Immune Activation Research Articles

Idiopathic nephrotic syndrome – contemporary views on immune-mediated pathogenetic mechanisms

Idiopathic nephrotic syndrome is a rare kidney disease characterised by nephrotic proteinuria, hypoalbuminemia, hyperlipidaemia and oedema. The incidence of idiopathic nephrotic syndrome ranges from 2 to 7 cases per 100,000 children per year. Children between 1 and 10 years of age are mainly affected. The pathogenesis is associated with damage to the microstructure of glomerular filtration barrier, which may be caused by a variety of immune-mediated factors. Circulating factors such as hemopexin, cathepsin, soluble form of urokinase plasminogen activator receptor may be responsible for proteinuria in idiopathic nephrotic syndrome. Another possible cause of nephrotic proteinuria is dysregulation of T cells, including regulatory T cells and B cells. Nephrotic proteinuria occurs in other diseases that are associated with pathological action of lymphocytes, such as immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX syndrome), and Hodgkin’s lymphoma. Numerous relapses of proteinuria in idiopathic nephrotic syndrome may be associated with latent Epstein–Barr virus infection via antigenic mimicry. Relapses of proteinuria may also occur in response to gluten or allergens in patients with coeliac disease or food allergy. Idiopathic nephrotic syndrome is managed with immunosuppressants. They inhibit immune system activity, which consequently allows for reaching and maintaining remission of the disease.

Breaking barriers: Smart vaccine platforms for cancer immunomodulation.

Despite significant advancements in cancer treatment, current therapies often fail to completely eradicate malignant cells. This shortfall underscores the urgent need to explore alternative approaches such as cancer vaccines. Leveraging the immune system's natural ability to target and kill cancer cells holds great therapeutic potential. However, the development of cancer vaccines is hindered by several challenges, including low stability, inadequate immune response activation, and the immunosuppressive tumor microenvironment, which limit their efficacy. Recent progress in various fields, such as click chemistry, nanotechnology, exosome engineering, and neoantigen design, offer innovative solutions to these challenges. These achievements have led to the emergence of smart vaccine platforms (SVPs), which integrate protective carriers for messenger ribonucleic acid (mRNA) with functionalization strategies to optimize targeted delivery. Click chemistry further enhances SVP performance by improving the encapsulation of mRNA antigens and facilitating their precise delivery to target cells. This review highlights the latest developments in SVP technologies for cancer therapy, exploring both their opportunities and challenges in advancing these transformative approaches.

Biomarkers associated with recurrence after salvage surgery for localized anal cancer (AC).

9 Background: While most patients with localized AC are cured by chemoradiation (cRT), some recur and require salvage surgery (SS). No adjuvant therapies are effective after SS. We profiled cRT-refractory AC tumors from SS to identify biomarkers linked to recurrence. Methods: Using an IRB-approved protocol, patients with localized, cRT-refractory AC were classified as recurrent (R; N=19) or non-recurrent (NR; N=10) according to outcome after SS. Digital spatial profiling whole transcriptome analysis (GeoMx) on FFPE AC evaluated expression of 18000+ genes on 40 regions of interest (ROI) for R vs 25 ROIs for NR AC cores, separated into “tumor” (panCK+) and “tumor microenvironment” (TME; panCK-). log2 transformed RNA counts were compared for expression between ROIs of R and NR AC (limma). For GSEA hallmark pathway analysis, normalized enrichment scores (NES) were calculated using genes with differential gene expression. Expression of immune biomarkers using multiplex immunofluorescence (mIF) were quantified (N/mm2) and compared with a student’s t-test. Results: With a median follow up of 26.6 months, median OS (29.1 months vs NR; p< .001) was shorter for R AC. For NR AC, higher expression of genes associated with immune activation (p-adj< .0001 for all) - B2M (fold change (FC) 33.0), HLA-DPA1 (FC 30.1), and HLA-DPB1 (FC 15.0) – and higher NES for “interferon alpha response” (NES 3.2) and “interferon gamma response” (NES 3.1) (FDR < .05 for both) were observed. R AC had higher expression of genes (p-adj < .0001 for all) regulating TGF-beta signaling – LY6K (FC 10.3) and BCAR3 (FC 3.6), and higher “EMT” (NES 2.1) and “TGF-beta” (NES 1.6) GSEA signatures (FDR< .05 for both). On mIF, greater CD3+CD8+ T cells were observed in tumor (148 vs 42 N/mm2; p=.02) and TME (8.2 vs 2.8 N/mm2; p=.008) for NR AC. Increased Thy1+ cancer-associated fibroblasts were noted in tumor (4.2 vs 1.2 N/mm2; p=.04) and in TME (149 vs 69 N/mm2; p=.04) for R AC. Conclusions: Signatures of immune activation were observed with gene expression and mIF in AC patients cured by SS. R AC had higher immune suppressing profiles. These data support developing novel therapeutics that promote immune activation in trials of patients with cRT-refractory AC at high risk for recurrence after SS.

