Search Results (24)

Background: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of relapsed/refractory large B-cell lymphoma (LBCL), but its administration is often complicated by cytokine release syndrome (CRS). Interleukin-6 (IL-6) is widely used to monitor CRS, though its clinical value diminishes after tocilizumab administration. We aimed to evaluate serum amyloid A (SAA), a dynamic acute-phase reactant, as a treatment-independent biomarker of inflammation and toxicity in CAR-T recipients. Methods: This retrospective study included 43 adults with LBCL treated with axicabtagene ciloleucel. SAA and other inflammatory markers were assessed from lymphodepletion through day +11 post-infusion. CRS and ICANS were graded per ASTCT criteria. Statistical analyses included Mann–Whitney U tests, Spearman’s correlation, and ROC curve analysis to evaluate predictive performance. Results: SAA levels peaked at day +4 and normalized by day +11, displaying wave-like kinetics. Levels were significantly higher in patients with any-grade CRS at early timepoints but showed no association with ICANS. SAA correlated strongly with CRP, suPAR, sST2, fibrinogen, ferritin, procalcitonin, and IL-6. Compared to IL-6, SAA was more predictive of CRS at day +2 and +4, and unaffected by tocilizumab. Baseline SAA also correlated with the mEASIX score, suggesting linkage to endothelial stress. Non-responders at 3-month PET had higher baseline SAA than responders (196.0 vs. 17.7 mg/L, p = 0.036), with ROC analysis yielding an AUC of 0.74 and an optimal threshold of 79.8 mg/L. Conclusions: SAA is a robust and dynamic marker of systemic inflammation, with potential utility in both toxicity monitoring and response prediction in the CAR-T setting. Its independence from IL-6 modulation positions it as a promising biomarker for future integration into clinical algorithms. Full article

Autoimmune diseases arise from complex interactions of genetic, environmental, and hormonal factors, yet their precise causes remain elusive. Beyond its canonical role in fibrin degradation, the fibrinolytic system is increasingly recognized as both a pathogenic driver and a regulatory modulator in autoimmunity. Key factors—plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1)—not only reflect secondary responses to vascular and immune dysregulation but also actively shape innate and adaptive immunity. They influence macrophage activation, dendritic cell maturation, T cell responses, and cytokine production, thereby bridging coagulation, inflammation, and tissue repair. This review integrates current evidence on the dual pathogenic and regulatory roles of fibrinolytic factors, organizing autoimmune diseases into systemic, organ-specific, and secondary syndromes. We further discuss how the imbalance of fibrinolysis can either promote inflammatory persistence or, conversely, facilitate resolution through fibrin clearance and immune homeostasis. By highlighting this bidirectional influence, the review aims to refine our understanding of fibrinolytic components as both contributors to and regulators of autoimmune disease pathogenesis. Full article

Bovine mastitis is a condition typically induced by various pathogens, with Escherichia coli (E. coli) being a common causative agent known for its propensity to cause persistent infections. In experimental models of bovine mastitis, lipopolysaccharide (LPS), a key component of the E. coli cell wall, is frequently employed as an inducer. The extracellular matrix (ECM) is regulated by MMPs, TIMPs, and the uPA system. They collectively participate in ECM degradation and remodeling and have been identified as promising targets for mastitis treatment. However, investigations into the precise mechanisms underlying E. coli and LPS-induced mastitis, as well as the relationship between bovine mastitis and the MAPK signaling pathway, remain limited. In this study, bovine mammary epithelial cells (BMECs) were treated in vitro with 10⁶ CFU/mL heat-inactivated E. coli, 7.5 µg/mL LPS, or a combination of both. The treatments resulted in varying degrees of activation of the MAPK signaling pathway, specifically ERK1/2, JNK, and P38. BMECs were exposed to MAPK inhibitors (the JNK inhibitor SP600125, the ERK inhibitor PD98059, and the P38 inhibitor SB203580) after treatments with heat-inactivated E. coli (10⁶ CFU/mL), LPS (7.5 µg/mL), or a combination of the two for 6, 12, 24, and 48 h. The mRNA and protein levels of MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, TIMP-1, TIMP-2, uPA, uPAR, and PAI-1 were assessed using RT-qPCR and Western blot analysis. The findings indicated that heat-inactivated E. coli and LPS stimulated the expression of MAPK mRNAs (ERK1/2, P38, and JNK) in BMECs, along with corresponding increases in the phosphorylated proteins. Furthermore, MAPK inhibitors substantially upregulated the expression of TIMP-1, TIMP-2, and PAI-1. However, no significant changes were observed in the mRNA and protein levels of MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, uPA, or uPAR. In conclusion, heat-inactivated E. coli and LPS can activate the MAPK signaling pathway in BMECs. Inhibiting this signaling pathway can modulate the expression of TIMP-1, TIMP -2, and PAI-1 at both mRNA and protein levels. Full article

