Immunological Role Research Articles

Intraperitoneal Administration of S100A8 Ameliorates Experimental Acute Colitis in Rats

S100A8 is a protein that is abundant in neutrophils and macrophages (MΦ), but its role in inflammation remains unclear. This study aimed to assess the immunological role(s) of S100A8 in acute intestinal inflammation in rats and its role in MΦ. Rat recombinant S100A8 (rr-S100A8, 1.0 mg/kg) was intraperitoneally administered daily to rats with 3% dextran sulfate sodium (DSS) (DSS + A8 group)-induced experimental acute colitis. The histological severity score (6.50 ± 0.51, p = 0.038) in the DSS + A8 group rats remained lower than that (9.75 ± 1.48) of the rats without S100A8 (DSS group) administration. The tumor necrosis factor-alpha (TNF-α) production in the colon tissues of the rats in the DSS + A8 group (4.76 ± 0.90 pg/mL/g, p = 0.042) was significantly suppressed, compared with that of the DSS group (10.45 ± 2.04 pg/mL/g). To stimulate rat peritoneal MΦ, rr-S100A8, the anti-rat S100A8 antibody, and a lipopolysaccharide (LPS) were used in the in vitro experiments. In the MΦ stimulated with rr-S100A8 for 2 h, the mRNA level of intracellular S100A8 (47.41 ± 24.44, p = 0.002) increased in an autocrine manner, whereas that of S100A9 (0.24 ± 0.43, p = 0.782) was not significant. The TNF-α mRNA level in the MΦ treated with LPS and the anti-rat S100A8 antibody significantly increased (102.26 ± 18.60, p = 0.001) compared to that with LPS alone (16.9 ± 8.56). These results indicate that S100A8 can serve as an anti-inflammatory protein in acute inflammation by negatively regulating S100A9 and TNF-α production through inflammatory signaling pathways in MΦ.

Pan-cancer analysis of IRF1 focusing on prognostic and immunological roles in non-small cell lung cancer

Interferon regulatory factor 1 (IRF1) significantly affects tumour occurrence and development. This study aimed to analyse its function as a pan-cancer prognostic indicator. We compared IRF1 expression and prognostic significance in normal and tumour samples from different databases. Accordingly, we performed in vitro experiments and immunohistochemistry (IHC) to investigate the role of IRF1 in non-small cell lung cancer (NSCLC). Our findings indicate that IRF1 expression is significantly correlated with prognosis, the tumour microenvironment, and immune cell infiltration. Furthermore, receiver operating characteristic (ROC) analysis revealed that IRF1 had high accuracy in distinguishing cancerous tissues from normal ones. Notably, IRF1 expression was linked to immune-related and immune checkpoint genes. Cell proliferation, invasion, and migration were significantly related to IRF1 expression. IHC indicated that IRF1 was downregulated in NSCLC tissues. Our study provides comprehensive bioinformatic analysis and experimental verification of IRF1, suggesting its potential as a prognostic biomarker in cancer.

Polymer nanotherapeutics: A promising approach toward microglial inhibition in neurodegenerative diseases.

Nanoparticles (NPs) that target multiple transport mechanisms facilitate targeted delivery of active therapeutic agents to the central nervous system (CNS) and improve therapeutic transport and efficacy across the blood-brain barrier (BBB). CNS nanotherapeutics mostly target neurons and endothelial cells, however, microglial immune cells are the first line of defense against neuronal damage and brain infections. Through triggering release of inflammatory cytokines, chemokines and proteases, microglia can however precipitate neurological damage-a significant factor in neurodegenerative diseases. Thus, microglial inhibitory agents are attracting much attention among those researching and developing novel treatments for neurodegenerative disorders. The most established inhibitors of microglia investigated to date are resveratrol, curcumin, quercetin, and minocycline. Thus, there is great interest in developing novel agents that can bypass or easily cross the BBB. One such approach is the use of modified-nanocarriers as, or for, delivery of, therapeutic agents to the brain and wider CNS. For microglial inhibition, polymeric NPs are the preferred vehicles for choice. Here, we summarize the immunologic and neuroinflammatory role of microglia, established microglia inhibitor agents, challenges of CNS drug delivery, and the nanotherapeutics explored for microglia inhibition to date. We also discuss applications of the currently considered "most useful" polymeric NPs for microglial-inhibitor drug delivery in CNS-related diseases.

