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Many powerful methods have been employed to elucidate the global transcriptomic, proteomic, or metabolic responses to pathogen-infected host cells. However, the host glycome responses to bacterial infection remain largely unexplored, and hence, our understanding of the molecular mechanisms by which bacterial pathogens manipulate the host glycome to favor infection remains incomplete. Here, we address this gap by performing a systematic analysis of the host glycome during infection by the bacterial pathogen Brucella spp. that cause brucellosis. We discover, surprisingly, that a Brucella effector protein (EP) Rhg1 induces global reprogramming of the host cell N-glycome by interacting with components of the oligosaccharide transferase complex that controls N-linked protein glycosylation, and Rhg1 regulates Brucella replication and tissue colonization in a mouse model of brucellosis, demonstrating that Brucella exploits the EP Rhg1 to reprogram the host N-glycome and promote bacterial intracellular parasitism, thereby providing a paradigm for bacterial control of host cell infection.
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Brucella , Brucelosis , Animales , Ratones , Brucella/fisiología , Proteómica , Brucelosis/metabolismo , Retículo Endoplásmico/metabolismoRESUMEN
BACKGROUND: Liver cancer, particularly hepatocellular carcinoma (HCC), is characterized by a high mortality rate, attributed primarily to the establishment of an immunosuppressive microenvironment. Within this context, we aimed to elucidate the pivotal role of eukaryotic elongation factor 2 kinase (eEF2K) in orchestrating the infiltration and activation of natural killer (NK) cells within the HCC tumor microenvironment. By shedding light on the immunomodulatory mechanisms at play, our findings should clarify HCC pathogenesis and help identify potential therapeutic intervention venues. METHODS: We performed a comprehensive bioinformatics analysis to determine the functions of eEF2K in the context of HCC. We initially used paired tumor and adjacent normal tissue samples from patients with HCC to measure eEF2K expression and its correlation with prognosis. Subsequently, we enrolled a cohort of patients with HCC undergoing immunotherapy to examine the ability of eEF2K to predict treatment efficacy. To delve deeper into the mechanistic aspects, we established an eEF2K-knockout cell line using CRISPR/Cas9 gene editing. This step was crucial for verifying activation of the cGAS-STING pathway and the subsequent secretion of cytokines. To further elucidate the role of eEF2K in NK cell function, we applied siRNA-based techniques to effectively suppress eEF2K expression in vitro. For in vivo validation, we developed a tumor-bearing mouse model that enabled us to compare the infiltration and activation of NK cells within the tumor microenvironment following various treatment strategies. RESULTS: We detected elevated eEF2K expression within HCC tissues, and this was correlated with an unfavorable prognosis (30.84 vs. 20.99 months, P = 0.033). In addition, co-culturing eEF2K-knockout HepG2 cells with dendritic cells led to activation of the cGAS-STING pathway and a subsequent increase in the secretion of IL-2 and CXCL9. Moreover, inhibiting eEF2K resulted in notable NK cell proliferation along with apoptosis reduction. Remarkably, after combining NH125 and PD-1 treatments, we found a significant increase in NK cell infiltration within HCC tumors in our murine model. Our flow cytometry analysis revealed reduced NKG2A expression and elevated NKG2D expression and secretion of granzyme B, TNF-α, and IFN-γ in NK cells. Immunohistochemical examination confirmed no evidence of damage to vital organs in the mice treated with the combination therapy. Additionally, we noted higher levels of glutathione peroxidase and lipid peroxidation in the peripheral blood serum of the treated mice. CONCLUSION: Targeted eEF2K blockade may result in cGAS-STING pathway