Search Results (740)

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors, largely due to its profound intratumoral heterogeneity and immunosuppressive microenvironment. Various classifications of GBM subtypes were created based on transcriptional and methylation profiles. This effort, followed by the development of new technology such as single-nuclei sequencing (snRNAseq) and spatial transcriptomics, led to a better understanding of the glioma cells’ plasticity and their ability to transition between diverse cellular states. GBM cells can mimic neurodevelopmental programs to resemble oligodendrocyte or neural progenitor behavior and hitchhike the local neuronal network to support their growth. The tumor microenvironment, especially under hypoxic conditions, drives the tumor cell clonal selection, which then reshapes the immune cells’ functions. These adaptations contribute to immune evasion by progressively disabling T cell and myeloid cell functions, ultimately establishing a highly immunosuppressive tumor milieu. This complex and metabolically constrained environment poses a major barrier to effective antitumor immunity and limits the success of conventional therapies. Understanding the dynamic interactions between glioma cells and their microenvironment is essential for the development of more effective immunotherapies and rational combination strategies aimed at overcoming resistance and improving patient outcomes. Full article

Sepsis is a life-threatening condition caused by a dysregulated immune response to infection, characterized by an initial hyperinflammatory phase frequently followed by compensatory immunosuppression (CARS). Regulatory T cells (Tregs) play a critical, biphasic role: inadequate suppression during early hyperinflammation fails to control cytokine storms, while excessive/persistent activity in late-phase immunosuppression drives immune paralysis and secondary infection susceptibility. This review explores advances in targeting Treg immunoregulation across bacterial, viral, and fungal sepsis, where pathogenic type critically influenced the types of immunoresponses, shaping Treg heterogeneity in terms of phenotype, survival, and function. Understanding this multifaceted Treg biology offers novel therapeutic avenues, highlighting the need to decipher functional heterogeneity and develop precisely timed, pathogen-tailored immunomodulation to safely harness beneficial Treg roles while mitigating detrimental immunosuppression. Full article

Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article

Background: Anti-synthetase Syndrome (ASyS) is an idiopathic inflammatory myopathy characterized by muscle weakness and inflammatory infiltrates in muscles. Sjogren’s disease (SD) is an autoimmune condition primarily affecting exocrine glands. Both these conditions may present lung involvement. We describe a female patient with anti-synthetase/SD overlap syndrome and review the literature to identify published cases describing this overlap, aiming to better define its clinical, radiological, and serological features. Methods: The case description was based on a retrospective collection of clinical, laboratory, and imaging data related to the patient’s diagnostic process and clinical course. Data were anonymized and handled in accordance with the competent territorial Ethics Committee. A literature review was performed using the MEDLINE and Scopus databases by combining the keywords “Anti-Synthetase syndrome”, “Sjögren disease”, “Sjögren syndrome”, “Myositis”, and “Interstitial lung disease” (ILD). Published cases were selected if they met the 2016 EULAR/ACR criteria for SD and at least one of the currently proposed classification criteria for ASyS. Results: The described case concerns a 68-year-old woman with rapidly progressive ILD. The diagnosis of anti-synthetase/SD overlap syndrome was based on clinical, serological (anti-Ro52 and anti-PL7 antibodies), histological, and radiological findings. Despite immunosuppressive and antifibrotic treatment, the clinical course worsened, leading to a poor outcome. In addition, six relevant cases were identified in the literature. Clinical presentations, autoantibody profiles, radiological findings, and outcomes were highly heterogeneous. Among the reported cases, no standardized treatment protocols were adopted, reflecting the lack of consensus in managing this rare condition. Conclusions: In anti-synthetase/SD overlap syndrome, ILD may follow a rapidly progressive course. Early recognition can be challenging, especially in the absence of muscular involvement. This case-based review highlights the need for more standardized approaches to the diagnosis and management of this rare and complex overlap syndrome. Full article