Poly(ADP-ribosyl)ation (PARylation) is a dynamic protein post-translational modification (PTM) mediated by ADP-ribosyltransferases (ARTs), which regulates a plethora of essential biological processes, such as DNA repair, gene expression, and signal transduction. Among these, PAR-dependent ubiquitination (PARdU) plays a pivotal role in tagging PARylated substrates for subsequent ubiquitination and degradation events through the coordinated action of enzymes, including the E3 ligase RNF146 and the ADP-ribosyltransferase tankyrase. Notably, this pathway has emerged as a key regulator of tumorigenesis, immune modulation, and cell death. This review elucidates the molecular mechanisms of the PARdU pathway, including the RNF146–tankyrase interaction, substrate specificity, and upstream regulatory pathways. It also highlights the biological functions of PARdU in DNA damage repair, signaling pathways, and metabolic regulation, with a focus on its therapeutic potential in cancer treatment. Strategies targeting PARdU, such as tankyrase and RNF146 inhibitors, synthetic lethality approaches, and immune checkpoint regulation, offer promising avenues for precision oncology. These developments underscore the potential of PARdU as a transformative therapeutic target in combating various types of human cancer. Full article

The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as a key regulator of inflammation. Initially, uPA/uPAR was considered thrombolytic (clot-dissolving); however, recent studies have demonstrated its predominant immunomodulatory functions in inflammation and cancer. The uPA/uPAR complex has a multifaceted central role in both normal physiological and also pathological responses. uPAR is expressed as a glycophosphatidylinositol (GPI)-linked receptor interacting with vitronectin, integrins, G protein-coupled receptors, and growth factor receptors within a large lipid raft. Through protein-to-protein interactions, cell surface uPAR modulates intracellular signaling, altering cellular adhesion and migration. The uPA/uPAR also modifies extracellular activity, activating plasminogen to form plasmin, which breaks down fibrin, dissolving clots and activating matrix metalloproteinases that lyse connective tissue, allowing immune and cancer cell invasion and releasing growth factors. uPAR is now recognized as a biomarker for inflammatory diseases and cancer; uPAR and soluble uPAR fragments (suPAR) are increased in viral sepsis (COVID-19), inflammatory bowel disease, and metastasis. Here, we provide a comprehensive overview of the structure, function, and current studies examining uPAR and suPAR as diagnostic markers and therapeutic targets. Understanding uPAR is central to developing diagnostic markers and the ongoing development of antibody, small-molecule, nanogel, and virus-derived immune-modulating treatments that target uPAR. Full article

Cancer stem cells (CSCs), found within tumors, are powerful drivers of disease recurrence and metastasis. Their abilities to self-renew and maintain stem-like properties make treatment difficult, as their heterogeneity and metastatic properties can lead to resistance and limit the effectiveness of standard therapies. Given their significance, CSCs are typically isolated based on combinations of markers, which often indicate heterogeneous populations of CSCs. The lack of consensus in cell characterization poses challenges in defining and targeting these cells for effective therapeutic interventions. In this review, we suggest five promising molecules—ABCB5, CD26, CD66c, uPAR, and Trop-2—chosen specifically for their distinct distribution within cancer types and clinical relevance. These markers, expressed at the cell surface of CSCs, could significantly enhance the specificity of cancer stemness characterization. This review focuses on describing their pivotal roles as biomarker checkpoints for metastasis. Additionally, this review outlines existing literature on glycosylation modifications, which present intriguing epitopes aimed at modulating the stability and function of these markers. Finally, we summarize several promising in vivo and clinical trial approaches targeting the mentioned surface markers, offering potential solutions to overcome the therapeutic resistance of CSCs and addressing current gaps in treatment strategies. Full article