Crucial immunological roles of the invasion front in innate and adaptive immunity in cervical cancer.

The immunostimulatory actions of innate and adaptive immune responses play a crucial role in the cancer-immunity cycle. Although cervical cancer (CC) exhibits a high recurrence rate, the relation with lymphocytes in the tumor tissue have not been analyzed. We analyzed NKT, NK, and T cells, not only in peripheral blood (PB), but also tumor tissue through histological analysis from 23 patients with CC collected before treatment. A correlation of them between PB and the tumor tissue were assessed. We detected functional NKT and NKG2Dhi NK cells and effector CD4+ Tregs in PB. In the tumor, we detected the infiltration of LAG-3+ TIM-3+ CD4+ and CD8+ T cells rather than NK cells particularly in the invasion front (IF) by fluorescent multiplex immunohistochemistry. The heatmap and correlation analysis revealed that LAG-3+ TIM-3+ CD8+ T cells are highly associated with CD69+ CD103- exhausted CD8+ T cells. We identified the statistical relationship between CD4+Tregs in PB and the number of LAG-3+ TIM-3+ CD4+ T cells in the IF, which may be related to recurrence in patients with CC. LAG-3+ TIM-3+ T cells located in the IF may play a key role in regulation of the tumor immune microenvironment.

Solute carrier family 4 member 4 (SLC4A4) is associated with cell proliferation, migration and immune cell infiltration in colon cancer

BackgroundSolute Carrier Family 4 Member 4 (SLC4A4) is a membrane protein‐coding gene for a Na+/HCO3− cotransporter and plays a crucial role in regulating pH, bicarbonate secretion and homeostasis. However, the prognostic and immunological role of SLC4A4 in colon cancer remains unknown.MethodIn this study, expression profiles of SLC4A4 were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, to which a variety of bioinformatic analyses were performed. Sangerbox, Xiantao, ESTIMATE and TIMER online tools were used to delve into the relationship between SLC4A4 expression and immune cell infiltration. The role of SLC4A4 in the proliferation and migration of colon cancer cells was verified by CCK8, EdU and wound healing assays. The related molecules and pathways that SLC4A4 may affect were validated by bioinformatic prediction and western blotting analysis.ResultsThe expression levels of SLC4A4 were significantly lower in colon cancer tissues than in normal tissues and its low expression was positively correlated with poor prognosis. TIMER and ESTIMATE showed that SLC4A4 broadly influenced immune cell infiltration. Experiments in vitro demonstrated that SLC4A4 inhibited partial epithelial-mesenchymal transition (EMT) phenotypes.ConclusionsTo conclude, our study revealed that SLC4A4 is lowly expressed in colon cancer tissues, and SLC4A4 may inhibit the progression of colon cancer via regulating partial EMT phenotypes and immune cell infiltration, which may provide new perspectives for the development of more precise and personalized immune anti-tumor therapies.

