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PubMed2026

Exploring the Genetic Link between Irritable Bowel Syndrome and Polycystic Ovary Syndrome: Bidirectional Mendelian Randomization and Machine Learning Approaches.

BACKGROUND: Research has shown a certain correlation between polycystic ovary syndrome (PCOS) and irritable bowel syndrome (IBS). The study aims to determine the directionality and underlying biological processes influencing the relationship between these two disorders. METHODS: We explored the causal relationship between IBS and PCOS by conducting a comprehensive bidirectional Mendelian randomization (MR) analysis using five different methods and conducted robustness assessments. We extracted differentially expressed genes from the IBS and PCOS datasets for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Additionally, we developed a protein-protein interaction (PPI) network and applied the Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine (SVM) methodologies to pinpoint key diagnostic markers. Diagnostic efficacy was further assessed through Receiver Operating Characteristic (ROC) curve analysis for selected genes. Finally, single-sample gene set enrichment analysis (ssGSEA) was carried out to examine immune cell infiltration in IBS and PCOS. RESULTS: MR analysis identified a causal effect of PCOS on IBS (IVW, OR = 1.034, 95% CI: 1.003-1.065, P = 0.029). Conversely, no relationship between IBS and PCOS was observed in the reverse analysis. Furthermore, integrative bioinformatics and machine learning analyses identified CD14 and CASP1 as key diagnostic biomarkers for both IBS and PCOS, which were significantly associated with immune cell infiltration. CONCLUSION: MR analysis has demonstrated a significant positive causal relationship between PCOS and IBS, though the reverse causality from IBS to PCOS appeared non-significant. The genes CD14 and CASP1 emerged as potential shared diagnostic markers between these two conditions.

Polycystic Ovary Syndrome↗

PubMed2024

Developing a machine learning-based prognosis and immunotherapeutic response signature in colorectal cancer: insights from ferroptosis, fatty acid dynamics, and the tumor microenvironment.

INSTRUCTION: Colorectal cancer (CRC) poses a challenge to public health and is characterized by a high incidence rate. This study explored the relationship between ferroptosis and fatty acid metabolism in the tumor microenvironment (TME) of patients with CRC to identify how these interactions impact the prognosis and effectiveness of immunotherapy, focusing on patient outcomes and the potential for predicting treatment response. METHODS: Using datasets from multiple cohorts, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we conducted an in-depth multi-omics study to uncover the relationship between ferroptosis regulators and fatty acid metabolism in CRC. Through unsupervised clustering, we discovered unique patterns that link ferroptosis and fatty acid metabolism, and further investigated them in the context of immune cell infiltration and pathway analysis. We developed the FeFAMscore, a prognostic model created using a combination of machine learning algorithms, and assessed its predictive power for patient outcomes and responsiveness to treatment. The FeFAMscore signature expression level was confirmed using RT-PCR, and ACAA2 progression in cancer was further verified. RESULTS: This study revealed significant correlations between ferroptosis regulators and fatty acid metabolism-related genes with respect to tumor progression. Three distinct patient clusters with varied prognoses and immune cell infiltration were identified. The FeFAMscore demonstrated superior prognostic accuracy over existing models, with a C-index of 0.689 in the training cohort and values ranging from 0.648 to 0.720 in four independent validation cohorts. It also responses to immunotherapy and chemotherapy, indicating a sensitive response of special therapies (e.g., anti-PD-1, anti-CTLA4, osimertinib) in high FeFAMscore patients. CONCLUSION: Ferroptosis regulators and fatty acid metabolism-related genes not only enhance immune activation, but also contribute to immune escape. Thus, the FeFAMscore, a novel prognostic tool, is promising for predicting both the prognosis and efficacy of immunotherapeutic strategies in patients with CRC.

Ferroptosis↗

PubMed2026

Predicting diagnostic gene biomarkers associated with immune infiltration in patients with diabetes.

