Introduction In this paper we present a case of monocytic sarcoma of the vertebral canal with a review of relevant literature references. According to the extensive morphological and immunohistochemical analyses, mono...Introduction In this paper we present a case of monocytic sarcoma of the vertebral canal with a review of relevant literature references. According to the extensive morphological and immunohistochemical analyses, monocytic sarcoma is one type of myeloid sarcoma, and can be diagnosed from extensive morphological and immunohistochemical analysis. Most cases of myeloid sarcomas are associated with acute, or chronic leukemia, or myelo-proliferative disorders, as well as monocytic sarcoma. Rarely, the tumors may be identified before the diagnosis of any hematological malignancy and most of them predict portend existing, or pending acute myeloid leukemia （AML）. Myeloid sarcomas may occur in almost every part of the bodyt, but spinal monocytic sarcomas are relatively uncommon.展开更多
Human Ehrlichiosis infrequently occurs and can be missed, but attention to history and a meticulous physical examination would raise the index for suspicion and is documented with proper investigations. We report the ...Human Ehrlichiosis infrequently occurs and can be missed, but attention to history and a meticulous physical examination would raise the index for suspicion and is documented with proper investigations. We report the first case of human monocytic Ehrlichiosis (HME) in a young female patient who lives in the Suburb city of Madaba, Jordan. She presented with fever, severe headache, skin rash, and confusion. She rapidly deteriorated and was admitted to our hospital. She had arrhythmias, convulsions, lapsed into a coma and respiratory failure and needed non-invasive ventilation. In addition to her clinical and epidemiological characteristics, the diagnosis was confirmed by the buffy coat. She had a swift response to oral doxycycline and was discharged home.展开更多
Background: Unique receptor involved in leukemogenesis is CD85k;an immuneglobulin receptor for immune tolerance, CD36 is glycoprotein mediates cellular adhesion and metastatic spread, CD14, CD15 considered common mono...Background: Unique receptor involved in leukemogenesis is CD85k;an immuneglobulin receptor for immune tolerance, CD36 is glycoprotein mediates cellular adhesion and metastatic spread, CD14, CD15 considered common monocytic markers. Aims: to investigate CD85k with monocytic lineage involved leukemia (MLIL) markers in leukemia pathogenesis and clinical presentation. Patients and Methods: 47 patients (32 diagnosed acute myeloid leukemia (AML);15 non-malignant hematological disease as a control), were included, aged from 2 to 80 years, all subjected to peripheral blood (P.Bl) and bone marrow (B.M) examination, immunophenotyping (IPT) using FASC Canto four color flow cytometer (FCM) Becton Dickenson (BD) USA, for CD13, CD33, MPO, HLA-DR, CD34, CD38, CD117, CD14, CD15 and CD36 the Mo Abs supplied by B.D Bioscience, and anti CD85k Mo Abs by Aveda de Coimbra Flamenco, reference No. 1399990130. Results: Frequency of CD85k is 19/32 (59.37%) of AML;14/14 (M4/M5) 100% positive CD85k, insignificant correlations of CD85k to sex, lymphadenopathy or organomegaly, platelets count and P.Bl blast (P > 0.05), significant to age 50,000 × 109/l, Hb 0.05). Conclusion: Although CD85k is MLIL associated marker, it is not correlated with other MLIL markers with frequency 100% in MLIL and 59.37% in AML, age predisposition is <35 years with no sex variation, significant correlation to progenitor and myeloid markers, it’s a crucial role in leukemogenesis biology, not in clinical presentations, considered good follow up predictor MLIL marker.展开更多
Background:The adhesion of monocytes to the endothelium following accumulation of low-density lipoprotein (LDL) in subendothelial spaces is an important step in the development of intimal hyperplasia in arterially imp...Background:The adhesion of monocytes to the endothelium following accumulation of low-density lipoprotein (LDL) in subendothelial spaces is an important step in the development of intimal hyperplasia in arterially implanted vein grafts and atherosclerosis in both animals and humans. However, it is not well known how serum factors affect the adhesion of monocytes. Methods: We have studied the effect of fetal calf serum (FCS), which we considered a source of LDL, on the adhesion of monocytes to endothelial cells (ECs) by using human monocytic THP-1 cells and both a monolayer of cultured bovine aortic endothelial cells (EC monoculture) and a co-culture with bovine aortic smooth muscle cells (EC-SMC co-culture). Results: It was found that the addition of FCS to the medium greatly affected the adhesion of THP-1 cells, and the higher the concentration of FCS in the medium, the greater the adhesion of THP-1 cells to endothelial cells. Adhesion of THP-1 cells to an EC-SMC co-culture was approximately twofold greater than that to an EC monoculture, and after adhering to endothelial cells, many THP-1 cells trans-migrated into the layer of smooth muscle cells. Conclusion: The results suggest that the elevation of the LDL (cholesterol) level in blood provides a favorable condition for the development of intimal hyperplasia and atherosclerosis by promoting the adhesion of monocytes to the endothelium and their subsequent migration into subendothelial spaces.展开更多
Objective: To identify the changes in the proteome of U937 cells infected with dengue virus(DENV).Methods: In this study, differentiated U937 cultures were infected with two DENV-2strains, one of which was associated ...Objective: To identify the changes in the proteome of U937 cells infected with dengue virus(DENV).Methods: In this study, differentiated U937 cultures were infected with two DENV-2strains, one of which was associated with dengue(DENV-2/NG) and the other one with severe dengue(DENV-2/16681), with the aim of determining the cellular proteomic profiles under different infection conditions. Cellular proteins were extracted and separated by two-dimensional electrophoresis, and those proteins with differential expression profiles were identified by mass spectrometry. The obtained results were correlated with cellular viability, the number of infectious viral particles, and the viral DNA/protein quantity.Results: In comparison with non-infected cultures, in the cells infected with the DENV-2/NG strain, nine proteins were expressed differentially(five were upregulated and four were downregulated); in those cultures infected with the DENV-2/16681 strain, six proteins were differentially expressed(two were downregulated and four were upregulated). The downregulated proteins included fatty acid-binding protein, heterogeneous nuclear ribonucleoprotein 1, protein disulfide isomerase, enolase 1, heat shock 70 k Da protein 9, phosphotyrosyl phosphatase, and annexin IV. The upregulated proteins included heat shock 90 k Da protein AA1, tubulin beta, enolase 1, pyruvate kinase,transaldolase and phospholipase C-alpha.Conclusions: Because the monocyte/macrophage lineage is critical for disease pathogenicity, additional studies on these proteins could provide a better understanding of the cellular response to DENV infection and could help identify new therapeutic targets against infection.展开更多
Periodontal diseases are chronic inflammation caused by particular types of bacteria and have been recognized as a cause of tooth loss in adults. These bacteria which invade periodontal tissue are phagocytosed mainly ...Periodontal diseases are chronic inflammation caused by particular types of bacteria and have been recognized as a cause of tooth loss in adults. These bacteria which invade periodontal tissue are phagocytosed mainly by monocytes and macrophages in this immune response, and will be presented to lymphocytes. Recently, therapies for regenerating periodontal tissues have been used extensively to treat periodontal disease, and in particular, enamel matrix derivative (EMD) is commonly used for such therapies in Japan. Amelogenin is a type of the extracellular matrix protein that accounts for 90% of the constituents of EMD. In this study, we carried out a detailed microarray analysis in order to evaluate a gene group involved in amelogenin stimuli in the human monocytic cell line U-937. Microarray analysis revealed that statistically significant changes were apparent in 273 genes (163 up-regulated and 110 down-regulated) subsequent to 4 h of amelogenin stimulation. The most highly enriched categories included “cell cycle”, “DNA replication”, and “DNA repair” in up-regulated annotation terms. On the other hand, “type I diabetes mellitus”, “allograft rejection”, and “graft versus host disease” were observed in down-regulated annotation terms. Specifically, the gene expression of major to compatibility complex (MHC) class I/II and CD80/86 was impaired in U937 cells after stimulation with amelogenin. In addition, the results of heat-map showed that the gene expression of inflammatory cytokine such as tumor necrosis factor (TFN), interleukin-18 (IL-18), and CXCL16 was markedly decreased after stimulation of monocytes with amelogenin. In conclusion, the findings of our study showed that by inducing monocyte growth through the suppression of the antigen-presenting ability of U937 cells, amelogenin may affect the immune responses of periodontal tissues originating from monocytes. Examining the effects of amelogenin on the transformation of macrophages differentiating from monocytes may establish a molecular basis for the anti-inflammatory effect of amelogenin in periodontal tissues.展开更多
