Search Results (1,107)

Peripheral nerves provide a direct connection between the brain and the tumor microenvironment. This connection allows the nervous system to influence processes associated with the development, progression, and metastasis of different tumor types. Therefore, tumor innervation by peripheral nerve fibers is currently emerging as a characteristic that contributes to multiple hallmarks of cancer. Several experimental studies have shown that cancer progression involves actively inducing the ingrowth of autonomic and sensory nerve fibers into tumor tissue. In this process, known as neoaxonogenesis, cancer and other cells in the tumor microenvironment play an important role by synthesizing and releasing neurotrophic factors (e.g., nerve growth factor, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor), axonal guidance molecules (netrins, semaphorins, ephrins, slits), exosomes (containing microRNA and axonal guidance molecules), and other molecules present in the tumor microenvironment (e.g., granulocyte colony-stimulating factor, leukemia inhibitory factor), which modulate the ingrowth of nerve fibers into the tumor. This results in an increased nerve supply to tumor tissue, which is primarily linked to its growth. However, there are also studies demonstrating the protective effects of increased nerve fiber density against processes associated with cancer progression in certain types of cancer. The findings from these studies contribute to the complexity of neuro-cancer interactions, which is probably based on the type of cancer and the physiological specializations of the nerve fibers in a given organ. Despite contrasting findings, the stimulatory effects of nerve fibers on cancer growth are supported by several studies that described reducing the negative impact of nerve fibers on tumors and thus inhibiting cancer progression. The most significant approaches to reducing neural effects appear to be denervation, the administration of neurotransmitter receptor antagonists, the administration of local anesthetics, and the administration of antibodies against neurotrophic factors. Other significant approaches include methods that improve quality of life, such as psychotherapy and heart rate variability biofeedback. Despite their therapeutic potential, there are several limitations to using approaches that manipulate cancer innervation in clinical practice. These limitations include impaired normal tissue function and nervous system function, as well as the problematic direct application of the therapeutic agent to the tumor site, dosage-dependent, cancer type-dependent, cancer stage-dependent, duration-dependent, and timing-dependent effects. Procedures that modify neoaxonogenesis and nerve fiber signaling appear to be a promising new therapeutic approach in oncology. However, more research is needed to better understand their effects on cancer progression. In the future, the assessment of the presence and density of nerve fibers in tumors, as well as the evaluation of approaches aimed at reducing their negative impact, could be part of personalized anticancer therapy. As part of this therapy, a fresh tumor sample would be collected from the patient to generate patient-derived organoid models to test and consider the possibility of using supportive therapy and to predict its efficacy. Based on these results, it would be possible to evaluate the applicability of nerve-fiber-targeted therapy for a given patient. This review article summarizes and describes the current knowledge concerning the significance of nerve fibers in cancer progression, with a particular emphasis on neoaxonogenesis in tumors and the various factors that influence this process. Full article

Clonal hematopoiesis refers to the clonal expansion of hematopoietic stem and progenitor cells, driven by somatic mutations. Major mutated genes in clonal hematopoiesis include genes involved in epigenetic regulation including DNA methylation and/or chromatin modification (e.g., DNMT3A, TET2, and ASXL1), tumor suppressors (e.g., TP53), signal transduction (e.g., JAK2), and RNA splicing (e.g., SF3B1 and SRSF2). Clonal hematopoiesis includes clonal hematopoiesis of indeterminate potential (CHIP), clonal cytopenia of unknown significance (CCUS), and myelodysplastic syndromes/neoplasms (MDS). CHIP occurs when the frequency of the variant allele equals or exceeds 2% (4% for X-linked genes in males) in the absence of cytopenias. CHIP is common among older persons and is associated with an increased risk of hematologic cancer. CHIP is also associated with an increased risk of atherosclerotic disease including acute myocardial infarction, stroke, cardiac failure, and abdominal aneurysm. Increasing evidence suggests that CHIP is associated with venous thromboembolic disease. Somatic mutations lead to proliferation of hematopoietic progenitor cells and their progeny, resulting in excessive activation of granulocytes and monocytes. It could be postulated that chronic inflammation caused by clonal expansion of myeloid cells carrying mutations in DNMT3A, TET2, and ASXL1 (“DTA”) genes may constitute an independent risk factor in clot formation and endothelial-cell damage. DTA mutations correlate with elevated proinflammatory cytokines such as IL-1β and IL-6 and enhanced activation of inflammasomes. Moreover, JAK2 mutations may have a direct role in the activation of platelets and coagulation. In vivo murine studies have demonstrated that activation of the JAK-STAT signaling pathway promotes neutrophil extracellular trap (NET) formation, contributing to a prothrombotic state. Insights from related clonal disorders such as paroxysmal nocturnal hemoglobinuria and the VEXAS syndrome support the concept that mutation-driven innate immune activation can directly perturb hemostatic balance. This review aims to summarize the association between clonal expansion of hematopoietic cells and thrombotic disease, and highlight how somatic mutations in hematopoietic cells may contribute to vascular disease and thrombogenesis. Full article

