RESUMO
Objective: Current scoring systems for short-term prognosis in patients with acute myocardial infarction (AMI) lack coverage of risk factors and have limitations in risk stratification. The aim of this study was to develop a novel assessment system based on laboratory indicators and frailty quantification to better infer short-term prognosis and risk indication in patients with AMI. Methods: A total of 365 patients with MI from January 2022 to June 2023 in Northern Jiangsu Province Hospital were included. The primary endpoint was all-cause mortality and major adverse cardiac events (MACE) during follow-up. A novel scoring model ranging from 0 to 12 was constructed, and the predictive ability of this scoring system was evaluated using the area under the receiver operating characteristic curve (AUC). Results: During follow-up, 68 patients experienced MACE. Five scoring indicators were selected through multivariate logistic regression analysis, resulting in a composite score with an AUC of 0.925, demonstrating good prognostic accuracy. Conclusion: The novel prognostic assessment system, which integrates age, Stress Hyperglycemia Ratio (SHR), Neutrophil to Lymphocyte Ratio (NLR), lactate, and frailty score, exhibits good predictive value for short-term MACE in patients with acute myocardial infarction and may enable more accurate risk classification for future use in MI patient risk management.
Assuntos
Fragilidade , Infarto do Miocárdio , Curva ROC , Humanos , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Feminino , Idoso , Estudos Retrospectivos , Fragilidade/diagnóstico , Prognóstico , Pessoa de Meia-Idade , Medição de Risco/métodos , Fatores de Risco , Neutrófilos , Idoso de 80 Anos ou mais , China , Modelos Logísticos , Ácido Láctico/sangueRESUMO
Disrupted N6-methyladenosine (m6A) modification modulates various inflammatory disorders. However, the role of m6A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m6A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of Mettl3 in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m6A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m6A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m6A reader IGF2BP3, leading to a rewiring of fatty acid metabolism with a reduction in palmitic acid accumulation and, consequently, suppressing neutrophil chemotaxis in cutaneous inflammation. Our findings highlight a previously unrecognized epithelial-intrinsic m6A modification-lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m6A modulators to attenuate inflammatory skin diseases.
Assuntos
Adenosina , Homeostase , Queratinócitos , Metabolismo dos Lipídeos , Metiltransferases , Neutrófilos , Pele , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Neutrófilos/metabolismo , Neutrófilos/imunologia , Camundongos , Queratinócitos/metabolismo , Humanos , Metiltransferases/metabolismo , Metiltransferases/genética , Pele/metabolismo , Pele/patologia , Pele/imunologia , Inflamação/metabolismo , Inflamação/patologia , Quimiotaxia , Elongases de Ácidos Graxos/metabolismo , Elongases de Ácidos Graxos/genéticaRESUMO
OBJECTIVE: The aim of this study was to investigate the role of systemic immune-inflammation index, neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, and platelet-lymphocyte ratios calculated in the first trimester as inflammatory markers in predicting gestational diabetes mellitus diagnosis. METHODS: This study was conducted retrospectively at a tertiary center between January 2020 and June 2023. A total of 111 pregnant women with gestational diabetes and 378 pregnant women in the control group were included in the study. Systemic immune-inflammation index, neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, and platelet-lymphocyte ratios values were compared between the gestational diabetes mellitus group patients and the healthy group. Receiver operating characteristic analysis curve was used for predicting gestational diabetes mellitus using systemic immune-inflammation index and lymphocyte-monocyte ratio. RESULTS: In pregnant women in the first trimester, systemic immune-inflammation index and lymphocyte-monocyte ratio values based on routine complete blood count parameters were found to be statistically significantly higher in gestational diabetes mellitus patients compared to healthy patients, while neutrophil-lymphocyte ratio and platelet-lymphocyte ratios values were found to be similar (p=0.033, p=0.005, p=0.211, and p=0.989). For predicting gestational diabetes mellitus, a cut-off value of 655.75 for systemic immune-inflammation index resulted in 80.2% sensitivity and 34.4% specificity, and a cut-off value of 3.62 for lymphocyte-monocyte ratio resulted in 56.8% sensitivity and 63.2% specificity, indicating good discriminatory ability. CONCLUSION: We believe that systemic immune-inflammation index and lymphocyte-monocyte ratio values measured in the first-trimester complete blood count parameters are effective in predicting gestational diabetes mellitus but are not effective in determining insulin requirement.
