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PubMed2006

Microglial cells initiate vigorous yet non-protective immune responses during HSV-1 brain infection.

Central nervous system (CNS) infection with herpes simplex virus (HSV)-1 triggers neuroinflammatory responses leading to peripheral immune cell infiltration into the brain. Previous in vitro studies from our laboratory, using primary human brain cells, implicated microglia as the cellular source of infection-induced chemokines, such as CXC ligand 10 (CXCL10) and CC ligand 2 (CCL2). Here, we evaluated the role of microglial cells in HSV-induced neuroimmune responses using an in vivo murine model of herpes encephalitis. Data obtained during this study demonstrated robust levels of CXCL10, CCL2 and CXCL9 detectable in the brains of infected BALB/c mice between 5 and 8 days post-infection (p.i.). Microglial cells were identified as a source of this HSV-induced chemokine production. Additional experiments established that induction of these immune mediators preceded the presence of CD3, CD4, CD8, and CD45 mRNA in the brain, and immunohistochemical analysis confirmed the presence of infiltrating CD3(+) cells. Further analysis suggested that microglia-derived chemokines drive peripheral immune cell chemotaxis, as antibodies to CXCL10 and CCL2 blocked the migration of murine splenocytes toward HSV-infected microglia by approximately 59.3+/-4.1% and 17.5+/-1.4%, respectively. Taken together, these results demonstrate that a vigorous microglia-driven cascade of pro-inflammatory immune responses is not sufficient to protect susceptible mice from HSV-1 brain infection.

Animals↗

PubMed2002

Significance of changes in local immunity in patients with hepatocellular carcinoma after percutaneous microwave coagulation therapy.

OBJECTIVE: To assess the local immune response in patients with hepatocellular carcinoma after percutaneous microwave coagulation therapy (PMCT). METHODS: Seventy-eight patients with hepatocellular carcinoma underwent PMCT. Both cancerous and adjacent liver tissue were taken before, and 3, 17 and 30 days after PMCT using ultrasound-guided liver biopsy. Specimens were stained by immunohistochemical techniques for detecting CD3, CD45RO, CD56, CD68, and CD20 positive cells. RESULTS: A few CD3, CD45RO, CD56, CD68 and CD20 positive cells were observed in the cancer stroma and surrounding sinusoids in liver tissue pre-PMCT. The number of immunocytes, except for CD20 positive cells, was significantly increased both within the cancer and the adjacent liver tissue, with a larger increase in tumor tissue at day 3 post-PMCT compared with pre-PMCT. These immunocytes were enlarged in size. The number of CD3, CD45RO and CD56 positive cells peaked at day 17 and CD68 positive cells peaked at days 3 post-PMCT. At day 30 post-PMCT, this increase still existed. These infiltrating immunocytes distributed in the parenchyma of the tumor, and within the lumen of small blood vessels after PMCT. In addition, more infiltrated immune cells were seen in cancer cell spaces. CONCLUSIONS: A change in immunocyte infiltration takes place in number, configuration and location after patients with HCC are treated with percutaneous microwave coagulation, suggesting that local immune function is enhanced post-PMCT.

Adult↗

PubMed1998

Permanent skin replacement using engineered epidermis containing fewer than 5% syngeneic keratinocytes.

This study was conducted to investigate permanent skin replacement using heterologous (syngeneic-allogeneic) epidermal substitutes containing fewer than 5% syngeneic keratinocytes. Keratinocytes were isolated from the skin of new-born Balb/c (B) and C3H/HeN (C) mice and cocultured in different ratios: 20%B-80%C, 10%B-90%C, 5%B-95%C, and 2%B-98%C (and vice versa). After 4 to 5 days, graftable epidermal substitutes were obtained and transplanted onto adult Balb/c or C3H/HeN male mice. Recipients always received the heterografts containing the lower percentage of their own keratinocytes. On Days 15 and 30 postgrafting, all heterografts showed significant graft take (> 75%) and skin replacement compared with allografts. Regenerated tissues were well structured and well vascularized. These tissues contained only syngeneic keratinocytes. These results led us to question whether this was an active immune situation. Structural analyses revealed the presence of leukocyte infiltration that was dependent on the percentage of allogeneic keratinocytes present in the heterologous implant. However, even with the 2% syngeneic-98% allogeneic implant, infiltration was lower than with the allograft. Leukocyte phenotyping confirmed the presence of immune cells infiltrating the heterologous implants and revealed the involvement of CD8+ and CD4+ lymphocytes in this immune activation. The percentages of these two cell populations were lower than those obtained with the allografts, suggesting moderate cellular activation after each heterograft compared with the allografts. In conclusion, it is possible to generate functional skin even after 2% syngeneic-98% allogeneic heterografts; there was moderate cellular immune activation compared with the allografts.