Post-COVID-19 sequelae are associated with sustained SARS-CoV-2-specific CD4+ immune responses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to widespread post-acute sequelae of COVID-19 (PASC), affecting multiple body systems. Despite its prevalence, PASC's pathogenesis remains unclear, with hypotheses suggesting viral persistence, immune activation, and autoimmune responses among the pathogenetic mechanism. This study aimed to evaluate T cell memory response in PASC patients, one year post-hospital discharge and correlate it with clinical parameters to identify a potential PASC-associated fingerprint. Peripheral blood mononuclear cells (PBMCs) from PASC patients and healthy controls (HC) were stimulated with a pool of spike peptides. CD4+ and CD8+ T cell responses were evaluated by flow cytometry using the activation-induced markers assay (AIM). Findings showed significant activation of the CD4+ T cell compartment, with a higher proportion of responders among PASC patients. Central memory (CM) T cells expressing pro-inflammatory cytokines were more prevalent in responders. Clinical correlations revealed higher SARS-CoV-2-specific T cell responses in patients with reduced diffuse lung capacity for carbon monoxide (DLCO) and residual symptoms. These immune changes, especially in CM T cells, could play a pivotal role in PASC's development and persistence, impacting patients' daily lives.

Prolonged interval hypofractionated radiotherapy facilitates better antitumor immunity.

To evaluate the impact of hypofractionated radiotherapy (Hypo-RT) with different interfraction intervals on tumor growth, immune response, and synergistic effects with anti-PD-1 immunotherapy. The mouse MC38 colon cancer model was utilized. Various radiation regimens were designed to investigate the effects of fraction interval and fraction size on tumor growth, immune mobilization, and combination effects with anti-PD-1 immunotherapy. For a fixed-dose experiment, the 6×5 Gy for every other day (qod) regimen demonstrated an equivalent effect on tumor growth compared to the 6×5 Gy once daily (qd) regimen, while the 6×5 Gy for twice weekly (biw) regimen failed to inhibit tumor growth. Both qod and biw regimens induced an enhanced immune response, unlike the qd regimen. For a fixed biologically equivalent dose experiment, 6×5 Gy qod, 4×7 Gy biw, and 2×11Gy once weekly (qw) regimens exhibited similar tumor suppression to the 12×3 Gy qd regimen. The long-interval Hypo-RT regimens significantly mobilized host immunity, whereas 12×3 Gy qd did not. The peripheral and intratumoral T cells increased as the fraction interval and size increased. All Hypo-RT regimens combined with anti-PD-1 immunotherapy demonstrated higher intratumoral CD8+T cells and more effective tumor growth delay compared to the 12×3 Gy qd regime. The current study suggested that a prolonged inter-fraction interval with an increased fraction size in Hypo-RT may be a promising option to balance the therapeutic effect on tumor and immune activation.

Brain transcriptomics of a social challenge and maternal aggression in incubating female tree swallows.

