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Endometriosis is a gynecological disorder among reproductive-aged women. Recent epidemiological investigations suggest endometriosis increases the risk of endometrial cancer. However, the molecular entity leading to endometriosis-to-endometrial cancer is largely unknown. This study aimed to combine a variety of computational approaches to identify the key therapeutic target promoting endometriosis-to-endometrial cancer and screen potential inhibitors against target to prevent cancer development. Our systematic investigations, includes transcriptomic profiling, protein network, pharmacophore modeling, docking, binding free energy calculation, dynamics simulation, and quantum mechanics. The gene expression analysis on endometriosis and endometrial cancer was performed and showed 108 shared upregulated genes in both conditions. Further construction of interaction network with 108 genes showed intercellular adhesion molecule 1 (ICAM1) to be a crucial molecule with a high degree of connectivity that influences vital mechanisms related to cancer pathways. We then generated ligand-based pharmacophore models using established ICAM1 inhibitors. Among the models, the ADRRR_8 pharmacophore exhibited a robust area under curve (AUC = 0.83), was employed to screen 1739 anti-cancer drugs. On screening, 421 anti-cancer drugs displayed ICAM1-inhibiting pharmacophore features. Further, the docking of 421 drugs with ICAM1 showed lanreotide (−7.80 kcal/mol) with better affinity than the reference ICAM1 inhibitor (−3.59 kcal/mol). Further validation though binding free energy and dynamics simulation of the lanreotide-ICAM1 complex showed a high binding affinity of −55.90 kcal/mol and contributed stable confirmation. According to quantum chemical calculations, lanreotide's electronic properties favour ICAM1 binding with highest occupied molecular orbital was −6.91 eV and lowest unoccupied molecular orbital was −3.93 eV. Our study supports using lanreotide to treat endometriosis, which could delay or prevent endometrial cancer. These predictions need to be confirmed and examined to determine the use of lanreotide in endometriosis treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Triple-negative breast cancer (TNBC) is recognized as the most aggressive and immunologically infiltrated subtype of breast cancer. A high circulating neutrophil-to-lymphocyte ratio (NLR) is strongly linked to a poor prognosis among patients with breast cancer, emphasizing the critical role of neutrophils. Although the involvement of neutrophils in tumor metastasis is well documented, their interactions with primary tumors and tumor cells are not yet fully understood. Methods Clinical data were analyzed to investigate the role of neutrophils in breast cancer. In vivo mouse model and in vitro co-culture system were used for mechanism researches. Blocking experiments were further performed to identify therapeutic agents against TNBC. Results TNBC cells secreted GM-CSF to sustain the survival of mature neutrophils and upregulated CD11b expression. Through CD11b, neutrophils specifically binded to ICAM1 on TNBC cells, facilitating adhesion. Transcriptomic sequencing combined with human and murine functional experiments revealed that neutrophils, through direct CD11b-ICAM1 interactions, activated the MAPK signaling pathway in TNBC cells, thereby enhancing tumor cell invasion and migration. Atorvastatin effectively inhibited ICAM1 expression in tumor cells, and tumor cells with ICAM1 knockout or treated with atorvastatin were unresponsive to neutrophil activation. The MAPK pathway and MMP9 expression were significantly inhibited in the tumor tissues of TNBC patients treated with atorvastatin. Conclusions Targeting CD11b-ICAM1 with atorvastatin represented a potential clinical approach to reduce the malignant characteristics of TNBC. Graphical Abstract

Therapeutic benefits and underlying biomechanism(s) of antibody drug conjugates (ADC) in combination with other targeted therapeutics are largely unknown. Here, the synergy between ADC and epigenetic drug decitabine (DAC), a clinically approved DNA methylation inhibitor, in multiple preclinical models of melanoma specifically investigated. Mechanistically, the underlying biomechanisms of how DAC cooperatively worked with ICAM1 antibody conjugated DNA topoisomerase I inhibitor DXd (I1‐DXd) is elucidated. DAC treatment significantly enhanced anti‐tumor efficacy of I1‐DXd by upregulating antigen expression, enhancing antibody internalization and potentiating tumor sensitivity by epigenetically reprogramming of melanoma. Meanwhile, I1‐DXd/DAC combination also exerted regulatory effects on tumor microenvironment (TME) by enhancing tumor infiltration of innate and adaptive immune cells and improving penetration of ADCs with a boosted antitumor immunity. This study provides a rational ADC combination strategy for solid tumor treatment. [ABSTRACT FROM AUTHOR]

Objective To investigate the pathogenic role and underlying mechanisms of long noncoding RNAs (lncRNAs) in ANCA-associated vasculitis (AAV). Methods RNA-sequencing (RNA-seq) was applied to screen the expression profile of lncRNAs in peripheral leukocytes from five AAV patients and five healthy controls (HC). Candidate lncRNAs were preliminarily verified in peripheral leukocytes from 46 AAV patients and 35 HC by qRT-PCR. Then, the identified LINC02193 was further validated in peripheral neutrophils from 67 AAV patients, 45 HC and 64 disease controls. Correlation between LINC02193 levels and disease activity was analysed. Then, a loss-of-function study was conducted to investigate the role of LINC02193 in neutrophils activation. Furthermore, bioinformatics analysis, dual luciferase reporter and RNA immunoprecipitation assays were performed to explore the mechanism of LINC02193 regulating neutrophils activation. Results A total of 467 upregulated and 412 downregulated lncRNAs were identified in AAV patients. From the top five upregulated lncRNAs, an elevation of LINC02193 was validated in a larger sample of AAV patients, and positively correlated with disease activity. Knockdown of LINC02193 inhibited reactive oxygen species and nitric oxide production, neutrophil extracellular traps release and adhesion to endothelial cells of differentiated human promyelocytic leukaemia HL-60 cells, whereas overexpression of ICAM1 counteracted these effects. Mechanistic analysis demonstrated that LINC02193 acted as an miR-485-5p sponge to relieve the repressive effect of miR-485-5p on ICAM1, thus promoting ICAM1 expression. Conclusion LINC02193, a novel lncRNA identified in AAV, could function as competing endogenous RNAs for miR-485-5p to promote ICAM1 expression and neutrophils activation, suggesting its potential as a therapeutic target of AAV. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) is recognized as the most aggressive and immunologically infiltrated subtype of breast cancer. A high circulating neutrophil-to-lymphocyte ratio (NLR) is strongly linked to a poor prognosis among patients with breast cancer, emphasizing the critical role of neutrophils. Although the involvement of neutrophils in tumor metastasis is well documented, their interactions with primary tumors and tumor cells are not yet fully understood. Methods: Clinical data were analyzed to investigate the role of neutrophils in breast cancer. In vivo mouse model and in vitro co-culture system were used for mechanism researches. Blocking experiments were further performed to identify therapeutic agents against TNBC. Results: TNBC cells secreted GM-CSF to sustain the survival of mature neutrophils and upregulated CD11b expression. Through CD11b, neutrophils specifically binded to ICAM1 on TNBC cells, facilitating adhesion. Transcriptomic sequencing combined with human and murine functional experiments revealed that neutrophils, through direct CD11b-ICAM1 interactions, activated the MAPK signaling pathway in TNBC cells, thereby enhancing tumor cell invasion and migration. Atorvastatin effectively inhibited ICAM1 expression in tumor cells, and tumor cells with ICAM1 knockout or treated with atorvastatin were unresponsive to neutrophil activation. The MAPK pathway and MMP9 expression were significantly inhibited in the tumor tissues of TNBC patients treated with atorvastatin. Conclusions: Targeting CD11b-ICAM1 with atorvastatin represented a potential clinical approach to reduce the malignant characteristics of TNBC. [ABSTRACT FROM AUTHOR]

Purpose: Uveal melanoma (UM) with BAP1 inactivating mutations has a high risk of metastasis, but the mechanism behind BAP1 deficiency driving UM metastasis is unknown. Methods: We analyzed the single-cell RNA sequencing (scRNA-Seq) data comprised primary and metastatic UM with or without BAP1 mutations (MUTs) to reveal inter- and intra-tumor heterogeneity among different groups. Then, an immune-competent mouse liver metastatic model was used to explore the role of ITGB2-ICAM1 in BAP1-associated UM metastasis. Results: Cluster 1 tumor cells expressed high levels of genes linked to tumor metastasis, such as GDF15, ATF3, and CDKN1A, all of which are associated with poor prognosis. The strength of communication between terminally exhausted CD8+ T cells and GDF15hiATF3hiCDKN1Ahi tumor cells was enhanced in BAP1-mutated UM, with CellChat analysis predicting strong ITGB2-ICAM1 signaling between them. High expression of either ITGB2 or ICAM1 was a worse prognostic indicator. Using an immune-competent mouse liver metastatic model, we indicated that inhibiting either ICAM1 or ITGB2 prevented liver metastasis in the BAP1-mutated group in vivo. The inhibitors primarily inhibited hypoxia- and ECM-related pathways indicated by changes in the expression of genes such as ADAM8, CAV2, ENO1, PGK1, LOXL2, ITGA5, and VCAN. etc. Conclusion: This study suggested that the ITGB2-ICAM1 axis may play a crucial role for BAP1-associated UM metastasis by preserving hypoxia- and ECM- related signatures, which provide a potential strategy for preventing UM metastasis in patients with BAP1 mutation. [ABSTRACT FROM AUTHOR]