Animals↗

PubMed1995

Studies of adenovirus-induced eye disease in the rabbit model.

PURPOSE: To achieve a better understanding of the pathogenic processes associated with human adenovirus (Ad)-induced ocular disease. METHODS: Growth curves of Ad5 and Ad14 were performed in cell cultures derived from rabbit and human corneal epithelium (CE) and corneal keratocytes (CK). For in vivo studies, rabbit eyes were inoculated intrastromally and topically with 10(6) plaque-forming units per eye of Ad5 and ultraviolet light-inactivated (UV-1) Ad5 or Ad14, and the clinical features of the eyes were evaluated by biomicroscopic slit lamp examinations. Duration and quantitation of virus in tear samples were monitored. Humoral response was evaluated by enzyme-linked immunosorbent assay and serum neutralization titrations. Histopathologic and immunocytochemical staining of frozen corneal tissues was performed to determine the expression of major histocompatibility complex (MHC) class I and II and the presence of CD4+ and CD8+ T lymphocytes and CD18+ cells after the immunopathologic response elicited by virus inoculation. RESULTS: Both Ad5 and Ad14 replicated in all human cell cultures studied. In cells of rabbit origin, Ad5 replicated in cultured CE and CK cells, whereas Ad14 replication appeared restricted. Virus titers in ocular samples from Ad5-inoculated eyes peaked on postinoculation days 3 through 4, with approximately a 100-fold increase in infectious virus in comparison to initial titers. The duration of Ad5 shedding was 8.9 +/- 2.4 days. Ad5, Ad5 UV-I, and Ad14 induced seroconversion and subepithelial opacities. CD4+ and CD8+ T lymphocytes and CD18+ cells were present in these intrastromal immune cell infiltrates. Expression of MHC class I and II was observed in keratocytes and immune cells; MHC class I also was expressed on CE cells in inflamed areas. CONCLUSIONS: Ad5 is capable of replicating in both CE and CK cells of the rabbit eye. The presence of Ad antigens within the corneal stroma originating from infectious virus (Ad5), UV-inactivated virus (Ad5), or nonreplicating infectious virus (Ad14) can elicit indistinguishable immunopathologic responses in the stroma composed of CD4+, CD8+, and CD18+ cells.

Adenoviridae↗

PubMed2002

Microglia as liaisons between the immune and central nervous systems: functional implications for multiple sclerosis.

Multiple sclerosis is a chronic demyelinating inflammatory disease of the central nervous system (CNS). As the tissue macrophage of the CNS, microglia have the potential to regulate and be regulated by cells of the CNS and by CNS-infiltrating immune cells. The exquisite sensitivity of microglia to these signals, coupled with their ability to develop a broad range of effector functions, allows the CNS to tailor microglial function for specific physiological needs. However, the great plasticity of microglial responses can also predispose these cells to amplify disproportionately the irrelevant or dysfunctional signals provided by either the CNS or immune systems. The consequences of such an event could be the conversion of self-limiting inflammatory responses into chronic neurodegeneration and may explain in part the heterogeneous nature of multiple sclerosis.

Animals↗

PubMed2026

HLA class I expression and tumor immune infiltration together shape colon cancer immune contexture.