Previously, we reported that M-CSF induced monocyte survival through the activation of Akt, p38MAPK and Erk1/2 kinases. Here, we found that Src family kinases were upstream of these kinases and played a central role i...Previously, we reported that M-CSF induced monocyte survival through the activation of Akt, p38MAPK and Erk1/2 kinases. Here, we found that Src family kinases were upstream of these kinases and played a central role in regulating M-CSF-induced monocyte survival. We observed that M-CSF promoted c-Src activation in monocytes and MDMs in a time-dependent manner. Src inhibitors reduced M-CSF-mediated phosphorylation of the M-CSF receptor (M-CSFR), Akt, Erk1/2, and p38 MAPK. We also observed that Src directly phosphorylated the M-CSFR. Notably, the inhibitors blocked phosphorylation of specific tyrosine residues within the M-CSFR. We further demonstrated that the Src inhibitor, PP2, attenuated M-CSF-induced NF-κB activation and M-CSF-induced monocyte survival. These findings indicated that Src family kinases mediate monocyte survival through the regulation of receptor phosphorylation and modulation of downstream signaling events. Thus, we predict that targeting Src family kinases may have therapeutic implication in inflammatory diseases.展开更多
Background and aims:Cancer cachexia is prevalent in various cancers and is associated with chemotherapy toxicity.However,limited data exist on the relationship between cachexia and immune-related adverse events(irAEs)...Background and aims:Cancer cachexia is prevalent in various cancers and is associated with chemotherapy toxicity.However,limited data exist on the relationship between cachexia and immune-related adverse events(irAEs).The aim of this study is to explore the correlation between cancer cachexia and irAEs and its possible mechanism.-Methods:A murine model of orthotopic hepatocellular carcinoma(HCC)with cachexia was developed to evaluate the impact of T-cell infiltration into multiple tumor-free organs on the occurrence of irAEs.Single-cell RNA sequencing of thymic stromal cells was performed.Additionally,patients with advanced cancers receiving anti-programmed cell death protein 1/ligand 1(PD-1/L1)antibody treatment were followed to investigate the relationship between cachexia and irAEs.Results:Inflammatory cell infiltration was observed in multiple tumor-free organs of cachexic HCC mice but not in non-cachexic controls.Immunofluorescence confirmed that the infiltrating cells included CD4^(+)and CD8^(+)T cells.Morphological assessment and hematoxylin-eosin staining revealed thymic atrophy in cachexic HCC mice.Single-cell RNA sequencing of thymic stromal cells showed a reduction in medullary thymic epithelial cells(mTECs)Ⅱ and Ⅲ in cachexic mice.Autoimmune regulator(Aire)downregulation was accompanied by decreased expression of tissue-restricted antigens in mTECs.T cells from cachexic HCC mice induced organ-specific inflammation and T-cell infiltration in multiple organs of tumor-free mice.Following anti-mouse PD-1 antibody treatment,the incidence of inflammation in multiple organs markedly increased in cachexic HCC mice and in tumor-free mice that had received T cells from the cachexic HCC mice.Flow cytometry and immunofluorescence analyses revealed enrichment of thymic monocytic myeloid-derived suppressor cells(M-MDSCs)in cachexic HCC mice.M-MDSCs infiltrated the thymus in cachexic mice with cancer,and they induced apoptosis of mTECs from tumor-free mice in vitro via nitric oxide production.Transfer of M-MDSCs led to inflammatory cell infiltration in multiple organs and thymic involution in tumor-free mice without affecting body weight.Sixty-four patients with advanced cancer receiving anti-PD-1/L1 therapy were enrolled.Patients who developed irAEs had higher levels of circulating M-MDSCs than those who did not.Moreover,patients with cachexia(body mass index(BMI)<20 kg/m^(2) or≥5% weight loss over the past 6 months)had elevated M-MDSC levels.Patients with both high M-MDSC levels and low BMI or weight loss≥5% experienced more irAEs(hazard ratio:2.333;95% confidence interval:1.231-4.423).Conclusions:M-MDSCs in cachexic mice induced mTEC apoptosis through nitric oxide production,impairing T-cell negative selection and promoting autoimmune T-cell infiltration into tumor-free organs.Cancer cachexia-related M-MDSCs may serve as predictive biomarkers for irAEs in patients with advanced cancer.展开更多
RNA-binding proteins(RBPs)are widely involved in the transcriptional and posttranscriptional regulation of multiple biological processes.The transcriptional regulatory ability of RBPs was indicated by the identificati...RNA-binding proteins(RBPs)are widely involved in the transcriptional and posttranscriptional regulation of multiple biological processes.The transcriptional regulatory ability of RBPs was indicated by the identification of chromatin-enriched RBPs(Che-RBPs).One of these proteins,KH-type splicing regulatory protein(KHSRP),is a multifunctional RBP that has been implicated in mRNA decay,alternative splicing,and miRNA biogenesis and plays an essential role in myeloid differentiation by facilitating the maturation of miR-129.In this study,we revealed that KHSRP regulates monocytic differentiation by regulating gene transcription and RNA splicing.KHSRP-occupied specific genomic sites in promoter and enhancer regions to regulate the expression of several hematopoietic genes through transcriptional activation and bound to pre-mRNA intronic regions to modulate alternative splicing during monocytic differentiation.Of note,KHSRP had co-regulatory effects at both the transcriptional and posttranscriptional levels on MOGOH and ADARB1.Taken together,our analyses revealed the dual DNA-and RNA-binding activities of KHSRP and have provided a paradigm to guide the analysis of other functional Che-RBPs in different biological systems.展开更多
Interleukin 34(IL-34)is a cytokine that shares the receptor with colony-stimulating factor 1(CSF-1).IL-34 is involved in a broad range of pathologic processes including cancer.We previously demonstrated that IL-34 pro...Interleukin 34(IL-34)is a cytokine that shares the receptor with colony-stimulating factor 1(CSF-1).IL-34 is involved in a broad range of pathologic processes including cancer.We previously demonstrated that IL-34 promoted the proliferation and colony formation of human acute monocytic leukemia(AMoL)cells.However,the mechanism has not been elucidated.Here,by analyzing the gene profiles of Molm13 and THP1 cells overexpressing IL-34(Molm13-IL-34 and THP1-IL-34),upregulation of the DNA damageinducible transcript 4(DDIT4)was detected in both series.Knockdown of DDIT4 effectively inhibited the proliferation,promoted apoptosis and colony formation in Molm13-IL-34 and THP1-IL-34 cells.Our results suggest that DDIT4 mediates the proliferationpromotive effect of IL-34 whereas does not mediate the promotive effect of IL-34 on colony formation in AMoL cells.展开更多
Peripheral artery disease(PAD)remains a significant global health issue,with current treatments primarily focused on relieving symptoms and addressingmacrovascular issues.However,critical immunoinflammatory mechanisms...Peripheral artery disease(PAD)remains a significant global health issue,with current treatments primarily focused on relieving symptoms and addressingmacrovascular issues.However,critical immunoinflammatory mechanisms are often overlooked.Recent evidence suggests that monocyte phenotypic plasticity plays a central role in PAD development,affecting atherogenesis,plaque progression,ischemia-reperfusion injury,and chronic ischemic remodeling.This narrative review aims to summarize the latest advances(2023-2025)in understanding monocyte diversity,functional states,and their changes throughout different stages of PAD.We discuss both established and emerging biomarkers,such as circulating monocyte subset proportions,functional assays,immune checkpoint expression,and multi-omics signatures,highlighting their potential for prognosis and the challenges in translating them to clinical practice.We also present a stage-specific approach to mapping out potential therapies,linking monocyte phenotypes to molecular targets and possible interventions.Additionally,we address regulatory,economic,and implementation considerations for applying these findings in a clinical setting.The goal of this review is to facilitate the development of targeted immunomodulatory strategies to improve limb and cardiovascular outcomes in PAD by combining mechanistic understanding with therapeutic innovation.展开更多