Background: Endothelial cell dysfunction and microcirculatory disturbances play crucial roles in the pathogenesis of sepsis. This systematic review and meta-analysis explored the relationship of the plasma levels of the key endothelial proteins intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) with clinical outcomes in patients with sepsis. Methods: MEDLINE and EMBASE were searched through November 28, 2023. ICAM1 and VCAM1 levels and patient outcomes were evaluated. The primary outcome was the relationship of sepsis with ICAM1 or VCAM1. The secondary outcomes were the relationships of septic shock and multiple-organ dysfunction syndrome (MODS) with ICAM1 and VCAM1. Variables were compared using standardized mean differences (SMDs) with 95 % confidence intervals (CIs). Results: Forty-one studies were included. ICAM1 (SMD = 1.12, 95 % CI = 0.67, 1.57; P

Sturge-Weber syndrome (SWS), a neurocutaneous disorder, is characterized by capillary malformations (CM) in the skin, brain, and eyes. Patients may suffer from seizures, strokes, and glaucoma, and only symptomatic treatment is available. CM are comprised of enlarged vessels with endothelial cells (ECs) and disorganized mural cells. Our recent finding indicated that the R183Q mutation in ECs leads to heightened signaling through phospholipase Cβ3 and protein kinase C, leading to increased angiopoietin-2 (ANGPT2). Furthermore, knockdown of ANGPT2, a crucial mediator of pro-angiogenic signaling, inflammation, and vascular remodeling, in EC-R183Q rescued the enlarged vessel phenotype in vivo. This prompted us to look closer at the microenvironment in CM-affected vascular beds. We analyzed multiple brain histological sections from patients with GNAQ-R183Q CM and found enlarged vessels devoid of mural cells along with increased macrophage-like cells co-expressing MRC1 (CD206, a mannose receptor), CD163 (a scavenger receptor and marker of the monocyte/macrophage lineage), CD68 (a pan macrophage marker), and LYVE1 (a lymphatic marker expressed by some macrophages). These macrophages were not found in non-SWS control brain sections. To investigate the mechanism of increased macrophages in the perivascular environment, we examined THP1 (monocytic/macrophage cell line) cell adhesion to EC-R183Q versus EC-WT under static and laminar flow conditions. First, we observed increased THP1 cell adhesion to EC-R183Q compared to EC-WT under static conditions. Next, using live cell imaging, we found THP1 cell adhesion to EC-R183Q was dramatically increased under laminar flow conditions and could be inhibited by anti-ICAM1. ICAM1, an endothelial cell adhesion molecule required for leukocyte adhesion, was strongly expressed in the endothelium in SWS brain histological sections, suggesting a mechanism for recruitment of macrophages. In conclusion, our findings demonstrate that macrophages are an important component of the perivascular environment in CM suggesting they may contribute to the CM formation and SWS disease progression. [ABSTRACT FROM AUTHOR]

Abstract Therapeutic benefits and underlying biomechanism(s) of antibody drug conjugates (ADC) in combination with other targeted therapeutics are largely unknown. Here, the synergy between ADC and epigenetic drug decitabine (DAC), a clinically approved DNA methylation inhibitor, in multiple preclinical models of melanoma specifically investigated. Mechanistically, the underlying biomechanisms of how DAC cooperatively worked with ICAM1 antibody conjugated DNA topoisomerase I inhibitor DXd (I1‐DXd) is elucidated. DAC treatment significantly enhanced anti‐tumor efficacy of I1‐DXd by upregulating antigen expression, enhancing antibody internalization and potentiating tumor sensitivity by epigenetically reprogramming of melanoma. Meanwhile, I1‐DXd/DAC combination also exerted regulatory effects on tumor microenvironment (TME) by enhancing tumor infiltration of innate and adaptive immune cells and improving penetration of ADCs with a boosted antitumor immunity. This study provides a rational ADC combination strategy for solid tumor treatment.

Doxorubicin (Dox) is an anti-tumor drug with a broad spectrum, whereas the cardiotoxicity limits its further application. In clinical settings, liposome delivery vehicles are used to reduce Dox cardiotoxicity. Here, we substitute extracellular vesicles (EVs) for liposomes and deeply investigate the mechanism for EV-encapsulated Dox delivery. The results demonstrate that EVs dramatically increase import efficiency and anti-tumor effects of Dox in vitro and in vivo, and the efficiency increase benefits from its unique entry pattern. Dox-loading EVs repeat a “kiss-and-run” motion before EVs internalization. Once EVs touch the cell membrane, Dox disassociates from EVs and directly enters the cytoplasm, leading to higher and faster Dox import than single Dox. This unique entry pattern makes the adhesion between EVs and cell membrane rather than the total amount of EV internalization the key factor for regulating the Dox import. Furthermore, we recognize ICAM1 as the molecule mediating the adhesion between EVs and cell membranes. Interestingly, EV-encapsulated Dox can induce ICAM1 expression by irritating IFN-γ and TNF-α secretion in TME, thereby increasing tumor targeting of Dox-loading EVs. Altogether, EVs and EV-encapsulated Dox synergize via ICAM1, which collectively enhances the curative effects for tumor treatment.

Abstract Background Beef marbling is considered a desirable trait in the meat industry. Therefore, understanding the genetic factors that cause marbling is important. Previously, we performed a genome-wide association study to examine genetic factors associated with beef marbling in Japanese Black cattle and identified a candidate region between 10–30 Mbp on chromosome 7. We verified the effect of the SNPs in this region on beef marbling using linkage disequilibrium block analysis. We narrowed down the candidate region to a range of 15.8–16.1 Mbp. In this study, we comprehensively detected all of the SNPs in this region and verified their effects on beef marbling. Results Genome resequencing using four animals exhibiting high beef marbling standard (BMS) and four with low BMS revealed a total of 1,846 polymorphisms within the candidate region. Based on the annotation, we selected 13 SNPs exhibiting a moderate impact, as no high-impact SNPs were detected. All of the SNPs represented missense polymorphisms and were located in the following seven genes: RDH8, ANGPTL6, DNMT1, MRPL4, ICAM1, ICAM3, and ICAM5. Finally, we determined the effects of these SNPs on the BMS of a Japanese Black cattle population (n = 529). Analysis of variance revealed that the five SNPs were located in genes encoding the intercellular adhesion molecules (ICAM1, ICAM3, and ICAM5), and showed a highly significant association compared with the remainder (p A (p = 1.18E-04). Previous studies have suggested that intercellular adhesion molecules (ICAM) may be an upstream factor that regulates adipocyte differentiation. Therefore, considering the polymorphism and putative gene function, we suggest that ICAM1 is potentially responsible for beef marbling. c.470C > G and/or c.994G > A on ICAM1 may be responsible for this quantitative trait locus. Conclusions Promising SNP candidates responsible for beef marbling were identified using extensive polymorphism verification in a previously reported QTL region. We aim to elucidate the mechanism of beef marbling in future studies by investigating how these polymorphisms alter protein structure and function.

Background: Beef marbling is considered a desirable trait in the meat industry. Therefore, understanding the genetic factors that cause marbling is important. Previously, we performed a genome-wide association study to examine genetic factors associated with beef marbling in Japanese Black cattle and identified a candidate region between 10–30 Mbp on chromosome 7. We verified the effect of the SNPs in this region on beef marbling using linkage disequilibrium block analysis. We narrowed down the candidate region to a range of 15.8–16.1 Mbp. In this study, we comprehensively detected all of the SNPs in this region and verified their effects on beef marbling. Results: Genome resequencing using four animals exhibiting high beef marbling standard (BMS) and four with low BMS revealed a total of 1,846 polymorphisms within the candidate region. Based on the annotation, we selected 13 SNPs exhibiting a moderate impact, as no high-impact SNPs were detected. All of the SNPs represented missense polymorphisms and were located in the following seven genes: RDH8, ANGPTL6, DNMT1, MRPL4, ICAM1, ICAM3, and ICAM5. Finally, we determined the effects of these SNPs on the BMS of a Japanese Black cattle population (n = 529). Analysis of variance revealed that the five SNPs were located in genes encoding the intercellular adhesion molecules (ICAM1, ICAM3, and ICAM5), and showed a highly significant association compared with the remainder (p < 0.01). The lowest p-value was observed for ICAM3_c.739G > A (p = 1.18E-04). Previous studies have suggested that intercellular adhesion molecules (ICAM) may be an upstream factor that regulates adipocyte differentiation. Therefore, considering the polymorphism and putative gene function, we suggest that ICAM1 is potentially responsible for beef marbling. c.470C > G and/or c.994G > A on ICAM1 may be responsible for this quantitative trait locus. Conclusions: Promising SNP candidates responsible for beef marbling were identified using extensive polymorphism verification in a previously reported QTL region. We aim to elucidate the mechanism of beef marbling in future studies by investigating how these polymorphisms alter protein structure and function. [ABSTRACT FROM AUTHOR]