Background/Objectives: High-grade serous ovarian cancer (HGSOC) is usually discovered in advanced stages and often relapses shortly after initial conventional therapy. Survival in HGSOC patients might be improved with the use of novel immune therapies, which potentiate autologous anti-tumor responses. Dendritic cells (DCs) are potent antigen-presenting cells that can initiate immune responses, activate cytotoxic T cells and drive T-cell differentiation. This pilot trial evaluated the safety and efficacy of a unique DC vaccine (α-DC-1) in relapsed, advanced HGSOC patients with minimal tumor burden. Methods: Monocytes from patient leukaphereses were used to propagate a unique autologous DC, the α-DC-1, generated with granulocyte–macrophage colony-stimulating factor and interleukin-4, pulsed with keyhole limpet hemocyanin (KLH) and tumor lysate (from debulking surgery) on day 5, and matured with a cocktail of cytokines and chemokines on day 6. Mature α-DC-1 were harvested on day 7 and administered intranodally (inguinal nodes) every other week for three doses/cycle for up to three DC vaccine cycles (nine vaccines). The primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: In 19 patients treated, the median PFS was 9.7 months (95% CI: (5, NA)) and the median OS was 42.2 months (95% CI: (31.2, 68.3)). In 5/19 (26.3%) patients, OS exceeded five years. Administration of six or more vaccines was associated with a significant improvement in PFS. No grade 2 or higher toxicities were noted. Conclusions: Our α-DC-1 vaccine was safe, and 94.2% elicited an immune response to KLH. The long OS, exceeding 5 years in some patients, suggests this DC vaccine may improve survival for some with relapsed HGSOC. Full article

Candida albicans is a ubiquitous commensal fungus that may be lethal once it gains access to the bloodstream, following a breach in protective barriers such as skin or gut lining. Intravenous injection of C. albicans (4.5 × 10⁴ yeasts/gm of mouse) leads reproducibly to systemic infection with a median survival of about 75 h. We studied the effects of two human innate immune effectors on the course of systemic infections. The soluble human pentraxin serum amyloid P component (hSAP) retards death in murine disseminated candidiasis. In contrast, another soluble pentraxin, human C-reactive protein (hCRP), hastens death. To examine the pathological basis for these differences, necropsies were performed, and the right kidney was removed for study. Candidiasis caused abundant collagen deposition (the precursor to fibrosis) and loss of contrast between the kidney medulla and cortex. Daily administration of subcutaneous hSAP following the intravenous injection of C. albicans preserved the discrete histological difference between cortex and medulla and lessened host collagen deposition. Yeasts and hyphae within abscesses were decorated with hSAP. Contrastingly, kidneys from animals administered C. albicans and hCRP showed extensive collagen deposition and loss of the boundary between the cortex and the medulla of the kidney. hCRP did not bind to fungi but bound to damaged tissue surrounding abscesses, leading to a more destructive infection with loss of tissue. Staining cells with antibodies to CD45 (to detect T-lymphocytes, myelocytes, monocytes, and macrophages) and antibodies to Ly-6G (neutrophils, and granulocytes) showed that hSAP retarded infiltration of inflammatory cells into diseased areas. The results are consistent with the hypothesis that early administration of hSAP represses the migration of inflammatory cells, dampens the production of collagen by fibroblasts, and dampens the overall immune response of the host to infection. In doing so, hSAP prolonged life, whereas hCRP facilitated the infectious process and hastened death. Full article