BACKGROUND:Bloodstream infections(BSIs) caused by gram-positive cocci(GPC) and gramnegative bacilli(GNB) are major causes of sepsis.However,their distinct effects on host responses remain poorly characterized at the s...BACKGROUND:Bloodstream infections(BSIs) caused by gram-positive cocci(GPC) and gramnegative bacilli(GNB) are major causes of sepsis.However,their distinct effects on host responses remain poorly characterized at the single-cell level.This study used single-cell transcriptomics to define pathogenspecific monocyte heterogeneity in BSIs to identify the mechanisms underlying clinical differences.METHODS:Single-cell RNA sequencing(sc RNA-seq) was performed on peripheral blood mononuclear cells obtained from healthy volunteers,two patients with GNB-BSI sepsis,and two patients with GPC-BSI sepsis.Differential gene expression,particularly in monocytes,was analyzed.The key findings were validated with clinical characteristics and outcomes of 45 patients with GNBBSI sepsis and 40 patients with GPC-BSI sepsis.The distinguishing performances of identified biomarkers were evaluated via receiver operating characteristic(ROC) curve.RESULTS:In pathogen-specific transcriptomes,54 identified genes were significantly associated with GNB-BSI(upregulated genes enriched in inflammatory pathways and downregulated genes enriched in oxidative phosphorylation).Twenty-one identified genes were associated with GPC-BSI(downregulated genes associated with cell adhesion molecules and upregulated genes involved in PI3K-Akt signaling).Nineteen genes were common to both groups,with distinct pathogen sensitivities.Patients with GNB-BSI presented with significantly greater disease severity,systemic inflammation and lymphopenia than patients with GPC-BSI.Conversely,patients with GPC-BSI had higher S100A12 and globulin levels and platelet counts.The combination of S100A12^(high) and procalcitonin(PCT)^(low) discriminated GPC-BSI from GNB-BSI(area under the curve=0.882,sensitivity 75%,specificity 91%;cutoff value 0.56).CONCLUSION:Sc RNA-seq reveals the heterogeneity of GPC-BSI and GNB-BSI.Compared with GPC-BSI,GNB-BSI causes severe inflammation and metabolic suppression,which are associated with poor outcomes.The S100A12^(high)+PCT^(low) combination may have potential to discriminate among the major causes of BSI.展开更多
As the prevalence of obesity increases dramatically,obesity-associated cardiac dysfunction constitutes a considerable challenge to human health.This study aimed to identify more useful lipid/inflammatory markers to pr...As the prevalence of obesity increases dramatically,obesity-associated cardiac dysfunction constitutes a considerable challenge to human health.This study aimed to identify more useful lipid/inflammatory markers to predict the risk of obesity-associated cardiac dysfunction.By retrospectively analyzing the clinical characteristics of 5648 cardiac disease patients,we found that both the plasma level of high-density lipoprotein cholesterol(HDLC)and the blood monocyte count were significantly associated with impairment of the left ventricular ejection fraction(LVEF).Univariate and multivariate regression analyses revealed that the monocyte to HDL-C ratio(MHR)was a more powerful predictor of the risk of LVEF decline than either HDL-C or monocyte alone.Mediation analysis further revealed a mediating effect of a high MHR on the decline in obesity-associated cardiac systolic function.Collectively,our results demonstrate a superior role of MHR in predicting the risk of an obesityassociated decline in cardiac systolic function among routine metabolic/inflammatory markers.展开更多
Monocytes play a crucial role in post-stroke immune infiltration,yet the intricate immune regulatory networks they orchestrate in ischemic stroke remain poorly understood.This knowledge gap has hindered the developmen...Monocytes play a crucial role in post-stroke immune infiltration,yet the intricate immune regulatory networks they orchestrate in ischemic stroke remain poorly understood.This knowledge gap has hindered the development of targeted monocyte-based therapies for stroke.Here,we used a multi-omics approach combining single-cell and bulk transcriptomics.CellChat analysis revealed intercellular communication networks,while key genes were identified and predictive models built through Lasso regression.Immune cell infiltration dynamics were quantified using single-sample gene set enrichment analysis.Gene set enrichment analysis and gene set variation analysis identified disease-regulated pathways of core genes.MicroRNA networks and transcription factors were investigated using mircode and RcisTarget.Experimental validation was performed using oxygen-glucose deprivation and transient middle cerebral artery occlusion models,focusing on the influence of abhydrolase domain-containing protein 2 on monocyte function.We observed significantly elevated monocyte content in stroke brain tissue samples,and identified key monocyte genes associated with immune inflammation,chemokine signaling,and cell receptor function.A robust seven-gene predictive model for ischemic stroke was developed.CD274 strongly correlated with these seven genes,suggesting a potential immunomodulatory axis.In vivo transient middle cerebral artery occlusion experiments validated the predictive value of key genes.In vitro studies demonstrated that abhydrolase domain-containing protein 2 overexpression enhanced monocyte proliferation and phagocytic activity post-oxygen-glucose deprivation while reducing reactive oxygen species generation.In conclusion,this study maps post-stroke monocyte communication networks,identifies key signaling pathways,identifies regulatory mechanisms,and validates the functional importance of key genes,particularly abhydrolase domain-containing protein 2.These findings provide a foundation for developing targeted immunomodulatory therapies and precision diagnostics in ischemic stroke management.展开更多
Objectives:The PACIFIC trial established the benefit of durvalumab following chemo-radiotherapy for stage III non-small cell lung cancer(NSCLC).However,the concurrent use of radiotherapy(RT)and durvalumab(PACIFIC-2 tr...Objectives:The PACIFIC trial established the benefit of durvalumab following chemo-radiotherapy for stage III non-small cell lung cancer(NSCLC).However,the concurrent use of radiotherapy(RT)and durvalumab(PACIFIC-2 trial)showed no additional advantage.The PD-RAD study was set up to understand the immunological effects of RT on the tumor microenvironment(TME)to aid in optimizing sequencing of combination therapies.Methods:The PD-RAD trial(ClinicalTrials.gov identifier:NCT03258788)aimed to enroll thirty NSCLC patients receiving radical-intent RT.Tumor biopsies and blood samples were collected pre-RT and at week 2 during RT and analyzed using multiplex immunohistochemistry(mIHC)and high-dimensional mass cytometry(CyTOF),respectively.Results:Paired biopsies were collected from only three patients(Pts 1,3&4)and blood from four patients(Pts 1-4)before the study was closed early during the COVID-19 pandemic.Programmed Death-Ligand 1(PD-L1)expression in the TME was raised in Patient 1,who responded well to treatment,and unaltered in two patients with progressive disease.CyTOF analysis revealed elevated circulating classical monocytes,highest in the patient with a good response.Conclusions:This study underscores the challenges of integrating advanced immune monitoring during RT delivery and did not meet its primary endpoint.The hypothesis-generating findings highlight PD-L1+macrophages in the TME and classical monocytes in the blood as potential immune biomarkers of RT response,but larger studies are needed to validate these observations and characterize the immune changes following curative-intent RT in patients with NSCLC.展开更多