Diabetes is a global public health problem with various complications, which can lead to disability and mortality. This study identified potential diagnostic markers for diabetes and explored the immunometabolic mechanisms in the pathological process. The gene expression of 17 diabetes cases and 16 normal controls were obtained from the Gene Expression Omnibus (GEO) database. The "limma" package was employed for screening differentially expressed genes (DEGs). Gene functions and enriched pathways of DEGs were analyzed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Candidate key genes were screened using the least absolute shrinkage and selection operator (LASSO) regression model and support vector machine recursive feature elimination (SVM-RFE) analysis. The diagnostic effectiveness of identified markers was further verified via the receiver operating characteristic (ROC) curve. The compositional patterns of immune cell infiltration and signaling pathway enrichment associated with key genes were explored via single sample Gene Set Enrichment Analysis (ssGSEA) and GSEA analysis, respectively. Possible miRNAs interacting with key genes were predicted via miRcode database. B2M, FTL, SH3BGRL3, and SOD2 were recognized as diagnostic markers for diabetes based on LASSO regression and the support vector machine recursive feature elimination (SVM-RFE) feature selection algorithm. Analysis of immune cell infiltration demonstrated that the four key genes were related to B cells, neutrophils, macrophages, and CD8+ T cells. The diagnostic value of B2M, FTL, and SOD2 for diabetes was higher than that of SH3BGRL3 according to the ROC curve. Validation experiments indicated that the mRNA expression of B2M and FTL was increased in liver tissues of diabetic mice. B2M and FTL can act as diagnostic markers for diabetes and contribute to new understandings of the disease's molecular mechanisms.

Humans↗

PubMed2025

DNA damage repair gene alterations influence the tumor immune microenvironment in advanced non-small cell lung cancer.

PURPOSE: DNA damage response and repair (DDR) gene alterations contribute to genomic instability and increased tumor immunogenicity, yet their clinical significance in non-small cell lung cancer (NSCLC) remains unclear. Using a large real-world dataset, we evaluated the prevalence of DDR alterations and their relation to the tumor immune microenvironment in metastatic NSCLC. EXPERIMENTAL DESIGN: We retrospectively analyzed real-world data from patients with metastatic NSCLC using the Tempus AI database. Tumors were sequenced with Tempus xT DNA and xR RNA assays and classified based on the presence (DDRmt) or absence (DDRwt) of a pathogenic somatic alteration or copy number deletion in a DDR pathway gene. Associations between DDR alterations and immune cell infiltration, PD-L1 immunohistochemistry, tumor mutational burden (TMB), and microsatellite instability (MSI-H) were examined. RESULTS: Among 14,127 patients (median age = 67, 49% female), 5,276 (37%) were DDRmt. There was a higher prevalence of current/former smokers in the DDRmt group (86% vs. 82%; p<0.001). DDRmt tumors were more likely to have higher levels of TMB (median: 5.4 vs. 4.6; p<0.001), MSI-H (1.1 % vs. <0.1 %; p<0.001), and infiltrating CD8+ T cells (p=0.003) compared to DDRwt tumors. A lower frequency of macrophages (p<0.001) were observed among DDRmt compared with DDRwt tumors with no difference in PDL1 positivity. CONCLUSIONS: Among patients with metastatic NSCLC, 37% present with DDRmt tumors characterized by higher TMB, frequency of MSI-H, and changes in immune cell infiltrates. These findings provide insight into the immunogenic landscape of DDR-altered NSCLC and may inform biomarker selection and therapeutic strategies.

Humans↗

PubMed1994

Functional characterization of middle ear mucosa residues in cholesteatoma samples.

Cholesteatoma epithelium is characterized by a keratinocyte dysregulation with an aggressive growth that leads to the destruction of normal middle ear mucosa. The abnormal behavior of cholesteatoma epithelium seems to be induced by the presence of a heavy immune cell infiltrate releasing different cytokines and growth factors in high amounts. Middle ear mucosa rests are often observed within the cholesteatoma stroma or adjacent to the advancing front of cholesteatoma epithelium. This study investigated the presence of interleukin-1 (IL-1), transforming growth factor-alpha (TGF-alpha), epidermal growth factor (EGF), and epidermal growth factor-receptor (EGF-R) in the mucosa rests as well as the expression of an activation marker, 4F2. The findings were correlated with the features of a surrounding stroma with an enhanced immune cell infiltrate. Cholesteatoma epithelium showed a high staining intensity of IL-1, TGF-alpha, and EGF-R. In contrast to this, middle ear mucosa did not show any positive reactions for the mentioned factors. Epidermal growth factor immunoreactivity was found in neither cholesteatoma epithelium nor in middle ear mucosa residues. The authors found a high concentration of lymphocytes and macrophages in the surrounding stroma. Most of these cells expressed TGF-alpha, IL-1, and 4F2, suggesting an activated form. Results indicate that keratinocytes present in the middle ear mucosa do not appear to react to the stimuli released by the inflamed stroma, reflecting important differences in the cell biological features of the keratinocytes that form parts of both types of epithelium.