Comprehensive analysis of clinical features, mRNA splicing, and immunological role of REEP5 in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy within the digestive system, characterized by high incidence and mortality rates. The biological role of REEP5 in ESCC progression remains poorly understood, despite its associations with various diseases, potentially accelerating tumor malignancy. We retrieved RNA-seq data and clinical information from 179 ESCC patients from the Gene Expression Omnibus (GEO) and 93 patients from The Cancer Genome Atlas (TCGA) databases. Bioinformatics analyses were conducted to explore the biological functions of REEP5 in ESCC, its role in the tumor microenvironment, and its prognostic value. Additionally, utilizing single-cell RNA-seq (scRNA-seq) data from 3 ESCC patients in the GEO database, we performed cluster analyses to investigate cell-specific expression differences of REEP5 between cancerous and adjacent non-cancerous tissues. Molecular biology experiments were also conducted to validate REEP5 expression disparities between tumor and non-tumor tissues. Compared to normal tissues, REEP5 was significantly enriched in ESCC tissues. High REEP5 expression was closely associated with poor prognosis in ESCC patients. Gene Ontology (GO) analysis revealed strong correlations between REEP5 and processes such as mRNA splicing and protein stabilization. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) indicated positive correlations between REEP5 and mRNA spliceosome assembly and disassembly. Pearson correlation analysis demonstrated positive associations between REEP5 and cancer-inhibitory immune checkpoints CTLA-4, TIM-3, and HVEM. Single-cell clustering and CIBERSORT analysis showed that REEP5 expression was closely related to T-cell infiltration in ESCC, with significant enrichment effects observed in CD8+ T-cell infiltration. REEP5 expression is closely correlated with the pathological and molecular pathology of ESCC, potentially playing a crucial role in Mast cell or T-cell-mediated immune responses in ESCC. Therefore, REEP5 holds promise as a novel therapeutic target for ESCC.

Immunological role of zinc in preterm neonates

Zinc (Zn), an essential trace element, plays a significant role in fetal development and biological defense during the embryonic and neonatal periods. Therefore, exploring the kinetics of Zn related to immune disturbances in preterm neonates is important. We here performed the measurement of Zn concentration along with immunological analysis of neonates and investigated the role of Zn in the neonatal period. Serum Zn concentrations were measured immediately after birth in neonates (329 cases). Moreover, for 25 cases, the kinetics of various immune cells and cytokines were measured by flow cytometry and electrochemiluminescence. We observed that Zn levels were inversely correlated with gestational weeks. Immune cell and cytokine analysis revealed an inverse correlation between HLA-DR on monocytes and Zn levels and between inflammatory cytokine interleukin-12 and Zn levels. Furthermore, oxidative stress status was inversely correlated with Zn levels. Our results suggested that the Zn dynamics immediately after birth, which show a negative correlation with the gestational week, can provide an anti-inflammatory and anti-oxidative environment for preterm neonates. The increased Zn concentration in the blood of preterm neonates may consequently protect neonates from perinatal stress.

Selenium, Immunity, and Inflammatory Bowel Disease.

Dietary intervention is a subject of growing interest in the management of inflammatory bowel disease (IBD), as new incident cases across the globe are rapidly rising, suggesting environmental factors as contributing elements. Dietary components and micronutrients have been associated with IBD pathogenesis or reductions in disease severity. Selenium, a diet-derived essential micronutrient that is important for proper immune system function, has received limited attention in the context of IBD. Selenium deficiency is a common finding in patients with IBD, but few clinical trials have been published to address the consequences of this deficiency. Here, we review the physiological and immunological roles of selenium and its putative role in IBD, and draw attention to knowledge gaps and unresolved issues, with the goal of stimulating more research on selenium in IBD.

The prognostic value and immunological role of calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2) in pan-cancer study.

A thorough assessment of calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2) in pan-cancer studies is currently absent. We integrate multi-omics and clinical data to conduct a molecular landscape of CAMKK2. Gene variation results revealed abnormal high frequency mutations of CAMKK2 in uterine corpus endometrial carcinoma, while expression level analysis demonstrated relatively high expression of CAMKK2 in prostate adenocarcinoma. The aberrant expression of CAMKK2 was found to be predictive of survival outcomes in several cancer types. Additionally, we identified potential regulators of CAMKK2 expression, including miRNAs such as miR.129.1.3p, as well as small-molecule drugs such as EPZ004777, which significantly correlated with CAMKK2 expression. Single-cell transcriptome analysis of kidney renal clear cell carcinoma further revealed a significantly higher expression of CAMKK2 in and monocyte and macrophage M1. Furthermore, in the kidney renal clear cell carcinoma IMvigor210 cohort, patients ongoing immunotherapy with higher CAMKK2 expression experienced a significantly longer median overall survival, but it was observed that in bladder urothelial carcinoma GSE176307 and skin cutaneous melanoma GSE78220 cohorts, CAMKK2 might significantly prolong overall survival. Briefly, CAMKK2 emerges as a promising molecular biomarker that holds potential implications for prognostic evaluation and predicting the effectiveness of immunotherapy across cancers.