Aggressive behavior is ubiquitous across many contexts, including defense of territories, mates, and offspring. For decades, researchers have detailed the effect of aggressive behavior on physiology, but our understanding of these mechanisms in females lags behind that of males, despite the fact that female aggression is widespread, particularly in the context of maternal defense of eggs or offspring (i.e., maternal aggression). Here, we measured effects of a social challenge on brain gene expression in free-living incubating females. We hypothesized that the social challenge would generate at least one of three transcriptomic effects: (1) sensitizing the brain to otherwise low levels of sex steroids, (2) changing other neuroendocrine signaling pathways associated with social behavior (e.g., dopamine), or (3) broad shifts related to metabolism or immune function. We tested these hypotheses in incubating female tree swallows (Tachycineta bicolor), exposing 10 females to a 30-min simulated territorial intrusion, which elicited maternal aggression. After this challenge, we measured neural gene expression via RNA-seq and compared gene expression to 10 unchallenged controls. We saw no global treatment effect on gene expression. However, within the experimental group, more maternal aggression was correlated with upregulation of genes associated with immune activation and downregulation of genes associated with synaptic plasticity. Though more research is needed to understand the downstream effects of these transcriptional differences, our findings generate key questions about how the brain responds to social challenges across different contexts.

MiR-142 deficit in T cells during blast crisis promotes chronic myeloid leukemia immune escape

We reported that an acquired miR-142 deficit transforms chronic phase (CP) chronic myeloid leukemia (CML) leukemic stem cells (LSCs) into blast crisis (BC) LSCs. Given the role of miR-142 in the development and activity of the immune system, we postulated that this deficit also promotes LSC immune escape. Herein, we report on IL-6-driven miR-142 deficit occurring in T cells during BC transformation. In CML murine models, miR-142 deficit impairs thymic differentiation of lymphoid-primed multipotent progenitors (LMPP) into T cells and prevents T cells’ metabolic reprogramming, thereby leading to loss of T cells and leukemia immune escape. Correcting miR-142 deficit with a miR-142 mimic compound (M-miR-142), alone or in combination with immune checkpoint antibodies, restores T cell number and immune activity, leading to LSC elimination and prolonged survival of BC CML murine and patient-derived xenograft models. These observations may open new therapeutic opportunities for BC CML and other myeloid malignancies.

Synergistic Effects of Ocean Acidification and Sulfamethoxazole on Immune Function, Energy Allocation, and Oxidative Stress in Trochus niloticus

Ocean acidification, a major consequence of climate change, poses significant threats to marine organisms, particularly when combined with other environmental stressors such as chemical pollution. This study investigated the physiological responses of Trochus niloticus to a 28-day exposure of ocean acidification and/or sulfamethoxazole, a commonly detected antibiotic in the South China Sea. Exposure to either acidification or sulfamethoxazole individually triggered adaptive responses through immune activation, antioxidant reactions, and metabolic adjustments. However, concurrent exposure resulted in significant adverse effects, including compromised immunity, oxidative damage, and disrupted energy budget. These findings provide new insights into how ocean acidification interacts with antibiotic pollution to synergistically impact marine gastropods, suggesting that multiple stressors may pose greater threats to T. niloticus populations than single stressors alone.

GSH/pH-responsive copper-based cascade nanocomplexes inducing immunogenic cell death through cuproptosis/ferroptosis/necroptosis in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) remains a formidable challenge due to high recurrence rates and limited efficacy of conventional treatments. Immunotherapy holds potential, but its effectiveness is often restricted by low patient responsiveness. This study presents a novel therapeutic strategy using GSH/pH-responsive copper-based cascade nanocomplexes to induce immunogenic cell death (ICD) in OSCC. The fabricated nanocomplex, PC@B-H, leverages the acidic and reducing tumor microenvironment to release copper ions and plumbagin, triggering a cascade of cell death mechanisms including cuproptosis, ferroptosis, and necroptosis. This multifunctional system not only enhances oxidative stress but also depletes glutathione, promotes lipid peroxidation, and disrupts mitochondrial function, leading to robust tumor inhibition. Additionally, the induction of ICD facilitates dendritic cell maturation and cytotoxic T lymphocyte infiltration, providing durable anti-tumor immunity. The study demonstrates that PC@B-H achieves a 92.3% tumor growth inhibition rate with minimal systemic toxicity, offering a promising avenue for enhancing the efficacy of OSCC treatment through combined cell death pathways and immune activation.