Background:With a total of 1.46 million new cases and 396,792 deaths in 2022,prostate cancer is a major medical challenge around the world.Detecting and treating cancer at earlier,preferably localized stages can signi...Background:With a total of 1.46 million new cases and 396,792 deaths in 2022,prostate cancer is a major medical challenge around the world.Detecting and treating cancer at earlier,preferably localized stages can significantly increase survival rates.Here,a novel blood-based cancer screening as a pre-test in combination with targeted MRI imaging enabled the early diagnosis of prostate cancer.Case Description:We present the case of a 64-year-old man who participated in a prospective,interventional,multicenter cancer screening study where an immunological biopsy-based technique served as a part of a novel screening technique.This immunology technique represents a blood test exploiting two biomarkers,which may allow for the identification of individuals at an early stage of tumor development.Due to the elevated biomarker levels of Transketolase-like protein 1(TKTL1)and Apoptoic-associated cell population 10(Apo10),magnetic resonance imaging(MRI)was indicated for further clarification.A multiparametric MRI of the pelvis/prostate revealed an enlarged prostate gland and several suspicious lesions classified as Prostate Imaging Reporting and Data System(PI-RADS)4 and PI-RADS 5.In further assessments,both lesions were categorized as an acinar adenocarcinoma of the prostate(Gleason Score 6,International Society of Urological Pathology(ISUP)1,no perineural infiltration).After surgical resection,the tumor was classified histopathologically as an adenocarcinoma,pT2c pN0(0/7),L0,V0,Pn1,R0,Gleason score 7a,ISUP 2.Conclusions:The combination of the TKTL1/Apo10 blood test and subsequent imaging made it possible to detect a developing prostate carcinoma in a localized stage.All in all,this case report proves not just the ability but also the potential of the TKTL1/Apo10 blood test for early detection of(pre-)malignant lesions,which still present with a promising prospect for a cure.展开更多
Objective To investigate the expression of mRNA and proteins ofβ-catenin,TCF-4(ICAT)and Wnt signaling pathway-related genes in the monocytic differentiation of acute myeloid leukemia HL-60 cells induced by a new ster...Objective To investigate the expression of mRNA and proteins ofβ-catenin,TCF-4(ICAT)and Wnt signaling pathway-related genes in the monocytic differentiation of acute myeloid leukemia HL-60 cells induced by a new steroidal drug NSC67657.Methods Wright’s staining andα-NBE staining were used to observe the differentiation of HL-60 cells after 5 days of展开更多
Background:It has recently been recognized that serum vimentin is elevated in infectious diseases,and that vimentin plays a role in regulating neutrophils and macrophages associated inflammation.However,the mechanisms...Background:It has recently been recognized that serum vimentin is elevated in infectious diseases,and that vimentin plays a role in regulating neutrophils and macrophages associated inflammation.However,the mechanisms are unclear.This study was designed to explore the role of vimentin in regulating monocyte survival or apoptosis as well as inflammatory cytokine secretion in response to lipopolysaccharides(LPSs).Methods:A human monocytic leukemia cell line(THP-1)was transfected with vimentin-specific small interfering RNA(siRNA)or vimentin over-expressing plasmid.Apoptosis was assessed by TdT-mediated dUTP Nick-End Labeling(TUNEL)and DNA content assay.Immunoblotting was performed to detect apoptosis-associated proteins.Cytokines(interleukin[IL]-6,IL-10,and tumor necrosis factorα[TNF-α])were measured by enzyme-linked immuno sorbent assay.Two-way analysis of variance followed by Student's t test was used to compare means between different groups.Results:Suppression of vimentin in THP-1 cells resulted in increased apoptotic response in the presence of LPS,while overexpression of vimentin could prevent the cells from apoptosis in response to LPS.LPS alone or suppression of vimentin resulted in significant up-regulation of caspase-3(1.42±0.20 of LPS alone and 1.68±0.10 of vimentin suppression vs.control,t=5.21 and 10.28,respectively,P<0.05).In addition,pro-inflammatory cytokines(IL-6 and TNF-α)was significantly increased(IL-6:577.90±159.90 pg/day/105 cells vs.283.80±124.60 pg/day/105 cells of control,t=14.76,P<0.05;TNF-α:54.10±5.80 vs.17.10±0.10 pg/day/105 cells of control,t=6.71,P<0.05),while anti-inflammatory cytokine(IL-10)was significantly up-regulated in the THP-1 cells that over-expressed vimentin(140.9±17.2 pg/day/105 cells vs.undetectable in control cells).Contusions:In summary,the vimentin may regulate innate immunity through modulating monocytes viability as well as inflammatory response in sepsis through shifting the balance of pro-inflammatory and anti-inflammatory cytokines.展开更多
Dendritic cells （DCs） are professional antigen-presenting cells with the ability to induce primary T-cell responses. They are commonly produced by culturing monocytes in the presence of IL-4 and GM-CSF （cells produ...Dendritic cells （DCs） are professional antigen-presenting cells with the ability to induce primary T-cell responses. They are commonly produced by culturing monocytes in the presence of IL-4 and GM-CSF （cells produced in this manner are called conventional DCs）. Here we report the generation of two functionally distinct subsets of DCs derived from programmable cells of monocytic origin （PCMOs） in the presence of IL-3 or tumor necrosis factor alpha （TNF-e）. Monocytes were treated with macrophage colony-stimulating factor （M-CSF） and IL-3 for 6 days and then incubated with IL-4 and IL-3 （for IL-3 DCs） or with IL-4, GM-CSF and TNF-a （for TNF-a DCs） for 7 days. Monocytes were then loaded with tumor lysate （used as antigen）, and poly （I ： C） was added. The maturation factors TNF-e and monocyte conditioned medium （MCM） were added on days 4 and 5, respectively. The phenotypes of the DCs generated were characterized by flow cytometry, and the cells＇ phagocytic activities were measured using FITC-conjugated latex bead uptake. T-cell proliferation and cytokine release were assayed using MTT and commercially available ELISA kits, respectively. We found that either IL-3DCs or TNF-α DCs induce T-cell proliferation and cytokine secretion; the cytokine release pattern showed reduced IL-12/IL- 10 and IFN-γ/IL-4 ratios in both types of DCs and in DC-primed T-cell supernatant, respectively, which confirmed that the primed T cells were polarized toward aTh2-type immune response. We concluded that PCMOs are a new cell source that can develop into two functionally distinct DCs that both induce a Th2-type response in vitro. This modality can be used as a DC-based immunotherapy for autoimmune diseases.展开更多
Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple rol...Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple roles of mononuclear macrophages in the neuroinflammatory process. Monocytes play a significant role in neuroinflammation, and managing neuroinflammation by manipulating peripheral monocytes stands out as an effective strategy for the treatment of multiple sclerosis, leading to improved patient outcomes. This review outlines the steps involved in the entry of myeloid monocytes into the central nervous system that are targets for effective intervention: the activation of bone marrow hematopoiesis, migration of monocytes in the blood, and penetration of the blood–brain barrier by monocytes. Finally, we summarize the different monocyte subpopulations and their effects on the central nervous system based on phenotypic differences. As activated microglia resemble monocyte-derived macrophages, it is important to accurately identify the role of monocyte-derived macrophages in disease. Depending on the roles played by monocyte-derived macrophages at different stages of the disease, several of these processes can be interrupted to limit neuroinflammation and improve patient prognosis. Here, we discuss possible strategies to target monocytes in neurological diseases, focusing on three key aspects of monocyte infiltration into the central nervous system, to provide new ideas for the treatment of neurodegenerative diseases.展开更多
文摘Introduction In this paper we present a case of monocytic sarcoma of the vertebral canal with a review of relevant literature references. According to the extensive morphological and immunohistochemical analyses, monocytic sarcoma is one type of myeloid sarcoma, and can be diagnosed from extensive morphological and immunohistochemical analysis. Most cases of myeloid sarcomas are associated with acute, or chronic leukemia, or myelo-proliferative disorders, as well as monocytic sarcoma. Rarely, the tumors may be identified before the diagnosis of any hematological malignancy and most of them predict portend existing, or pending acute myeloid leukemia （AML）. Myeloid sarcomas may occur in almost every part of the bodyt, but spinal monocytic sarcomas are relatively uncommon.