Epithelial RANKL Limits Experimental Periodontitis via Langerhans Cells

Due to its capacity to drive osteoclast differentiation, the receptor activator of nuclear factor kappa-β ligand (RANKL) is believed to exert a pathological influence in periodontitis. However, RANKL was initially identified as an activator of dendritic cells (DCs), expressed by T cells, and exhibits diverse effects on the immune system. Hence, it is probable that RANKL, acting as a bridge between the bone and immune systems, plays a more intricate role in periodontitis. Using ligature-induced periodontitis (LIP), rapid alveolar bone loss was detected that was later halted even though the ligature was still present. This late phase of LIP was also linked with immunosuppressive conditions in the gingiva. Further investigation revealed that the ligature prompted an immediate migration of RANK-expressing Langerhans cells (LCs) and EpCAM+ DCs, the antigen-presenting cells (APCs) of the gingival epithelium, to the lymph nodes, followed by an expansion of T regulatory (Treg) cells in the gingiva. Subsequently, the ligatured gingiva was repopulated by monocyte-derived RANK-expressing EpCAM+ DCs, while gingival epithelial cells upregulated RANKL expression. Blocking RANKL signaling with monoclonal antibodies significantly reduced the frequencies of Treg cells in the gingiva and prevented gingival immunosuppression. In addition, RANKL signaling facilitated the differentiation of LCs from bone marrow precursors. To further investigate the role of RANKL, we used K14-RANKL mice, in which RANKL is overexpressed by gingival epithelial cells. The elevated RANKL expression shifted the steady-state frequencies of LCs and EpCAM+ DCs within the epithelium, favoring LCs over EpCAM+ DCs. Following ligature placement, heightened levels of Treg cells were observed in the gingiva of K14-RANKL mice, and alveolar bone loss was significantly reduced. These findings suggest that RANKL-RANK interactions between gingival epithelial cells and APCs are crucial for suppressing gingival inflammation, highlighting a protective immunological role for RANKL in periodontitis that was overlooked due to its osteoclastogenic activity.

Pan-cancer analysis of the prognostic and immunological roles of SHP-1/ptpn6

SHP-1, a nonreceptor protein tyrosine phosphatase encoded by ptpn6, has been regarded as a regulatory protein of hematopoietic cell biology for years. However, there is now increasing evidence to support its role in tumors. Thus, the role of ptpn6 for prognosis and immune regulation across 33 tumors was investigated, aiming to explore its functional heterogeneity and clinical significance in pan-cancer. Differential expression of ptpn6 was found between cancer and adjacent normal tissues, and its expression was significantly correlated with the prognosis of tumor patients. In most cancers, ptpn6 expression was significantly associated with immune infiltration. This was further confirmed by ptpn6-related genes/proteins enrichment analysis. Additionally, genetic alterations in ptpn6 was observed in most cancers. As for epigenetic changes, it’s phosphorylation levels significantly altered in 6 tumors, while methylation levels significantly altered in 12 tumors. Notably, the methylation levels of ptpn6 were significantly decreased in 11 tumors, accompanied by its increased expression in 8 of them, suggesting that the hypomethylation may be related to its increased expression. Our results show that ptpn6 plays a specific role in tumor immunity and exerts a pleiotropic effect in a variety of tumors. It can serve as a prognostic factor for some cancers. Especially in LGG, KIRC, UCS and TGCT, the increased expression of ptpn6 is associated with poor prognosis and high immune infiltration. This aids in understanding the role of ptpn6 in tumor biology, and can provide insight into presenting a potential biomarker for poor prognosis and immune infiltration in cancers.