Abstract TP346: Investigating Transcriptomic Profiles of Peripheral Blood Mononuclear Cells in Moyamoya Disease Using Single-Cell RNAseq

Objectives: Moyamoya Disease (MMD) is a complex cerebrovascular disease marked by progressive narrowing in the cerebral arteries. Previous studies have suggested that dysregulated genes in the peripheral blood of MMD patients are involved in extracellular matrix organization and immune responses. However, the mechanism by which the immune response contributes to MMD progression is unclear. In this study we investigated the immune landscape in the peripheral blood mononuclear cells (PBMCs) of MMD patients using single-cell RNA sequencing (scRNA-seq). Methods: Blood samples were collected from 3 bilateral MMD patients and 2 healthy controls. PBMCs were isolated and processed for 10x single-cell RNA sequencing. Immune cell heterogeneity and differentially expressed genes (DEGs) in each cell type were identified. Top biological pathways were determined using Ingenuity Pathway Analysis (IPA). Flow cytometry with an 11-fluorochrome panel was use to validate key immune populations and fluorescence-activated cell sorting (FACS) was used to isolate specific immune populations for transcriptome analysis. Results: Preliminary analysis revealed notable increase of cell percentages in certain cell types in MMD, such as CD8+T (9.21% vs 7.11%), B cells (6.94% vs 3.45%) and CD4+NKT (5.78% vs 3.22%), and decrease in CD8+NKT (9.59% vs 15.74%), compared to controls. Higher transcriptome dynamics were observed in certain cell type in MMD, with 2402 DEGs in classical monocytes, 1379 DEGs in CD4+T, 1312 DEGs in CD8+NKT and 997 DEGs in B cells. Interestingly, many cell types, except for classical and non-classical monocytes, displayed a higher number of downregulated DEGs in MMD, particularly in T cells, B cells, and NKT cells. Pathway analysis indicated that CD4+T, CD8+NKT, and B cells show predicted inhibition in several pathways, including T cell receptor and mTOR signaling, interleukins and CXCR4 signaling, as well as cell surface interactions at the vascular wall. Conclusion: These preliminary findings point to a distinct immunological profile in MMD, suggesting significant alterations in both immune cell activity and interaction within the vascular environment. Ongoing studies utilize FACS to validate specific immune populations and their transcriptomes in a larger cohort. These findings reveal unique transcriptomic signatures of peripheral blood immune cells in MMD and highlight key immune cell types that may contribute to its pathogenesis.

PD-L1 upregulation in activated fibroblasts promotes silica particle-induced pulmonary fibrosis.

Silicosis is a severe interstitial lung disease resulting from prolonged exposure to silica dust in working environment, characterized by inflammation and fibrosis. This condition is closely associated with immune dysregulation, although the precise regulatory mechanisms remain elusive. Immune checkpoints (ICs) comprise receptor-ligand pairs crucial for immune cell activation and coordination of immune responses. Among these, PD-1 and its ligand PD-L1 have garnered significant attention in tumor research and have recently been implicated in the regulation of fibrotic diseases. Nonetheless, their involvement in silicosis remains unexplored. In this study, we observed a global upregulation of PD-1 and PD-L1 expression concomitant with the progression of silicosis, exhibiting cell specificity. Targeting PD-1/PD-L1 signaling mitigated silicosis in mice by modulating T cell homeostasis, macrophage polarization, and activation of fibrotic effector cells. Notably, PD-L1 expression on activated fibroblasts emerged as a pivotal driver of silicosis progression. Mechanistically, elevated PD-L1 levels in fibroblast activation fostered a positive feedback loop by binding to p-Smad2/3 and p-STAT3 proteins, thereby facilitating their nuclear translocation and augmenting protein stability, ultimately promoting fibroblast transdifferentiation. Consistently, knockdown of PD-L1 in lung fibroblasts significantly ameliorated silicosis in mice. In summary, PD-1/PD-L1 signaling mediates critical profibrotic signals during the progression of silicosis.