activation, leading to enhanced infiltration and activity of NK cells within HCC tumors. The synergistic effect achieved by combining an eEF2K inhibitor with PD-1 antibody therapy represents a novel and promising approach for the treatment of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Humanos , Ratones , Carcinoma Hepatocelular/tratamiento farmacológico , Quinasa del Factor 2 de Elongación/genética , Quinasa del Factor 2 de Elongación/metabolismo , Células Asesinas Naturales , Neoplasias Hepáticas/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/metabolismo , Microambiente TumoralRESUMEN
Electrochemical water splitting offers a most promising pathway for "green hydrogen" generation. Even so, it remains a struggle to improve the electrocatalytic performance of non-noble metal catalysts, especially bifunctional electrocatalysts. Herein, aiming to accelerate the hydrogen and oxygen evolution reactions, an oxygen-bridged cobalt-chromium (Co-O-Cr) dual-sites catalyst anchored on cobalt phosphide synthesized through MOF-mediation are proposed. By utilizing the filling characteristics of 3d orbitals and modulated local electronic structure of the catalytic active site, the well-designed catalyst requires only an external voltage of 1.53 V to deliver the current density of 20 mA cm-2 during the process of water splitting apart from the superb HER and OER activity with a low overpotential of 87 and 203 mV at a current density of 10 mA cm-2 , respectively. Moreover, density functional theory (DFT) calculations are utilized to unravel mechanistic investigations, including the accelerated adsorption and dissociation process of H2 O on the Co-O-Cr moiety surface, the down-shifted d-band center, a lowered energy barrier for the OER and so on. This work offers a design direction for optimizing catalytic activity toward energy conversion.
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BACKGROUND: Magnetic resonance imaging (MRI) reference ranges for ventricular morphology and function in the Chinese population are lacking. PURPOSE: To establish the MRI reference ranges of left and right ventricular (LV and RV) morphology and function based on a large multicenter cohort. STUDY TYPE: Prospective. POPULATION: One thousand and twelve healthy Chinese Han adults. FIELD STRENGTH/SEQUENCE: Balanced steady-state free procession cine sequence at 3.0 T. ASSESSMENT: Biventricular end-diastolic, end-systolic, stroke volume, and ejection fraction (EDV, ESV, SV, and EF), LV mass (LVM), end-diastolic and end-systolic dimension (LVEDD and LVESD), anteroseptal wall thickness (AS), and posterolateral wall thickness (PL) were measured. Body surface area (BSA) and height were used to index biventricular parameters. Parameters were compared between age groups and sex. STATISTICAL TESTS: Independent-samples t-tests or Mann-Whitney U test to compare mean values between sexes; ANOVA or Kruskal-Wallis test to compare mean values among age groups; linear regression to assess the relationships between cardiac parameters and age (correlation coefficient, r). A P value <0.05 was considered statistically significant. RESULTS: The biventricular volumes, LVM, LVEDD, RVEDV/LVEDV ratio, LVESD, AS, and PL were significantly greater in males than in females, even after indexing to BSA or height, while LVEF and RVEF were significantly lower in males than in females. For both sexes, age was significantly negatively correlated with biventricular volumes (male and female: LVEDV [r = -0.491; r = -0.373], LVESV [r = -0.194; r = -0.184], RVEDV [r = -0.639; r = -0.506], RVESV [r = -0.270; r = -0.223]), with similar correlations after BSA normalization. LVEF (r = 0.043) and RVEF (r = 0.033) showed a significant correlation with age in females, but not in males (P = 0.889; P = 0.282). DATA CONCLUSION: MRI reference ranges for biventricular morphology and function in Chinese adults are presented and show significant associations with age and sex. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.