CircRNome-wide characterisation reveals the promoting role of circAATF in anti-PD-L1 immunotherapy of gallbladder carcinoma.

Circular RNAs (circRNAs) have been shown to play important roles in tumour development and tumour immunology. However, genome-wide characterisation of circRNAs and their roles in the immunology and immunotherapy of gallbladder carcinoma (GBC) has been lacking. We present a comprehensive characterisation of the circRNA landscape in GBC, revealing GBC-specific circRNAs. Our analysis found that circRNAs are significantly enriched in cell proliferation and are involved in cancer-related hallmarks. In particular, circAATF was upregulated in GBC, which was positively correlated with AATF mRNA expression, and promoted GBC cell growth. Through integrating computational and experimental approaches, we revealed that circAATF is positively associated with the CD4+ T cell abundance and PD-L1 level, and enhances the clinical benefits of anti-PD-L1 immunotherapy for GBC. We further demonstrate that circAATF elevates the PD-L1 level by activating phosphorylated AKT and acting as a sponge for miR-142-5p. CircAATF is positively associated with CD4+ T cells and PD-L1 levels and shows potential to aid anti-PD-L1 immunotherapy for GBC. Our study provides insights into roles of circAATF in the tumour development and immunology of GBC and accelerates the development of therapeutic strategies for GBC immunotherapy. HIGHLIGHTS: We present a comprehensive characterisation of circRNA landscape in gallbladder carcinoma (GBC). CircAATF is positively associated with CD4+ T cell abundance and PD-L1 expression and is shown to promote PD-L1 treatment in mouse model. CircAATF can elevate PD-L1 level through phosphorylated AKT and linear AATF, which upregulates PD-L1 by acting as a sponge of miR-142-5p.

Comprehensive analysis of prognostic and immunological role of basement membrane-related genes in soft tissue sarcoma.

Soft tissue sarcoma (STS) represents highly multifarious malignant tumors that often occur in adolescents and have a poor prognosis. The basement membrane, as an ancient cellular matrix, was recently proven to play a vital role in developing abundant tumors. The relationship between basement membrane-related genes and STS remains unknown. Consensus clustering was employed to identify subgroups related to differentially expressed basement membrane-related genes. Cox and least absolute shrinkage and selection operator regression analyses were utilized to construct this novel signature. Then, we established a nomogram and calibration curve, including the risk score and available clinical characteristics. Finally, we carried out functional enrichment analysis and immune microenvironment analysis to investigate enriched pathways and the tumor immune microenvironment related to the novel signature. A prognostic predictive signature consisting of eight basement membrane-related genes was established. Kaplan-Meier survival curves demonstrated that the patients in the high-risk group had a poor prognosis. Independent analysis illustrated that this risk model could be an independent prognostic predictor. We validated the accuracy of our signature in the validation data set. In addition, gene set enrichment analysis and immune microenvironment analysis showed that patients with low-risk scores were enriched in some pathways associated with immunity. Finally, in vitro experiments showed significantly differential expression levels of these signature genes in STS cells and PSAT1 could promote the malignant behavior of STS. The novel signature is a promising prognostic predictor for STS. The present study may improve the prognosis and enhance individualized treatment for STS in the future.

Granzyme K provides protection for Nile tilapia (Oreochromis niloticus) from acute bacterial infection.