Glycobiology of psoriasis: A review.

Psoriasis is a chronic inflammatory skin disease with etiologies related to genetics, immunity, and the environment. It is characterized by excessive proliferation of keratinocytes and infiltration of inflammatory immune cells. Glycosylation is a post-translational modification of proteins that plays important roles in cell adhesion, signal transduction, and immune cell activation. Abnormal glycosylation is associated with inflammation, tumors, autoimmunity, and several diseases. Glycan profiles and glycosylation-related enzymes are altered in patients with psoriasis. Specific glycan structures, such as glycosaminoglycans and gangliosides, inhibit the development of psoriasis through various pathways. Lectins are glycan-binding proteins that are widely involved in the pathogenesis of psoriasis. The differential serum, epidermal, and dermal expression of galectins in patients with psoriasis distinguishes psoriasis from other nonspecific psoriasis-like dermatitis. This article summarizes relevant literature on psoriasis-related glycans to help clarify the potential molecular mechanisms of psoriasis and identify novel biomarkers and targets for the treatment of psoriasis.

Structure, Properties, and Biomedical Activity of Natural Sweeteners Steviosides: An Update.

Stevioside is a natural sweetener with the characteristics of low calorie and high sweetness. It comprises a diverse range of monomers that play crucial roles in numerous biological processes. Due to these attributes, it has gained widespread application in agriculture, food, and pharmaceutical industries. As a substitute for sugar, stevioside also shows good pharmacological activities on glucose metabolism, bodyweight keeping, blood pressure maintenance, and shows anti-inflammatory, anti-oxidation, anti-tumor, antibacterial, and immune regulation activities. This review summarized the update on the food safety, sweet structure-activity relationship, pharmacological activity of stevia glycosides recently, and discussed the limitations of its application in food and medicine.

P2RX1-blocked neutrophils induce CD8+ T cell dysfunction and affect the immune escape of gastric cancer cells

BackgroundGastric cancer (GC) is one of the deadly malignancies of the gastrointestinal tract. Research has confirmed the linkage of P2RX1 with immune cell activation and tumor progression. This project focused on the impact of P2RX1 level in neutrophils on the efficacy of immune checkpoint inhibitor (ICI) treatment in GC. MethodsBlood samples from 23 GC patients eligible for camrelizumab treatment were collected. Flow cytometry was carried out to analyze the proportion of P2RX1 in neutrophils. IHC was utilized to detect the expression level of PD-L1. We also evaluated the chemotaxis ability of neutrophils using a Transwell system, assessed the viability and apoptosis rate of GC cells using CCK-8 and flow cytometry, measured the proportions of CD8+PD-1+ and CD8+GZMB+ cells, determined the expression levels of IL-6, TNFα, IFN-γ, IL-8, IL-12, IL-1β, and GZMB by utilizing enzyme-linked immunosorbent assay (ELISA), and examined the expression levels of P2RX1 and PD-L1 using western blot (WB). By establishing a xenograft mouse model, we studied the impact of P2RX1-blocked neutrophils on the efficacy of ICI treatment in the GC microenvironment. ResultsIn GC, clinical analysis revealed increased infiltration of P2RX1-lowly expressed neutrophil subsets and increased expression of PD-L1. In vitro experiments demonstrated that abnormal expression of P2RX1 affected neutrophil function. Furthermore, the blockage or knockdown of P2RX1 in neutrophils modulated CD8+ T cell function, promoting GC progression. In in vivo experiments, the blockage of P2RX1 in neutrophils inhibited the effectiveness of ICI treatment in the GC microenvironment. ConclusionThis project validated that the loss of P2RX1 in neutrophils induces CD8+ T cell dysfunction and affects the GC development, indicating that P2RX1 may be an accurate biomarker for predicting ICI response, thus providing a theoretical basis for the clinical application of ICI.