During tumorigenesis, urokinase (uPA) and uPA receptor (uPAR) play essential roles in mediating pathological progression in many cancers. To understand the crosstalk between the uPA/uPAR signaling and cancer, as well as to decipher their cellular pathways, we proposed to use cancer driver genes to map out the uPAR signaling. In the study, an integrated pharmaceutical bioinformatics approach that combined modulator identification, driver gene ontology networking, protein targets prediction and networking, pathway analysis and uPAR modulator screening platform construction was employed to uncover druggable targets in uPAR signaling for developing a novel anti-cancer modality. Through these works, we found that uPAR signaling interacted with 10 of 21 KEGG cancer pathways, indicating the important role of uPAR in mediating intracellular cancerous signaling. Furthermore, we verified that receptor tyrosine kinases (RTKs) and ribosomal S6 kinases (RSKs) could serve as signal hubs to relay uPAR-mediated cellular functions on cancer hallmarks such as angiogenesis, proliferation, migration and metastasis. Moreover, we established an in silico virtual screening platform and a uPAR–driver gene pair rule for identifying potential uPAR modulators to combat cancer. Altogether, our results not only elucidated the complex networking between uPAR modulation and cancer but also provided a paved way for developing new chemical entities and/or re-positioning clinically used drugs against cancer. Full article

Nicotinic acetylcholine receptors (nAChRs) present as many different subtypes in the nervous and immune systems, muscles and on the cells of other organs. In the immune system, inflammation is regulated via the vagus nerve through the activation of the non-neuronal α7 nAChR subtype, affecting the production of cytokines. The analgesic properties of α7 nAChR-selective compounds are mostly based on the activation of the cholinergic anti-inflammatory pathway. The molecular mechanism of neuropathic pain relief mediated by the inhibition of α9-containing nAChRs is not fully understood yet, but the role of immune factors in this process is becoming evident. To obtain appropriate drugs, a search of selective agonists, antagonists and modulators of α7- and α9-containing nAChRs is underway. The naturally occurring three-finger snake α-neurotoxins and mammalian Ly6/uPAR proteins, as well as neurotoxic peptides α-conotoxins, are not only sophisticated tools in research on nAChRs but are also considered as potential medicines. In particular, the inhibition of the α9-containing nAChRs by α-conotoxins may be a pathway to alleviate neuropathic pain. nAChRs are involved in the inflammation processes during AIDS and other viral infections; thus they can also be means used in drug design. In this review, we discuss the role of α7- and α9-containing nAChRs in the immune processes and in pain. Full article

Formaldehyde is a key Volatile Organic Compound (VOC) and ozone precursor that plays a vital role in the urban atmospheric radical budget on par with water vapor, ozone, and nitrous acid. In addition to modulating radical and ozone production, ambient formaldehyde has both carcinogenic and non-carcinogenic inhalation health effects. This study concludes that ambient formaldehyde in the Southeast Michigan (SEMI) ozone nonattainment area may be underestimated up to a factor of two or more by regional air quality models. The addition of plausible amounts of primary formaldehyde to the U.S. National Emissions Inventory based on estimated formaldehyde-to-CO emission ratios partially alleviates this modeling deficit and indicates the presence of formaldehyde concentrations above 5 ppb at a previously unsuspected location northeast of Detroit. Standard 24-h formaldehyde samples obtained during the Michigan-Ontario Ozone Source Experiment (MOOSE) verified the presence of high ambient formaldehyde concentrations at this location. Moreover, the addition of plausible amounts of primary formaldehyde to VOC emissions inventories may add more than 1 ppb of ozone to ambient air in the SEMI nonattainment area, where ozone design values exceeded the U.S. National Ambient Air Quality Standard (NAAQS) by 1–2 ppb for the 2018–2020 design value period. Full article