Granzyme K (GzmK) is a trypsin-like serine protease that functions as a pro-apoptotic protease, has non-cytotoxic functions, and is involved in various physiopathological processes. However, the impact of GzmK on the immunological response of Nile tilapia against bacterial challenge is still poorly explored. In this study, we identified the GzmK gene from Nile tilapia (On-GzmK) and investigated its immunologic roles through in vivo experiments. On-GzmK has an open reading frame of 786 bp and encodes 255 amino acids. On-GzmK has over 60 % genetic similarity with other fish and over 30 % similarity with mammals. Its transcript levels were highest in the liver and vastly increased after being challenged with Streptococcus agalactiae and Aeromonas hydrophila. In vivo experiments implied that On-GzmK might promote inflammatory responses and regulate apoptosis and pyroptosis by participating in the activation of multiple signaling pathways, such as JAK-STAT, MAPK, and NF-κB. The present observations offer additional theoretical support for investigating the processes by which GzmK shields fish against bacterial infections.

Pan-cancer analysis of the immunological and oncogenic roles of ATAD2 with verification in papillary thyroid carcinoma.

ATAD2 (ATPase Family AAA Domain-Containing 2) is highly expressed across varies tumor types, yet its common roles in tumor progression and immune interaction remain unclear. We analyzed the expression and alteration profiles of ATAD2, along with its diagnostic and prognostic role in pan-cancer, utilizing TCGA, GTEx, CPTAC, HPA, and cBioPortal databases. Furthermore, we examined the relationship between ATAD2 and immune infiltration utilizing single-cell sequencing data and TCGA database. Additionally, the expression and oncogenic functions of ATAD2 were verified in papillary thyroid carcinoma (PTC) through MTT, wound-healing, transwell, and flow cytometry assays. Our results revealed significant overexpression of ATAD2 in most cancers, strongly associated with poor prognosis. Amplification was the most frequent alteration type of ATAD2, with its mutation correlating with improved overall survival. ATAD2 was positively correlated with multiple inhibitory immune checkpoints and closely associated with the immunosuppressive microenvironment, particularly in PTC. In vitro experiments demonstrated that ATAD2 promoted the proliferation, migration, and invasion of PTC cells by activating the PI3K-AKT pathway and modulating the G1/S cell cycle checkpoint. Collectively, ATAD2 holds promise as a biomarker for pan-cancer diagnosis and prognosis, as well as a predictor of immunotherapeutic responsiveness and a therapeutic target to enhance the efficacy of existing anti-tumor immune therapies.

Pan-cancer analysis of the prognostic and immunological role of hippo-YAP signaling pathway

The Hippo-Yes-associated protein (Hippo-YAP) signaling pathway, a conserved pathway that regulates organ size, participates in tumor progression. However, there are few comprehensive analyses of tumor prognosis and immunity. In the present study, TCGA, GTEx, GEO, TIMER2, STRING, GSCA, ImmuCellAI, and other bioinformatics tools were used to reveal the involvement of the Hippo-YAP signaling pathway in the prognosis and immunity of pan-cancers. The obtained results showed that mRNA expression differences of Hippo-YAP pathway genes between normal samples and tumor samples in pan-cancers and some genes (such as TEAD4, MAP4K4, and STK3) might affect the prognosis of patients with skin cutaneous melanoma (SKCM) and pancreatic adenocarcinoma (PAAD). Furthermore, mutation and methylation of the Hippo-YAP signaling pathway genes in normal and primary tumor tissues differ in various cancers (KIRP, BRCA). Additionally, the relationship between the tumor microenvironment, molecular pathways, and the Hippo-YAP pathway indicated that it might lead to a suppressive immune microenvironment that affects the efficacy of immunotherapy. This is a pan-cancer overview of the Hippo-YAP signaling pathway genes, which explores the aberrant expression or mutation of this pathway that regulates the tumor microenvironment and immunotherapy.