Amivantamab with or without chemotherapy in right-sided metastatic colorectal cancer: Updated results from OrigAMI-1, an open-label, phase 1b/2 study.

197 Background: Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell-directing activity and is FDA approved in EGFR -mutated advanced non-small cell lung cancer. High MET expression is observed in ~68% of patients (pts) with metastatic colorectal cancer (mCRC). Additionally, MET amplification occurs in up to 23% of EGFR-resistant mCRC and is implicated in driving resistance to EGFR-targeting antibodies (EGFRi). Compared to left (L)-sided disease, right (R)-sided disease is less responsive to EGFRi and associated with poorer outcomes. We present longer follow-up data among pts with R-sided mCRC. Methods: OrigAMI-1 (NCT05379595) is assessing ami as monotherapy and combined with chemotherapy in mCRC. All pts were wild-type for KRAS , NRAS , BRAF , and EGFR ectodomain by central ctDNA testing, without ERBB2 / HER2 amplification. One ami monotherapy cohort (Cohort C) enrolled only pts with R-sided disease (all pts must have 2-3 prior lines; prior EGFRi allowed). The ami plus chemotherapy cohorts (Cohorts D [with FOLFOX] and E [with FOLFIRI) enrolled both L- and R-sided disease (1 prior line max; prior EGFRi use was exclusionary). Primary tumor locations of cecum, ascending colon, hepatic flexure, and transverse colon were considered R-sided. Response was assessed by the investigator per RECIST v1.1. Results: As of 26-Aug-2024, 23 pts with R-sided mCRC received ami monotherapy (median follow-up of 8.1 months [mo]). Median number of prior lines was 2, and 43% had prior EGFRi. There were 7 pts with R-sided disease who received ami plus FOLFOX or FOLFIRI (median follow-up of 6.5 mo); all 7 had received 1 prior line. Among pts receiving ami monotherapy, objective response rate (ORR) was 22% (5/23) and disease control rate (DCR) was 78% (18/23), with 1 achieving a complete response. Median duration of response (DoR) is 7.4 mo; response and treatment are ongoing for 3 of the 5 responders. In pts receiving ami plus FOLFOX or FOLFIRI, ORR was 43% (3/7) and DCR was 86% (6/7). Median DoR is 5.8 mo, with all 3 responders on treatment, of which 2 are ongoing response. Additional details are in the Table. Biomarker data will be presented at the meeting. Safety profile among R-sided disease was consistent with prior reports, with the most common ami-related grade 3+ AEs being rash and hypoalbuminemia (2 pts each). Conclusions: Ami monotherapy or combined with FOLFOX or FOLFIRI demonstrated durable antitumor activity in R-sided mCRC. Clinical trial information: NCT05379595 . Efficacy. Ami monotherapy (n=23) Ami + FOLFOX or FOLFIRI (n=7) Median follow-up, mo (range) 8.1 (0.6–17.5) 6.5 (3.2–8.8) Median number prior lines 2 1 Prior EGFRi, n (%) 10 (43) 0 ORR, % (95% CI) 22 (8–44) 43 (10–82) Median DoR, mo (95% CI) 7.4 (3.7–NE) 5.8 (NE–NE) a DCR, % (95% CI) 78 (56–93) 86 (42–100) Median progression-free survival, mo (95% CI) 3.7 (3.4–5.5) 7.4 (1.8–NE) a All 3 responders remain on treatment; 2 of 3 responders are ongoing response.

Vibrio harveyi uses both type III secretion system and quorum sensing for the colonization of the European abalone.