Cholesteatoma↗

PubMed2005

Effector memory T cells, early metastasis, and survival in colorectal cancer.

BACKGROUND: The role of tumor-infiltrating immune cells in the early metastatic invasion of colorectal cancer is unknown. METHODS: We studied pathological signs of early metastatic invasion (venous emboli and lymphatic and perineural invasion) in 959 specimens of resected colorectal cancer. The local immune response within the tumor was studied by flow cytometry (39 tumors), low-density-array real-time polymerase-chain-reaction assay (75 tumors), and tissue microarrays (415 tumors). RESULTS: Univariate analysis showed significant differences in disease-free and overall survival according to the presence or absence of histologic signs of early metastatic invasion (P<0.001). Multivariate Cox analysis showed that an early conventional pathological tumor-node-metastasis stage (P<0.001) and the absence of early metastatic invasion (P=0.04) were independently associated with increased survival. As compared with tumors with signs of early metastatic invasion, tumors without such signs had increased infiltrates of immune cells and increased levels of messenger RNA (mRNA) for products of type 1 helper effector T cells (CD8, T-BET [T-box transcription factor 21], interferon regulatory factor 1, interferon-gamma, granulysin, and granzyme B) but not increased levels of inflammatory mediators or immunosuppressive molecules. The two types of tumors had significant differences in the levels of expression of 65 combinations of T-cell markers, and hierarchical clustering showed that markers of T-cell migration, activation, and differentiation were increased in tumors without signs of early metastatic invasion. The latter type of tumors also had increased numbers of CD8+ T cells, ranging from early memory (CD45RO+CCR7-CD28+CD27+) to effector memory (CD45RO+CCR7-CD28-CD27-) T cells. The presence of high levels of infiltrating memory CD45RO+ cells, evaluated immunohistochemically, correlated with the absence of signs of early metastatic invasion, a less advanced pathological stage, and increased survival. CONCLUSIONS: Signs of an immune response within colorectal cancers are associated with the absence of pathological evidence of early metastatic invasion and with prolonged survival.

Analysis of Variance↗

PubMed2026

Papillary Thyroid Carcinoma with Terminal Immune Exhaustion Phenotype Correlates with Increased Risk of Lymph Node Metastasis: An Exploratory Study Combining Flow Cytometry and TCGA.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, with lymph node metastasis (LNM) being a key predictor of recurrence and poor prognosis. Preoperative detection of LNM remains challenging due to the limitations of imaging modalities, leading to inadequate surgical resection in 20-30% of patients. While immune checkpoint molecules have been implicated in PTC progression, the heterogeneity of CD8+ T cell exhaustion subsets and their specific association with LNM remain poorly defined. In this study, we aimed to perform an exploratory characterization of the distinct immune landscape of PTC prone to LNM, with a focus on terminal immune exhaustion, in order to generate hypotheses for improved risk stratification and therapeutic strategies. METHODS: Fresh PTC tissues from 40 patients (22 LNM-positive and 18 LNM-negative) were analyzed via flow cytometry (FCM) to quantify immune cell subsets, inflammatory cytokines, and chemokines. Immunohistochemistry (IHC) validated CD45+ immune cell infiltration. Transcriptomic and clinical data from 448 PTC patients in The Cancer Genome Atlas (TCGA-PTC) cohort were used for bioinformatic analysis consistent with the observed phenotype, including Gene Set Variation Analysis (GSVA) of terminal exhaustion gene signatures. RESULTS: LNM-positive PTC exhibited a unique inflammatory milieu with significantly elevated IL-6, IL-1ra, CCL5, and IL-9 levels (all p < 0.05) in tumor interstitial fluid. FCM analysis revealed that LNM-positive PTC had increased infiltration of total CD45+ immune cells, CD3+ T cells, and CD3+CD8+ T cells (all p < 0.05). Critically, terminally exhausted PD-1hiTIM-3+ CD8+ T cells were significantly enriched in LNM-positive PTC (p = 0.022) and positively correlated with extrathyroidal extension (p = 0.044). Additionally, LNM risk was associated with increased CD4+ regulatory T (Treg) cell frequency (p = 0.023) and elevated CTLA-4 expression on CD4+ T cells (p = 0.047). In TCGA-PTC validation, the terminal exhaustion gene signature was predominantly enriched in LNM-positive (p < 0.0001) and advanced-stage PTC (p < 0.001) and strongly correlated with BRAF mutation (predominantly V600E) (p < 0.0001)-the most common oncogenic driver in aggressive PTC. CONCLUSIONS: Our findings suggest a terminal immune exhaustion phenotype (characterized by PD-1hiTIM-3+ CD8+ T cells and Treg enrichment) as a potential key feature associated with LNM-prone PTC. This phenotype shows consistency across clinical samples and TCGA datasets, linking BRAF mutation (predominantly V600E) to immune suppression and metastatic potential. These insights provide a novel exploratory immune-based biomarker for LNM risk stratification and support the potential of combining anti-PD-1/TIM-3 therapy with BRAF inhibitors for high-risk PTC, which should be confirmed in future studies.