BACKGROUND: The relative contribution of HLA class I molecules-including classical HLA class Ia (HLA-A, -B, -C) and non-classical HLA class Ib (HLA-E, -F, -G)-to shaping the tumor immune microenvironment in colon cancer remains insufficiently defined. We investigated how their expression patterns relate to immune infiltration and clinical outcome. METHODS: In a retrospective cohort of 280 colon cancers, we assessed HLA class Ia and class Ib expression and quantified CD45-positive immune cell infiltration by immunohistochemistry. These features were correlated with clinicopathological variables, microsatellite instability (MSI) status, and previously established genomic immune signatures. RESULTS: High HLA class Ia expression and increased CD45-positive cell infiltration were each associated with improved overall, disease-specific, and progression-free survival. CD45-positive density correlated strongly with Immunologic Constant of Rejection scores. HLA class Ia loss was more frequent in advanced stages and in MSI-H tumors. Among HLA class Ib molecules, only HLA-E expression was associated with favorable disease-specific and progression-free survival. Integrative analysis identified three immune phenotypes with distinct prognostic profiles; tumors characterized by high HLA class Ia expression, low HLA class Ib expression, and high CD45-positive infiltration had the best outcomes. CONCLUSION: Colon cancer immunogenicity is shaped by coordinated patterns of HLA class I expression and immune infiltration. Integrating HLA class Ia/Ib expression with immune cell density provides a refined stratification of tumor immune phenotypes and may support personalized immunotherapeutic decision-making.

Antigen presentation↗

PubMed2001

Cd40 expression in uterine tissues: a key regulator of cytokine expression by fibroblasts.

CD40 is a cell surface receptor initially discovered on cells of the hemopoietic lineage. Its primary role on immune cells is to enhance their activation and hence their production of cytokines and immunomodulatory molecules. Recently, CD40 has also been detected on human fibroblasts. An emerging view of the fibroblast is that it is far more than a structural cell, being capable of intimate interaction with cells of the immune system. In fibroblasts from several tissues, the engagement of CD40 with its ligand (CD40L) resulted in the secretion of proinflammatory molecules such as interleukin-6 (IL-6) and IL-8. Currently, there are few data about the presence of the CD40-CD40L system in female reproductive tissues. This study investigates the expression of CD40 by human endometrium, myometrium, and cervix both in situ and in tissue explant-derived fibroblasts. CD40 was detected mainly in the perivascular region of endometrium, myometrium, and cervix. Light staining for CD40 was observed in stromal elements. Additionally, the basal epithelium of cervix expressed CD40. Fibroblastic cells derived from all three sources express low levels of CD40, and this is up-regulated with interferon-gamma treatment (500 U/mL; 72 h). When activated with interferon-gamma and CD40L, the fibroblasts secreted increased amounts of IL-6, IL-8, and MCP-1. These data suggest that the CD40-CD40L system may provide a link between the resident structural cells of these reproductive tissues and the infiltrating immune cells or activated platelets that may express CD40L. The possible interaction of CD40 with CD40L may be particularly important during events such as menstruation and cervical ripening, where up-regulation of the proinflammatory molecules IL-6 and IL-8 is viewed as critical for these processes. In addition, dysregulation of this system may be a contributory factor to problems such as menstrual dysfunction and preterm labor.

CD40 Antigens↗

PubMed2001

Induction and inhibition of apoptosis by pseudorabies virus in the trigeminal ganglion during acute infection of swine.

We examined the ability of pseudorabies virus (PRV) to induce and suppress apoptosis in the trigeminal ganglion during acute infection of its natural host. Eight pigs were intranasally inoculated with a virulent field strain of PRV, and at various early times after inoculation, the trigeminal ganglia were assessed histologically. PRV-infected cells were detected by use of immunohistochemistry and in situ hybridization, and apoptosis was identified by in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling. Light and electron microscopy was also used for morphological studies. Apoptosis was readily detected among infiltrating immune cells that were located surrounding PRV-infected neurons. The majority of PRV-infected neurons did not show morphological or histochemical evidence of apoptosis, even including those neurons that were surrounded by numerous inflammatory cells and exhibited profound pathological changes. However, neuronal virus-induced apoptosis also occurred but at a sporadic low level. These findings suggest that PRV is able to block apoptosis of infected trigeminal ganglionic neurons during acute infection of swine. Furthermore, our results also suggest that apoptosis of infiltrating inflammatory cells may represent an important viral mechanism of immune evasion.