Protein-losing nephropathy (PLN) involves a heterogeneous group of pathologies leading to selective glomerular damage and development of renal disease. ICGN, the main cause of PLN, requires immunosuppressive treatment. However, the scientific evidence in veterinary medicine on immunosuppressive therapeutic schemes in this condition is limited. The aim of this study is to describe the clinical and paraclinical evolution of five dogs with PLN, presumably associated with ICGN, treated with chlorambucil as immunosuppressive monotherapy. Suspected IGCN was established by the presence of a urine protein–creatinine ratio (UPC) ≥ 3 without response to standard therapy, hypoalbuminemia < 2, or progressive azotemia. Patients were treated with a dosage range of chlorambucil from 0.16 to 0.4 mg/kg (mean 0.25 mg/kg) every 24 h as the sole immunosuppressant. In the end, 4/5 patients showed significant clinical improvement, 3/3 had resolution of the nephrotic syndrome, 5/5 had a sustained decrease in UPC values during follow-up and no relevant adverse effects were observed. In this report, chlorambucil proved to be a well-tolerated and potentially effective monotherapy for immune-mediated PLN in dogs. Full article

Hypomagnesemia is a frequent and often underrecognized electrolyte disturbance with important clinical consequences, especially in hospitalized and critically ill patients. This multifactorial condition arises from impaired intestinal absorption, renal magnesium wasting, and the effects of various medications. Magnesium, the second most abundant intracellular cation, is crucial in enzymatic and physiological processes; its deficiency is associated with neuromuscular, cardiovascular, and metabolic complications. This narrative review focuses on the mechanisms and clinical consequences of drug-induced hypomagnesemia, highlighting the major drug classes involved such as diuretics, antibiotics, antineoplastic agents, and immunosuppressants. Management strategies include magnesium supplementation and adjunctive therapies like amiloride and SGLT2 inhibitors to reduce renal magnesium losses. Recognizing and addressing drug-induced hypomagnesemia is essential to improve patient outcomes and prevent long-term complications. Full article

Background: Oral lichen planus is a chronic, potentially malignant disorder affecting the mucous membrane. As the etiology remains not fully understood, the treatment of this condition is mainly symptomatic, involving corticosteroids and other immunosuppressive agents, e.g., calcineurin inhibitors. One of the alternative therapeutic approaches includes platelet concentrates, which are autologous bioactive materials. The aim of this review was to evaluate the effects of platelet concentrates in the treatment of oral lichen planus and to compare them to other therapeutic strategies. Methods: The electronic databases PubMed/Medline, Web of Science, and Cochrane Library were searched for articles published up to 30 March 2025, describing clinical studies focused on oral lichen planus and treatment with platelet concentrates. Results: Fourteen studies describing the effects of oral lichen planus therapy with three types of platelet concentrates (injectable platelet-rich plasma, injectable platelet-rich fibrin, and platelet-rich plasma gel) were included in this review. Comparative strategies included steroids and immunosuppressive agents. The treatment duration ranged from 3 weeks to 2 months. The follow-up period varied from 4 weeks to 6 months. In most of the studies, comparable efficacy was achieved for platelet derivatives and alternative treatments. Two of the studies demonstrated more beneficial effects for platelet concentrates compared to controls, while in one of the studies, more severe adverse reactions were revealed in the platelet group compared to the controls. Conclusions: Autologous platelet concentrates showed comparable efficacy in achieving clinical improvement in patients with oral lichen planus to steroids and immunosuppressive drugs. Platelet derivatives could be considered as an alternative treatment to topical immunosuppressives, especially in steroid-refractory cases. Full article