lymph node metastasis↗

PubMed1997

Glomerulointerstitial interaction of adhesion molecules in IgA nephropathy and membranoproliferative glomerulonephritis.

The expression of two adhesion molecules, ICAM1 (CD54) and ICAM3 (CD50), infiltrating cells positive for their ligand, LFA1 (CD11a), and the markers of total leukocytes (CD45), T cells (CD3), granulocytes/monocytes (CD15), and macrophages (CD68) in renal interstitium were examined by an indirect immunoperoxidase method. The study was longitudinally performed on repeat renal biopsy specimens from 69 patients with two different proliferative glomerulonephritides: 43 with IgA nephropathy (IgAN) and 26 with membranoproliferative glomerulonephritis (MPGN). Interstitial ICAM1 (iICAM1) was mainly expressed on endothelium of peritubular venules and sometimes on tubular epithelium, and interstitial ICAM3 (iICAM3) on infiltrating immune cells. In IgAN, iICAM1 was significantly correlated with glomerular infiltration of LFA1+ cells (gLFA1) and CD68+ cells (gCD68) (r = 0.478/0.500; P < 0.0001) as well as CD3+ cells (gCD3) (r = 0.402; P < 0.002). In MPGN, iICAM1 was significantly correlated only with gCD68 (r = 0.382; P < 0.05). In both diseases, iICAM1 and iICAM3 were significantly correlated with interstitial infiltration of LFA1+ cells (iLFA1) and CD68+ cells (iCD68) (r = 0.616 to 0.815; P < 0.0001) and with interstitial infiltration of CD3+ cells (iCD3) (r = 0.474 to 0.816; P < 0.01). The iICAM3 was also significantly correlated with interstitial CD45+ cells (iCD45) (r = 0.672 in IgAN and 0.769 in MPGN; P < 0.00001). Interstitial infiltration of these immune cells was significantly correlated with the histologic parameters indicating renal injury, such as the index of glomerular lesion and the percent interstitial volume (r = 0.410 to 692; P < 0.05). Longitudinal analysis revealed that the parameters described above showed corresponding change with each other at the follow-up biopsy. These findings suggest that the glomeruler infiltration of T cells and macrophages influences the ICAM1/ICAM3 expression of the interstitial cells, especially In IgAN, and that ICAM1/LFA1 and ICAM3/LFA1 interactions contribute to the persistent infiltration of the interstitium by immune cells in both diseases.

Adolescent↗

PubMed2005

The X-linked inhibitor of apoptosis protein enhances survival of murine islet allografts.