Acute Disease↗

PubMed1995

Clinical evidence that the human monoclonal anti-idiotypic antibody 105AD7, delays tumor growth by stimulating anti-tumor T-cell responses.

A human monoclonal anti-idiotypic antibody, 105AD7, which mimics a colorectal tumor associated antigen, 791Tgp72, has been developed. A Phase I trial in advanced colorectal cancer patients showed that 105AD7 therapy was nontoxic and that immunised patients had prolonged survival when compared to a contemporary group of patients treated in the same center. There is accumulating clinical evidence that 105AD7 delays tumor growth by stimulating anti-tumor T-cell responses. Stimulation of helper T-cells was exemplified in the phase I study as 105AD7 immunized patients showed antigen specific T-cell blastogenesis responses and enhanced IL-2 production. Further evidence was obtained from a new clinical study in which colorectal cancer patients were immunized prior to tumor resection. Immune infiltrating cells were analysed by immunohistochemistry and effector cell function was studied in immune cells from peripheral blood and tumor draining lymph nodes. Both activated CD4 and natural killer (NK) cells were observed at the tumor site, which is of interest as NK cells are rarely found in colorectal tumors. Effector studies confirmed that NK activity was enhanced in 3/6 patients. Increased autologous tumor killing was also found in 3/4 patients and accumulation of CD8RO cells following 105AD7 immunization also suggested that CD8 T cells were being stimulated.

Aged↗

PubMed1994

Cytokine networks in solid human tumors: regulation of angiogenesis.

The isolation, purification, and molecular cloning of an increasing number of cytokines and their receptors have allowed major advances in our understanding of the relevance of these proteins to the pathobiology and treatment of such human diseases as neoplasia. Cytokines produced by the multiple cell types present within the microenvironment of solid tumors from a complex, dynamic network, in which they have overlapping properties, induce other cytokines and alter the expression of soluble and cell surface-bound cytokine receptors. A broad number of such intratumoral cytokines have multiple effects on tumor progression. These include direct and indirect effects both on tumor cell growth and metastatic behaviors and on such cells in the stromal compartment as fibroblasts, infiltrating immune cells, and endothelial cells in the microvasculature. Here, we review the sites of production and multifaceted role of several key cytokines in the stimulation of a new blood supply within growing neoplasms. The clinical implications and new therapeutic targets suggested by this rapidly emerging picture of the cellular and molecular mechanisms subserving tumor angiogenesis are also discussed.

Cytokines↗

PubMed2001

Hydrogen peroxide triggers the expression of Fas/FasL in astrocytoma cell lines and augments apoptosis.

Fas expression increases in perinecrotic areas of glioblastoma. In this study the up-regulation of Fas/FasL by oxidative stress was shown. H(2)O(2) exposure increased Fas expression in two astrocytoma cell lines and cells became sensitive to agonistic anti-Fas antibody. FasL was up-regulated in astrocytoma cells. Apoptosis of Molt-4 cells was augmented by astrocytoma cells pretreated with H(2)O(2). Our findings suggest up-regulation of Fas in astrocytoma cells may lead them to be sensitive to apoptosis when cells are in oxidative stress. Whereas, the up-regulation of FasL may render astrocytoma cells cytotoxic to neighboring brain tissues and infiltrating immune cells.

Apoptosis↗

PubMed2026

Identification of JAML as an Immune-Associated Prognostic Marker in Non-Small Cell Lung Cancer.

