off-drug. The primary endpoint was change in Canine Brief Pain Inventory–Pain Severity Score (CBPI-PSS) at Day 28. EF-M2 produced dose–frequency-dependent benefits: LS-mean ΔPSS was −2.11 for thrice weekly, −1.42 for twice weekly, and −0.54 for placebo (arm effect p < 0.001). Objective measures showed parallel improvements in peak vertical force and accelerometery. Serum biomarkers confirmed macrophage repolarisation (ARG1/iNOS ratio, IL-10 increase, TNF-α decrease), correlating with clinical response. Adverse events were infrequent and mild, with no excess over placebo. In conclusion, EF-M2 achieved clinically meaningful pain relief, functional gains, and biomarker shifts without safety signals, establishing first-in-species proof that targeted macrophage modulation may be a viable disease-modifying approach for canine osteoarthritis. Full article

Background: CLEC5A is a C-type lectin expressed by monocytes and neutrophils, playing an important role in innate immunity. Although it has been shown to interact with the spike protein of SARS-CoV-2, its role during vaccination remains poorly understood. Methods: To address this question, we combined in vitro assays to characterize CLEC5A and spike expression and their impact on monocyte differentiation and T-cell activation; in vivo studies to evaluate CLEC5A expression, immune responses, and vaccine efficacy in a murine model; and in silico analyses to identify potential spike epitopes and CLEC5A interaction sites. Results: The Pfizer-BioNTech bivalent mRNA vaccine induced spike expression and CLEC5A upregulation in THP-1 monocytes, promoting M1-like differentiation and CD86⁺ activation. In PBMC co-cultures, CLEC5A⁺ monocytes acted as antigen-presenting cells, releasing inflammatory chemokines and activating both CD4⁺ and CD8⁺ T cells, thereby linking CLEC5A expression to adaptive immunity. In mice, CLEC5A expression was observed on inflammatory monocytes (CCR2⁺CX3CR1^low) within two days of vaccination. In vivo, CLEC5A expression increased during SARS-CoV-2 infection and after immunization, but declined following viral challenge in vaccinated animals. Consistently, robust humoral and cellular responses were detected post-immunization. In silico analysis further suggested differential CLEC5A binding across B- and T-cell epitopes within the spike glycoprotein. Conclusions: These findings suggest that CLEC5A may play a role in bridging innate and adaptive immune responses during SARS-CoV-2 vaccination. Although further studies with different vaccine platforms are necessary to confirm and expand these observations, our results provide preliminary evidence supporting the potential of CLEC5A as an exploratory biomarker of vaccine-induced immunity. Full article

The American cockroach (Periplaneta americana) serves as an exemplary model for regeneration research due to its exceptional regenerative capabilities, particularly in appendage regeneration. In this study, regenerated coxa tissue underwent histological analysis through H & E straining. Microscopic examination revealed the progression of regeneration. To elucidate the underlying mechanisms, a comparative transcriptomic analysis was conducted between regenerating legs and non-amputated control legs. This analysis identified 2343 differentially expressed genes (DEGs) between 0 days post-amputation (0 dpa) and 7 dpa, 2963 DEGs between 14 dpa and 0 dpa, and 3135 DEGs between 14 dpa and 7 dpa. Significantly, several DEGs are associated with growth- or regeneration-related processes, including extracellular matrix (different collagen, Pro-resilin isoforms, integrin beta (itgb) and matrix metalloproteinase (mmp)), immune-related genes (Toll-like receptor 13 (tlr13), defensin (def), drosomycin-like defensin (dld), Polyphenoloxidases2 (ppo2), cytochrome P450 (p450), peptidoglycan recognition protein (pgrp) and secreted C-type lectin (sClec)), insulin-like growth factor (IGF) and Epidermal Growth Factor Receptor (EGFR). Functional validation through RNA interference (RNAi) further suggested that EGFR and a specific C-type lectin (Regenectin) regulate leg regeneration in Periplaneta americana. These findings enhance our understanding of the molecular mechanisms governing regeneration in this species. Full article

Kupffer cells (KCs) play a pivotal role in the progression of metabolic-associated steatohepatitis (MASH). This study evaluated the impact of short-term KC depletion induced by gadolinium chloride (GdCl₃) in a rat model of MASH. The intervention with GdCl₃ effectively reduced KC markers CD68 and Clec4f, together with pro-inflammatory cytokines (IL-1β, TNFα, NOS2), without affecting anti-inflammatory markers (IL-10, MRC1). Histologically, GdCl₃ reduced hepatocyte ballooning and NAS despite persistent steatosis. KC depletion was associated with decreased oxidative stress markers (TBARS, 3-nitrotyrosine) and antioxidant enzyme activity (SOD, catalase). Additionally, markers of endoplasmic reticulum stress (ATF4, GRP78, CHOP, P58^IPK) and apoptosis (BAX/BCL2 ratio, cleaved caspase-3) were diminished. Despite these improvements, GdCl₃ had no effect on lipid or glucose metabolism in the liver, associated with persistent elevation of PTP1B expression induced by SRD intake. KC depletion, however, increased FGF21 expression. GdCl₃ treatment improved systemic insulin sensitivity and reduced fasting glucose and NEFA serum levels. In white adipose tissue, the treatment decreased adipocyte size, restored insulin signaling, and inhibited lipolysis (ATGL expression) without altering macrophage infiltration (IBA) or thermogenic protein levels (UCP1) in SRD rats. These findings suggest that KC depletion modulates liver-to-adipose tissue crosstalk, potentially through FGF21 signaling, contributing to improved systemic metabolic homeostasis of SRD animals. Full article