Allotransplantation of pancreatic islets represents a promising approach to treat type 1 diabetes. Destruction of beta-cells in islet allografts involves multiple immune mechanisms that lead to activation of caspases and apoptotic cell death. The X-linked inhibitor of apoptosis (XIAP) inhibits apoptosis induced by a variety of triggers, primarily by preventing the activation of caspases. To determine whether XIAP would protect beta-cells from apoptosis, we used a recombinant adenovirus to overexpress XIAP in transformed murine beta-cells and in freshly isolated islets. In vitro cytokine-induced beta-cell death was decreased to baseline levels in XIAP-transduced MIN-6 and NIT-1 cell lines compared with controls. To evaluate the potential of XIAP overexpression to prevent in vivo allogeneic graft rejection, we transduced Balb/c islets ex vivo with XIAP before transplantation into CBA mice with streptozotocin-induced diabetes. We observed that almost all mice receiving allografts of XIAP-expressing islets maintained normoglycemia until the experiment was terminated (45-72 days posttransplant), whereas control mice receiving islets transduced with adenovirus expressing LacZ were hyperglycemic by approximately 17 days posttransplantation due to graft rejection. Immunohistochemistry revealed preservation of beta-cells and clearance of infiltrating immune cells in the XIAP-expressing islet grafts. The in vitro allogeneic response of splenocytes isolated from recipients of XIAP-expressing grafts 8 weeks posttransplant was similar to that seen in nonprimed allogeneic mice, suggesting that XIAP overexpression may lead to the acceptance of islet allografts in diabetic recipients. Long-term protection of islet allografts by XIAP overexpression may enhance the survival of islet transplants in diabetes.

Animals↗

PubMed2006

S100A8 and S100A9 in inflammation and cancer.

Calprotectin (S100A8/A9), a heterodimer of the two calcium-binding proteins S100A8 and S100A9, was originally discovered as immunogenic protein expressed and secreted by neutrophils. Subsequently, it has emerged as important pro-inflammatory mediator in acute and chronic inflammation. More recently, increased S100A8 and S100A9 levels were also detected in various human cancers, presenting abundant expression in neoplastic tumor cells as well as infiltrating immune cells. Although, many possible functions have been proposed for S100A8/A9, its biological role still remains to be defined. Altogether, its expression and potential cytokine-like function in inflammation and in cancer suggests that S100A8/A9 may play a key role in inflammation-associated cancer.

Animals↗

PubMed1999

Effects of octreotide treatment on early TNF-alpha production and localization in experimental chronic colitis.

BACKGROUND: Colitis induced by trinitrobenzene sulphonic acid (TNB) is a model of Th1 disease, mainly explored from the third day of induction. It has recently been shown that octreotide and other somatostatin analogues can modify inflammatory/immune processes by acting on cytokines. AIM: To examine TNFalpha production and the effect of preventive treatment with octreotide, during the early phase of TNB-colitis. METHODS: Thirty milligrams TNB with 50% ethanol was instilled into the colon of male Wistar rats. Treated groups received octreotide (2x10 microg x day/rat) or dexamethasone (1x2 mg x day/kg), subcutaneously, with the first injection before TNB. Eight and 80 h later, the colon was excised and processed for histology, TNFalpha immunohistochemistry, quantification of cytokine release ex vivo and tissue-inducible NO synthase (iNOS) activity. RESULTS: Maximal TNFalpha production was observed at the 8th hour, associated with intense immunostaining of the external muscle layer. Octreotide treatment decreased TNFalpha expression (staining and activity) and iNOS activity. At the 80th hour, submucosal macrophages were positive for TNFalpha and colonic production of IL1beta and interferon gamma was increased; all these effects were reduced by octreotide treatment. CONCLUSIONS: TNFalpha was expressed early by resident muscle cells, before staining of infiltrated immune cells and increased production of interferon gamma. TNFalpha regulation by octreotide suggests that this drug might exert anti-inflammatory properties via smooth muscle cells.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗

PubMed2026

Multi-omics Approaches to CCAAT/Enhancer-Binding Protein Beta in Oral Squamous Cell Carcinoma: Crosstalk Between Tumor Cells and Tumor-Associated Macrophages Driving Disease Progression.