Hematopoietic stem and progenitor cells (HSPCs) in the bone marrow are highly vulnerable to radiation-induced damage. Systematic delineation of lineage-specific transcription factor (TF) programs, together with in silico perturbation analyses, provides a valuable approach for identifying regulators capable of accelerating hematopoietic reconstruction after irradiation. Here, using single-cell RNA sequencing (scRNA-seq), we characterized the dynamics of HSPCs at both cellular abundance and transcriptional regulation levels following irradiation and used in silico TF perturbation to predict their effects on lineage commitment. We found that granulocyte–macrophage progenitor (GMP) differentiation is consistently prioritized after irradiation, accompanied by enhanced activity of proliferation-associated drivers. Network-based TF profiling identified Tcf7l2 as a previously unrecognized regulator of early lymphoid differentiation. In silico perturbation further functionally predicted TFs driving differentiation in HSPCs after irradiation, and Hsf1, a factor with pharmacological activation potential, was selected for validation via in vivo celastrol treatment and in vitro knockdown. Collectively, our findings uncover the transcriptional programs governing HSPC lineage biases after radiation exposure and highlight the utility of in silico TF perturbation as a strategy for guiding the therapeutic interventions for radiation-induced hematopoietic injury. Full article

Microplastics are emerging environmental contaminants capable of crossing epithelial barriers and circulating systemically, potentially affecting organisms, including humans. This study investigated the hematological and biochemical effects of sub-chronic oral exposure to polystyrene microplastics (PS-MPs) in male Swiss albino mice. Animals received 1 μm PS-MPs in drinking water at 0.01 mg/day for four weeks, followed by a two-week recovery period. Blood samples were collected weekly for hematological and biochemical analysis. PS-MP exposure resulted in an increased number of certain immunocytes after the first week of treatment. The highest values compared with the control group were observed in Week 2, reaching 18.5 ± 4.61 vs. 7.2 ± 1.14; 10.9 ± 2.58 vs. 5.1 ± 1.20; and 5.8 ± 2.35 vs. 2.2 ± 0.69 × 10⁹ cells/L for white blood cells, lymphocytes, and granulocytes, respectively (p < 0.001). A significant increase in platelet count was also observed, becoming evident by Week 6 (725.8 ± 307.96 vs. 470.1 ± 121.87 × 10⁹ cells/L, p < 0.05). The elevated alanine aminotransferase and aspartate aminotransferase activities observed after PS-MP exposure were potentially associated with hepatic pathology, erythrocyte damage, and inflammatory responses. No significant recovery was observed during the period after exposure. These findings demonstrate that sub-chronic oral PS-MP exposure induces inflammatory responses and may disrupt organ function. Full article

Thalassemia is a hereditary hemoglobinopathy characterized by ineffective erythropoiesis, chronic hemolysis, and transfusion-related iron overload, which collectively contribute to oxidative stress and organ dysfunction. The present study aimed to investigate the relationships between iron metabolism, oxidative stress biomarkers, and immune cell function across different clinical conditions. Peripheral blood samples were obtained from healthy individuals and patients with iron deficiency anemia, obesity, thalassemia trait (TT), β-thalassemia HbE (BTE), and β-thalassemia major (BTM). Hematological parameters were measured using automated hematology analyzers, while biochemical indicators, including liver enzymes and bilirubin, were determined using clinical chemistry assays. Iron overload was evaluated using serum iron parameters and T2*-weighted magnetic resonance imaging. Oxidative stress biomarkers, including reduced glutathione, thiobarbituric acid-reactive substances, and total antioxidant capacity, were assessed spectrophotometrically. Flow cytometric analysis was used to measure reactive oxygen species, redox-active iron, and lipid peroxide levels in granulocytes and lymphocytes. Thalassemia patients exhibited severe anemia, elevated liver enzymes, increased bilirubin levels, and significant alterations in iron metabolism compared with healthy controls. Hepatic iron accumulation was more common than cardiac iron deposition, particularly in BTE patients. Granulocyte oxidative burst activity was significantly reduced in thalassemia patients, whereas lymphocyte responses remained relatively preserved. Increased variability in glutathione levels suggested activation of intracellular antioxidant defense mechanisms in response to chronic oxidative stress. These findings highlight the complex interplay between iron overload, oxidative stress, and the immune cell dysfunction associated with thalassemia, thereby providing insights into improved monitoring and therapeutic strategies. Full article