The vibriosis of the European abalone, Haliotis tuberculata, is characterized by the rapidity of the infection by the pathogen Vibrio harveyi ORM4, leading to death of animals only after two days. The lethality of the pathogen is linked to the production of the type III secretion system (T3SS) and to genes regulated by quorum sensing (QS). The aim of this study was to investigate the colonization of the European abalone by both virulent and avirulent V. harveyi strains, as well as the involvement of T3SS and QS during infection. Our results emphasize the importance of gills for the bacterial establishment as the bacterial concentration of the avirulent V. harveyi strain significantly decreased from 189.3 ± 98.6 CFU/mg to 0.8 ± 0.5 CFU/mg between 24 and 48 hours post-infection (hpi). In opposition, the pathogen V. harveyi ORM4 was able to maintain itself on the gills, with a concentration of 461.9 ± CFU/mg at 48 hpi, which was allowed by the production of T3SS and a functional QS. Following the infection cycle of V. harveyi ORM4 inside H. tuberculata, we also demonstrated that QS is essential for the ability of V. harveyi ORM4 to colonize the abalone hemolymph and to maintain in it. In response to the presence of V. harveyi, an increase in reactive oxygen species production was recorded, while the phagocytosis activity remained unchanged. We also highlighted the involvement of both QS and T3SS to escape the immune system activity, and that an overproduction of T3SS induced hemocyte mortality. This study provides the evidence that both T3SS and QS are essential for the establishment of V. harveyi ORM4 inside the European abalone.

Salivary peptidomic profiling of chronic gingivostomatitis in cats by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry and nanoscale liquid chromatography-tandem mass spectrometry.

Chronic gingivostomatitis in cats (FCGS) is a moderately to severely painful condition, potentially caused by inadequate immune response to oral antigenic stimulation. Salivary peptidome analysis can identify inflammatory protein mediators and pathways involved in oral mucosal immune activation and may indicate potential therapeutic options for FCGS. Evaluate the diversity and abundance of salivary peptides in cats with FCGS using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) and nanoscale liquid chromatography-tandem mass spectrometry (nano LC-MS/MS). Thirty-two cats with FCGS and 18 healthy controls. Case-control cross-sectional study. We compared the salivary peptide profiles of diseased and healthy cats. The diagnosis of FCGS was confirmed by histopathology. Saliva samples were analyzed for viral infections using polymerase chain reaction (PCR), peptide mass fingerprint (PMF) using MALDI-TOF MS, and peptide identification using nano LC-MS/MS. Distinct clusters of peptide profiles were observed between groups. In FCGS, 26 salivary peptides were altered, including apolipoprotein A1, nuclear receptor subfamily 1 group I member 3, fibrinogen alpha chain, interleukin 2 receptor gamma, interleukin 23 receptor, hemoglobin subunit alpha, and serpin peptidase inhibitor clade A (alpha-1 antiproteinase, antitrypsin) member 12, protein-tyrosine-phosphatase, and cholinergic receptor nicotinic alpha 10 subunit. Protein-anti-inflammatory drug interaction networks were observed. Peptide mass fingerprint and peptide profiles identified distinct clusters between FCGS and healthy cats. The 9 novel salivary peptide markers were associated with the JAK/STAT and PI3K/Akt pathways and immune responses. These potentially noninvasive biomarkers may facilitate understanding of FCGS pathophysiology and guide future therapeutic research.

Characterization of Novel Sialylation-Associated microRNA Signature for Prognostic Assessment in Breast Cancer and Its Implications for the Tumor Microenvironment.