Assuntos
Biomarcadores , Diabetes Gestacional , Neutrófilos , Primeiro Trimestre da Gravidez , Curva ROC , Humanos , Diabetes Gestacional/sangue , Diabetes Gestacional/imunologia , Diabetes Gestacional/diagnóstico , Feminino , Gravidez , Primeiro Trimestre da Gravidez/sangue , Primeiro Trimestre da Gravidez/imunologia , Estudos Retrospectivos , Adulto , Biomarcadores/sangue , Inflamação/sangue , Inflamação/imunologia , Linfócitos/imunologia , Valor Preditivo dos Testes , Monócitos/imunologia , Estudos de Casos e Controles , Contagem de Plaquetas , Contagem de Linfócitos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Since differentiating malignant ascites from benign ascites has always been a clinical difficult, recognition of novel biomarkers in malignant ascites of hepatocellular carcinoma (HCC) patients could be helpful for establishing a diagnosis for HCC patients with ascitic fluids. METHODS: Thirty-five HCC patients with malignant ascites and chronic liver diseases patients with benign ascites were enrolled. Serum and ascites specimens were collected to determine TAN subpopulations and NETs concentration. Then, the correlation between ascitic NETs levels and clinical features were analyzed, and ROC curves were generated to evaluate the diagnostic value of NETs. For in vitro study, fresh neutrophils were employed to explore the underlying mechanism of TAN polarization and NETs formation using RNAseq analysis. RESULTS: Significantly increased pro-tumor PD-L1+ TANs and higher lactate levels were measured in HCC ascites. RNAseq data showed that lactate regulated genes expression involving PD-L1 expression and NETs formation, suggesting that ascitic lactate might be responsible for tumor progression in TME. Then, NETs-related markers including calprotectin, dsDNA, CitH3, MPO and MPO-DNA were found dramatically elevated in malignant ascites. Next, correlation analysis revealed that ascitic NETs levels positively correlated with LDH, a classic ascitic biochemical indicator. Furthermore, we identified the diagnostic values of NETs in discriminating malignant ascites from benign ascites. CONCLUSIONS: Our findings highlighted that elevated ascitic NETs served as a biomarker in HCC patients with malignant ascites, which provided useful insights for both clinical and basic research for malignant ascites diagnosis and management.
Assuntos
Ascite , Antígeno B7-H1 , Biomarcadores Tumorais , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neutrófilos , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , Neutrófilos/metabolismo , Ascite/metabolismo , Ascite/patologia , Biomarcadores Tumorais/metabolismo , Masculino , Antígeno B7-H1/metabolismo , Feminino , Pessoa de Meia-Idade , Armadilhas Extracelulares/metabolismo , IdosoRESUMO
Background and purpose:
Mechanical thrombectomy is the most important treatment modality in acute stroke; despite successful thrombectomy, good functional outcome is not achieved in a significant proportion of patients. This study examined the effect of neutrophil lymphocyte ratio (NLR) values at admission on functional outcomes in successfully recanalized patients.
. Methods:Patients who underwent mechanical thrombectomy due to anterior system major vessel occlusion were retrospectively analyzed and compared with the admission NLR values and 3-month clinical modified Rankin Scale (mRS) scores of successfully recanalized patients.
. Results:Of a total of 126 patients who underwent thrombectomy within the specified period, 97 patients with successful recanalization were included in the study. The overall successful recanalization rate was calculated as 77%. The mean NLR of patients with mRS ≤2 (n=65) was found to be significantly lower than patients with mRS≥3 (n=32) (p<0.001). A weak and significant correlation was found between National Institutes of Health Stroke Scale (NIHSS) value and NLR (r= 0.315, p=.002).
. Conclusion:NLR value has been found to be associated with futile recanalization in mechanical thrombectomy patients. Therefore, we think that suppression of inflammation before thrombectomy will increase the chance of successful thrombectomy.
.Assuntos
Linfócitos , Neutrófilos , Acidente Vascular Cerebral , Trombectomia , Humanos , Acidente Vascular Cerebral/cirurgia , Prognóstico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Inflamação , Resultado do TratamentoRESUMO
Neutrophils are critical mediators of both the initiation and resolution of inflammation after myocardial infarction (MI). Overexuberant neutrophil signaling after MI exacerbates cardiomyocyte apoptosis and cardiac remodeling while neutrophil apoptosis at the injury site promotes macrophage polarization toward a pro-resolving phenotype. Here, we describe a nanoparticle that provides spatiotemporal control over neutrophil fate to both stymie MI pathogenesis and promote healing. Intravenous injection of roscovitine/catalase-loaded poly(lactic-co-glycolic acid) nanoparticles after MI leads to nanoparticle uptake by circulating neutrophils migrating to the infarcted heart. Activated neutrophils at the infarcted heart generate reactive oxygen species, triggering intracellular release of roscovitine, a cyclin-dependent kinase inhibitor, from the nanoparticles, thereby inducing neutrophil apoptosis. Timely apoptosis of activated neutrophils at the infarcted heart limits neutrophil-driven inflammation, promotes macrophage polarization toward a pro-resolving phenotype, and preserves heart function. Modulating neutrophil fate to tune both inflammatory and reparatory processes may be an effective strategy to treat MI.