Background: Treating triple-negative breast cancer (TNBC) is a difficult landscape owing to its short survival times and high risk of metastasis and recurrence among patients. Although involved in tumor invasion and metastasis, the mechanism of action of intercellular adhesion molecule 1 (ICAM1), a trans-membrane glycoprotein, in TNBC is ambiguous. Methods: We examined ICAM1's role in TNBC, focusing on its expression, cell survival, mutation, and tumor immunity. Then, a risk score model was created utilizing co-expressed genes associated with ICAM1. According to their respective risk scores, we divided patients into high- and low-risk groups. Immune function, drug susceptibility differences, and somatic variants were analyzed in the high-and low-risk groups. And we used the CMap database to predict potential medications. Then, TNBC cells with low expression of ICAM-1 were co-cultured with PMA-treated THP-1 cells and CD8 T cells. In addition, We detected the expression of PD-1 and CTLA4 of low ICAM-1 expressing TNBC cells when they were cocultured with CD8 T cells. Results: ICAM1 was found to be involved in leukocyte cell adhesion, motility, and immune activation. Patients with low-ICAM1 group had shorter disease-free survival (DFS) than those with high-ICAM1 group. The group with elevated levels of ICAM1 exhibited significantly increased levels of T-cell regulation, quiescence in natural killer (NK) cells, and M1 macrophage. ICAM1 expression was correlated with immune checkpoint drugs. The prognostic ability of the risk score model was found to be superior to that of individual genes. Patients categorized as high-risk exhibited elevated clinical stages, showed higher M1 macrophage numbers, and were able to benefit better from immunotherapy. Individuals belonging to the high-risk group exhibit significantly elevated mutation rates in TP53, TTN, and SYNE1 genes, along with increased TMB and PD-L1 levels and decreased TIDE scores. These findings suggest that immunotherapy may be advantageous for the high-risk group. Furthermore, low expression of ICAM1 was found to promote polarization to M2 macrophages along with T-cell exhaustion. Conclusion: In conclusion, Low ICAM1 expression may be related to immune escape, leading to poor treatment response and a worse prognosis. [ABSTRACT FROM AUTHOR]

People intake metals from their environment. This study investigated type 2 diabetes mellitus (T2DM) related to internal exposure to metals and attempted to identify possible biomarkers. A total of 734 Chinese adults were enrolled, and urinary levels of ten metals were measured. Multinomial logistic regression model was used to assess the association between metals and impaired fasting glucose (IFG) and T2DM. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction were used to explore the pathogenesis of T2DM related to metals. After adjustment, lead (Pb) was positively associated with IFG (odds ratio [OR] 1.31, 95% confidence interval [CI] 1.06–1.61) and T2DM (OR 1.41, 95% CI 1.01–1.98), but cobalt was negatively associated with IFG (OR 0.57, 95% CI 0.34–0.95). Transcriptome analysis showed 69 target genes involved in the Pb-target network of T2DM. GO enrichment indicated that the target genes are enriched mainly in the biological process category. KEGG enrichment indicated that Pb exposure leads to non-alcoholic fatty liver disease, lipid and atherosclerosis, and insulin resistance. Moreover, there is alteration of four key pathways, and six algorithms were used to identify 12 possible genes in T2DM related to Pb. SOD2 and ICAM1 show strong similarity in expression, suggesting a functional correlation between these key genes. This study reveals that SOD2 and ICAM1 may be potential targets of Pb exposure-induced T2DM and provides novel insight into the biological effects and underlying mechanism of T2DM related to internal exposure to metals in the Chinese population. [ABSTRACT FROM AUTHOR]

Background & aimsEosinophilic esophagitis (EoE) is an antigen-mediated eosinophilic disease of the esophagus that involves fibroblast activation and progression to fibrostenosis. Cytokines produced by T-helper type 2 cells and transforming growth factor beta 1 (TGFβ1) contribute to the development of EoE, but other cytokines involved in pathogenesis are unknown. We investigate the effects of tumor necrosis factor superfamily member 14 (TNFSF14, also called LIGHT) on fibroblasts in EoE.MethodsWe analyzed publicly available esophageal CD3+ T-cell single-cell sequencing data for expression of LIGHT. Esophageal tissues were obtained from pediatric patients with EoE or control individuals and analyzed by immunostaining. Human primary esophageal fibroblasts were isolated from esophageal biopsy samples of healthy donors or patients with active EoE. Fibroblasts were cultured; incubated with TGFβ1 and/or LIGHT; and analyzed by RNA sequencing, flow cytometry, immunoblots, immunofluorescence, or reverse transcription polymerase chain reaction. Eosinophils were purified from peripheral blood of healthy donors, incubated with interleukin 5, cocultured with fibroblasts, and analyzed by immunohistochemistry.ResultsLIGHT was up-regulated in the esophageal tissues from patients with EoE, compared with control individuals, and expressed by several T-cell populations, including T-helper type 2 cells. TNF receptor superfamily member 14 (TNFRSF14, also called HVEM) and lymphotoxin beta receptor are receptors for LIGHT that were expressed by fibroblasts from healthy donors or patients with active EoE. Stimulation of esophageal fibroblasts with LIGHT induced inflammatory gene transcription, whereas stimulation with TGFβ1 induced transcription of genes associated with a myofibroblast phenotype. Stimulation of fibroblasts with TGFβ1 increased expression of HVEM; subsequent stimulation with LIGHT resulted in their differentiation into cells that express markers of myofibroblasts and inflammatory chemokines and cytokines. Eosinophils tethered to esophageal fibroblasts after LIGHT stimulation via intercellular adhesion molecule-1.ConclusionsT cells in esophageal tissues from patients with EoE express increased levels of LIGHT compared with control individuals, which induces differentiation of fibroblasts into cells with inflammatory characteristics. TGFβ1 increases fibroblast expression of HVEM, a receptor for LIGHT. LIGHT mediates interactions between esophageal fibroblasts and eosinophils via ICAM1. This pathway might be targeted for the treatment of EoE.

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus does not only lead to pulmonary infection but can also infect other organs such as the gut, the kidney, or the liver. Recent studies confirmed that severe cases of COVID-19 are often associated with liver damage and liver failure, as well as the systemic upregulation of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFa). However, the impact these immune mediators in the liver have on patient survival during SARS-CoV-2 infection is currently unknown. Here, by performing a post-mortem analysis of 45 patients that died from a SARS-CoV-2 infection, we find that an increased expression of TNFA in the liver is associated with elevated mortality. Using publicly available single-cell sequencing datasets, we determined that Kupffer cells and monocytes are the main sources of this TNFa production. Further analysis revealed that TNFa signaling led to the upregulation of pro-inflammatory genes that are associated with an unfavorable outcome. Moreover, high levels of TNFA in the liver were associated with lower levels of interferon alpha and interferon beta. Thus, TNFa signaling in the infected SARS-CoV-2 liver correlates with reduced interferon levels and overall survival time. [ABSTRACT FROM AUTHOR]

Exosomes, which are nanosized extracellular vesicles, have emerged as crucial mediators of the crosstalk between tumor cells and the immune system. Intercellular adhesion molecule 1 (ICAM1) plays a crucial role in multiple immune functions as well as in the occurrence, development and metastasis of cancer. As a glycoprotein expressed on the cell membrane, ICAM1 is secreted extracellularly on exosomes and regulates the immunosuppressive microenvironment. However, the role of exosomal ICAM1 in the immune microenvironment of breast cancer bone metastases remains unclear. This study aimed to elucidated the role of exosomal ICAM1 in facilitating CD8+ T cell exhaustion and subsequent bone metastasis in triple-negative breast cancer (TNBC). We demonstrated that TNBC cells release ICAM1-enriched exosomes, and the binding of ICAM1 to its receptor is necessary for the suppressive effect of CD8 T cell proliferation and function. This pivotal engagement not only inhibits CD8+ T cell proliferation and activation but also initiates the development of an immunosuppressive microenvironment that is conducive to TNBC tumor growth and bone metastasis. Moreover, ICAM1 blockade significantly impairs the ability of tumor exosomes to bind to CD8+ T cells, thereby inhibiting their immunosuppressive effects. The present study elucidates the complex interaction between primary tumors and the immune system that is mediated by exosomes and provides a foundation for the development of novel cancer immunotherapies that target ICAM1 with the aim of mitigating TNBC bone metastasis. [Display omitted] [ABSTRACT FROM AUTHOR]

Despite aggressive treatment, the recurrence of glioma is an inevitable occurrence, leading to unsatisfactory clinical outcomes. A plausible explanation for this phenomenon is the phenotypic alterations that glioma cells undergo aggressive therapies, such as TMZ-therapy. However, the underlying mechanisms behind these changes are not well understood. The TMZ chemotherapy resistance model was employed to assess the expression of intercellular adhesion molecule-1 (ICAM1) in both in vitro and in vivo settings. The potential role of ICAM1 in regulating TMZ chemotherapy resistance was investigated through knockout and overexpression techniques. Furthermore, the mechanism underlying ICAM1-mediated TMZ chemotherapy resistance was examined using diverse molecular biological methods, and the lipid raft protein was subsequently isolated to investigate the cellular subcomponents where ICAM1 operates. Acquired TMZ resistant (TMZ-R) glioma models heightened production of intercellular adhesion molecule-1 (ICAM1) in TMZ-R glioma cells. Additionally, we observed a significant suppression of TMZ-R glioma proliferation upon inhibition of ICAM1, which was attributed to the enhanced intracellular accumulation of TMZ. Our findings provide evidence supporting the role of ICAM1, a proinflammatory marker, in promoting the expression of ABCB1 on the cell membrane of TMZ-resistant cells. We have elucidated the mechanistic pathway by which ICAM1 modulates phosphorylated moesin, leading to an increase in ABCB1 expression on the membrane. Furthermore, our research has revealed that the regulation of moesin by ICAM1 was instrumental in facilitating the assembly of ABCB1 exclusively on the lipid raft of the membrane. Our findings suggest that ICAM1 is an important mediator in TMZ-resistant gliomas and targeting ICAM1 may provide a new strategy for enhancing the efficacy of TMZ therapy against glioma. [ABSTRACT FROM AUTHOR]