INTRODUCTION: Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality worldwide, and the identification of novel prognostic biomarkers associated with tumor immunity is urgently needed. Junctional adhesion molecule-like (JAML), a member of the junctional adhesion molecule family, participates in leukocyte adhesion, migration, and T-cell activation. Although JAML has been implicated in immune regulation and tumor progression in other cancers, its expression pattern, prognostic significance, and association with the immune microenvironment in NSCLC remain unclear. This study aimed to investigate the clinical and immunological significance of JAML in NSCLC. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to evaluate JAML expression patterns in NSCLC subtypes. The prognostic value of JAML was assessed using Kaplan-Meier survival analysis and Cox regression models. The association between JAML expression and immune cell infiltration was investigated using TIMER2.0, CIBERSORT, and TISIDB analyses. Functional enrichment analyses were performed to explore potential biological pathways associated with JAML expression. In addition, JAML expression was validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in paired NSCLC and adjacent normal tissues. RESULTS: JAML expression was significantly decreased in NSCLC tissues compared with normal tissues (P < 0.005), with the lowest expression observed in lung squamous cell carcinoma (LUSC) and reduced expression in lung adenocarcinoma (LUAD). Survival analysis demonstrated that patients with high JAML expression had significantly improved overall survival compared with those with low expression (univariate HR = 0.68, 95% CI: 0.54-0.86, P = 0.001; multivariate HR = 0.76, 95% CI: 0.57-1.00, P = 0.049). Immune infiltration analysis revealed that JAML expression was significantly associated with multiple immune cell populations, including CD8+ T cells (r = 0.42, P < 0.001), suggesting a close relationship between JAML expression and the tumor immune microenvironment. qRT-PCR validation confirmed that JAML expression was approximately 2.3-fold higher in adjacent normal tissues than in NSCLC tissues (P < 0.05). CONCLUSION: JAML is downregulated in NSCLC and its high expression is associated with favorable overall survival and distinct immune infiltration patterns. These findings indicate that JAML may serve as a potential prognostic biomarker and provide insights into the relationship between JAML expression and the tumor immune microenvironment in NSCLC.

JAML protein↗

PubMed2002

Macrophages as effector cells in interleukin 12-induced T cell-dependent tumor rejection.

Interleukin (IL)-12 activates a T-cell-dependent antitumor immune response that is able to eradicate established large tumors in a number of immunogenic tumor models. The effector mechanisms in these dramatic antitumor responses have not yet been identified. In this report, we show that the effector mechanism of IL-12-induced rejection of established MCA207 tumors is unique in that it is not dependent on perforin, Fas/Fas ligand, and nitric oxide. Study of cyclophosphamide plus IL-12 (Cy + IL-12)-induced rejection of ascites Sa1 tumor demonstrates that macrophages are the predominant immune cell infiltration in the ascites. These macrophages possess nonspecific tumoricidal activity in vivo as immune distinct MCA207 tumor cells inoculated i.p., but not s.c., in mice bearing regressing Sa1 ascites tumors after Cy + IL-12 therapy are rejected. Furthermore, Cy + IL-12-treated Sa1 ascites cells or macrophages, but not spleen macrophages from the same mouse or inflammatory macrophages induced by thioglycollate, are able to suppress the development of immune-irrelevant s.c. tumors in a Winn assay. These macrophages kill various tumor cells in a contact-dependent manner in vitro, and the cytotoxicity is preserved after fixation with paraformaldehyde. These results demonstrate that activated macrophages function as effector cells in an IL-12-induced, T-cell-dependent eradication of established tumors through a novel contact-dependent, paraformaldehyde fixation-resistant, apoptosis-inducing mechanism.