BACKGROUND: CCAAT/Enhancer-Binding Protein Beta (CEBPB) is an important transcription factor that regulates tumor progression. However, the mechanism by which CEBPB regulates the progression of Oral Squamous Cell Carcinoma (OSCC) remains incompletely understood. Tumor progression depends on complex intercellular interactions within the tumor microenvironment. The purpose of this study was to investigate the role and epigenetic regulatory mechanisms of CEBPB in interactions between OSCC cells and tumor-infiltrating immune cells. METHODS: Bulk RNA-seq, ChIP-seq, and scRNA-seq data were obtained from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. The HOMER algorithm was employed to identify enhancers and predict the CEBPB-binding motif. Cell cluster analysis, functional enrichment, and intercellular interaction analysis were performed using the "Seurat" R package. H3K27ac enrichment at GAS6 enhancers was validated by ChIP-qPCR. Metastatic OSCC cells with CEBPB knockdown or GAS6 overexpression were established and co-cultured with THP-1 cells. IL-10 and IL-6 secretion from co-cultured THP-1 cells was detected via ELISA. Chemotaxis of OSCC cells toward THP-1 cells was assessed through a Transwell assay. RESULTS: CEBPB was upregulated in OSCC and correlated with poor prognosis. By integrating H3K27ac ChIP-seq and bulk RNA-seq data, 131 CEBPB-regulated enhancer-controlled genes were identified in lymph node metastatic OSCC cells. scRNA-seq analysis revealed eight major cell clusters in primary foci and lymph node metastases, including T/NK cells, malignant epithelial cells, B/plasma cells, macrophages, fibroblasts, dendritic cells, endothelial cells, and mast cells, with the malignant epithelial cells stratified into distinct sub-clusters. CEBPB expression was elevated in malignant epithelial cells of lymph node metastases compared to primary foci. Furthermore, 15 pairs of enhanced ligand-receptor interactions were identified in lymph node metastases relative to primary foci. GAS6 was a CEBPB-regulated enhancer-controlled gene, primarily mediating interactions between malignant cells and macrophages. CEBPB knockdown in metastatic OSCC cells significantly impaired their chemotaxis toward cocultured THP-1 cells, and downregulated IL-10/IL-6 secretion and CD206 expression in cocultured THP-1 cells. Conversely, GAS6 overexpression reversed these inhibitory effects. CONCLUSION: CEBPB activated GAS6 transcription in metastatic OSCC cells. The CEBPB/ GAS6 axis in metastatic OSCC cells enhanced their chemotaxis toward macrophages and promoted the M2 polarization of macrophages, thereby facilitating the establishment of an immunosuppressive microenvironment.

Humans↗

PubMed2005

Phenotypic characterization of the immune and mast cell infiltrates in the human testis shows normal and abnormal spermatogenesis.

OBJECTIVE: To assess the types, distributions, and numbers of immune cell infiltrates in the testes of men with azoospermia. DESIGN: Prospective study. SETTING: University research and clinical institutes. PATIENT(S): Thirty-one men with azoospermia showing normal spermatogenesis (n = 10), germ cell maturation arrest (GA, n = 12), and Sertoli cell-only syndrome (SCO, n = 9). INTERVENTION(S): Testicular tissue biopsies. Sections were stained with routine (hematoxyline and eosin), special (Masson Trichrome, Gordon, Periodic Acid Schiff, Aldehyde Fuchsin, and Orcein stains), and immunoperoxidase stains (using monoclonal antibodies for B and T cells and CD68 macrophages). MAIN OUTCOME MEASURE(S): Serum levels of T, FSH, and LH in addition to histopathological analysis. RESULT(S): Hormonal profiles were unremarkable in all patients. Marked deposition of the reticular and collagen fibers was seen more in abnormal than normal spermatogenesis. The immune (B and T lymphocytes and CD68 macrophages) and mast cells were found in the interstitium, tubular walls, and lumens of all the testes analyzed. The differential counts of these cells (B and T lymphocytes, CD68 macrophages, and mast cells, respectively) were higher in SCO (1.66 +/- 0.46, 9.14 +/- 1.30, 2.26 +/- 1.68, 3.35 +/- 0.23) and GA (2.03 +/- 0.48, 4.70 +/- 1.00, 2.61 +/- 0.70, and 4.18 +/- 0.13) when compared with those in normal spermatogenesis (1.22 +/- 0.19, 5.41 +/- 0.58, 1.55 +/- 0.33, and 2.26 +/- 0.13). Increased cellular counts were not statistically significant for T and B cells and macrophages. However, these differences were statistically significant for mast cells. CONCLUSION(S): Abnormal spermatogenesis is associated with increased numbers of the immune and mast cells. Our findings may reflect an exaggerated immune response in these cases.

Adult↗

PubMed1994

Nitric oxide synthase activity in human gynecological cancer.