文摘Human Ehrlichiosis infrequently occurs and can be missed, but attention to history and a meticulous physical examination would raise the index for suspicion and is documented with proper investigations. We report the first case of human monocytic Ehrlichiosis (HME) in a young female patient who lives in the Suburb city of Madaba, Jordan. She presented with fever, severe headache, skin rash, and confusion. She rapidly deteriorated and was admitted to our hospital. She had arrhythmias, convulsions, lapsed into a coma and respiratory failure and needed non-invasive ventilation. In addition to her clinical and epidemiological characteristics, the diagnosis was confirmed by the buffy coat. She had a swift response to oral doxycycline and was discharged home.
文摘Background: Unique receptor involved in leukemogenesis is CD85k;an immuneglobulin receptor for immune tolerance, CD36 is glycoprotein mediates cellular adhesion and metastatic spread, CD14, CD15 considered common monocytic markers. Aims: to investigate CD85k with monocytic lineage involved leukemia (MLIL) markers in leukemia pathogenesis and clinical presentation. Patients and Methods: 47 patients (32 diagnosed acute myeloid leukemia (AML);15 non-malignant hematological disease as a control), were included, aged from 2 to 80 years, all subjected to peripheral blood (P.Bl) and bone marrow (B.M) examination, immunophenotyping (IPT) using FASC Canto four color flow cytometer (FCM) Becton Dickenson (BD) USA, for CD13, CD33, MPO, HLA-DR, CD34, CD38, CD117, CD14, CD15 and CD36 the Mo Abs supplied by B.D Bioscience, and anti CD85k Mo Abs by Aveda de Coimbra Flamenco, reference No. 1399990130. Results: Frequency of CD85k is 19/32 (59.37%) of AML;14/14 (M4/M5) 100% positive CD85k, insignificant correlations of CD85k to sex, lymphadenopathy or organomegaly, platelets count and P.Bl blast (P > 0.05), significant to age 50,000 × 109/l, Hb 0.05). Conclusion: Although CD85k is MLIL associated marker, it is not correlated with other MLIL markers with frequency 100% in MLIL and 59.37% in AML, age predisposition is <35 years with no sex variation, significant correlation to progenitor and myeloid markers, it’s a crucial role in leukemogenesis biology, not in clinical presentations, considered good follow up predictor MLIL marker.
基金a Grant-in-Aid for Scientific Research onPriority Areas (No. 15086201) from the Ministry of Education, Culture, Sports, Science and Technology of Japanthe Health Bureauof Zhejiang Province (No. 2007B132), China
文摘Background:The adhesion of monocytes to the endothelium following accumulation of low-density lipoprotein (LDL) in subendothelial spaces is an important step in the development of intimal hyperplasia in arterially implanted vein grafts and atherosclerosis in both animals and humans. However, it is not well known how serum factors affect the adhesion of monocytes. Methods: We have studied the effect of fetal calf serum (FCS), which we considered a source of LDL, on the adhesion of monocytes to endothelial cells (ECs) by using human monocytic THP-1 cells and both a monolayer of cultured bovine aortic endothelial cells (EC monoculture) and a co-culture with bovine aortic smooth muscle cells (EC-SMC co-culture). Results: It was found that the addition of FCS to the medium greatly affected the adhesion of THP-1 cells, and the higher the concentration of FCS in the medium, the greater the adhesion of THP-1 cells to endothelial cells. Adhesion of THP-1 cells to an EC-SMC co-culture was approximately twofold greater than that to an EC monoculture, and after adhering to endothelial cells, many THP-1 cells trans-migrated into the layer of smooth muscle cells. Conclusion: The results suggest that the elevation of the LDL (cholesterol) level in blood provides a favorable condition for the development of intimal hyperplasia and atherosclerosis by promoting the adhesion of monocytes to the endothelium and their subsequent migration into subendothelial spaces.
基金Supported by the Administrative Department of Science,Technology,and Research-COLCIENCIAS(Projects 111549326092 and 111549326083)
文摘Objective: To identify the changes in the proteome of U937 cells infected with dengue virus(DENV).Methods: In this study, differentiated U937 cultures were infected with two DENV-2strains, one of which was associated with dengue(DENV-2/NG) and the other one with severe dengue(DENV-2/16681), with the aim of determining the cellular proteomic profiles under different infection conditions. Cellular proteins were extracted and separated by two-dimensional electrophoresis, and those proteins with differential expression profiles were identified by mass spectrometry. The obtained results were correlated with cellular viability, the number of infectious viral particles, and the viral DNA/protein quantity.Results: In comparison with non-infected cultures, in the cells infected with the DENV-2/NG strain, nine proteins were expressed differentially(five were upregulated and four were downregulated); in those cultures infected with the DENV-2/16681 strain, six proteins were differentially expressed(two were downregulated and four were upregulated). The downregulated proteins included fatty acid-binding protein, heterogeneous nuclear ribonucleoprotein 1, protein disulfide isomerase, enolase 1, heat shock 70 k Da protein 9, phosphotyrosyl phosphatase, and annexin IV. The upregulated proteins included heat shock 90 k Da protein AA1, tubulin beta, enolase 1, pyruvate kinase,transaldolase and phospholipase C-alpha.Conclusions: Because the monocyte/macrophage lineage is critical for disease pathogenicity, additional studies on these proteins could provide a better understanding of the cellular response to DENV infection and could help identify new therapeutic targets against infection.
文摘Periodontal diseases are chronic inflammation caused by particular types of bacteria and have been recognized as a cause of tooth loss in adults. These bacteria which invade periodontal tissue are phagocytosed mainly by monocytes and macrophages in this immune response, and will be presented to lymphocytes. Recently, therapies for regenerating periodontal tissues have been used extensively to treat periodontal disease, and in particular, enamel matrix derivative (EMD) is commonly used for such therapies in Japan. Amelogenin is a type of the extracellular matrix protein that accounts for 90% of the constituents of EMD. In this study, we carried out a detailed microarray analysis in order to evaluate a gene group involved in amelogenin stimuli in the human monocytic cell line U-937. Microarray analysis revealed that statistically significant changes were apparent in 273 genes (163 up-regulated and 110 down-regulated) subsequent to 4 h of amelogenin stimulation. The most highly enriched categories included “cell cycle”, “DNA replication”, and “DNA repair” in up-regulated annotation terms. On the other hand, “type I diabetes mellitus”, “allograft rejection”, and “graft versus host disease” were observed in down-regulated annotation terms. Specifically, the gene expression of major to compatibility complex (MHC) class I/II and CD80/86 was impaired in U937 cells after stimulation with amelogenin. In addition, the results of heat-map showed that the gene expression of inflammatory cytokine such as tumor necrosis factor (TFN), interleukin-18 (IL-18), and CXCL16 was markedly decreased after stimulation of monocytes with amelogenin. In conclusion, the findings of our study showed that by inducing monocyte growth through the suppression of the antigen-presenting ability of U937 cells, amelogenin may affect the immune responses of periodontal tissues originating from monocytes. Examining the effects of amelogenin on the transformation of macrophages differentiating from monocytes may establish a molecular basis for the anti-inflammatory effect of amelogenin in periodontal tissues.