Assuntos
Apoptose , Inflamação , Macrófagos , Infarto do Miocárdio , Nanopartículas , Neutrófilos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Roscovitina , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/tratamento farmacológico , Animais , Neutrófilos/imunologia , Neutrófilos/metabolismo , Inflamação/patologia , Nanopartículas/química , Apoptose/efeitos dos fármacos , Roscovitina/farmacologia , Macrófagos/imunologia , Macrófagos/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Masculino , Ácido Poliglicólico/química , Ácido Láctico/metabolismo , Modelos Animais de Doenças , HumanosRESUMO
OBJECTIVES: Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) is an adhesion molecule that acts as a coinhibitory receptor in the immune system. We previously demonstrated that CEACAM1 is predominantly expressed on peripheral blood neutrophils in patients with RA. The aim of the present study was to investigate the effects of Janus kinase inhibitors (JAKi) on cytokine-activated human neutrophils and CEACAM1 expression. METHODS: Peripheral blood neutrophils were obtained from healthy subjects. Isolated neutrophils were stimulated with tumor necrosis factor-alpha (TNF-α) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in the presence or absence of JAKi. The expression of CEACAM1 in peripheral blood neutrophils was analyzed by flow cytometry. Protein phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 was assessed by western blot using phospho-specific antibodies. RESULTS: We found that TNF-α-induced CEACAM1 expression was marginally suppressed after pretreatment with pan-JAK inhibitor, tofacitinib. Moreover, TNF-α induced STAT1 and STAT3 phosphorylation at the late stimulation phase (4 to 16 h). The expressions of CEACAM1 on neutrophils were markedly up-regulated by GM-CSF not by interleukin (IL)-6 stimulation. All JAKi inhibited GM-CSF-induced CEACAM1 expressions on neutrophils, however, the inhibitory effects of baricitinib were larger compared to those of tofacitinib or filgotinib. Moreover, CEACAM1 was marginally upregulated in interferon (IFN)-γ stimulated neutrophils. Similarly, JAKi inhibited IFN-γ-induced CEACAM1 expressions on neutrophils. CONCLUSIONS: We demonstrated that JAKi prevent GM-CSF-induced CEACAM1 expression in neutrophils, and JAKi-induced inhibition depends on their selectivity against JAK isoforms. These findings suggest that JAKi can modulate the expression of CEACAM1 in cytokine-activated neutrophils, thereby limiting their activation.
Assuntos
Antígenos CD , Moléculas de Adesão Celular , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Inibidores de Janus Quinases , Neutrófilos , Pirimidinas , Fator de Necrose Tumoral alfa , Humanos , Neutrófilos/metabolismo , Neutrófilos/imunologia , Neutrófilos/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Antígenos CD/metabolismo , Pirimidinas/farmacologia , Inibidores de Janus Quinases/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Pirróis/farmacologia , Ativação de Neutrófilo/efeitos dos fármacos , Citocinas/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
In end-stage heart failure, which is characterized by persistent or progressive ventricular dysfunction despite optimal medical therapy, a left ventricular assist device (LVAD) can be beneficial. Congestive heart failure provokes inflammatory and prothrombotic activation. The aim of this study was to evaluate the serum concentration of citrullinated histone 3 (CH3) representing neutrophil extracellular trap (NET) formation in patients referred for LVAD implantation. There were 10 patients with a median age of 61 (57-65) years enrolled in a prospective single-center analysis who underwent LVAD implantation. The CH3 plasma concentration was measured preoperatively and on the 1st and 7th postoperative days, followed by control measurements on the median (Q1-3) 88th (49-143) day. The preoperative CH3 concentration strongly correlated with brain natriuretic peptide (r = 0.879, p < 0.001). Significant differences in CH3 serum concentration were observed between pre- and postoperative measurements, including an increase on the first postoperative day (p < 0.001), as well as a decrease on the seventh day (p = 0.016) and in follow-up (p < 0.001). CH3 concentration, as a marker of NET formation, decreases after LVAD implantation.