Potential immunologic and prognostic roles of CHRNA6 in SCLC and pan-cancer

BackgroundSmall cell lung cancer (SCLC) is considered the most malignant subtype of lung cancer, and it has a restricted range of therapeutic choices. The emergence of immunotherapy has offered new possibilities for patients with SCLC. However, the scarcity of clinical specimens has hampered the progress of clinical studies and we still face a shortage of dependable indicators to forecast the effectiveness of immunotherapy for SCLC. MethodsIn our study, we assessed the ImmuneScore and StromalScore of 81 SCLC samples obtained from the cBioPortal database. By comparing gene expression differences between the high and low immune scores groups, we identified 24 differentially expressed genes. Subsequently, an intersection was performed with genes that exhibited differential expression between normal and SCLC tissues, leading us to isolate the gene CHRNA6. To gain a deeper insight into the possible significance of CHRNA6 in SCLC, we singled out 50 genes that showed the most pronounced positive and negative associations with its expression. We then pinpointed hub genes for subsequent functional enrichment analyses by establishing a protein-protein interactions network. We additionally assessed the link between CHRNA6 expression in SCLC and characteristics of the immune microenvironment, along with the efficacy of immunotherapy, using the CIBERSORT, immunophenoscores (IPS), and tumor immune dysfunction and exclusion (TIDE) algorithms. Furthermore, we confirmed the prognostic impact of CHRNA6 expression in SCLC patients undergoing immunotherapy within a clinical cohort. Lastly, we obtained data from The Cancer Genome Atlas (TCGA) to investigate CHRNA6 expression in various tumors and its associations with genetic alterations, DNA methylation, copy number variation, clinicopathological characteristics, biological processes, immune microenvironment, prognosis, and drug sensitivity. ResultsIn SCLC, we found that CHRNA6 function was associated with immune activation pathways such as antigen presentation processing and positive regulation of adaptive immune response, and that CHRNA6 demonstrated a strong correlation with immune cells infiltration. In addition, analysis of the clinical cohort revealed that patients with SCLC who exhibited elevated expression of CHRNA6 experienced better responses to immunotherapy. Our pan-cancer analysis disclosed that the expression of CHRNA6 is dysregulated in a multitude of cancers, potentially due to genetic mutations, copy number gains, and DNA demethylation. The gene set enrichment analysis (GSEA) outcomes indicated that CHRNA6 participates in immune responses and may play a positive immune regulatory role in most cancers. Furthermore, CHRNA6 has been observed to have a notable relationship with immune checkpoints, immunomodulators, immune cell infiltration, patient outcomes, and drug sensitivity across various cancers. ConclusionsOur findings indicate that the CHRNA6 may act as a predictive indicator for SCLC patients receiving immunotherapy. The study also uncovers the aberrant expression of CHRNA6 in a range of human cancers and its potential roles in immunology and prognosis, offering novel perspectives for tailored cancer therapies.

Understanding and Managing Adenotonsillar Hypertrophy in Pediatric Otolaryngology

Adenotonsillar hypertrophy (ATH) is a common pediatric condition marked by the growth of lymphoid tissues within the Waldeyer’s ring, which includes adenoids, palatine tonsils, and lingual tonsils. These tissues surround the upper airway and food passage, and play an immunological role, enlarging until about age 12, before gradually reducing during adolescence and adulthood. Untreated or poorly managed ATH can severely impact multiple health aspects of children. It is the primary cause of upper airway obstruction and obstructive sleep apnea (OSA) syndrome in children, which disrupts sleep and can severely impair cognitive development, school performance and behaviour. Chronic mouth breathing from ATH can alter dental arches and facial growth, known as adenoid facies. More severe outcomes include increased pulmonary pressures and the potential development of pulmonary hypertension and cor pulmonale due to chronic hypoxia and CO2 retention. As a result, tonsillectomy, with or without adenoidectomy (T&A), has become one of the most frequently performed surgeries in North America, with over 530,000 operations performed annually on children under age 15. This paper discusses the significant impact of ATH on pediatric health and the frequent need for surgical intervention. It covers the immunophysiology, influence of atopy, community-based assessments prior to specialist referrals, and an overview of available medical and surgical treatment options. Additionally, it outlines general indications for referring patients to otolaryngology.