文摘Previously, we reported that M-CSF induced monocyte survival through the activation of Akt, p38MAPK and Erk1/2 kinases. Here, we found that Src family kinases were upstream of these kinases and played a central role in regulating M-CSF-induced monocyte survival. We observed that M-CSF promoted c-Src activation in monocytes and MDMs in a time-dependent manner. Src inhibitors reduced M-CSF-mediated phosphorylation of the M-CSF receptor (M-CSFR), Akt, Erk1/2, and p38 MAPK. We also observed that Src directly phosphorylated the M-CSFR. Notably, the inhibitors blocked phosphorylation of specific tyrosine residues within the M-CSFR. We further demonstrated that the Src inhibitor, PP2, attenuated M-CSF-induced NF-κB activation and M-CSF-induced monocyte survival. These findings indicated that Src family kinases mediate monocyte survival through the regulation of receptor phosphorylation and modulation of downstream signaling events. Thus, we predict that targeting Src family kinases may have therapeutic implication in inflammatory diseases.
基金supported by the National Natural Science Foundation of China(No.82170749)the Guangdong Basic and Applied Basic Research Foundation(No.2022A1515010465 and 2022A1515012659)+1 种基金Guangzhou Science and Technology Program Key Projects(No.2023B01J1007)the Traditional Chinese Medicine Bureau of Guangdong Province,China(No.20241045).
文摘Background and aims:Cancer cachexia is prevalent in various cancers and is associated with chemotherapy toxicity.However,limited data exist on the relationship between cachexia and immune-related adverse events(irAEs).The aim of this study is to explore the correlation between cancer cachexia and irAEs and its possible mechanism.-Methods:A murine model of orthotopic hepatocellular carcinoma(HCC)with cachexia was developed to evaluate the impact of T-cell infiltration into multiple tumor-free organs on the occurrence of irAEs.Single-cell RNA sequencing of thymic stromal cells was performed.Additionally,patients with advanced cancers receiving anti-programmed cell death protein 1/ligand 1(PD-1/L1)antibody treatment were followed to investigate the relationship between cachexia and irAEs.Results:Inflammatory cell infiltration was observed in multiple tumor-free organs of cachexic HCC mice but not in non-cachexic controls.Immunofluorescence confirmed that the infiltrating cells included CD4^(+)and CD8^(+)T cells.Morphological assessment and hematoxylin-eosin staining revealed thymic atrophy in cachexic HCC mice.Single-cell RNA sequencing of thymic stromal cells showed a reduction in medullary thymic epithelial cells(mTECs)Ⅱ and Ⅲ in cachexic mice.Autoimmune regulator(Aire)downregulation was accompanied by decreased expression of tissue-restricted antigens in mTECs.T cells from cachexic HCC mice induced organ-specific inflammation and T-cell infiltration in multiple organs of tumor-free mice.Following anti-mouse PD-1 antibody treatment,the incidence of inflammation in multiple organs markedly increased in cachexic HCC mice and in tumor-free mice that had received T cells from the cachexic HCC mice.Flow cytometry and immunofluorescence analyses revealed enrichment of thymic monocytic myeloid-derived suppressor cells(M-MDSCs)in cachexic HCC mice.M-MDSCs infiltrated the thymus in cachexic mice with cancer,and they induced apoptosis of mTECs from tumor-free mice in vitro via nitric oxide production.Transfer of M-MDSCs led to inflammatory cell infiltration in multiple organs and thymic involution in tumor-free mice without affecting body weight.Sixty-four patients with advanced cancer receiving anti-PD-1/L1 therapy were enrolled.Patients who developed irAEs had higher levels of circulating M-MDSCs than those who did not.Moreover,patients with cachexia(body mass index(BMI)<20 kg/m^(2) or≥5% weight loss over the past 6 months)had elevated M-MDSC levels.Patients with both high M-MDSC levels and low BMI or weight loss≥5% experienced more irAEs(hazard ratio:2.333;95% confidence interval:1.231-4.423).Conclusions:M-MDSCs in cachexic mice induced mTEC apoptosis through nitric oxide production,impairing T-cell negative selection and promoting autoimmune T-cell infiltration into tumor-free organs.Cancer cachexia-related M-MDSCs may serve as predictive biomarkers for irAEs in patients with advanced cancer.
基金This work was supported by the National Key Research and Development Program of China(2019YFA0801800,2021YFA1102400,2019YFA0802600 and 2021YFA0805703)the National Natural Science Foundation of China(81530007,31900072,31725013,82022001,82122005,81970103 and 81970101)CAMS Innovation Fund for Medical Sciences[2021-I2M-1-019 and 2021-I2M-1-040].
文摘RNA-binding proteins(RBPs)are widely involved in the transcriptional and posttranscriptional regulation of multiple biological processes.The transcriptional regulatory ability of RBPs was indicated by the identification of chromatin-enriched RBPs(Che-RBPs).One of these proteins,KH-type splicing regulatory protein(KHSRP),is a multifunctional RBP that has been implicated in mRNA decay,alternative splicing,and miRNA biogenesis and plays an essential role in myeloid differentiation by facilitating the maturation of miR-129.In this study,we revealed that KHSRP regulates monocytic differentiation by regulating gene transcription and RNA splicing.KHSRP-occupied specific genomic sites in promoter and enhancer regions to regulate the expression of several hematopoietic genes through transcriptional activation and bound to pre-mRNA intronic regions to modulate alternative splicing during monocytic differentiation.Of note,KHSRP had co-regulatory effects at both the transcriptional and posttranscriptional levels on MOGOH and ADARB1.Taken together,our analyses revealed the dual DNA-and RNA-binding activities of KHSRP and have provided a paradigm to guide the analysis of other functional Che-RBPs in different biological systems.
基金This work was supported by grants 81770183 and 81970155 from the National Natural Science Foundation of China(NSFC)programs 2016-I2M-2-006 and 2017-I2M-1-015 from the CAMS Innovation Fund for Medical Sciences(CIFMS)+1 种基金State Key Laboratory of Experimental Hematology Research Grant(Z20-06)G.Z.is a recipient of the New Century Excellent Talents in University(NCET-08–0329).
文摘Interleukin 34(IL-34)is a cytokine that shares the receptor with colony-stimulating factor 1(CSF-1).IL-34 is involved in a broad range of pathologic processes including cancer.We previously demonstrated that IL-34 promoted the proliferation and colony formation of human acute monocytic leukemia(AMoL)cells.However,the mechanism has not been elucidated.Here,by analyzing the gene profiles of Molm13 and THP1 cells overexpressing IL-34(Molm13-IL-34 and THP1-IL-34),upregulation of the DNA damageinducible transcript 4(DDIT4)was detected in both series.Knockdown of DDIT4 effectively inhibited the proliferation,promoted apoptosis and colony formation in Molm13-IL-34 and THP1-IL-34 cells.Our results suggest that DDIT4 mediates the proliferationpromotive effect of IL-34 whereas does not mediate the promotive effect of IL-34 on colony formation in AMoL cells.
文摘Peripheral artery disease(PAD)remains a significant global health issue,with current treatments primarily focused on relieving symptoms and addressingmacrovascular issues.However,critical immunoinflammatory mechanisms are often overlooked.Recent evidence suggests that monocyte phenotypic plasticity plays a central role in PAD development,affecting atherogenesis,plaque progression,ischemia-reperfusion injury,and chronic ischemic remodeling.This narrative review aims to summarize the latest advances(2023-2025)in understanding monocyte diversity,functional states,and their changes throughout different stages of PAD.We discuss both established and emerging biomarkers,such as circulating monocyte subset proportions,functional assays,immune checkpoint expression,and multi-omics signatures,highlighting their potential for prognosis and the challenges in translating them to clinical practice.We also present a stage-specific approach to mapping out potential therapies,linking monocyte phenotypes to molecular targets and possible interventions.Additionally,we address regulatory,economic,and implementation considerations for applying these findings in a clinical setting.The goal of this review is to facilitate the development of targeted immunomodulatory strategies to improve limb and cardiovascular outcomes in PAD by combining mechanistic understanding with therapeutic innovation.