Assuntos
Armadilhas Extracelulares , Insuficiência Cardíaca , Coração Auxiliar , Histonas , Humanos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/terapia , Armadilhas Extracelulares/metabolismo , Pessoa de Meia-Idade , Masculino , Feminino , Idoso , Histonas/sangue , Histonas/metabolismo , Estudos Prospectivos , Biomarcadores/sangue , Neutrófilos/metabolismo , CitrulinaçãoRESUMO
Ankylosing spondylitis (AS) as a autoimmune disease involves inflammatory responses in the development of the disease, often causing changes in the neutrophil to lymphocyte ratio (NLR). In the past few decades, research on the relationship between NLR and AS has generally shown an upward trend. This study adopts the bibliometrics method to analyze the development trend, frontier, and hotspots of global research in this field in the past 2 decades. By searching for publications in the SCI-Expanded edition of the Web of Science Core Collection, the information of literature published between 2000 and 2023 is recorded. Based on the VOSviewer, CiteSpace and Excel, bibliometric analysis, and visualization analysis are conducted on the overall distribution of annual output, leading countries, active institutions, journals, authors, co-cited references, and keywords. Through retrieving and screening, a total of 1654 papers are obtained for analysis. In the past 2 decades, the number of publications related to this field has shown an increasing trend. The United States has the highest Hirsch index (H-index) and publication volume. The most productive institution is Harvard University, while the H-index of the University of Milan in Italy is far ahead. Frontiers in Immunology is the institution with the highest output. The H-index of the Annals of the Rheumatic holds the top position. This study has uncovered the main emphasis on NLR in AS research and has provided clarification regarding the value of NLR as a biomarker for immune inflammatory response in the diagnosis and prognosis of AS.
Assuntos
Bibliometria , Linfócitos , Neutrófilos , Espondilite Anquilosante , Espondilite Anquilosante/sangue , Humanos , Linfócitos/imunologiaRESUMO
Importance: Absolute neutrophil counts (ANCs) are used to determine cancer clinical trial (CCT) eligibility and systemic anticancer therapy (SACT) dose modifications. Duffy null-associated ANC (DANC) is a nonpathologic phenotype associated with lower ANC and most frequently seen in individuals with African and Middle Eastern ancestry. It is unclear whether CCTs exclude or SACT regimens modify doses for individuals with ANC within the DANC reference range. Objective: To investigate CCT exclusions and SACT dose modifications for ANC within the DANC reference range. Design, Setting, and Participants: This cross-sectional study of contemporary CCTs and SACT regimens included adult, interventional, phase 3 CCTs for the 5 most prevalent cancers in the US and United Kingdom (prostate, breast, melanoma, colorectal, and lung cancers) testing SACTs with start dates between November 1, 2021, and November 1, 2023, and that were registered on ClinicalTrials.gov. Preferred curative-intent SACT regimens were listed in National Comprehensive Cancer Network guidelines. Exposure: Cancer clinical trial exclusions and SACT regimen modifications. Main Outcome and Measures: Proportions of CCTs that exclude and SACT regimens that modify doses for individuals with an ANC within the DANC reference range. Results: For CCTs, 289 of 382 trials (75.7%) were eligible, of which 221 (76.5% [95% CI, 71.1%-81.2%]) excluded patients with ANC values within the DANC reference range. Colorectal CCTs had the highest (38 of 44 [86.4% (95% CI, 72.6%-94.8%)]) and prostate CCTs had the lowest (11 of 23 [47.8% (95% CI, 26.8%-69.4%)]) proportions of exclusions. Of CCTs testing cytotoxic chemotherapy, 116 of 142 (81.7% [95% CI, 74.3%-87.7%]) had exclusions; 93 of 123 (75.6% [95% CI, 67.0%-82.9%]) CCTs testing targeted therapies alone and 12 of 24 (50.0% [95% CI, 29.1%-70.9%]) testing hormonal therapies alone had exclusions. Among the 113 US- and UK-based trials, exclusions were present in 89 (78.8% [95% CI, 70.1%-85.9%]). Of 71 SACT regimens, 38 (53.5% [95% CI, 41.3%-65.5%]) included dose modifications for ANC values within the DANC reference range. Lung cancer regimens had the highest (23 of 31 [74.2% (95% CI, 55.4%-88.1%)]) and prostate cancer had the lowest (0 of 12 [0 (95% CI, 0%-26.4%)]) proportions of modifications. Regimens including chemotherapy had modifications in 32 of 44 (72.7% [95% CI, 57.2%-85.0%]); 11 of 20 (55.0% [95% CI, 31.5%-76.9%]) of targeted therapy regimens and 0 of 16 (0% [95% CI, 0%-20.6%]) of hormonal therapy regimens had modifications. Among regimens including chemotherapy and/or targeted therapy, modifications were present in 38 of 55 (69.1% [95% CI, 49.7%-73.2%]). Conclusions and Relevance: In this cross-sectional study, substantial proportions of CCTs excluded and SACT regimens modified doses for patients with ANCs in the DANC reference range. These practices structurally discriminate against patients of African and Middle Eastern ancestry. While determining optimal SACT dose modifications requires further study, CCT exclusion criteria should be revised.