Recurrent pregnancy loss (RPL) remains an unsolved problem in obstetrics and gynecology, and up to 50% of RPL cases are unexplained. Unexplained RPL (uRPL) is widely considered to be related to an aberrant endometrial microenvironment. BMP2 is an important factor involved in endometrial decidualization and embryo implantation, and intercellular adhesion molecule 1 (ICAM1) is a critical inflammatory regulator in the endometrium. In this study, we found that endometrial samples obtained from Unexplained RPL patients have significantly lower BMP2 and higher ICAM1 levels than fertile controls. For further research on the relationship between BMP2 and ICAM1 and the potential molecular mechanisms in Unexplained RPL, immortalized human endometrial stromal cells (HESCs) and primary human decidual stromal cells (HDSCs) were used as study models. Our results showed that BMP2 significantly decreased ICAM1 expression by upregulating DNA-binding protein inhibitor 3 (ID3) in both HESCs and HDSCs. Using kinase receptor inhibitors (dorsomorphin homolog 1 (DMH-1) and dorsomorphin) and siRNA transfection, it has been found that the upregulation of ID3 and the following downregulation of ICAM1 induced by BMP2 is regulated through the ALK3-SMAD4 signaling pathway. This research gives a hint of a novel mechanism by which BMP2 regulates ICAM1 in the human endometrium, which provides insights into potential therapeutics for unexplained RPL.

Metastasis is the leading cause of death for colorectal cancer (CRC) patients, and the spreading tumor cells adhesion to endothelial cells is a critical step for extravasation and further distant metastasis. Previous studies have documented the important roles of gut microbiota-host interactions in the CRC malignancy, and Fusobacterium nucleatum (F. nucleatum) was reported to increase proliferation and invasive activities of CRC cells. However, the potential functions and underlying mechanisms of F. nucleatum in the interactions between CRC cells and endothelial cells and subsequent extravasation remain unclear. Here, we uncovered that F. nucleatum enhanced the adhesion of CRC cells to endothelial cells, promoted extravasation and metastasis by inducing ICAM1 expression. Mechanistically, we identified that F. nucleatum induced a new pattern recognition receptor ALPK1 to activate NF-κB pathway, resulting in the upregulation of ICAM1. Interestingly, the abundance of F. nucleatum in tumor tissues of CRC patients was positively associated with the expression levels of ALPK1 and ICAM1. Moreover, high expression of ALPK1 or ICAM1 was significantly associated with a shorter overall survival time of CRC patients. This study provides a new insight into the role of gut microbiota in engaging into the distant metastasis of CRC cells.

Human rhinoviruses (HRVs) are small non-enveloped RNA viruses that belong to the Enterovirus genus within the Picornaviridae family and are known for causing the common cold. Though symptoms are generally mild in healthy individuals, the economic burden associated with HRV infection is significant. A vaccine could prevent disease. The Vero-cell-based viral vaccine platform technology was considered for such vaccine development. Unfortunately, most HRV strains are unable to propagate on Vero cells due to a lack of the major receptor of HRV group A and B, intercellular adhesion molecule (ICAM1, also known as CD54). Therefore, stable human ICAM1 expressing Vero cell clones were generated by transfecting the ICAM1 gene in Vero cells and selecting clones that overexpressed ICAM1 on the cell surface. Cell banks were made and expression of ICAM1 was stable for at least 30 passages. The Vero_ICAM1 cells and parental Vero cells were infected with four HRV prototypes, B14, A16, B37 and A57. Replication of all four viruses was detected in Vero_ICAM1, but not in the parental Vero cells. Altogether, Vero cells expressing ICAM1 could efficiently propagate the tested HRV strains. Therefore, ICAM1-expressing cells could be a useful tool for the development and future production of polyvalent HRV vaccines or other viruses that use ICAM1 as a receptor. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) are critical regulators of inflammation with great potential as new therapeutic targets. However, the role of lncRNAs in early atherosclerosis remains poorly characterized. This study aimed to identify the key lncRNA players in activated endothelial cells (ECs). The lncRNAs in response to pro-inflammatory factors in ECs were screened through RNA sequencing. ICAM-1-related non-coding RNA (ICR) was identified as the most potential candidate for early atherosclerosis. ICR is essential for intercellular adhesion molecule-1 (ICAM1) expression, EC adhesion and migration. In a high fat diet-induced atherosclerosis model in mice, ICR is upregulated in the development of atherosclerosis. After intravenous injection of adenovirus carrying shRNA for mouse ICR, the atherosclerotic plaque area was markedly reduced with the declined expression of ICR and ICAM1. Mechanistically, ICR stabilized the mRNA of ICAM1 in quiescent ECs; while under inflammatory stress, ICR upregulated ICAM1 in a nuclear factor kappa B (NF-κB) dependent manner. RNA-seq analysis showed pro-inflammatory targets of NF-κB were regulated by ICR. Furthermore, the chromatin immunoprecipitation assays showed that p65 binds to ICR promoter and facilitates its transcription. Interestingly, ICR, in turn, promotes p65 accumulation and activity, forming a positive feedback loop to amplify NF-κB signaling. Preventing the degradation of p65 using proteasome inhibitors rescued the expression of NF-κB targets suppressed by ICR. Taken together, ICR acts as an accelerator to amplify NF-κB signaling in activated ECs and suppressing ICR is a promising early intervention for atherosclerosis through ICR/p65 loop blockade. [Display omitted] • ICAM-1-related non-coding RNA (ICR) in endothelial cells (ECs) is a novel intervention target for early atherosclerosis. • lncRNA ICR regulates ICAM1 through distinct mechanisms in the quiescent and activated ECs. • ICR mediates the regulation of multiple inflammatory factors in activated ECs as a direct target of NF-κB. • ICR forms a positive feedback loop with p65 to amplify NF-κB signaling. [ABSTRACT FROM AUTHOR]

BackgroundRARRES1 is a tumor suppressor protein, and its expression is suppressed in various tumor cells. However, whether it participates in the immune response in kidney renal clear cell carcinoma (KIRC) is unknown, and the defined mechanism is not clear. Therefore, the mechanism of RARRES1 in KIRC is worthy of investigation.MethodsWe analysed the expression and function of RARRES1 with The Cancer Genome Atlas (TCGA) database. The Kaplan–Meier curve was adopted to estimate survival. RARRES1-correlated genes were obtained from the UALCAN database and subjected to Gene Ontology (GO) enrichment and protein–protein interaction (PPI) network analyses. The correlation analysis between tumor-infiltrating immune cells and selected genes were performed with TIMER database. We also investigated the possible function of RARRES1 in KIRC by coculturing Caki-1 cells with THP-1 cells. Immunofluorescence assay was performed to study the RARRES1 expression in difference grade KIRC tissues.ResultsThe expression of RARRES1 was negatively correlated with survival in KIRC patients. The GO biological process term most significantly enriched with the RARRES1-correlated genes was regulation of cell adhesion. ICAM1, which exhibited a relatively highest correlation with RARRES1, is positively correlated with the infiltration level of macrophages. RARRES1 could enhance the expression of ICAM1 in Caki-1 cells and then induce the activation of M1 THP-1 cells to decrease the viability and induce the apoptosis of Caki-1 cells.ConclusionRARRES1 plays an antitumor role by promoting ICAM1 expression and inducing the activation of M1 macrophages. We offer insights into the molecular mechanism of KIRC and reveal a potential therapeutic target.