基金supported by the Key R&D Program of Ningxia Hui Autonomous Region (2023BEG02024)Natural Science Foundation of Ningxia (2025AAC030942)the University-level Research Project of Ningxia Medical University (XM2023019)。
文摘BACKGROUND:Bloodstream infections(BSIs) caused by gram-positive cocci(GPC) and gramnegative bacilli(GNB) are major causes of sepsis.However,their distinct effects on host responses remain poorly characterized at the single-cell level.This study used single-cell transcriptomics to define pathogenspecific monocyte heterogeneity in BSIs to identify the mechanisms underlying clinical differences.METHODS:Single-cell RNA sequencing(sc RNA-seq) was performed on peripheral blood mononuclear cells obtained from healthy volunteers,two patients with GNB-BSI sepsis,and two patients with GPC-BSI sepsis.Differential gene expression,particularly in monocytes,was analyzed.The key findings were validated with clinical characteristics and outcomes of 45 patients with GNBBSI sepsis and 40 patients with GPC-BSI sepsis.The distinguishing performances of identified biomarkers were evaluated via receiver operating characteristic(ROC) curve.RESULTS:In pathogen-specific transcriptomes,54 identified genes were significantly associated with GNB-BSI(upregulated genes enriched in inflammatory pathways and downregulated genes enriched in oxidative phosphorylation).Twenty-one identified genes were associated with GPC-BSI(downregulated genes associated with cell adhesion molecules and upregulated genes involved in PI3K-Akt signaling).Nineteen genes were common to both groups,with distinct pathogen sensitivities.Patients with GNB-BSI presented with significantly greater disease severity,systemic inflammation and lymphopenia than patients with GPC-BSI.Conversely,patients with GPC-BSI had higher S100A12 and globulin levels and platelet counts.The combination of S100A12^(high) and procalcitonin(PCT)^(low) discriminated GPC-BSI from GNB-BSI(area under the curve=0.882,sensitivity 75%,specificity 91%;cutoff value 0.56).CONCLUSION:Sc RNA-seq reveals the heterogeneity of GPC-BSI and GNB-BSI.Compared with GPC-BSI,GNB-BSI causes severe inflammation and metabolic suppression,which are associated with poor outcomes.The S100A12^(high)+PCT^(low) combination may have potential to discriminate among the major causes of BSI.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82430018 to Q.C.,82270361 and 82570402 to H.Z.)the Nanjing Medical University Undergraduate Innovation and Entrepreneurship Training Program Fund(Grant No.202410312138Y to C.Z.)the Basic Sciences of Jiangsu Higher Education Institutions(Grant No.22KJA310002 to H.Z.)。
文摘As the prevalence of obesity increases dramatically,obesity-associated cardiac dysfunction constitutes a considerable challenge to human health.This study aimed to identify more useful lipid/inflammatory markers to predict the risk of obesity-associated cardiac dysfunction.By retrospectively analyzing the clinical characteristics of 5648 cardiac disease patients,we found that both the plasma level of high-density lipoprotein cholesterol(HDLC)and the blood monocyte count were significantly associated with impairment of the left ventricular ejection fraction(LVEF).Univariate and multivariate regression analyses revealed that the monocyte to HDL-C ratio(MHR)was a more powerful predictor of the risk of LVEF decline than either HDL-C or monocyte alone.Mediation analysis further revealed a mediating effect of a high MHR on the decline in obesity-associated cardiac systolic function.Collectively,our results demonstrate a superior role of MHR in predicting the risk of an obesityassociated decline in cardiac systolic function among routine metabolic/inflammatory markers.
基金National Natural Science Foundation of China,No.82471361(to MZ)the Natural Science Foundation for Excellent Young Scholars of Hunan Province,No.2021JJ20095(to MZ)+3 种基金the Key Research and Development Program of Hunan Province,No.2020SK2063(to MZ)the Research Project on Education and Teaching Innovation of Central South University,No.2021jy145(to MZ)the Natural Science Foundations of Hunan Province,No.2020JJ4134(to MZ)the Fundamental Research Funds for the Central Universities of Central South University,No.2023ZZTS0595(to YP).
文摘Monocytes play a crucial role in post-stroke immune infiltration,yet the intricate immune regulatory networks they orchestrate in ischemic stroke remain poorly understood.This knowledge gap has hindered the development of targeted monocyte-based therapies for stroke.Here,we used a multi-omics approach combining single-cell and bulk transcriptomics.CellChat analysis revealed intercellular communication networks,while key genes were identified and predictive models built through Lasso regression.Immune cell infiltration dynamics were quantified using single-sample gene set enrichment analysis.Gene set enrichment analysis and gene set variation analysis identified disease-regulated pathways of core genes.MicroRNA networks and transcription factors were investigated using mircode and RcisTarget.Experimental validation was performed using oxygen-glucose deprivation and transient middle cerebral artery occlusion models,focusing on the influence of abhydrolase domain-containing protein 2 on monocyte function.We observed significantly elevated monocyte content in stroke brain tissue samples,and identified key monocyte genes associated with immune inflammation,chemokine signaling,and cell receptor function.A robust seven-gene predictive model for ischemic stroke was developed.CD274 strongly correlated with these seven genes,suggesting a potential immunomodulatory axis.In vivo transient middle cerebral artery occlusion experiments validated the predictive value of key genes.In vitro studies demonstrated that abhydrolase domain-containing protein 2 overexpression enhanced monocyte proliferation and phagocytic activity post-oxygen-glucose deprivation while reducing reactive oxygen species generation.In conclusion,this study maps post-stroke monocyte communication networks,identifies key signaling pathways,identifies regulatory mechanisms,and validates the functional importance of key genes,particularly abhydrolase domain-containing protein 2.These findings provide a foundation for developing targeted immunomodulatory therapies and precision diagnostics in ischemic stroke management.
基金the National Institute for Health and Care Research(NHR)Manchester Biomedical Research Centre(BRC)(NIHR203308,NIHR-BRC-1215-20007)Astra-Zeneca(ESR-14-10711)+2 种基金CRUK RadNet(C19941/A27801)TMI and CFF are the recipient of an NIHR Senior Investigator Award(NIHR205054 and NIHR205061)CTH is supported by the NIHR University College London Hospitals NHS Foundation Trust BRC,the City of London CRUK RadNet and the CRUK Lung Cancer Centre of Excellence.
文摘Objectives:The PACIFIC trial established the benefit of durvalumab following chemo-radiotherapy for stage III non-small cell lung cancer(NSCLC).However,the concurrent use of radiotherapy(RT)and durvalumab(PACIFIC-2 trial)showed no additional advantage.The PD-RAD study was set up to understand the immunological effects of RT on the tumor microenvironment(TME)to aid in optimizing sequencing of combination therapies.Methods:The PD-RAD trial(ClinicalTrials.gov identifier:NCT03258788)aimed to enroll thirty NSCLC patients receiving radical-intent RT.Tumor biopsies and blood samples were collected pre-RT and at week 2 during RT and analyzed using multiplex immunohistochemistry(mIHC)and high-dimensional mass cytometry(CyTOF),respectively.Results:Paired biopsies were collected from only three patients(Pts 1,3&4)and blood from four patients(Pts 1-4)before the study was closed early during the COVID-19 pandemic.Programmed Death-Ligand 1(PD-L1)expression in the TME was raised in Patient 1,who responded well to treatment,and unaltered in two patients with progressive disease.CyTOF analysis revealed elevated circulating classical monocytes,highest in the patient with a good response.Conclusions:This study underscores the challenges of integrating advanced immune monitoring during RT delivery and did not meet its primary endpoint.The hypothesis-generating findings highlight PD-L1+macrophages in the TME and classical monocytes in the blood as potential immune biomarkers of RT response,but larger studies are needed to validate these observations and characterize the immune changes following curative-intent RT in patients with NSCLC.