Mitochondrial dysfunction drives persistent inflammation in severe asthma, yet its upstream metabolic regulation remains unclear. Induced sputum from patients with severe asthma was analyzed and integrated with transcriptomic datasets from independent cohorts. Two mouse models (C57BL/6J) were used for in vivo validation with multi-omics profiling, and mechanistic studies were performed in air–liquid interface-cultured primary human airway epithelial cells. Glutathione reduced form (GSHr) was markedly depleted in sputum and associated with poor disease control and mixed granulocytic inflammation in patients with severe asthma. Multi-omics analyses revealed coordinated disruption of glutathione (GSH) metabolism, including oxidized GSH accumulation, reduced synthesis and glutathione-S-transferase activity, and impaired mitochondrial GSH transport. GSH supplementation alleviated airway inflammation, oxidative stress, and mitochondrial dysfunction, whereas pharmacological inhibition of GST exacerbated these effects. Mitochondrial analyses identified suppressed SLC25A39 expression as a key mediator of defective GSH transport and redox imbalance. Transcriptomic profiling of airway biopsies showed upregulation of Neuropilin-1 (Nrp1), closely associated with altered glutathione pathways. Targeting the Nrp1 b1 domain restored mitochondrial GSH metabolism and attenuated airway inflammation. These findings identify an Nrp-centered metabolic pathway that disrupts mitochondrial homeostasis and drives inflammatory amplification, highlighting mitochondria-targeted therapeutic strategies for severe asthma. Full article

Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted predominantly through the bite of infected Hyalomma ticks, yet the earliest events at the vector–host–virus interface in human skin remain largely undefined. This review synthesizes current knowledge of human cutaneous structure and immunity, tick feeding biology, and salivary immunomodulation to propose how local skin responses may shape systemic outcomes of CCHFV disease. We detail the roles and permissiveness of major skin-resident and infiltrating cell types, including keratinocytes, melanocytes, Langerhans cells, dermal dendritic cells, monocytes/macrophages, fibroblasts, granulocytes, T cells, B cells, NK cells, and innate lymphoid cells, in antiviral defense and as potential early targets or carriers of CCHFV. Emphasis is placed on how tick saliva components reprogram the cutaneous microenvironment, alter interferon, complement, inflammasome, and cytokine pathways, and may enable saliva-assisted transmission and viral dissemination from the dermis. We highlight mounting evidence from other arboviruses demonstrating that the skin can act as both a barrier and a major amplifying organ, and we extrapolate testable hypotheses on how early cutaneous immune dynamics might influence CCHFV severity and hemorrhagic manifestations. Finally, we outline key knowledge gaps that, if answered, may inform the development of vaccines and therapeutics that harness cutaneous immunity to block systemic spread. Full article

Encapsulation is a major cellular defense reaction in lepidopterans. However, in the oriental armyworm (Mythimna separata), the molecular regulators that coordinate hemocyte adhesion and multilayer capsule assembly remain poorly defined. In this study, we identified Mythimna separata encapsulation related gene 1 (MysERG1) as a novel cellular immune regulatory gene. MysERG1 transcripts were most abundant in hemocytes and were notably upregulated in adherent hemocytes as well as in samples of capsules, indicating an association with adhesion-dependent hemocyte activation. Following separation of granulocytes and plasmatocytes, MysERG1 expression was observed to be higher in adherent plasmatocytes than in adherent granulocytes. However, recombinant MysERG1 selectively increased granulocyte adhesion but did not significantly affect plasmatocyte adhesion and was specifically localized on granulocytes. Additionally, recombinant MysERG1 enhanced hemocyte aggregation on foreign surfaces, highlighting its functional role in facilitating encapsulation. Functional knockdown using double-stranded RNA significantly reduced the size of the capsules, indicating that MysERG1 is required for robust capsule formation. This study identifies MysERG1 as a novel factor involved in hemocyte cooperation during encapsulation in M. separata and presents a conceptual framework for inter-hemocyte communication mechanisms in lepidopteran cellular immunity. Full article