Background/Objectives: Tacrolimus, an immunosuppressant, is increasingly used topically in ophthalmology, particularly for conditions like vernal keratoconjunctivitis and post-keratoplasty rejection prophylaxis. This systematic review aims to evaluate the efficacy and safety of topical tacrolimus in these ocular conditions. Methods: A thorough search was conducted in PubMed and Cochrane Library for relevant studies published up to 16 March 2025. Studies were eligible for inclusion if they were randomized controlled trials investigating topical tacrolimus in human ocular disease, were published in English, and reported clearly defined outcomes. Exclusion criteria included non-randomized studies, animal studies, systemic treatments, non-English publications, and studies lacking clearly reported outcomes. Data regarding study design, patient demographics, intervention details, and outcomes were extracted and analyzed. The Cochrane risk-of-bias tool (RoB 2.0) was used to assess the risk of bias. Results: A total of 10 studies met the inclusion criteria, were retrieved, and were categorized as not highly biased after the risk-of-bias assessment. These studies were included in the systematic review, where a qualitative analysis took place. Our analysis revealed that the topical use of tacrolimus showed promising results, as it improved clinical signs and symptoms in most patients. In half of the studies, tacrolimus demonstrated superior efficacy compared to the control group, while in the remaining studies, it showed equivalent efficacy. Adverse effects, such as a burning sensation, were noted in 7/10 studies but were generally mild. The methodologies were somewhat heterogeneous, and some studies had small sample sizes. Conclusions: Topical tacrolimus shows promising effects in managing various ocular surface diseases. While randomized controlled trials provide evidence, further research with larger sample sizes is necessary to solidify its efficacy and safety profile compared to other immunosuppressants. Full article

Background/objectives: This study evaluated the immunoenhancing effects of Agastache rugosa extract in a cyclophosphamide-induced immunosuppressed mouse model. Methods: Jeju A. rugosa was processed via hot water extraction and 20% ethanol extraction. For immunosuppression induction, 7-week-old male BALB/c mice received intraperitoneal CPA injections (150 mg/kg, day −3; 110 mg/kg, day −1), followed by oral administration of hot water extract (ARE-W) and ethanol extract (ARE-E) at 100 and 300 mg/kg for 14 days. Oral administration of ARE-W and ARE-E was started on day 0, immediately following the final CPA injection on day −1. Immune function was assessed through body weight changes, spleen weight, NK cell activity, IFN-γ production, and splenic lymphocyte proliferation. Results: Results demonstrated that CPA treatment induced comprehensive immune dysfunction, while A. rugosa extracts significantly ameliorated these immunosuppressive conditions. Notably, ARE-W (300 mg/kg) significantly enhanced NK cell cytotoxicity against tumor cells and IFN-γ production compared to the CPA group, and effectively restored spleen weight and lymphocyte proliferation. ARE-E also exhibited dose-dependent immune function recovery; however, ARE-W showed superior efficacy across most immune parameters. Conclusions: These findings suggest that A. rugosa extract, particularly ARE-W, effectively restores immune function in immunosuppressed conditions, indicating potential application as a natural functional material for ameliorating immunosuppression caused by cancer treatment or immune diseases. Full article

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by venous and arterial thrombosis and obstetric complications, driven by antiphospholipid antibodies (APLAs). This review synthesizes the latest advancements and current understanding, diagnosis, and treatment of APS. APLAs, including lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-β2-glycoprotein I (aβ2-GPI), interfere with coagulation and endothelial function, as well as with placental health. APS can be primary or secondary; it is often associated with systemic autoimmune diseases like lupus. The pathogenesis of APS remains only partially understood. APLAs promote thrombosis through endothelial damage, platelet activation, and inflammatory signaling pathways. Laboratory diagnosis relies on persistent positivity for APLAs and LAC through tests like ELISA and clotting assays, following a three-step confirmation process. New integrated test systems have been introduced to improve standardization. Classification criteria have evolved, with the 2023 EULAR-ACR criteria providing a weighted, domain-based scoring system, enhancing diagnostic precision. Catastrophic APS (CAPS) is a severe, rare manifestation of APS, characterized by multi-organ failure due to rapid, widespread microthrombosis and systemic inflammation, which requires urgent anticoagulation. Seronegative APS is proposed for patients with clinical features of APS but negative standard antibody tests, possibly due to non-criteria antibodies or transient immunosuppression. Treatment primarily involves long-term anticoagulation with vitamin K antagonists; direct oral anticoagulants are generally not recommended. APS diagnosis and management remain complex due to clinical heterogeneity and laboratory challenges. Continued refinement of diagnostic tools and criteria is essential for improving outcomes in this life-threatening condition. Full article