基金This study was conducted and financed by the sponsor Zyagnum AG,https://www.zyagnum.com/Zyagnum AG has not received any grants,rather,this study was fully financed by Zyagnum AG.The authors S.B.and A.L.C.G.participated in the study as investigators.The University Hospital Hamburg-Eppendorf received reimbursement for the study from Zyagnum AG.
文摘Background:With a total of 1.46 million new cases and 396,792 deaths in 2022,prostate cancer is a major medical challenge around the world.Detecting and treating cancer at earlier,preferably localized stages can significantly increase survival rates.Here,a novel blood-based cancer screening as a pre-test in combination with targeted MRI imaging enabled the early diagnosis of prostate cancer.Case Description:We present the case of a 64-year-old man who participated in a prospective,interventional,multicenter cancer screening study where an immunological biopsy-based technique served as a part of a novel screening technique.This immunology technique represents a blood test exploiting two biomarkers,which may allow for the identification of individuals at an early stage of tumor development.Due to the elevated biomarker levels of Transketolase-like protein 1(TKTL1)and Apoptoic-associated cell population 10(Apo10),magnetic resonance imaging(MRI)was indicated for further clarification.A multiparametric MRI of the pelvis/prostate revealed an enlarged prostate gland and several suspicious lesions classified as Prostate Imaging Reporting and Data System(PI-RADS)4 and PI-RADS 5.In further assessments,both lesions were categorized as an acinar adenocarcinoma of the prostate(Gleason Score 6,International Society of Urological Pathology(ISUP)1,no perineural infiltration).After surgical resection,the tumor was classified histopathologically as an adenocarcinoma,pT2c pN0(0/7),L0,V0,Pn1,R0,Gleason score 7a,ISUP 2.Conclusions:The combination of the TKTL1/Apo10 blood test and subsequent imaging made it possible to detect a developing prostate carcinoma in a localized stage.All in all,this case report proves not just the ability but also the potential of the TKTL1/Apo10 blood test for early detection of(pre-)malignant lesions,which still present with a promising prospect for a cure.
文摘Objective To investigate the expression of mRNA and proteins ofβ-catenin,TCF-4(ICAT)and Wnt signaling pathway-related genes in the monocytic differentiation of acute myeloid leukemia HL-60 cells induced by a new steroidal drug NSC67657.Methods Wright’s staining andα-NBE staining were used to observe the differentiation of HL-60 cells after 5 days of
基金National Science Foundation for Young Scientists of China(No.81501707).
文摘Background:It has recently been recognized that serum vimentin is elevated in infectious diseases,and that vimentin plays a role in regulating neutrophils and macrophages associated inflammation.However,the mechanisms are unclear.This study was designed to explore the role of vimentin in regulating monocyte survival or apoptosis as well as inflammatory cytokine secretion in response to lipopolysaccharides(LPSs).Methods:A human monocytic leukemia cell line(THP-1)was transfected with vimentin-specific small interfering RNA(siRNA)or vimentin over-expressing plasmid.Apoptosis was assessed by TdT-mediated dUTP Nick-End Labeling(TUNEL)and DNA content assay.Immunoblotting was performed to detect apoptosis-associated proteins.Cytokines(interleukin[IL]-6,IL-10,and tumor necrosis factorα[TNF-α])were measured by enzyme-linked immuno sorbent assay.Two-way analysis of variance followed by Student's t test was used to compare means between different groups.Results:Suppression of vimentin in THP-1 cells resulted in increased apoptotic response in the presence of LPS,while overexpression of vimentin could prevent the cells from apoptosis in response to LPS.LPS alone or suppression of vimentin resulted in significant up-regulation of caspase-3(1.42±0.20 of LPS alone and 1.68±0.10 of vimentin suppression vs.control,t=5.21 and 10.28,respectively,P<0.05).In addition,pro-inflammatory cytokines(IL-6 and TNF-α)was significantly increased(IL-6:577.90±159.90 pg/day/105 cells vs.283.80±124.60 pg/day/105 cells of control,t=14.76,P<0.05;TNF-α:54.10±5.80 vs.17.10±0.10 pg/day/105 cells of control,t=6.71,P<0.05),while anti-inflammatory cytokine(IL-10)was significantly up-regulated in the THP-1 cells that over-expressed vimentin(140.9±17.2 pg/day/105 cells vs.undetectable in control cells).Contusions:In summary,the vimentin may regulate innate immunity through modulating monocytes viability as well as inflammatory response in sepsis through shifting the balance of pro-inflammatory and anti-inflammatory cytokines.
文摘Dendritic cells （DCs） are professional antigen-presenting cells with the ability to induce primary T-cell responses. They are commonly produced by culturing monocytes in the presence of IL-4 and GM-CSF （cells produced in this manner are called conventional DCs）. Here we report the generation of two functionally distinct subsets of DCs derived from programmable cells of monocytic origin （PCMOs） in the presence of IL-3 or tumor necrosis factor alpha （TNF-e）. Monocytes were treated with macrophage colony-stimulating factor （M-CSF） and IL-3 for 6 days and then incubated with IL-4 and IL-3 （for IL-3 DCs） or with IL-4, GM-CSF and TNF-a （for TNF-a DCs） for 7 days. Monocytes were then loaded with tumor lysate （used as antigen）, and poly （I ： C） was added. The maturation factors TNF-e and monocyte conditioned medium （MCM） were added on days 4 and 5, respectively. The phenotypes of the DCs generated were characterized by flow cytometry, and the cells＇ phagocytic activities were measured using FITC-conjugated latex bead uptake. T-cell proliferation and cytokine release were assayed using MTT and commercially available ELISA kits, respectively. We found that either IL-3DCs or TNF-α DCs induce T-cell proliferation and cytokine secretion; the cytokine release pattern showed reduced IL-12/IL- 10 and IFN-γ/IL-4 ratios in both types of DCs and in DC-primed T-cell supernatant, respectively, which confirmed that the primed T cells were polarized toward aTh2-type immune response. We concluded that PCMOs are a new cell source that can develop into two functionally distinct DCs that both induce a Th2-type response in vitro. This modality can be used as a DC-based immunotherapy for autoimmune diseases.
基金supported by the National Natural Science Foundation of China,Nos.82060219,82271234the Natural Science Foundation of Jiangxi Province,Nos.20212ACB216009,20212BAB216048+1 种基金Jiangxi Province Thousands of Plans,No.jxsq2019201023Youth Team Project of the Second Affiliated Hospital of Nanchang University,No.2019YNTD12003(all to FH)。
文摘Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple roles of mononuclear macrophages in the neuroinflammatory process. Monocytes play a significant role in neuroinflammation, and managing neuroinflammation by manipulating peripheral monocytes stands out as an effective strategy for the treatment of multiple sclerosis, leading to improved patient outcomes. This review outlines the steps involved in the entry of myeloid monocytes into the central nervous system that are targets for effective intervention: the activation of bone marrow hematopoiesis, migration of monocytes in the blood, and penetration of the blood–brain barrier by monocytes. Finally, we summarize the different monocyte subpopulations and their effects on the central nervous system based on phenotypic differences. As activated microglia resemble monocyte-derived macrophages, it is important to accurately identify the role of monocyte-derived macrophages in disease. Depending on the roles played by monocyte-derived macrophages at different stages of the disease, several of these processes can be interrupted to limit neuroinflammation and improve patient prognosis. Here, we discuss possible strategies to target monocytes in neurological diseases, focusing on three key aspects of monocyte infiltration into the central nervous system, to provide new ideas for the treatment of neurodegenerative diseases.