Feline panleukopenia (FPL) is a serious viral disease caused by Feline panleukopenia virus (FPV) that causes leukopenia, lymphopenia, and neutropenia, particularly in young or unvaccinated cats. There is no specific antiviral treatment available for FPL, and treatment protocols generally consist of fluid therapy and supportive care. This study evaluated the clinical and hematological efficacy of filgrastim, a granulocyte colony-stimulating factor (G-CSF) that has shown successful results in treating FPL in various studies, and the paraimmune activator-inactivated Parapoxvirus ovis (iPPVO) in 49 cats naturally infected with FPV. Cats were randomly assigned to four groups: low-dose filgrastim (5 µg/kg, n = 13), high-dose filgrastim (20 µg/kg, n = 14), iPPVO (n = 12), and standard supportive treatment (n = 10). Clinical signs and complete blood counts were assessed on days 0 and 7. By day 7, high-dose filgrastim showed greater increases in white blood cell, lymphocyte, monocyte, and neutrophil counts compared with the other groups (p < 0.05), whereas moderate improvements were observed in the iPPVO group. Leukopenia and lymphopenia resolved faster in the high-dose filgrastim group than in the low-dose filgrastim and standard treatment groups. Clinical recovery, including reduction in vomiting and lethargy, was more pronounced in the high-dose filgrastim and iPPVO groups. Survival rates did not differ significantly among groups (p = 0.615), although the high-dose filgrastim group showed the lowest mortality (42.9%). These findings suggest that high-dose filgrastim may contribute to cytopenias and promote hematological recovery in FPL, while iPPVO may serve as a supportive immunomodulatory therapy. However, it should be noted that the efficacy of filgrastim and/or iPPVO treatments has not been definitively confirmed, likely due to the small sample size and the lack of well-controlled randomized studies. Full article

This study estimates the association between respiratory outcomes among employees of a secondary aluminum plant and airborne pollutants. Additionally, it looks into the relationship between pulmonary dysfunction in workers and X-Ray repair cross-complementing one (XRCC1) gene polymorphisms. 110 exposed workers and 58 non-exposed workers were enrolled in the study. Measurements were conducted on sulfur dioxide (SO₂), nitrogen dioxide (NO₂), and particulate particles. Pulmonary function was tested. Eosinophil cationic protein (ECP), C-reactive protein (CRP), matrix metalloproteinase-1 (MMP-1), interleukin 6 (IL6), granulocyte-macrophage colony-stimulating factor (GM-CSF), XRCC1 protein, and genotyping of XRCC1 gene polymorphisms were examined. The annual average concentrations of particulate matter (PM_2.5, PM₁₀), total suspended particulates (TSP), SO₂, and NO₂ were lower than the permissible limit. The areas around ovens, evaporators, and cold rolling mills exhibited the highest amounts. The majority of employees in these departments had impaired lung function. Prolonged exposure was associated with a significant decrease in forced expiratory volume in 1 s (FEV1%) and forced vital capacity (FVC%) among the exposed group (p = 0.001 & 0.04, respectively). Serum XRCC1 levels were significantly higher among exposed workers (p = 0.02). Inflammatory biomarkers showed no statistically significant differences between groups. Aluminum workers are at risk of developing respiratory disorders. The level of serum XRCC1 may serve as a potential biomarker for detecting susceptible workers. Full article