Nitric oxide is generated by the NO synthases, a family of isoenzymes expressed in a wide range of mammalian cells. In the vascular and nervous systems distinct isoforms generate NO to act as a signal transduction mechanism. The isoform induced by cytokines, on the other hand, provides a sustained release of NO which mediates some cytotoxic and cytostatic effects of the immune system. Solid tumors are a heterogeneous population of cell types, including tumor, vascular, and infiltrating immune cells. Studies in vitro show that NO synthase can be present in many of these cells. However, its presence in situ in solid human tumors has not been reported. In this study, we have investigated NO synthase activity and its cellular localization in malignant and nonmalignant human gynecological tissue. Nitric oxide synthase activity was observed in malignant tissue, was highest (> or = 250 pmol/min/g tissue) in poorly differentiated tumors, and was below detectable levels in normal gynecological tissue. Furthermore, investigations with a polyclonal NO synthase antibody revealed immunoreactivity only in malignant tissue. This was associated with NO synthase activity and localized to tumor cells. Thus NO synthase is present in human gynecological tumors, and its presence seems to correlate inversely with the differentiation of the tumor.

Amino Acid Oxidoreductases↗

PubMed2026

SERPINE1-centric inflammatory signature associates with treatment resistance and survival in laryngeal squamous cell carcinoma.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) prognosis remains poor despite treatment advances. More accurate prognostic assessment models can help guide individualized treatment and improve prognosis. Chronic inflammation contributes to tumorigenesis, yet inflammatory response-related genes (IRGs) in LSCC prognosis are underexplored. This study aimed to construct an IRG prognostic signature for LSCC and further dissect core IRG-mediated mechanisms of immune escape and chemoresistance. METHODS: Transcriptional profiles and clinical data from LSCC patients were retrieved from The Cancer Genome Atlas (TCGA). IRGs were sourced from Gene Set Enrichment Analysis (GSEA) hallmark gene set. We identified differentially expressed IRGs linked to survival outcomes in LSCC. Key IRGs were subsequently selected using least absolute shrinkage and selection operator (LASSO) Cox regression analysis to establish an inflammatory risk score model. This model underwent internal validation within the TCGA cohort and external validation using independent Gene Expression Omnibus (GEO) datasets. We further assessed the model's association with the tumor immune microenvironment and the impact of IRGs on chemotherapy response. Finally, the functional roles of interested signature IRG were experimentally validated in LSCC cell lines. RESULTS: Four significant IRGs (AQP9, ITGA5, LCK, SERPINE1) were identified to build the risk score model. The model stratified LSCC patients into distinct prognostic groups: TCGA cohort: 5-year area under the curve (AUC) =0.836, P<0.001; GSE25727 cohort: 5-year AUC =0.706, P=0.02; GSE27020 cohort: 5-year AUC =0.798, P<0.01. Multivariate analysis confirmed the risk score as an independent prognostic factor (P<0.05). High-risk patients showed reduced immune cell infiltration (CD8+ T cells, dendritic cells) and suppressed immune pathways. Multi-algorithm immune analysis further revealed defective antigen presentation and reduced anti-tumor immune infiltration in high-risk LSCC, promoting tumor immune escape. GSEA/Gene Ontology (GO) enrichment combined with drug sensitivity prediction further revealed that high-risk tumors activate invasive signaling and acquire broad chemoresistance alongside impaired anti-tumor immunity. SERPINE1 might be associated with chemotherapy resistance and exhibited the highest alteration frequency (predominantly amplification) and overexpression in LSCC tissues. Its knockdown significantly suppressed proliferation, migration, invasion and chemoresistance in LSCC cells. Immunohistochemistry (IHC) confirmed tumor SERPINE1 overexpression (P=0.002 vs. normal tissues), correlating with poor survival (P<0.001). CONCLUSIONS: The 4-IRG risk signature is a reliable prognostic indicator reflecting immune dysfunction in LSCC. SERPINE1 is validated as a therapeutic target and biomarker, enriching our understanding of gene regulation dynamics in LSCC.

Laryngeal cancer↗

PubMed2002

Toll-like receptors and inflammation in the CNS.