Background and Clinical Significance: Antisynthetase syndrome (ASyS) is a rare autoimmune entity defined by the presence of anti-aminoacyl-t ribonucleic acid (RNA) synthetase autoantibodies and classically associated with a triad of interstitial lung disease (ILD), inflammatory myopathy, and arthritis. Additional clinical features may include Raynaud’s phenomenon and “mechanic’s hands”. Among antisynthetase antibodies, anti-PL-12 is notably associated with predominant or isolated ILD and may occur in the absence of clinically evident myositis, thereby complicating timely diagnosis. Case Presentation: We are presenting a 45-year-old non-smoking female patient with a prior diagnosis of seronegative rheumatoid arthritis (RA) who developed progressive dyspnea, dry cough, and sicca symptoms. High-resolution computed tomography revealed a nonspecific interstitial pneumonia (NSIP) pattern. Despite normal creatine kinase and lactate dehydrogenase levels, serological work-up revealed positive anti-PL-12 and anti-Ro52 antibodies, supporting a diagnosis of antisynthetase syndrome without myositis, fulfilling the diagnostic criteria for ASyS per Connors and Solomon. Treatment with corticosteroids and cyclophosphamide induced clinical and functional respiratory improvement, while azathioprine was initiated for maintenance. Conclusions: This case underscores the clinical heterogeneity of antisynthetase syndrome and highlights the diagnostic challenge posed by anti-PL-12–associated ILD in the absence of myositis. Importantly, it demonstrates that in patients with pre-existing rheumatologic diagnoses, the emergence of atypical pulmonary manifestations warrants repeat serologic evaluation to assess ASyS and other autoimmune conditions. Early diagnosis and immunosuppressive treatment are essential to optimize outcomes. Full article

Everolimus (EVE), an mTOR inhibitor, is widely used in solid organ transplantation (SOT) because of its immunosuppressive properties. Due to its narrow therapeutic window and significant pharmacokinetic variability, therapeutic drug monitoring (TDM) is essential for achieving optimal outcomes. We developed and thoroughly validated a robust LC-MS/MS method to measure EVE levels in venous whole blood (WB) and capillary blood collected using two microsampling devices: Mitra™ (volumetric absorptive microsampling, VAMS) and Capitainer^® (quantitative dried blood spot, qDBS). The validation followed EMA and IATDMCT guidelines, assessing linearity (1.27–64.80 ng/mL for WB and 0.50–60 ng/mL for VAMS/qDBS), as well as selectivity, accuracy, precision, matrix effects, recovery, stability, and incurred sample reanalysis. Clinical validation involved 66 matched samples from 33 adult SOT recipients. The method demonstrated high accuracy and precision across all matrices, with no significant carryover or matrix interference. Statistical analysis using Passing–Bablok regression and Bland–Altman plots showed excellent agreement between the microsampling methods and the venous reference. Hematocrit effects were tested both in laboratory conditions and on clinical samples and were found to be negligible. This study provides the first comprehensive analytical and clinical validation of the Mitra and Capitainer devices for EVE monitoring. The validated LC-MS/MS microsampling method supports decentralized, patient-centred TDM, offering a reliable alternative to conventional blood sampling in transplant care. Full article