Assuntos
Neoplasias , Neutrófilos , Humanos , Estudos Transversais , Masculino , Feminino , Neoplasias/tratamento farmacológico , Contagem de Leucócitos , Pessoa de Meia-Idade , Adulto , Definição da Elegibilidade/estatística & dados numéricos , Sistema do Grupo Sanguíneo Duffy , Antineoplásicos/uso terapêutico , Estados Unidos , Ensaios Clínicos como Assunto , Idoso , Reino UnidoRESUMO
BACKGROUND: At present, hepatic ischemia-reperfusion injury (IRI) is an important complication of partial hepatectomy and liver transplantation, and it is an important cause of poor prognosis. Spleen tyrosine kinase(SYK) plays an important role in a variety of signaling pathways in the liver, but its role in hepatic IRI is still unclear. This study aims to investigate the role and mechanism of SYK in hepatic IRI and tumor recurrence. METHODS: We first observed the activation of SYK in the liver of mice in response to hepatic IRI. Subsequently, Pharmacological inhibitions of SYK were used to evaluated the effect of SYK on neutrophil recruitment and NETosis, and further explored the effect of SYK on IRI and tumor recurrence. RESULTS: Our study shows that SYK is activated in response to hepatic IRI and aggravates liver injury. On the one hand, neutrophils SYK during the early stage of liver reperfusion increases neutrophil extracellular traps (NETs) production by promoting Pyruvate kinase M2(PKM2) nuclear translocation leading to upregulation of phosphorylated STAT3, thereby exacerbating liver inflammation and tumor recurrence. On the other hand, macrophages SYK can promote the recruitment of neutrophils and increase the activation of NLRP3 inflammasome and IL1ß, which further promotes the formation of NETs. CONCLUSIONS: Our study demonstrates that neutrophil and macrophage SYK synergistically promote hepatic IRI and tumor recurrence, and SYK may be a potential target to improve postoperative hepatic IRI and tumor recurrence.
Assuntos
Armadilhas Extracelulares , Proteínas de Membrana , Neutrófilos , Traumatismo por Reperfusão , Fator de Transcrição STAT3 , Quinase Syk , Quinase Syk/metabolismo , Animais , Fator de Transcrição STAT3/metabolismo , Armadilhas Extracelulares/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Fosforilação , Camundongos , Proteínas de Membrana/metabolismo , Masculino , Neutrófilos/metabolismo , Proteínas de Transporte/metabolismo , Piruvato Quinase/metabolismo , Fígado/metabolismo , Fígado/patologia , Proteínas de Ligação a Hormônio da Tireoide , Recidiva Local de Neoplasia/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Humanos , Transdução de SinaisRESUMO
BACKGROUND: Tumor-associated neutrophils (TANs) constitute an abundant component among tumor-infiltrating immune cells and have recently emerged as a critical player in pancreatic ductal adenocarcinoma (PDAC) progression. This study aimed to elucidate the pro-tumor mechanisms of TAN and identify a novel target for effective immunotherapy against PDAC. METHODS: Microarray and cytokine array analyses were performed to identify the mechanisms underlying the function of TANs. Human and mouse TANs were obtained from differentiated HL-60 cells and orthotopically transplanted PDAC tumors, respectively. The interactions of TANs with cancer and cytotoxic T-cells were evaluated through in vitro co-culture and in vivo orthotopic or subcutaneous models. Single-cell transcriptomes from patients with PDAC were analyzed to validate the cellular findings. RESULTS: Increased neutrophil infiltration in the tumor microenvironment was associated with poor survival in patients with PDAC. TANs secreted abundant amounts of chemokine ligand 5 (CCL5), subsequently enhancing cancer cell migration and invasion. TANs subpopulations negatively correlated with cytotoxic CD8+ T-cell infiltration in PDAC and promoted T-cell dysfunction. TANs upregulated the membranous expression of Nectin2, which contributed to CD8+ T-cell exhaustion. Blocking Nectin2 improved CD8+ T-cell function and suppressed tumor progression in the mouse model. Single-cell analysis of human PDAC revealed two immunosuppressive TANs phenotypes: Nectin2+ TANs and OLR1+ TANs. Endoplasmic reticulum stress regulated the protumor activities in TANs. CONCLUSIONS: TANs enhance PDAC progression by secreting CCL5 and upregulating Nectin2. Targeting the immune checkpoint Nectin2 could represent a novel strategy to enhance immunotherapy efficacy in PDAC.