The innate immune system recognizes "non-self" by employing a set of germline-encoded receptors called Toll-like receptors (TLRs), originally characterized in Drosophila. TLRs are involved in the recognition of various microbial-derived molecules, including lipopolysaccharide (LPS), lipoteichoic acid (LTA), and peptidoglycan (PGN), as well as unmethylated bacterial DNA. The TLR-mediated intracellular signaling pathways converge to activate nuclear factor-kappa B (NF-kappaB) and c-Jun N-terminal kinases (JNKs), which induce the transcription of a series of cytokine/chemokine genes that are involved in the initiation or regulation of the inflammatory response. It is now known that, like other peripheral organs, the central nervous system (CNS) is also under constitutive immune surveillance by CNS-resident glial cells (microglia and astrocytes) and CNS-infiltrating immune cells. The recent progress in our understanding of TLR functions in the innate immune response sheds new light on how inflammatory immune responses are initiated within the CNS. In this review, we discuss recent studies on TLRs and their ligands, signal transduction pathways activated by TLRs, and the mechanisms through which these various activation events occur. Finally, we discuss how TLRs might play similar important roles in CNS inflammation.

Animals↗

PubMed1996

Phenotypical characterization of lymphocytes infiltrating regressing papillomas.

Papillomavirus-induced lesions often regress spontaneously in both humans and animals. Papilloma regression is deemed to be due to a cell-mediated immune response, the nature of which is still ill defined, and is accompanied by immune cell infiltrates. To gain further information on the nature and role of the immune cells present in regressing papillomas, we have analyzed biopsies of papillomas induced in the soft palate of cattle by bovine papillomavirus type 4 (BPV-4) and have phenotypically characterized and quantified the lymphocytes present in these lesions. Eleven papilloma biopsies and seven biopsies of noninfected palate were analyzed for the presence of activated CD4+, CD8+, and gamma delta(WC1+) lymphocytes. We found large numbers of lymphocytes in the subepithelial derma of papillomas but not in normal palate tissue; these cellular masses consisted predominantly of CD4+ lymphocytes, with only a few CD8+ and gamma delta(WC1+) lymphocytes, generally positioned at the periphery of these masses. All three subtypes of lymphocytes were found interdigitated with the cells of the basal layer both in papillomas and in normal palate tissue, but while basal layer CD8+ and gamma delta(WC1+) T cells were detected with similar frequencies in papillomas and uninfected palate, basal layer CD4+ T cells were much more frequent in papillomas. CD4+, CD8+, and gamma delta(WC1+) lymphocytes were found in the suprabasal layers of papillomas, but the CD8+ and gamma delta(WC1+) T cells were more numerous and had migrated further into the differentiating keratinocytes of the papilloma fronds than the CD4+ T cells. We conclude that T-cell infiltration is characteristic of regressing BPV-4 papillomas, that CD4+ lymphocytes are specifically and massively recruited into the regressing papillomas, and that although all three lymphocyte subsets can penetrate the papilloma, only the CD8+ and gamma delta(WC1+) lymphocytes are able to migrate into the fronds. These results suggest that all three lymphocyte subsets have an important role to fulfill during natural regression of papillomas.

Animals↗

PubMed1995

Altered HLA expression by metastatic cervical carcinoma cells as a factor in impaired immune surveillance.

The altered expression of histocompatibility leukocyte antigens (HLA) in the development to cervical carcinoma suggests that tumor progression may be related to impaired recognition by host immune defense mechanisms. To investigate whether this phenomenon plays a role in the process of metastasis of cervical cancer, we analyzed and compared the HLA expression with the number of infiltrating immune cells in primary cervical carcinoma and related autologous metastases (n = 30) by staining serial paraffin and corresponding frozen sections with a panel of monoclonal antibodies. In 60% of the cervical metastases, compared to 21% of the primary tumors, a downregulation of monomorphic HLA class I antigens was observed, with frequent allele-specific alterations. In 50% the HLA class II expression was slightly increased on the metastatic tumor cells in comparison to the primary tumor. In addition, variability of alterations in HLA expression was observed between different metastases in the same patient. A minor infiltration of immune cells was present in cervical metastases compared to the primary tumors, especially in the HLA class I-downregulated metastases. Furthermore, loss of HLA class I expression on the metastatic tumor cells resulted in a significant decrease of tumor-infiltrating CD8+ T lymphocytes. These findings suggest that in cervical carcinoma loss of HLA class I expression plays a decisive role in the escape from immune surveillance leading to a greater metastatic potential of tumor cells.

Adult↗