In our previous study, we used genome resequencing to detect all candidate polymorphisms within a quantitative trait loci (QTL) region for beef marbling reported previously at 10–30 Mbp on bovine chromosome 7, and we selected 6044 polymorphisms as candidate quantitative trait nucleotides (QTNs). In the present study, we aimed to identify quantitative trait genes (QTGs) and QTNs in this QTL region by verifying the effect of SNPs on beef marbling in two Japanese Black cattle populations using a Dynamic Array integrated fluidic circuit. In total, 96 selected SNPs were genotyped in 441 and 529 animals in Hyogo and Miyazaki cattle populations, respectively. The most significant p-values were detected in a SNP in a splice region of ALDH7A1 (SNP93_ALDH7A1; p = 3.46 × 10−5) in Hyogo cattle and a missense polymorphism of intercellular adhesion molecule-1 (ICAM1) (SNP37_ICAM1; p = 3.33 × 10−4) in Miyazaki cattle. Interestingly, SNP93_ALDH7A1 was not significant (p = 0.459) in Miyazaki cattle, and SNP37_ICAM1 showed a weakly significant association (p = 0.043) in Hyogo cattle. Thus, each population would likely have different QTGs and QTNs for beef marbling in the QTL region. In the Hyogo population, it was not possible to determine the accurate range of the linkage disequilibrium (LD) block in LD block analysis because of a strong LD structure throughout the assessed region. In Miyazaki cattle, however, an LD block containing SNP37_ICAM1 had a range of 15.8–16.1 Mbp, suggesting that QTNs would be located within this region. The functions of 19 genes in the LD block were investigated. ICAM1 is known to play an important role in adipocyte differentiation; given this function and the effect of amino acid substitution, SNP37_ICAM1 was identified as a promising candidate QTN for beef marbling. Further research on the effect of SNP37_ICAM1 on adipocyte differentiation is expected to provide insights into the mechanism underlying beef marbling formation. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) is a major health concern and can be devastating, especially for the elderly. It causes a systemic inflammatory response, involving dysregulation and misexpression of many inflammatory cytokines. Objectives: To assess the cytokine profile in COVID-19 patients and detect its relation with disease severity. Patients and methods: This study included 50 COVID-19 patients confirmed by reverse transcription–polymerase chain reaction (RT-PCR), of whom 20 with severe pneumonia, 20 with moderate and 10 with mild disease, and 50 healthy control. Quantitative ELISA tests were performed for tumour necrosis factor alfa (TNF-α) and intercellular adhesion molecule1 (ICAM-1). Results: Level of ICAM-1 is higher in cases of COVID-19 than healthy controls (median for cases = 420 ng/ml). Also TNF-α level is higher in cases with a median of 165 both levels were higher in CORADS 6 and positively correlated with CT findings. Conclusion: Patients with severe COVID-19 might have a cytokine storm syndrome and increased expression of endothelial cell adhesion molecules as ICAM-1, which is related to COVID-19 and disease severity and may contribute to coagulation dysfunction. Levels of ICAM 1 were associated with more severe CT findings and longer hospital stay, also ICAM 1 and TNF can be used as diagnostic measures as they have a higher sensitivity specificity and predictive values. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum, the deadliest form of human malaria, remains one of the major threats to human health in endemic regions. Its virulence is attributed to its ability to modify infected red blood cells (iRBC) to adhere to endothelial receptors by placing variable antigens known as PfEMP1 on the iRBC surface. PfEMP1 expression determines the cytoadhesive properties of the iRBCs and is implicated in severe malaria. To evade antibody‐mediated responses, the parasite undergoes continuous switches of expression between different PfEMP1 variants. Recently, it became clear that in addition to antibody‐mediated responses, PfEMP1 triggers innate immune responses; however, the role of neutrophils, the most abundant white blood cells in the human circulation, in malaria remains elusive. Here, we show that neutrophils recognize and kill blood‐stage P. falciparum isolates. We identify neutrophil ICAM‐1 and specific PfEMP1 implicated in cerebral malaria as the key molecules involved in this killing. Our data provide mechanistic insight into the interactions between neutrophils and iRBCs and demonstrate the important influence of PfEMP1 on the selective innate response to cerebral malaria. SYNOPSIS: As first line of defense against severe malaria, neutrophils recognize specific PfEMP1 molecules on the infected erythrocyte via ICAM‐1. This ligand‐receptor interaction leads to efficient killing of Plasmodium falciparum parasites associated with cerebral malaria. Neutrophils kill blood stage P. falciparum by phagocytosis of infected erythrocytes and targeted oxidative burst.Neutrophil's ICAM‐1 and parasite's PfEMP1 are important mediators of neutrophil interactions with infected erythrocytes.Neutrophils impose strong selective pressure against parasites expressing PfEMP1. [ABSTRACT FROM AUTHOR]

Background: The high social significance of cervical cancer, the shortcomings of the performed cervical screening is prerequisites for research in the field of mproving the diagnosis of this disease. We hypothesized that the systemic level of some inflammatory proteins could be used as a diagnostic criterion for cervical cancer.The aim of the study was to study the level of some vascular-inflammatory markers in the blood serum in patients with precancerous diseases and cervical cancer in order to improve their diagnosis and also to identify markers for predicting an unfavorable outcome in patients with cervical cancer.Materials and methods. A non-randomized prospective controlled study was carried out, the participants of which were patients with the diagnosis of cervical cancer (n = 49) and cervical intraepithelial neoplasia of the III degree (n = 13). The control group included 15 relatively healthy women. The following spectrum of inflammatory proteins was determined in blood serum by flow cytometry using the Human Vascular Inflammation Panel 1: myoglobin, calprotectin, lipocalin A, matrix metal peroxidase 2, osteopontin, myeloperoxidase, serum amyloid A, protein 4, which binds insulin-like growth factor cell-cell adhesion 1, vascular cell adhesion molecule, matrix metalloperoxidase 9, cystatin C. Statistical analysis was carried out by calculating the Mann-Whitney test with Bonferroni’s correction. The model was created using binary logistic regression to diagnose cervical cancer.Results. In the intergroup comparison of the protein`s spectrum in the blood serum, no significant differences were obtained. However, using the binary logistic regression method, an equation was drawn up to calculate the diagnostic coefficient of cervical cancer, which allows diagnosing cervical cancer with an accuracy of 82%, and in terms of information content is not inferior to cytological diagnostics. The developed coefficient can be used to predict an unfavorable outcome of cervical cancer after 1 year from the moment of diagnosis. Conclusion. The developed diagnostic coefficient makes it possible to diagnose cervical cancer with high accuracy and can be used to predict cervical cancer.

Doxorubicin (Dox) is an anti-tumor drug with a broad spectrum, whereas the cardiotoxicity limits its further application. In clinical settings, liposome delivery vehicles are used to reduce Dox cardiotoxicity. Here, we substitute extracellular vesicles (EVs) for liposomes and deeply investigate the mechanism for EV-encapsulated Dox delivery. The results demonstrate that EVs dramatically increase import efficiency and anti-tumor effects of Dox in vitro and in vivo , and the efficiency increase benefits from its unique entry pattern. Dox-loading EVs repeat a "kiss-and-run" motion before EVs internalization. Once EVs touch the cell membrane, Dox disassociates from EVs and directly enters the cytoplasm, leading to higher and faster Dox import than single Dox. This unique entry pattern makes the adhesion between EVs and cell membrane rather than the total amount of EV internalization the key factor for regulating the Dox import. Furthermore, we recognize ICAM1 as the molecule mediating the adhesion between EVs and cell membranes. Interestingly, EV-encapsulated Dox can induce ICAM1 expression by irritating IFN-γ and TNF-α secretion in TME, thereby increasing tumor targeting of Dox-loading EVs. Altogether, EVs and EV-encapsulated Dox synergize via ICAM1, which collectively enhances the curative effects for tumor treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Plasmodium falciparum variant surface antigens (VSAs) contribute to malaria pathogenesis by mediating cytoadhesion of infected red blood cells to the microvasculature endothelium. In this study, we investigated the association between anti-VSA antibodies and clinical outcome in a controlled human malaria infection (CHMI) study. Method: We used flow cytometry and ELISA to measure levels of IgG antibodies to VSAs of five heterologous and one homologous P. falciparum parasite isolates, and to two PfEMP1 DBLβ domains in blood samples collected a day before the challenge and 14 days after infection. We also measured the ability of an individual's plasma to inhibit the interaction between PfEMP1 and ICAM1 using competition ELISA. We then assessed the association between the antibody levels, function, and CHMI defined clinical outcome during a 21-day follow-up period post infection using Cox proportional hazards regression. Results: Antibody levels to the individual isolate VSAs, or to two ICAM1-binding DBLβ domains of PfEMP1, were not associated with a significantly reduced risk of developing parasitemia or of meeting treatment criteria after the challenge after adjusting for exposure. However, anti-VSA antibody breadth (i.e., cumulative response to all the isolates) was a significant predictor of reduced risk of requiring treatment [HR 0.23 (0.10-0.50) p= 0.0002]. Conclusion: The breadth of IgG antibodies to VSAs, but not to individual isolate VSAs, is associated with protection in CHMI. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that circular RNA (circRNA) is implicated in the development of atherosclerosis (AS). This study investigated the effect of circ_0003204 on endothelial cell function and explored the functional mechanism of circ_0003204 in AS progression. AS cell models were constructed by treating human umbilical vein endothelial cells (HUVEC) with oxidized low-density lipoprotein (ox-LDL). The expression of circ_0003204 was detected by quantitative real-time PCR (qPCR). The releases of pro-inflammatory factors were determined by ELISA. Cell viability was checked by CCK-8 assay. Cell apoptosis was monitored by flow cytometry assay. The ability of angiogenesis was assessed by tube formation assay. The protein levels of cell development- and apoptosis-related markers were measured by western blot. The binding relationship between miR-491-5p and circ_0003204 or intercellular adhesion molecule 1 (ICAM1) was verified by dual-luciferase reporter assay or RIP assay. The expression of circ_0003204 was strengthened in ox-LDL-treated HUVECs. Circ_0003204 knockdown inhibited ox-LDL-induced inflammation and cell apoptosis, and promoted ox-LDL-depleted cell viability and tube formation ability in HUVECs. MiR-491-5p was a target of circ_0003204, and miR-491-5p directly bound to ICAM1 3′UTR. Accordingly, circ_0003204 positively regulated ICAM1 expression by targeting miR-491-5p. Rescue experiments presented that miR-491-5p inhibition reversed the effects of circ_0003204 knockdown, and ICAM1 overexpression abolished the effects of miR-491-5p restoration. Circ_0003204 knockdown protects HUVECs against ox-LDL-induced injuries by targeting the miR-491-5p-ICAM1 pathway, hinting that circ_0003204 inhibition might prevent AS development. [ABSTRACT FROM AUTHOR]