Meniscal degradation is considered a driver of osteoarthritis (OA) progression, but the underlying mechanisms leading to age-related meniscus degeneration remain unknown. This study aimed to identify key genes and pathways involved in meniscal degradation through a computational analysis. Gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. Differential expression gene (DEG) analysis was performed using DESeq2 accompanied by functional enrichment analysis, protein–protein interaction (PPI) and clustering analysis. Additionally, gene set enrichment analysis (GSEA) was performed. A total of 85 mRNAs (DEMs) and 8 long non-coding RNAs (DE LncRNAs) were found to be differentially expressed in OA meniscus tissues. Among 85 DEMs, 12 genes were found to be known OA-related genes, whereas 15 genes acted as transcription regulators, including RUNX2 and TBX4, which were identified as effector genes for OA. Enrichment analysis revealed the implication of DEMs in cartilage-degradation-related processes, including inflammatory pathways, lipid metabolism, extracellular matrix organization and superoxide/nitric oxide metabolic processes. Target genes of DE lncRNAs were found to be involved in chondrocyte differentiation and pathways related to cartilage degradation. A comparative analysis of meniscus, synovium and cartilage datasets identified three genes (GJB2, PAQR5 and CLEC12A) as being differentially expressed across all three OA-affected tissues, which were implicated in inflammatory and cholesterol metabolism processes. Our results support that shared mechanisms lead to meniscal and cartilage degradation during OA progression, providing further insights into the processes underlying OA pathogenesis and potential therapeutic targets for knee OA. Full article

Staphylococcus aureus is a significant bacterial pathogen responsible for a wide range of diseases in both humans and animals. This study aimed to investigate nucleotide sequence variations, gene expression patterns, and serum biomarkers, including acute phase proteins (APPs), hormonal fluctuations, and iron profile parameters in sheep affected by pneumonia. Additionally, the study focused on the isolation and characterization of S. aureus from pneumonic sheep, with particular emphasis on the prevalence of methicillin-resistant S. aureus (MRSA) strains. Blood samples were collected from both healthy and pneumonic sheep for gene expression and biochemical analyses, while nasal swabs from pneumonic sheep were used for bacterial isolation and identification. Out of 100 nasal swabs analyzed, 44% tested positive for Staphylococcus spp., and 61.4% of these were confirmed as S. aureus by PCR. The mecA gene, a key marker of methicillin resistance, was identified in 17 isolates (38.6% of the S. aureus-positive samples). MRSA isolates showed complete resistance to amoxicillin, cloxacillin, and erythromycin, and high resistance to penicillin, amoxicillin, and tetracycline; however, all MRSA strains remained fully susceptible to vancomycin. Gene expression analysis revealed that TLR2, CLEC4E, PTX3, CXCL8, and IL15RA were significantly upregulated (p < 0.05) in pneumonic ewes, while SOCS3 expression was markedly downregulated. Sequence analysis of immune-related genes revealed notable nucleotide differences between healthy and affected animals. Furthermore, the pneumonic group exhibited significantly elevated levels of APPs, cortisol, and growth hormone, along with reduced levels of insulin, T3, and T4. These findings underscore the zoonotic risk posed by MRSA and emphasize the need for robust surveillance and antibiotic stewardship to control its spread. The study also highlights the importance of molecular diagnostics in accurately identifying MRSA and elucidating resistance mechanisms, thereby facilitating targeted treatment and informed management strategies. Full article

Currently, there are two major theories regarding the pathogenesis of sepsis: hyperimmune and hypoimmune. The hyperimmune theory suggests that a cytokine storm causes the symptoms of sepsis. On the contrary, the hypoimmune theory suggests that immunosuppression causes the manifestations of sepsis. By conducting a microarray analysis on peripheral leukocytes from patients with sepsis, this study found that hyperactivity of TH17 immunity was noted in sepsis patients. Innate immunity-related genes are significantly upregulated, including CD14, TLR1,2,4,5,8, HSP70, CEBP proteins, AP1 (JUNB and FOSL2), TGFB1, IL6, TGFA, CSF2 receptor, TNFRSF1A, S100A binding proteins, CCR2, FPR2, amyloid proteins, pentraxin, defensins, CLEC5A, whole complement machinery, CPD, NCF, MMP, neutrophil elastase, caspases, IgG and IgA Fc receptors (CD64, CD32), ALOX5, PTGS, LTB4R, LTA4H, and ICAM1. The majority of adaptive immunity genes were downregulated, including MHC-related genes, TCR genes, granzymes/perforin, CD40, CD8, CD3, TCR signaling, BCR signaling, T and B cell-specific transcription factors, NK killer receptors, and TH17 helper-specific transcription factors (STAT3, RORA, and REL), as well as Treg-related genes, including TGFB1, IL15, STAT5B, SMAD2/4, CD36, and thrombospondin. The findings of this study show that Th17 with Treg over-presentation play an important role in the pathophysiology of sepsis. Full article