Animals↗

PubMed2026

Genome-wide Association Studies of the Pathogenic Sphingosine-1-Phosphate Gene in Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease that can lead to malignancies over time. Sphingosine-1-phosphate (S1P) receptor signaling affects lymphocyte trafficking and vascular integrity, influencing intestinal inflammation. This study aimed to identify S1P-related key genes in UC. METHODS: Differentially expressed genes (DEGs) between the UC and control groups were analyzed in the GSE87473 (training) dataset. Genes overlapping between the DEGs and S1P-related genes were considered candidate genes. These genes were incorporated into machine learning algorithms and subjected to expression analysis to identify key genes. Gene functions were determined through a gene–gene interaction network, enrichment analysis, and immune cell infiltration analysis. In addition, transcription factor–mRNA and mRNA–miRNA–lncRNA networks were constructed. Finally, reverse transcription–quantitative polymerase chain reaction (RT-qPCR) was performed to evaluate the expression of key candidate genes in UC and control tissues. RESULTS: This study identified two key genes (SPHK2 and SPNS2) associated with UC. Notably, SPHK2 expression was lower and SPNS2 expression was higher in the UC group in both training and validation datasets and in clinical UC tissues (RT-qPCR). The area under the curve values of SPHK2 and SPNS2 exceeded 0.7 in both datasets, indicating that the genes had good diagnostic efficacy for UC. Consistently, the nomogram showed that the two genes had promising diagnostic value in UC. SPHK2 and SPNS2 were found to be localized to the plasma membrane. The correlations of the two genes with different immune cells showed significantly opposite trends. In particular, SPHK2 had the strongest positive correlation with M2 macrophages (r = 0.6) and the strongest negative correlation with neutrophils. Moreover, mRNA–miRNA–lncRNA and transcription factor– mRNA networks of the key genes were constructed. CONCLUSION: This study suggests that SPHK2 and SPNS2 are key genes associated with UC, highlighting their potential as effective diagnostic biomarkers.

Humans↗

PubMed2026

Unveiling the power of TIIC: A prognostic tool for esophageal adenocarcinoma.

BACKGROUND: Esophageal adenocarcinoma (EAC) remains a lethal malignancy with limited prognostic tools for guiding immunotherapy. Tumor-infiltrating immune cells (TIICs) play a critical role in EAC prognosis and treatment response. METHODS: We integrated single-cell RNA sequencing and bulk transcriptome data from TCGA and GEO databases. TIIC-specific RNAs were identified via tissue specificity index calculation combined with machine learning feature selection. Twenty machine learning algorithms were benchmarked to construct an optimal TIIC signature score (TIIC-Score) based on the comprehensive C-index. Immunotherapy response, genomic mutation, and copy number variation were analyzed. Summary-data-based Mendelian randomization (SMR) and two-sample Mendelian randomization (MR) were performed to explore genetic associations. Core prognostic TIIC-related genes were functionally validated in esophageal cancer cell lines through loss-of-function assays. RESULTS: The TIIC-Score demonstrated robust prognostic value for 1-, 2-, and 3-year overall survival across multiple cohorts, outperforming 22 published models. High TIIC-Score was associated with poor survival and increased chromosomal instability. Mutation profiling revealed high frequencies of TP53 (78.2%), TTN (48.7%), and SYNE1 (30.8%). MR analysis identified a significant association between gastro-oesophageal reflux and EAC risk at SNP rs8130507. Functionally, CCNI was upregulated in esophageal cancer cells, and its knockdown suppressed malignant phenotypes while promoting apoptosis, supporting its pro-tumorigenic role. CONCLUSION: The TIIC-Score provides a novel prognostic framework for EAC that effectively stratifies patient risk and may help identify individuals most likely to benefit from immunotherapy.

Esophageal adenocarcinoma↗

PubMed2026

A cuproptosis-related lncRNAs-based risk signature for predicting prognosis and immune status in glioma.

BACKGROUND: Glioma is one of the most prevalent primary malignant brain tumors, characterized by poor prognosis and limited treatment options. Recent studies have identified cuproptosis, a novel copper-dependent form of regulated cell death, as a critical mechanism involved in tumor progression. However, the role of cuproptosis-related long non-coding RNAs (lncRNAs) in glioma remains not fully clarified. This study aimed to develop and validate a prognostic model based on cuproptosis-associated lncRNAs to predict patient outcomes and guide individualizing therapeutic strategies. METHODS: Transcriptomic profiles and clinical data were obtained from The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and the Chinese Glioma Genome Atlas (CGGA) databases. Cuproptosis -related prognostic lncRNAs were filtered via univariate and multivariate Cox and Least absolute shrinkage and selection operator (LASSO) regression analyses, which were selected to establish a prognostic model for glioma. Samples were divided into high- and low-risk groups, and the predictive performance of the prognostic model was evaluated based on receiver operating characteristic (ROC) curves, Kaplan-Meier (K-M) survival curves, and a nomogram. In addition, immune cell infiltration, tumor mutational burden (TMB), immunophenoscore (IPS), Tumor Immune Dysfunction and Exclusion (TIDE) and drug sensitivity were analyzed. Expression levels of selected lncRNAs and proteins were validated using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting. RESULTS: An 11-lncRNA signature associated with cuproptosis was established, and the risk score derived from this model was identified as an independent prognostic factor for glioma. The model exhibited excellent predictive ability, with area under the curve (AUC) values of 0.880, 0.913, and 0.866 for 1-, 3-, and 5-year survival, respectively. Higher TMB, immune checkpoint expression, and IPS were observed in the high-risk group and no significant difference was observed in TIDE between risk groups. Drug sensitivity analysis identified TPCA-1, KIN001-135, and ispinesib mesylate as potential therapeutic agents. Expression validation in glioma cells further supported the biological relevance of the selected lncRNAs. CONCLUSIONS: This cuproptosis-related lncRNA-based signature demonstrates strong prognostic value and may serve as a promising tool for glioma risk stratification and personalized treatment selection.