Mycobacterium tuberculosis (Mtb) remains a significant public health threat, responsible for 1.6 million deaths in 2021. The development of new treatments is particularly urgent for immunocompromised individuals, including those with Mtb/HIV coinfection, who experience severe disease outcomes. Previous studies demonstrated that blockade of VEGFR1, a receptor expressed on monocytes that mediates their recruitment to infection sites, limits Mtb-induced pathology in immunocompetent mice of both Mtb-resistant (C57BL/6J) and Mtb-susceptible (B6.C3H-sst1) strains. The present study extends these findings by evaluating the VEGFR1/2 blockade strategy in immunocompromised hosts. Treatment with the VEGFR1/2 blocker SU5416 (semaxanib) reduced monocyte infiltration into the lungs of Mtb-infected immunocompromised RAG1KO mice without affecting bacterial protection. Reduced monocyte recruitment improved lung pathology. VEGFR1/2 blockade also decreased the number of NK cells in the lungs of RAG1KO mice. Notably, an elevated ratio and increased absolute number of neutrophil granulocytes were observed in the Mtb-infected lungs of both immunocompetent and immunocompromised mice following SU5416 administration. However, this increase in neutrophils did not exacerbate lung pathology, as most recruited granulocytes remained within the lung vasculature. The beneficial effect of VEGFR1/2 blockade in RAG1KO animals suggests that further investigation of VEGFR blockers, such as SU5416, as adjunctive therapy to anti-tuberculosis drug regimens for immunocompromised populations with tuberculosis is warranted. Full article

Background and Clinical Significance: Mixed-phenotype acute leukemia (MPAL) is a rare hematologic malignancy characterized by the co-expression of myeloid and lymphoid markers and is associated with poor prognosis. Myeloid sarcoma (MS), particularly in the mediastinum, is an uncommon extramedullary manifestation and is rarely reported in association with MPAL. Case Presentation: We report a rare case of mediastinal MS with biphenotypic features and pericardial extension occurring concurrently with MPAL, highlighting diagnostic challenges, therapeutic strategies, and long-term outcomes. We describe the clinical course, diagnostic workup, treatment, and follow-up of a 21-year-old woman who presented with cardiac tamponade secondary to a mediastinal mass. Histopathology and immunophenotyping established the diagnosis of mediastinal MS associated with MPAL (B/myeloid, NOS). Management included surgical cytoreduction, intensive induction chemotherapy, and consolidation with allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor. Fertility preservation with oocyte retrieval, in vitro fertilization (IVF), and embryo cryopreservation was performed prior to conditioning. A focused literature review of MPAL cases with extramedullary involvement was conducted. The patient achieved complete remission following induction therapy and underwent allo-HSCT. Despite the historically poor prognosis of mediastinal MS and MPAL, she remains in sustained complete remission 13 years after diagnosis. A literature review identified only eight reported cases of MPAL with extramedullary disease, with mediastinal involvement described in a single case and allo-HSCT performed in only two patients. Conclusions: This case illustrates a rare presentation of MPAL with mediastinal myeloid sarcoma and cardiac tamponade, demonstrating that aggressive multimodal therapy including allo-HSCT may achieve durable remission even in high-risk presentations. Early multidisciplinary management and consideration of fertility preservation are essential in young patients. Full article

Background: The integration of anti-disialoganglioside GD2 (anti-GD2) immunotherapy during induction chemotherapy has emerged as a promising strategy to improve outcomes in high-risk neuroblastoma (HR-NB). This study evaluated the end-of-induction (EOI) response and tolerability of a modified N7 induction regimen combined with dinutuximab beta in a Hong Kong paediatric cohort. Methods: A retrospective territory-wide analysis was conducted on nine HR-NB patients treated from 2022 to 2025. They received a modified N7 chemotherapy backbone with dinutuximab beta (17.5 mg/m²/day for 4 days per cycle), alongside granulocyte–macrophage colony-stimulating factor (GM-CSF) and low-dose interleukin-2. Response was assessed using the Revised International Neuroblastoma Response Criteria (INRC), and toxicity was graded according to the Common Terminology Criteria for adverse events (CTCAE). Results: The EOI objective response rate was 78% (7/9 patients) for the primary tumour site and 100% at metastatic sites. No patient exhibited progressive disease. A modified Curie score of ≤2 on MIBG scan was achieved in 78% of patients. Grade 3 or higher toxicities, including neutropenic fever, enterocolitis, and capillary leak syndrome, were observed in eight patients but were manageable. Conclusions: The incorporation of dinutuximab beta into a modified N7 induction regimen demonstrates a satisfactory EOI response rate and a manageable safety profile in children with HR-NB. These preliminary results support the feasibility of this chemoimmunotherapy approach and warrant further investigation in larger cohorts to confirm its efficacy in long-term survival outcomes. Full article