Background: In recent years, the involvement of the soluble urokinase Plasminogen Activator Receptor (suPAR) in the pathophysiological modulation of Rheumatoid Arthritis (RA) has been documented, resulting in the activation of several intracellular inflammatory pathways. Methods: We investigated the correlation of urokinase Plasminogen Activator (uPA)/urokinase Plasminogen Activator Receptor (uPAR) expression and suPAR with inflammation and joint damage in RA, evaluating their potential role in a precision medicine context. Results: Currently, suPAR has been shown to be a potential biomarker for the monitoring of Systemic Chronic Inflammation (SCI) and COVID-19. However, the effects due to suPAR interaction in immune cells are also involved in both RA onset and progression. To date, the literature data on suPAR in RA endorse its potential application as a biomarker of inflammation and subsequent joint damage. Conclusion: Available evidence about suPAR utility in the RA field is promising, and future research should further investigate its use in clinical practice, resulting in a big step forward for precision medicine. As it is elevated in different types of inflammation, suPAR could potentially work as an adjunctive tool for the screening of RA patients. In addition, a suPAR system has been shown to be involved in RA pathogenesis, so new data about the therapeutic response to Jak inhibitors can represent a possible way to develop further studies. Full article

A Matrigel-based tube formation assay is a simple and widely accepted 2D angiogenesis model in vitro. Extracellular matrix (EM) proteins and growth factors (GFs) from Matrigel^TM exclusively trigger endothelial cell (EC) tubular network (ETN) formation. Co-culture of ECs with mesenchymal stromal cells (MSCs) is another and more reliable in vitro angiogenesis assay. MSCs modulate ETN formation through intercellular interactions and as a supplier of EM and GFs. The aim of the present study was to compare the expression profile of ECs in both models. We revealed upregulation of the uPA, uPAR, Jagged1, and Notch2 genes in dividing/migrating ECs and for ECs in both experimental models at 19 h. The expression of endothelial–mesenchymal transition genes largely increased in co-cultured ECs whereas Notch and Hippo signaling pathway genes were upregulated in ECs on Matrigel^TM. We showed that in the co-culture model, basement membrane (BM) deposition is limited only to cell-to-cell contacts in contrast to Matrigel^TM, which represents by itself fully pre-assembled BM matrix. We suggest that ETN in a co-culture model is still in a dynamic process due to immature BM whereas ECs in the Matrigel^TM assay seem to be at the final stage of ETN formation. Full article

The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of millions of people around the world. Severe vitamin D deficiency can increase the risk of death in people with COVID-19. There is growing evidence that acute kidney injury (AKI) is common in COVID-19 patients and is associated with poorer clinical outcomes. The kidney effects of SARS-CoV-2 are directly mediated by angiotensin 2-converting enzyme (ACE2) receptors. AKI is also caused by indirect causes such as the hypercoagulable state and microvascular thrombosis. The increased release of soluble urokinase-type plasminogen activator receptor (suPAR) from immature myeloid cells reduces plasminogen activation by the competitive inhibition of urokinase-type plasminogen activator, which results in low plasmin levels and a fibrinolytic state in COVID-19. Frequent hypercoagulability in critically ill patients with COVID-19 may exacerbate the severity of thrombosis. Versican expression in proximal tubular cells leads to the proliferation of interstitial fibroblasts through the C3a and suPAR pathways. Vitamin D attenuates the local expression of podocyte uPAR and decreases elevated circulating suPAR levels caused by systemic inflammation. This decrease preserves the function and structure of the glomerular barrier, thereby maintaining renal function. The attenuated hyperinflammatory state reduces complement activation, resulting in lower serum C3a levels. Vitamin D can also protect against COVID-19 by modulating innate and adaptive immunity, increasing ACE2 expression, and inhibiting the renin–angiotensin–aldosterone system. We hypothesized that by reducing suPAR levels, appropriate vitamin D supplementation could prevent the progression and reduce the severity of AKI in COVID-19 patients, although the data available require further elucidation. Full article