Assuntos
Carcinoma Ductal Pancreático , Nectinas , Neutrófilos , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Microambiente Tumoral/imunologia , Animais , Camundongos , Nectinas/metabolismo , Nectinas/genética , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Regulação para Cima , Feminino , Linhagem Celular Tumoral , Masculino , Modelos Animais de DoençasRESUMO
Seminal plasma (SP) is the main vector of C. trachomatis (CT) during heterosexual transmission from male to female. It has immunomodulatory properties and impacts the susceptibility to HIV-1 infection, but its role has not been explored during CT infection. In the female reproductive tract (FRT), CT infection induces cytokine production and neutrophil recruitment. The role of neutrophils during CT infection is partially described, they could be at the origin of the pathology observed during CT infection. During this study, we developed an experimental in vitro model to characterize the impact of CT infection and SP on endocervical epithelial cell immune response in the FRT. We also studied the impact of the epithelial cell response on neutrophil phenotype and functions. We showed that the production by epithelial cells of pro-inflammatory cytokines increased during CT infection. Moreover, the pool of SP as well as individuals SP inhibited CT infection in a dose-dependent manner. The pool of SP inhibited cytokine production in a dose-dependent manner. The pool of SP altered gene expression profiles of infected cells. The culture supernatants of cells infected or not with CT, in presence or not of the pool of SP, had an impact on neutrophil phenotype and functions: they affected markers of neutrophil maturation, activation and adhesion capacity, as well as the survival, ROS production and phagocytosis ability. This study proposes a novel approach to study the impact of the environment on the phenotype and functions of neutrophils in the FRT. It highlights the impact of the factors of the FRT environment, in particular SP and CT infection, on the mucosal inflammation and the need to take into account the SP component while studying sexually transmitted infections during heterosexual transmission from male to female.
Assuntos
Infecções por Chlamydia , Chlamydia trachomatis , Citocinas , Imunidade nas Mucosas , Neutrófilos , Sêmen , Chlamydia trachomatis/imunologia , Chlamydia trachomatis/fisiologia , Humanos , Feminino , Sêmen/imunologia , Sêmen/microbiologia , Sêmen/metabolismo , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/microbiologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Citocinas/metabolismo , Masculino , Células Epiteliais/microbiologia , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Fagocitose , Colo do Útero/microbiologia , Colo do Útero/imunologiaRESUMO
This study aims to evaluate the neutrophil-to-lymphocyte ratio (NLR) as a predictive biomarker for cardiovascular mortality among cancer patients, utilizing data from the National Health and Nutrition Examination Survey (NHANES). From the NHANES dataset (2007-2018), we analyzed 4974 cancer survivors, investigating the prognostic significance of NLR for all-cause, cardiovascular, and cancer-specific mortality. Survival outcomes were analyzed using Cox regression and Kaplan-Meier methods. Optimal NLR cutoffs were identified as 2.61 for differentiating the higher NLR group from lower NLR group. Elevated NLR levels significantly correlated with increased all-cause mortality (HR 1.11, 95% CI 1.07-1.14, P < 0.001) and cardiovascular mortality (HR 1.14, 95% CI 1.08-1.21, P < 0.001) in adjusted models. Subgroup analyses revealed that age, sex, smoking status, and hypertension significantly influence NLR's association with cardiovascular mortality. Specific cancers including breast, prostate, non-melanoma skin, colon and melanoma experience increased all-cause and cardiovascular mortality in the higher NLR group compared to lower NLR group. Elevated NLR is a significant predictor of increased mortality in cancer patients, particularly for cardiovascular outcomes. These findings support that NLR acts as a pivotal prognostic tool with significant implications for clinical practice in the realm of cardio-oncology.
Assuntos
Sobreviventes de Câncer , Doenças Cardiovasculares , Linfócitos , Neoplasias , Neutrófilos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/sangue , Sobreviventes de Câncer/estatística & dados numéricos , Idoso , Prognóstico , Neoplasias/mortalidade , Neoplasias/sangue , Neoplasias/complicações , Adulto , Contagem de Linfócitos , Inquéritos Nutricionais , Estimativa de Kaplan-Meier , Contagem de LeucócitosRESUMO
The inducers of neutrophil extracellular trap (NET) formation are heterogeneous and consequently, there is no specific pathway or signature molecule indispensable for NET formation. But certain events such as histone modification, chromatin decondensation, nuclear envelope breakdown, and NET release are ubiquitous. During NET formation, neutrophils drastically rearrange their cytoplasmic, granular and nuclear content. Yet, the exact mechanism for decoding each step during NET formation still remains elusive. Here, we investigated the mechanism of nuclear envelope breakdown during NET formation. Immunofluorescence microscopic evaluation revealed a gradual disintegration of outer nuclear membrane protein nesprin-1 and alterations in nuclear morphology during NET formation. MALDI-TOF analysis of NETs that had been generated by various inducers detected the accumulation of nesprin-1 fragments. This suggests that nesprin-1 degradation occurs before NET release. In the presence of a calpain-1, inhibitor nesprin-1 degradation was decreased in calcium driven NET formation. Microscopic evaluation confirmed that the disintegration of the lamin B receptor (LBR) and the collapse of the actin cytoskeleton occurs in early and later phases of NET release, respectively. We conclude that the calpain-1 degrades nesprin-1, orchestrates the weakening of the nuclear membrane, contributes to LBR disintegration, and promoting DNA release and finally, NETs formation.