Songda Chen,1 Shan Pan,1 Huijie Wu,1 Jingyuan Zhou,1 Yueli Huang,1 Shuai Wang,2 Aiqun Liu1 1Department of Endoscopy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People’s Republic of China; 2Department of Colorectal Anal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People’s Republic of ChinaCorrespondence: Aiqun LiuDepartment of Endoscopy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People’s Republic of ChinaEmail liuaiqun_2004@163.comBackground: Gastric cancer (GC) is among the most common forms of cancer affecting the digestive system. This study sought to identify hub genes regulating early GC (EGC) in order to explore their potential for early diagnosis and prognosis of patients.Methods: We utilized a publically available dataset from the Gene Expression Omnibus database (GSE55696). Differences between EGC and LGIN with respect to gene expression were compared using the limma software. Identified differentially expressed genes (DEGs) were subjected to gene ontology (GO) and pathway enrichment analyses with the DAVID application, and the STRING website and Cytoscape software were used to construct a protein-protein interaction (PPI) network incorporating these DEGs. This network was in turn used to identify hub genes among selected DEGs, which were analyzed with the Kaplan-Meier Plotter database. In addition, Western blotting, qRT-PCR, immunohistochemistry, and UALCAN were all employed to validate the relationship between the expression of these genes and GC patient prognosis.Results: A total of 482 DEGs were identified, with GO analyses indicating an increase in the expression of genes linked with the development of cancer. Pathway analyses also indicated that these genes play a role in certain cancer-related pathways. The PPI network highlighted four potential hub genes, of which only ICAM1 was linked to a poor GC patient prognosis. This link between ICAM1 and GC patient outcomes was confirmed via UALCAN, Western blotting, immunohistochemistry, and qRT-PCR.Conclusion: ICAM1 may therefore modulate tumor progression in GC, thus potentially representing a valuable prognostic and diagnostic biomarker of EGC.Keywords: bioinformatics analysis, gastric cancer, early diagnosis, ICAM1, biomarker

Objective: The capacity to generate new adipocytes from precursor cells is critical for maintaining metabolic health. Adipocyte precursor cells (APCs) constitute a heterogenous collection of cell types; however, the contribution of these various cell types to adipose tissue expansion in vivo remains unknown. The aim of the current study is to investigate the contribution of Dpp4+ progenitors to de novo adipogenesis. Methods: Single cell analysis has identified several transcriptionally distinct subpopulations of APCs, including Dpp4+ progenitor cells concentrated in the connective tissue surrounding many organs, including white adipose tissue (WAT). Here, we generated a Dpp4CreER mouse model for in vivo lineage tracing of these cells and their downstream progeny in the setting of basal or high fat diet (HFD)-stimulated adipogenesis. Results: Dpp4CreER mice enabled specific temporal labeling of Dpp4+ progenitor cells within their native connective tissue niche. Following a dietary chase period consisting of chow or HFD feeding for 18 weeks, Dpp4+ progenitors differentiated into mature adipocytes within the gonadal and subcutaneous WAT. HFD stimulated adipogenic contribution from Dpp4+ cells in the gonadal but not the subcutaneous depot. Flow cytometry analysis revealed that Dpp4+ progenitors give rise to DPP4(−)/ICAM1+ preadipocytes in vivo. HFD feeding did not perturb the flux of Dpp4+ cell conversion into ICAM1+ preadipocytes in gonadal WAT. Conversely, in subcutaneous WAT, HFD feeding/obesity led to an accumulation of ICAM1+ preadipocytes without a corresponding increase in mature adipocyte differentiation. Examination of non-classical murine visceral depots with relevance to humans, including omentum and retroperitoneal WAT, revealed robust contribution of Dpp4+ progenitors to de novo adipogenesis, which was further stimulated by HFD. Conclusion: Our data demonstrate that Dpp4+ interstitial progenitor cells contribute to basal adipogenesis in all fat depots and are recruited to support de novo adipogenic expansion of visceral WAT in the setting of HFD-induced obesity.

Tumor-associated microglia/macrophages (TAMs) are the main innate immune effector cells in malignant gliomas and have both pro- and anti-tumor functions. The plasticity of TAMs is partially dictated by oncogenic mutations in tumor cells. Heterozygous IDH1 mutation is a cancer driver gene prevalent in grade II/III gliomas, and IDH1 mutant gliomas have relatively favorable clinical outcomes. It is largely unknown how IDH mutation alters TAM phenotypes to influence glioma growth. Here we established clinically relevant isogenic glioma models carrying monoallelic IDH1 R132H mutation (IDH1R132H/WT) and found that IDH1R132H/WT significantly downregulated immune response-related pathways in glioma cells, indicating an immunomodulation role of mutant IDH1. Co-culturing IDH1R132H/WT glioma cells with human macrophages promoted anti-tumor phenotypes of macrophages and increased macrophage migration and phagocytic capacity. In orthotopic xenografts, IDH1R132H/WT decreased tumor growth and prolonged animal survival, accompanied by increased TAM recruitment and upregulated phagocytosis markers, suggesting the induction of anti-tumor TAM functions. Using human cytokine arrays that query 36 proteins, we identified significant downregulation of ICAM-1/CD54 in IDH1R132H/WT gliomas, which was further confirmed by ELISA and immunoblotting analyses. ICAM1 gain-of-function studies revealed that ICAM1 downregulation in IDH1R132H/WT cells played a mechanistic role to mediate the immunomodulation function of IDH1R132H/WT. ICAM-1 silencing in IDH1 wild-type glioma cells decreased tumor growth and increased the anti-tumor function of TAMs. Together, our studies support a new TAM-mediated phagocytic function within IDH1 mutant gliomas, and improved understanding of this process may uncover novel approaches to targeting IDH1 wild type gliomas. [ABSTRACT FROM AUTHOR]

Human rhinoviruses (HRVs) are small non-enveloped RNA viruses that belong to the Enterovirus genus within the Picornaviridae family and are known for causing the common cold. Though symptoms are generally mild in healthy individuals, the economic burden associated with HRV infection is significant. A vaccine could prevent disease. The Vero-cell-based viral vaccine platform technology was considered for such vaccine development. Unfortunately, most HRV strains are unable to propagate on Vero cells due to a lack of the major receptor of HRV group A and B, intercellular adhesion molecule (ICAM1, also known as CD54). Therefore, stable human ICAM1 expressing Vero cell clones were generated by transfecting the ICAM1 gene in Vero cells and selecting clones that overexpressed ICAM1 on the cell surface. Cell banks were made and expression of ICAM1 was stable for at least 30 passages. The Vero_ICAM1 cells and parental Vero cells were infected with four HRV prototypes, B14, A16, B37 and A57. Replication of all four viruses was detected in Vero_ICAM1, but not in the parental Vero cells. Altogether, Vero cells expressing ICAM1 could efficiently propagate the tested HRV strains. Therefore, ICAM1-expressing cells could be a useful tool for the development and future production of polyvalent HRV vaccines or other viruses that use ICAM1 as a receptor.

Hepatocellular carcinoma (HCC) remains a devastating malignancy worldwide due to lack of effective therapy. The immune-rich contexture of HCC tumor microenvironment (TME) makes this tumor an appealing target for immune-based therapies; however, the immunosuppressive TME is still a major challenge for more efficient immunotherapy in HCC. Using bioinformatics analysis based on the TCGA database, here we found that MAPK10 is frequently down-regulated in HCC tumors and significantly correlates with poor survival of HCC patients. HCC patients with low MAPK10 expression have lower expression scores of tumor infiltration lymphocytes (TILs) and stromal cells in the TME and increased scores of tumor cells than those with high MAPK10 expression. Further transcriptomic analyses revealed that the immune activity in the TME of HCC was markedly reduced in the low-MAPK10 group of HCC patients compared to the high-MAPK10 group. Additionally, we identified 495 differentially expressed immune-associated genes (DIGs), with 482 genes down-regulated and 13 genes up-regulated in parallel with the decrease of MAPK10 expression. GO enrichment and KEGG pathway analyses indicated that the biological functions of these DIGs included cell chemotaxis, leukocyte migration and positive regulation of the response to cytokine–cytokine receptor interaction, T cell receptor activation and MAPK signaling pathway. Protein–protein interaction (PPI) analyses of the 495 DIGs revealed five potential downstream hub genes of MAPK10, including SYK, CBL, VAV1, LCK, and CD3G. Several hub genes such as SYK, LCK, and VAV1 could respond to the immunological costimulatory signaling mediated by the transmembrane protein ICAM1, which was identified as a down-regulated DIG associated with low-MAPK10 expression. Moreover, ectopic overexpression or knock-down of MAPK10 could up-regulate or down-regulate ICAM1 expression via phosphorylation of c-jun at Ser63 in HCC cell lines, respectively. Collectively, our results demonstrated that MAPK10 down-regulation likely contributes to the immunosuppressive TME of HCC, and this gene might serve as a potential immunotherapeutic target and a prognostic factor for HCC patients.