Effectively integrating the local features and their spatial distribution information for more effective point cloud analysis is a subject that has been explored for a long time. Inspired by convolutional neural networks (CNNs), this paper studies the relationship between local features and their spatial characteristics and proposes a concise architecture to effectively integrate them instead of designing more sophisticated feature extraction modules. Different positions in the feature map of the 2D image correspond to different weights in the convolution kernel, making the obtained features that are sensitive to local distribution characteristics. Thus, the spatial distribution of the input features of the point cloud within the receptive field is critical for capturing abstract regional aggregated features. We design a lightweight structure to extract local features by explicitly supplementing the distribution information of the input features to obtain distinctive features for point cloud analysis. Compared with the baseline, our model shows improvements in accuracy and convergence speed, and these advantages facilitate the introduction of the snapshot ensemble. Aiming at the shortcomings of the commonly used cosine annealing learning schedule, we design a new annealing schedule that can be flexibly adjusted for the snapshot ensemble technology, which significantly improves the performance by a large margin. Extensive experiments on typical benchmarks verify that, although it adopts the basic shared multi-layer perceptrons (MLPs) as feature extractors, the proposed model with a lightweight structure achieves on-par performance with previous state-of-the-art (SOTA) methods (e.g., MoldeNet40 classification, 0.98 million parameters and 93.5% accuracy; S3DIS segmentation, 1.4 million parameters and 68.7% mIoU). Full article

The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system. Full article

Vitamin D presents a plethora of different functions that go beyond its role in skeletal homeostasis. It is an efficient endocrine regulator of the Renin–Angiotensin–Aldosterone System (RAAS) and erythropoiesis, exerts immunomodulatory effects, reduces the cardiovascular events and all-cause mortality. In Chronic Kidney Disease (CKD) patients, Vitamin D function is impaired; the renal hydrolyzation of its inactive form by the action of 1α-hydroxylase declines at the same pace of reduced nephron mass. Moreover, Vitamin D major carrier, the D-binding protein (DBP), is less represented due to Nephrotic Syndrome (NS), proteinuria, and the alteration of the cubilin–megalin–amnionless receptor complex in the renal proximal tubule. In Glomerulonephritis (GN), Vitamin D supplementation demonstrated to significantly reduce proteinuria and to slow kidney disease progression. It also has potent antiproliferative and immunomodulating functions, contributing to the inhibitions of kidney inflammation. Vitamin D preserves the structural integrity of the slit diaphragm guaranteeing protective effects on podocytes. Activated Vitamin D has been demonstrated to potentiate the antiproteinuric effect of RAAS inhibitors in IgA nephropathy and Lupus Nephritis, enforcing its role in the treatment of glomerulonephritis: calcitriol treatment, through Vitamin D receptor (VDR) action, can regulate the heparanase promoter activity and modulate the urokinase receptor (uPAR), guaranteeing podocyte preservation. It also controls the podocyte distribution by modulating mRNA synthesis and protein expression of nephrin and podocin. Maxalcalcitol is another promising alternative: it has about 1/600 affinity to vitamin D binding protein (DBP), compared to Calcitriol, overcoming the risk of hypercalcemia, hyperphosphatemia and calcifications, and it circulates principally in unbound form with easier availability for target tissues. Doxercalciferol, as well as paricalcitol, showed a lower incidence of hypercalcemia and hypercalciuria than Calcitriol. Paricalcitol demonstrated a significant role in suppressing RAAS genes expression: it significantly decreases angiotensinogen, renin, renin receptors, and vascular endothelial growth factor (VEGF) mRNA levels, thus reducing proteinuria and renal damage. The purpose of this article is to establish the Vitamin D role on immunomodulation, inflammatory and autoimmune processes in GN. Full article