Assuntos
Calpaína , Armadilhas Extracelulares , Receptor de Lamina B , Neutrófilos , Membrana Nuclear , Membrana Nuclear/metabolismo , Calpaína/metabolismo , Humanos , Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Cálcio/metabolismo , Proteínas do CitoesqueletoRESUMO
INTRODUCTION: Early childhood caries (ECC) is closely associated with poor oral hygiene and cariogenic diet. Untreated ECC results in recurrent odontogenic infections and local and systemic consequences. In this study, our goal is to assess the relationship between the intensity of odontogenic infection-associated periapical periodontitis and new generation of systemic inflammatory markers (SII, NLR, PLR) in ECC-affected children. MATERIAL AND METHOD: 95 healthy patients in early childhood and demonstrating periapical periodontitis who underwent dental treatment under general anesthesia (GA) in the last two years were included in the present study. Their periapical statuses were dichotomized as mild and severe. Periapical Index (PAI) scores of 2 and 3 were regarded as "mild" whereas 4 and 5 as "severe". Of the complete blood test (CBC) parameters, systemic inflammatory index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), neutrophilic granulocyte (NEUT), lymphocyte (LYMPH) and platelet (PLT) were recorded. The relationship between the degree of periapical pathology and the evaluated markers was assessed using Receiver Operating Characteristic (ROC) analysis. RESULTS: Results of the present study revealed that mean NLR, SII and NEUT index scores of the patients having severe periapical periodontitis were statistically higher than those of the ones with mild pathology (p < 0.05). A positive, statistically significant interrelationship was found between the number of teeth demonstrating a PAI score of severe periapical periodontitis with the signs of exacerbation (PAI 5) and NLR and SII values (p < 0.05). Area under the ROC curve (AUC) values for NLR and SII were determined as 66.8% and 66.6% respectively, indicating that classification performance was sufficient and statistically significant (p < 0.05). CONCLUSION: Postponing the management of odontogenic infections will induce some complications such as, infective endocarditis and cause the systemic inflammatory process to continue by aggravating the systemic effects of local lesions. Thus, underlying mechanism should be eliminated and oral hygiene should be maintained, also novel biomarkers may be recommended to be used for the decision-making process for the teeth with persistent periapical lesions unresponsive to treatment.
Assuntos
Biomarcadores , Cárie Dentária , Periodontite Periapical , Humanos , Periodontite Periapical/sangue , Periodontite Periapical/complicações , Biomarcadores/sangue , Feminino , Masculino , Cárie Dentária/sangue , Pré-Escolar , Criança , Índice de Gravidade de Doença , Neutrófilos , Inflamação/sangueRESUMO
Introduction: G-protein coupled receptors (GPCRs) expressed on neutrophils regulate their mobilization from the bone marrow into the blood, their half-live in the circulation, and their pro- and anti-inflammatory activities during inflammation. Chronic kidney disease (CKD) is associated with systemic inflammatory responses, and neutrophilia is a hallmark of CKD onset and progression. Nonetheless, the role of neutrophils in CKD is currently unclear. Methods: Blood and renal tissue were collected from non-dialysis CKD (grade 3 - 5) patients to evaluate GPCR neutrophil expressions and functions in CKD development. Results: CKD patients presented a higher blood neutrophil-to-lymphocyte ratio (NLR), which was inversely correlated with the glomerular filtration rate (eGFR). A higher frequency of neutrophils expressing the senescent GPCR receptor (CXCR4) and activation markers (CD18+CD11b+CD62L+) was detected in CKD patients. Moreover, CKD neutrophils expressed higher amounts of GPCR formyl peptide receptors (FPR) 1 and 2, known as neutrophil pro- and anti-inflammatory receptors, respectively. Cytoskeletal organization, migration, and production of reactive oxygen species (ROS) by CKD neutrophils were impaired in response to the FPR1 agonist (fMLP), despite the higher expression of FPR1. In addition, CKD neutrophils presented enhanced intracellular, but reduced membrane expression of the protein Annexin A1 (AnxA1), and an impaired ability to secrete it into the extracellular compartment. Secreted and phosphorylated AnxA1 is a recognized ligand of FPR2, pivotal in anti-inflammatory and efferocytosis effects. CKD renal tissue presented a low number of neutrophils, which were AnxA1+. Conclusion: Together, these data highlight that CKD neutrophils overexpress GPCRs, which may contribute to an unbalanced aging process in the circulation, migration into inflamed tissues, and efferocytosis.