Hepatocellular carcinoma (HCC) remains a devastating malignancy worldwide due to lack of effective therapy. The immune-rich contexture of HCC tumor microenvironment (TME) makes this tumor an appealing target for immune-based therapies; however, the immunosuppressive TME is still a major challenge for more efficient immunotherapy in HCC. Using bioinformatics analysis based on the TCGA database, here we found that MAPK10 is frequently down-regulated in HCC tumors and significantly correlates with poor survival of HCC patients. HCC patients with low MAPK10 expression have lower expression scores of tumor infiltration lymphocytes (TILs) and stromal cells in the TME and increased scores of tumor cells than those with high MAPK10 expression. Further transcriptomic analyses revealed that the immune activity in the TME of HCC was markedly reduced in the low-MAPK10 group of HCC patients compared to the high-MAPK10 group. Additionally, we identified 495 differentially expressed immune-associated genes (DIGs), with 482 genes down-regulated and 13 genes up-regulated in parallel with the decrease of MAPK10 expression. GO enrichment and KEGG pathway analyses indicated that the biological functions of these DIGs included cell chemotaxis, leukocyte migration and positive regulation of the response to cytokine–cytokine receptor interaction, T cell receptor activation and MAPK signaling pathway. Protein–protein interaction (PPI) analyses of the 495 DIGs revealed five potential downstream hub genes of MAPK10, including SYK, CBL, VAV1, LCK, and CD3G. Several hub genes such as SYK, LCK, and VAV1 could respond to the immunological costimulatory signaling mediated by the transmembrane protein ICAM1, which was identified as a down-regulated DIG associated with low-MAPK10 expression. Moreover, ectopic overexpression or knock-down of MAPK10 could up-regulate or down-regulate ICAM1 expression via phosphorylation of c-jun at Ser63 in HCC cell lines, respectively. Collectively, our results demonstrated that MAPK10 down-regulation likely contributes to the immunosuppressive TME of HCC, and this gene might serve as a potential immunotherapeutic target and a prognostic factor for HCC patients. [ABSTRACT FROM AUTHOR]

Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1 -mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity. [Display omitted] • Multimodal screens identify T cell fitness regulators impeding antitumor activity • Dap5 ablation increases translation enhancing T cell fitness upon various stimulations • Perturbing ICAM1-LFA1-mediated T cell clustering amplifies T cell effector functions • Ctbp1 inactivation strengthens T cell persistence exclusively upon chronic stimulation Lin et al. perform multimodal genome-wide CRISPR knockout screens in primary CD8 T cells for genes controlling fitness upon differential stimulation. They identify Dap5 , Icam1 , and Ctbp1 , which are functionally annotated and characterized based on their unique or shared contribution to traits limiting T cell antitumor activity. [ABSTRACT FROM AUTHOR]

Abstract Background At the beginning of tumorigenesis, newly born cancer cells must successfully avoid attack by the immune system. Although most abnormal cells are efficiently identified and destroyed by the immune system, particularly by NK cells, the molecular mechanisms by which newly born cancer cells evade NK cell surveillance are not fully understood. Methods NK cell resistance of highly tumorigenic population of human prostate cancer (PCa) cells were confirmed by xenograft in SCID mice with or without NK cell neutralization. The mechanisms by which the tumorigenic PCa cells evaded NK cell attack were investigated by RNAseq, ChIPseq, generation of several transformants and xenograft in SCID mice. Results Here, we show that PCa cells have a strengthened ability to escape NK cell attack due to NANOG, a pluripotent-related transcription factor, mediating the repression of ICAM1, a cell adhesion molecule, during tumorigenesis. Mechanistically, NANOG directly binds to the region upstream of ICAM1. As the binding between NANOG and the upstream ICAM1 region increases, p300 binding to this region is diminished, resulting in decreased ICAM1 expression. High NANOG expression confers PCa cells the ability to resist NK cell attack via the repression of ICAM1. Consistent with these results, low ICAM1 expression is significantly correlated with a high recurrence rate in patients with PCa. Conclusions Our findings indicate that repression of ICAM1 is a critical mechanism by which cancer cells evade attack from NK cells during tumorigenesis. These results suggest a pivotal role of NANOG in establishing a gene expression profile for escaping the immune system.

Background: Ewing's sarcoma (ES) is a kind of malignant tumor, which often occurs in the long bone, pelvis, and other bone tissues, as well as some soft tissues. It often occurs in children and adolescents, second only to osteosarcoma and rhabdomyosarcoma. In the past 30 years, little progress has been made on the genomic mechanism of ES metastasis. Methods: The gene expression sequence of ES metastasis samples was compared with that of primary tumor samples to obtain differentially expressed genes (DEGs). Subsequently, we annotated the gene functions and enriched pathways of DEGs. Additionally, the protein and protein interaction network were constructed to screen key genes that can lead to the metastasis in ES. Then, cell and molecular biology experiments were conducted to verify the results obtained from the bioinformatics analysis. Finally, we assessed the correlation of expression between the key genes EWSR and FLI1, and conducted a survival analysis of ICAM1. Results: Our study revealed 153 DEGs. Of these, 82 (53.59%) were upregulated and the remaining 71 (46.41%) were downregulated. The bioinformatics analysis showed that ICAM1 was the key gene leading to the invasion and metastasis of ES. Through cell biology and molecular biology experiments, inactivation of ICAM1 inhibited the metastasis of ES cells. The survival and correlation analyses showed that ICAM1 was a risk factor in patients with ES, and that ICAM1 expression was correlated with EWSR and FLI1 expression. Conclusion: Our study shows that inactivation of ICAM1 inhibits metastasis and improves the prognosis of ES. Additionally, our findings provide a better understanding of the underlying mechanisms of metastatic ES, a basis for an accurate diagnosis, and therapeutic targets for ES patients. [ABSTRACT FROM AUTHOR]

Objective: The dysfunction of pulmonary microvascular endothelial cells (PMVECs) is one of the critical characteristics of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) induced by severe infection. PIM1 is a constitutively active serine/threonine kinase that is involved in multiple biological processes. However, the underlying correlation between PIM1 and PMVECs injury remains unclear. The main purpose of this study was to reveal roles of PIM1 and explore the potential mechanisms during the development of endotoxin-induced ALI induced by intraperitoneal LPS administration. Materials and methods: PIM1 level in the lung tissues of endotoxin-induced ALI mice or plasma derived from cardiopulmonary bypass (CPB)-induced ALI patients were measured. The protective roles of PIM1 specific inhibitor SMI-4a on endotoxin-induced lung injuries were evaluated through histological, permeability, neutrophil infiltration and survival assessment. The relationship between PIM1 and ELK3/ICAM-1 axis was validated in vivo and vitro. The correlation between plasma PIM1 and indicative vascular endothelium injury biomarkers (PaO2/FiO2 ratio, Ang-II, E-selectin and PAI-1) levels derived from CPB-induced ALI patient were analyzed. Results: PIM1 expression in the lung tissues was increased in the mice of endotoxin-induced ALI. The PIM1 specific inhibitor SMI-4a administration relieved the severity of endotoxin-induced ALI. More importantly, PIM1 modulates ICAM1 expression through regulating transcription factor ELK3 expression in vitro. Eventually, plasma PIM1 level was positively correlated with Ang-II and PAI-1 levels but negatively correlated with SpO2/FiO2 ratio among CPB induced ALI patients. Conclusion: Our results indicated that PIM1 inhibition carried a protective role against endotoxin-induced ALI by modulating the ELK3/ICAM1 axis on PMVECs. PIM1 may be a potential therapeutic target for endotoxin-induced ALI. [ABSTRACT FROM AUTHOR]

Outcomes for pancreatic cancer (PC) patients remain strikingly poor with a 5‐year survival of less than 8% due to the lack of effective treatment modalities. Here, a novel precision medicine approach for PC treatment is developed, which is composed of a rationally designed tumor‐targeting ICAM1 antibody‐drug conjugate (ADC) with optimized chemical linker and cytotoxic payload, complemented with a magnetic resonance imaging (MRI)‐based molecular imaging approach to noninvasively evaluate the efficiency of ICAM1 ADC therapy. It is shown that ICAM1 is differentially overexpressed on the surface of human PC cells with restricted expression in normal tissues, enabling ICAM1 antibody to selectively recognize and target PC tumors in vivo. It is further demonstrated that the developed ICAM1 ADC induces potent and durable tumor regression in an orthotopic PC mouse model. To build a precision medicine, an MRI‐based molecular imaging approach is developed that noninvasively maps the tumoral ICAM1 expression that can be potentially used to identify ICAM1‐overexpressing PC patients. Collectively, this study establishes a strong foundation for the development of a promising ADC to address the critical need in the PC patient care. [ABSTRACT FROM AUTHOR]

Although lung cancer is one of the greatest threats to human health, its signaling pathway and related genes are still unknown. This study integrates data from three groups of people to study potential key candidate genes and pathways related to lung cancer. Expression profiles (GSE18842, GSE19188 and GSE27262), including 162 tumor tissue and 135 adjacent normal lung tissue samples, were integrated and analyzed. Differentially expressed genes (DEGs) and candidate genes were identified, their expression pathways were analyzed, and the diethylene glycol-related protein–protein interaction (PPI) network was analyzed. We identified 232 shared DEGs (40 upregulated and 192 down-regulated) from the three GSE datasets. The DEGs were clustered according to function and signaling pathway for significant enrichment analysis. In total, 129 nodes/DEGs were identified from the DEG PPI network complex. An improved prognosis was associated with increased Helicase, Lymphoid-Specific (HELLS) and decreased Intercellular adhesion molecule 1 (ICAM1) mRNA expression in lung cancer patients. In conclusion, we used integrated bioinformatics analysis to identify candidate genes and pathways in lung cancer to show that HELLS and ICAM1 might be the key genes related to tumorigenesis or tumor progression in lung cancer. Additional studies are needed to further explore the involved functional mechanisms.