Glioma↗

PubMed2005

Stat3 activity in melanoma cells affects migration of immune effector cells and nitric oxide-mediated antitumor effects.

Infiltration of immune effector cells in tumors is critical for antitumor immune responses. However, what regulates immune cell infiltration of tumors remains to be identified. Stat3 is constitutively activated with high frequency in diverse cancers, promoting tumor cell growth and survival. Blocking Stat3 signaling in tumors in vivo results in tumor growth inhibition that involves killing of nontransfected tumor cells and infiltration of immune effector cells, suggesting that Stat3 activity in tumor cells might affect immune cell recruitment. However, dying tumor cells can also attract immune cells. In this study, we show in isogenic murine melanomas that natural Stat3 activity is associated with tumor growth and reduction of T cell infiltration. Blocking Stat3 signaling in the melanoma cells containing high Stat3 activity results in expression of multiple chemoattractants, leading to increased migration of lymphocytes, NK cells, neutrophils, and macrophages. In addition, blocking Stat3 triggers tumor cells to produce soluble factors capable of activating macrophage production of NO in vitro and in vivo. TNF-alpha and IFN-beta, which are secreted by Stat3-inhibited tumor cells, are able to activate macrophage NO production, whereas neutralizing TNF-alpha in the tumor supernatant from Stat3-blocked tumor cells abrogates nitrite production. Moreover, interrupting Stat3 signaling in tumor cells leads to macrophage-mediated, nitrite-dependent cytostatic activity against nontransduced tumor cells. These results suggest that tumor Stat3 activity affects recruitment of diverse immune effectors and it can be manipulated to activate the effector phase of innate immune responses.

Animals↗

PubMed2001

Endocrine and paracrine regulation of endometrial angiogenesis.

The human endometrium is a complex tissue comprised of different cell types, including epithelial, stromal, inflammatory, perivascular, and blood vessel cells. The hormonal receptivity and distribution of these cell populations change during the menstrual cycle. Cyclical endometrial growth is dependent on its ability to regenerate a vascular capillary network, which grows in parallel with the proliferation and differentiation of the endometrial lining. Natural hormonal effects on the endometrium and endocrine manipulation of this tissue, in response to the use of exogenous steroid therapies, can affect endometrial capillary proliferation and function, leading to clinical abnormalities of uterine bleeding. We propose that the regulation of endometrial angiogenesis is mediated indirectly via complex interactions among cell types. Our laboratory has focused on a prototypical member of the angiogenic proteins, vascular endothelial growth factor (VEGF)-A. In this paper we present data demonstrating that VEGF-A expression in normal endometrial epithelial and stromal cells and in Ishikawa adenocarcinoma cells is increased by an ovarian steroid, estradiol. Infiltrating immune cells, particularly polymorphonuclear granulocytes, also are sources of VEGF-A. In inflammatory conditions involving the endometrium (e.g., endometriosis), a proinflammatory cytokine, IL-1beta, can mediate neoangiogenesis by inducing VEGF-A gene transcription. Thus, endometrial vascularization is effected by both endocrine and paracrine pathways.

Cells, Cultured↗