Spores of filamentous fungi are common biological particles in indoor air that can negatively impact human health, particularly among immunocompromised individuals and patients with chronic respiratory conditions. Airborne viruses represent an equally pervasive threat, with some carrying the potential for pandemic spread, affecting both healthy individuals and the immunosuppressed alike. This study investigated the abundance and diversity of airborne fungal spores in both hospital and residential environments, using custom designed air samplers with or without the presence of negative air ions (NAIs) inside the sampler. The main purpose of investigation was the assessment of biological effects of NAIs on fungal spore viability, deposition, mycelial growth, and sporulation, as well as airborne viral load. The precise assessment of mentioned biological effects is otherwise difficult to carry out due to low concentrations of studied specimens; therefore, specially devised and designed, ion-bioaerosol interaction air samplers were used for prolonged collection of specimens of interest. The total fungal spore concentrations were quantified, and fungal isolates were identified using cultural and microscopic methods, complemented by MALDI-TOF mass spectrometry. Results indicated no significant difference in overall spore concentration between environments or treatments; however, presence of NAIs induced a delay in the sporulation process of Cladosporium herbarum, Aspergillus flavus, and Aspergillus niger within 72 h. These effects of NAIs are for the first time demonstrated in this work; most likely, they are mediated by oxidative stress mechanisms. A parallel experiment demonstrated a substantially reduced concentration of aerosolized equine herpesvirus 1 (EHV-1) DNA within 10–30 min of exposure to NAIs, with more than 98% genomic load reduction beyond natural decay. These new results on the NAIs interaction with a virus, as well as new findings regarding the fungal sporulation, resulted in part from a novel interaction setup designed for experiments with the bioaerosols. Our findings highlight the potential of NAIs as a possible approach for controlling fungal sporulation and reducing airborne viral particle quantities in indoor environments. Full article

Individuals with immunosuppressive conditions are at a higher risk of developing malignancies than those in the general population. Immunosuppression weakens tumor immunity, hinders the detection of pro-oncogenic cells, and activates oncogenic viruses. Malignancies arising in immunosuppressed patients tend to be aggressive, have a high incidence of virus-associated cancers, and are reversible in some cases. Notably, immunosuppressive agents influence the frequency and type of malignancies, as well as their clinicopathological features. Organ transplant recipients receive long-term immunosuppressants to prevent acute rejection. Post-transplant malignancies vary depending on the type of drug administered before the onset of these diseases. Patients with rheumatoid arthritis (RA) are treated with long-term immunosuppressive medications, such as methotrexate (MTX). MTX is widely recognized as being associated with a specific type of lymphoproliferative disorder (LPD), known as MTX-associated LPD. Our recent report indicated that the clinicopathological features of rheumatoid arthritis-associated lymphoproliferative disorder (RA-LPD) also vary based on the other anti-RA agents used, such as tacrolimus and tumor necrosis factor inhibitors. Therefore, the clinicopathological characteristics of post-transplant LPD and RA-LPD evolve alongside the changes in the immunosuppressants/immunomodulators administered. Understanding the various characteristics and time trends of immunosuppressive neoplasms, particularly LPDs, in relation to different immunosuppressant/immunomodulator medications is highly valuable in clinical practice. Full article

Inflammation is a self-defense mechanism that controls the homeostasis of an organism, and its alteration by persistent noxious stimuli could lead to an imbalance in the regulation of inflammatory responses mediated by innate and adaptive immunity. During chronic inflammation, sustained exposure of myeloid cells to the various inflammatory signals derived from inflamed tissue could lead to the generation of myeloid cells with an immunosuppressive state, called myeloid-derived suppressor cells (MDSCs), which can exert protective or deleterious functions depending on the nature of signals and the specific inflammatory conditions created by different pathophysiological contexts. Initially identified in various tumor models and cancer patient samples, these cells have long been recognized as negative regulators of anti-tumor immunity. Consequently, researchers have focused on elucidating the molecular mechanisms underlying their potent immunosuppressive activity. As a key component of the signal transducing processes, protein kinases play a central role in regulating the signal transduction mechanisms of many cellular activities, including differentiation and immunosuppression. Over the past decade, at least a dozen kinases, including mechanistic target of rapamycin (mTOR), phosphoinositide 3-kinases (PI3Ks), TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases (TAM RTKs), mitogen-activated protein kinases (MAPKs), and others, have emerged as key contributors to the generation and differentiation of MDSCs. Here, we discuss the recent findings on these kinases that directly contribute to the immunosuppressive functions of MDSCs. Full article