Pseudomonas aeruginosa exotoxin A as a novel allergen induced Non-TH2 inflammation in a murine model of steroid-insensitive asthma

BackgroundDespite the immediate in vivo occurrence of anaphylactic and allergic reactions following treatment with Pseudomonas aeruginosa exotoxin A (PEA)-based immunotoxins, the immunological role of PEA in asthma pathogenesis remains unclear. ObjectiveThis study investigated the allergenic potential of PEA and the specific type of asthma induced. MethodsRecombinant PEA (rPEA) lacking domain Ia (to eliminate non-specific cytotoxicity) was expressed, purified, and employed to detect serum PEA-specific IgE levels in asthmatic patients. Competitive ELISA assays were used to assess rPEA's IgE binding capacity and allergenicity. Additionally, rPEA-challenged C57BL/6 mice were subjected to inflammatory endotyping and therapeutic assays to characterize the allergic nature of PEA. ResultsPEA-specific IgE was identified in 17 (14.2 %) of 120 asthma patients. The rPEA-sensitized and challenged mice had increased PEA-specific immunoglobulins (such as IgE, IgG1 and IgG2a) and developed asthma-like phenotypes with airway hyperresponsiveness, severe airway inflammation, and airway remodeling. Lungs from these mice displayed significant increases in neutrophils and IL-17A+ cells. Innate lymphoid cells (ILCs) produced type 2 cytokines (IL-4, IL-5, and IL-13), whereas Th cells did not. Nonetheless, airway inflammation, rather than hyperresponsiveness, was elicited in non-sensitized mice upon challenge with rPEA. Importantly, rPEA-induced asthmatic mice were unresponsive to dexamethasone treatment. ConclusionPEA is a novel allergen that sensitizes asthmatic patients. Furthermore, mice developed steroid-resistant asthma, characterized by an atypical cytokine profile associated with non-TH2 inflammation, only after being sensitized and challenged with rPEA. These findings suggest a potentially significant role for PEA in asthma development, warranting consideration in clinical diagnosis and treatment strategies.

Comprehensive pan-cancer analysis reveals EPHB2 is a novel predictive biomarker for prognosis and immunotherapy response

PurposeRecent studies have increasingly linked Ephrin receptor B2 (EPHB2) to cancer progression. However, comprehensive investigations into the immunological roles and prognostic significance of EPHB2 across various cancers remain lacking.MethodsWe employed various databases and bioinformatics tools to investigate the impact of EPHB2 on prognosis, immune infiltration, genome instability, and response to immunotherapy. Validation of the correlation between EPHB2 expression and M2 macrophages included analyses using bulk and single-cell transcriptomic datasets, spatial transcriptomics, and multi-fluorescence staining. Moreover, we performed cMap web tool to screen for EPHB2-targeted compounds and assessed their potential through molecular docking and dynamics simulations. Additionally, in vitro validation using lung adenocarcinoma (LUAD) cell lines was conducted to confirm the bioinformatics predictions about EPHB2.ResultsEPHB2 dysregulation was observed across multiple cancer types, where it demonstrated significant diagnostic and prognostic value. Gene Set Enrichment Analysis (GSEA) indicated that EPHB2 is involved in enhancing cellular proliferation, invasiveness of cancer cells, and modulation of the anti-cancer immune response. Furthermore, it is emerged as a pan-cancer marker for M2 macrophage infiltration, supported by integrated analyses of transcriptomics and multiple fluorescence staining. In LUAD cells, knockdown of EPHB2 expression led to a decrease in both cell proliferation and migratory activity.ConclusionEPHB2 expression may serve as a pivotal indicator of M2 macrophage infiltration, offering vital insights into tumor dynamics and progression across various cancers, including lung adenocarcinoma, highlighting its significant prognostic and therapeutic potential for further exploration.