Assuntos
Neutrófilos , Receptores de Formil Peptídeo , Insuficiência Renal Crônica , Humanos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptores de Formil Peptídeo/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Lipoxinas/metabolismo , Receptores CXCR4/metabolismoRESUMO
Neutrophilia occurs in patients infected with SARS-CoV-2 (COVID-19) and is predictive of poor outcomes. Here, we link heterogenous neutrophil populations to disease severity in COVID-19. We identified neutrophils with features of cellular aging and immunosuppressive capacity in mild COVID-19 and features of neutrophil immaturity and activation in severe disease. The low-density neutrophil (LDN) number in circulating blood correlated with COVID-19 severity. Many of the divergent neutrophil phenotypes in COVID-19 were overrepresented in the LDN fraction and were less detectable in normal-density neutrophils. Functionally, neutrophils from patients with severe COVID-19 displayed defects in neutrophil extracellular trap formation and reactive oxygen species production. Soluble factors secreted by neutrophils from these patients inhibited T cell proliferation. Neutrophils from patients with severe COVID-19 had increased expression of arginase-1 protein, a feature that was retained in convalescent patients. Despite this increase in intracellular expression, there was a reduction in arginase-1 release by neutrophils into serum and culture supernatants. Furthermore, neutrophil-mediated T cell suppression was independent of arginase-1. Our results indicate the presence of dysfunctional, activated, and immature neutrophils in severe COVID-19.
Assuntos
Arginase , COVID-19 , Neutrófilos , SARS-CoV-2 , Índice de Gravidade de Doença , Humanos , COVID-19/imunologia , COVID-19/sangue , Arginase/metabolismo , Neutrófilos/metabolismo , Neutrófilos/imunologia , SARS-CoV-2/imunologia , Masculino , Pessoa de Meia-Idade , Feminino , Linfócitos T/imunologia , Linfócitos T/metabolismo , Idoso , Adulto , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/imunologia , Espécies Reativas de Oxigênio/metabolismo , Ativação de NeutrófiloRESUMO
With the increasing incidence of coronary heart disease (CHD), contrast-associated nephropathy (CAN) caused by contrast agents required in coronary angiography has gradually become a clinical concern that needs to be solved urgently. At present, CAN has become one of the most common causes of hospital-acquired acute kidney injury, which seriously affects the prognosis and health of patients. How to effectively identify high-risk CAN patients and prevent the occurrence of CAN has become a hotspot of clinical research. In this study, we attempted to evaluate the effect of contrast agents on renal injury in diabetes mellitus (DM) and non-DM patients by observing some indexes of early renal injury and inflammatory factors, so as to provide a more comprehensive reference for early identification of CAN in the future. The results showed that compared with non-DM patients, contrast agents caused more obvious renal damage in DM patients and more significantly activated inflammatory responses, increasing the risk of CAN. Cystatin C (CysC), neutrophil gelatinase-associated lipocalin (NGAL), C-reactive protein (CRP), and neutrophil-lymphocyte ratio (NLR) all showed excellent predictive effects for the occurrence of CAN after coronary angiography in both DM and non-DM patients.
Assuntos
Injúria Renal Aguda , Meios de Contraste , Angiografia Coronária , Inflamação , Humanos , Meios de Contraste/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Inflamação/patologia , Idoso , Injúria Renal Aguda/induzido quimicamente , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Lipocalina-2 , Diabetes Mellitus , Cistatina C/sangue , Biomarcadores/sangue , Neutrófilos/metabolismo , Relevância ClínicaRESUMO
Acute respiratory distress syndrome is a severe lung condition resulting from various causes, with life-threatening consequences that necessitate intensive care. The phenomenon can be modeled in preclinical models, notably through the use of lipopolysaccharide (LPS) instillation in mice. The phenotype induced closely recapitulates the human syndrome, including pulmonary edema, leukocyte infiltration, acute inflammation, impaired pulmonary function, and histological damage. However, the experimental designs using LPS instillations are extremely diverse in the literature. This highly complicates the interpretation of the induced phenotype chronology for future study design and hinders the proper identification of the optimal time frame to assess different readouts. Therefore, the definition of the treatment window in relation to the beginning of the disease onset also presents a significant challenge to address questions or test compound efficacy. In this context, the temporality of the different readouts usually measured in the model was evaluated in both normal and neutrophil-depleted male C57bl/6 mice using LPS-induction to assess the best window for proper readout evaluation with an optimal dynamic response range. Ventilation parameters were evaluated by whole-body plethysmography and neutrophil recruitment were evaluated in bronchoalveolar lavage fluids and in lung tissues directly. Imaging evaluation of myeloperoxidase along with activity in lung lysates and fluids were compared, along with inflammatory cytokines and lung extravasation by enzyme-linked immunoassays. Moreover, dexamethasone, the gold standard positive control in this model, was also administered at different times before and after phenotype induction to assess how kinetics affected each parameter. Overall, our data demonstrate that each readout evaluated in this study has a singular kinetic and highlights the key importance of the timing between ARDS phenotype and treatment administration and/or analysis. These findings also strongly suggest that analyzes, both in-life and post-mortem should be conducted at multiple time points to properly capture the dynamic phenotype of the LPS-ARDS model and response to treatment.