Myelodysplastic syndromes (MDS) are a group of malignant clonal diseases presenting abnormal development of acquired hematopoietic progenitor/stem cell myeloid differentiation. MDS have been clinically divided into different types. There is a lack of clear gold standard, which makes the diagnosis of MDS with clinical signs and laboratory examination difficult. Cell-free DNA (cfDNA) is a resource of DNA fragments from apoptotic or necrotic cells, and has been considered as a measurement with ample sensitive, specific, and effective traits for auxiliary diagnosis. In this study, we collected 25 cases of relatively high-risk MDS (HRM), 22 cases of low-risk MDS (LRM), and 15 cases of benign blood diseases (control) and conducted reduced representation bisulfite sequencing (RRBS) to investigate the variants and DNA methylation of cfDNA in serum of three cases of each group. We observed increased single-nucleotide polymorphisms (SNPs) particularly distributed in intergenic and intronic regions in HRM compared with LRM and control. Moreover, HRM presented more nonsynonymous and harmful variants that would affect amino acid sequence. Meanwhile, we also observed that global DNA methylation on non-CpG sites (CHG and CHH) in HRM was obviously higher than that in LRM and control. Finally, we picked up the candidate genes with specific variants and abnormal methylation at the promoter in HRM and LRM, and combined to examine the specificity and sensitivity of HRM and LRM diagnosis in our collection. We found that FANCM with T49G mutation at first exon and promoter hypermethylation (−835 to transcription start site [TSS]) was indicated as the most confident factor with the highest area under curve (AUC) value (0.9271) for HRM. Similarly, ICAM1 with C1211T mutation at sixth exon and promoter hypermethylation (−282 to TSS) was suggested to identify LRM (AUC = 0.9338). Taken together, our study characterized the variants and methylation pattern of cfDNA in MDS, and provided the potential biomarkers for HRM and LRM identification. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence indicates that CCN1 is a novel inflammation‐regulated mediator involved in the pathogenesis of some immune‐mediated inflammatory diseases. The objective of this study was to investigate the preliminary roles of CCN1 and its related cytokines IL‐1β, CCL5, and ICAM1 in oral lichen planus (OLP). Methods: CCN1 expression levels in biopsies from OLP patients against normal oral mucosa (NOM) using immunohistochemistry (42 OLP vs 9 NOM) and RT‐qPCR (20 OLP vs 20 NOM) were compared, respectively. The correlation of CCN1 and IL‐1β, CCL5, and ICAM1 expression was examined by RT‐qPCR in tissue samples and an in vitro cell culture system using keratinocyte HaCaT cells incubated with lipopolysaccharides. Results: Immunohistochemistry showed that CCN1 protein mainly expressed in the cytoplasm of epithelial keratinocytes of OLP. Consistently, RT‐qPCR revealed that mRNA expression of CCN1 was increased in OLP compared with NOM (P <.05) and positively correlated with the high expression of IL‐1β, ICAM1, and CCL5 (P <.001), respectively. Importantly, an in vitro study showed that keratinocyte proliferation significantly (P <.05) increased by CCN1 stimulation. Moreover, IL‐1β, ICAM1, and CCL5 expression in keratinocytes stimulated by CCN1 was increased (P <.05), respectively. Conclusions: This preliminary study for the first time reported that altered expression of CCN1 was associated with high expression of IL‐1β, ICAM1, and CCL5 in OLP. And we demonstrated CCN1 promoted keratinocyte activation, as well as IL‐1β, ICAM1, and CCL5 production in keratinocytes. Our data indicated that the potential role of CCN1 and its related cytokines was involved in the pathogenesis of OLP. [ABSTRACT FROM AUTHOR]

Increased cytokine and inflammatory-related transcripts are found in the ventral midbrain, a dopamine neuron-rich region associated with schizophrenia symptoms. In fact, half of schizophrenia cases can be defined as having a "high inflammatory/immune biotype." Recent studies implicate both complement and macrophages in cortical neuroinflammation in schizophrenia. Our aim was to determine whether measures of transcripts related to phagocytosis/macrophages (CD163, CD64, and FN1), or related to macrophage adhesion [intercellular adhesion molecule 1 (ICAM1)], or whether CD163+ cell density, as well as protein and/or gene expression of complement pathway activators (C1qA) and mediators (C3 or C4), are increased in the midbrain in schizophrenia, especially in those with a high inflammatory biotype. We investigated whether complement mRNA levels correlate with macrophage and/or microglia and/or astrocyte markers. We found CD163+ cells around blood vessels and in the parenchyma and increases in ICAM1, CD163, CD64, and FN1 mRNAs as well as increases in all complement transcripts in the midbrain of schizophrenia cases with high inflammation. While we found positive correlations between complement transcripts (C1qA and C3) and microglia or astrocyte markers across diagnostic and inflammatory subgroups, the only unique strong positive correlation was between CD163 and C1qA mRNAs in schizophrenia cases with high inflammation. Our study is the first to suggest that more circulating macrophages may be attracted to the midbrain in schizophrenia, and that increased macrophages are linked to increased complement pathway activation in tissue and may contribute to dopamine dysregulation in schizophrenia. Single-cell transcriptomic studies and mechanistic preclinical studies are required to test these possibilities. [ABSTRACT FROM AUTHOR]

Background: MiR-27 has been found to present an overt myocardial expression during cardiogenesis. However, whether miR-27 involves in myocarditis development and the possible molecular mechanism remain unknown. The purpose of this study was to investigate the biological characteristic of miR-27 in LPS-damaged H9c2 cells. Methods: H9c2 cells were treated with lipopolysaccharide (LPS, 10 µg/ml) for 12 h to form cell injury. MiR-27 mimic and inhibitor were used to up-regulate or down-regulate miR-27 expression. MTT assay and flow cytometry analysis were conducted to test cell viability and apoptosis. The relative RNA expression level of miR-27 and intercellular adhesion molecule 1 (ICAM1) was determined by qRT-PCR. Luciferase reporter gene assay was utilized to confirm the interaction between miR-27 and ICAM1. Western blot was used to determine the protein expression levels. Results: We observed that LPS treatment significantly decreased the level of miR-27 in H9c2 cells. Moreover, LPS exposure suppressed cell viability, promoted cell apoptosis and increased the relative expression of p-NF-κB p65/NF-κB p65 and p-IκBα/IκBα. Up-regulation of miR-27 increased cell proliferation and reduced cell apoptosis, while down-regulation of miR-27 suppressed cell growth and promoted cell apoptosis. ICAM1 was predicted and verified as a target of miR-27, and the expression of ICAM1 is negatively regulated by miR-27. The relative expression of p-NF-κB p65/NF-κB p65 and p-IκBα/IκBα was dramatically decreased by miR-27 mimic and increased by miR-27 inhibitor. Conclusion: Our study illustrated that up-regulation of miR-27 exhibits a protective effect on LPS-damaged H9c2 cells, which may be achieved by regulating ICAM1 and NF-κB signaling. [ABSTRACT FROM AUTHOR]

Immunological memory is a cardinal feature of the immune system. The intestinal mucosa is the primary exposure and entry site of infectious organisms. For an effective and long-lasting safeguard, a robust immune memory system is required, especially by the mucosal immunity. It is well known that tissue-resident memory T cells (Trms) provide a first response against infections reencountered at mucosal tissues surfaces, where they accelerate pathogen clearance. However, their function in intestinal immunization remains to be investigated. Here, we report enhanced local mucosal and systemic immune responses through oral administration of H9N2 influenza whole inactivated virus (H9N2 WIV) plus Bacillus subtilis spores. Subsequently, H9N2 WIV plus spores led to the generation of CD103+ CD69+ Trms, which were independent of circulating T cells during the immune period. Meanwhile, we also found that Bacillus subtilis spores could stimulate Acrp30 expression in 3T3-L1 adipocytes. Moreover, spore-stimulated adipocyte supernatant also upregulated the expression of intercellular adhesion molecule-1 (ICAM1) in dendritic cells (DCs). Furthermore, the proportion of HA-tetramer+ cells was severely curtailed upon suppressed ICAM1 expression, which also depended on HA-loaded DCs. Taken together, our data demonstrated that spore-promoted H9N2 WIV induced an immune response by enhancing Trms populations, which were associated with the activation of ICAM1 in DCs.

Abstract Background Guillain–Barre Syndrome (GBS) is considered a complex disorder with significant environmental effect and genetic susceptibility. Genetic polymorphisms in CD1E, CD1A, IL‐17, and/or ICAM1 had been proposed as susceptibility genetic variants for GBS mainly in Caucasian population. This study explores the association between selected polymorphisms in these genes and GBS susceptibility in confirmed GBS cases reported in mestizo population from northern Peru during the most recent GBS outbreak of May 2018. Methods A total of nine nonrelated cases and 11 controls were sequenced for the polymorphic regions of CD1A, CD1E, IL‐17, and ICAM1. Results We found a significant protective association between heterozygous GA genotype in ICAM1 (241Gly/Arg) and GBS (p