Sialylation, a key post-translational modification essential for protein function, is regulated by steroid hormones, along with other glycosylations like fucosylation. These modifications influence tumor growth and metastasis by modulating immune activation. MicroRNAs (miRNAs), crucial in gene expression, affect sialylation and are emerging as promising biomarkers in breast cancer, though their prognostic value remains unclear. Sialylation-related miRNAs were identified through Pearson correlation analysis, and an eight-miRNA risk signature was developed using univariate and Least Absolute Shrinkage and Selection Operator (LASSO) regression in the TCGA dataset. The prognostic value was validated in two independent GEO datasets. Multivariate analysis confirmed that the miRNA risk score is an independent predictor of overall survival (OS). A nomogram integrating clinical characteristics and the risk score was created to predict 1-, 3-, and 5-year OS, assessed through calibration curves, ROC curves, and area under the ROC curve (AUC). Biological pathways were explored using GSEA and GSVA, while immune infiltrates were identified through CIBERSORT and TIMER. The eight-miRNA signature effectively predicted OS, recurrence-free survival, and disease-free survival. High-risk patients exhibited increased macrophage and neutrophil levels, indicative of a poor prognosis. High-risk patients, especially those with triple-negative breast cancer, had significantly worse outcomes. This risk score could inform personalized treatment strategies in breast cancer management.

Neoadjuvant Clinical Trials in Adults with Newly Diagnosed High-Grade Glioma: A Systematic Review.

High-grade gliomas are devastating cancers that remain incurable with standard surgical resection and radiochemotherapy. Although beneficial against neoplasms, radiation lowers lymphocyte counts, weakens immune activation, and recruits suppressive myeloid cells impairing immune responses. Tumor environments treated with radiation experience long-term immunosuppression, reducing immunotherapy effectiveness and contributing to recurrence. Investigating pre-radiation treatments in newly diagnosed patients could identify active agents, assess immunotherapy impact, and enable multiomic analyses without radiation-induced confounding factors. This literature review was conducted to describe the feasibility, safety, and outcomes of postsurgical, pre-radiation clinical trials for adults with newly diagnosed high-grade glioma. A systematic review was performed of the English-language literature reporting results of clinical trials for adults with newly diagnosed high-grade glioma administered postsurgical treatment prior to radiation therapy. A search was conducted in PubMed and references cited in research and review articles were also considered. From 1991 to 2024, 52 clinical trials were identified: 3 phase I, 38 phase II, 4 phase III, and 7 of unknown phase. Nine trials were randomized, 24 were multicenter trials, 21 investigated temozolomide-containing regimens, and 12 focused on inoperable tumors, involving a total of 2,737 patients. Pre-radiation neoadjuvant studies are feasible and may identify active drugs. This is particularly relevant in the era of personalized medicine with brain-penetrant drugs, targeted therapy, and immuno-oncology advancements. Investigating pre-radiation treatments in newly diagnosed high-grade glioma is a viable approach to rapidly identify active and inactive regimens while the immune system and tumor microenvironment remain intact.

Berberine shaping the tumor immune landscape via pyroptosis.

Pyroptosis is a programmed cell death (PCD) mainly mediated by the Gasdermin family of proteins, among which Gasdermin E (GSDME) is considered a tumor suppressor gene. GSDME can recruit immune cells to the tumor microenvironment (TME) and promote their effects. Activating and enhancing adaptive immunity through GSDME is a potential solution for anti-tumor therapy. Here we reported that berberine (BBR), a small molecule from traditional Chinese medicine, as a GSDME activator, induced caspase-3 (C-3)/GSDME pathway-mediated pyroptosis through the mitochondrial pathway, improved the immunosuppressive state of the tumor microenvironment, and thus promoted anti-tumor immunity. We determined the induction of pyroptosis of 4T1 cells by BBR through various experiments, and investigated the immune activation effect of BBR by co-culture in vitro, which induced DCs maturation and macrophage polarization. Zebrafish embryo toxicity experiments were used to evaluate the in vivo safety of berberine. Furthermore, the in vivo antitumor and immune activation effects of BBR were investigated using 4T1 orthotopic model mice, and the results showed that BBR could eliminate orthotopic tumor cells by activating local and systemic immunity. Moreover, we observed that BBR significantly inhibited breast cancer lung metastasis. In summary, our results showd the role of BBR as a GSDME activator stimulated both local and systemic antitumor immune responses by inducing pyroptosis, effectively preventing tumor development and metastasis.