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Ventrículos Cardíacos , Imagen por Resonancia Magnética , Adulto , Humanos , Masculino , Femenino , Volumen Sistólico , Valores de Referencia , Estudios Prospectivos , Imagen por Resonancia Magnética/métodos , China , Función Ventricular Izquierda , Función Ventricular DerechaRESUMEN
Immunotherapy has emerged as a crucial treatment option, particularly for types of cancer that display resistance to conventional therapies. A remarkable breakthrough in this field is the development of chimeric antigen receptor (CAR) T cell therapy. CAR T cells are generated by engineering the T cells of a patient to express receptors that can recognize specific tumor antigens. This groundbreaking approach has demonstrated impressive outcomes in hematologic malignancies, including diffuse large B cell lymphoma, B cell acute lymphoblastic leukemia and multiple myeloma. Despite these significant successes, CAR T cell therapy has encountered challenges in its application against solid tumors, leading to limited success in these cases. Consequently, researchers are actively exploring novel strategies to enhance the efficacy of CAR T cells. The focus lies on augmenting CAR T cell trafficking to tumors while preventing the development of CAR T cell exhaustion and dysfunction. The present review aimed to provide a comprehensive analysis of the achievements and limitations of CAR T cell therapy in the context of cancer treatment. By understanding both the successes and hurdles, further advancements in this promising area of research can be developed. Overall, immunotherapy, particularly CAR T cell therapy, has opened up novel possibilities for cancer treatment, offering hope to patients with previously untreatable malignancies. However, to fully realize its potential, ongoing research and innovative strategies are essential in overcoming the challenges posed by solid tumors and maximizing CAR T cell efficacy in clinical settings.
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The immune system functions as a sophisticated defense mechanism, shielding the body from harmful pathogenic invaders [...].
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BACKGROUND: Although reference ranges of T1 and T2 mapping are well established for cardiovascular magnetic resonance (CMR) at 1.5T, data for 3T are still lacking. The objective of this study is to establish reference ranges of myocardial T1 and T2 based on a large multicenter cohort of healthy Chinese adults at 3T CMR. METHODS: A total of 1015 healthy Chinese adults (515 men, age range: 19-87 years) from 11 medical centers who underwent CMR using 3T Siemens scanners were prospectively enrolled. T1 mapping was performed with a motion-corrected modified Look-Locker inversion recovery sequence using a 5(3)3 scheme. T2 mapping images were acquired using T2-prepared fast low-angle shot sequence. T1 and T2 relaxation times were quantified for each slice and each myocardial segment. The T1 mapping and extracellular volume standardization (T1MES) phantom was used for quality assurance at each center prior to subject scanning. RESULTS: The phantom analysis showed strong consistency of spin echo, T1 mapping, and T2 mapping among centers. In the entire cohort, global T1 and T2 reference values were 1193 ± 34 ms and 36 ± 2.5 ms. Global T1 and T2 values were higher in females than in males (T1: 1211 ± 29 ms vs. 1176 ± 30 ms, p < 0.001; T2: 37 ± 2.3 ms vs. 35 ± 2.5 ms, p < 0.001). There were statistical differences in global T2 across age groups (p < 0.001), but not in global T1. Linear regression showed no correlation between age and global T1 or T2 values. In males, positive correlation was found between heart rate and global T1 (r = 0.479, p < 0.001). CONCLUSIONS: Using phantom-validated imaging sequences, we provide reference ranges for myocardial T1 and T2 values on 3T scanners in healthy Chinese adults, which can be applied across participating sites. Trial registration URL: http://www.chictr.org.cn/index.aspx . Unique identifier: ChiCTR1900025518. Registration name: 3T magnetic resonance myocardial quantitative imaging standardization and reference value study: a multi-center clinical study.
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Pueblos del Este de Asia , Corazón , Masculino , Femenino , Adulto , Humanos , Adulto Joven , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Valores de Referencia , Valor Predictivo de las Pruebas , Corazón/diagnóstico por imagen , Miocardio/patología , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética , Reproducibilidad de los ResultadosRESUMEN
CD4+ T cells, particularly IL-17-secreting helper CD4+ T cells, play a central role in the inflammatory processes underlying autoimmune disorders. Eukaryotic Elongation Factor 2 Kinase (eEF2K) is pivotal in CD8+ T cells and has important implications in vascular dysfunction and inflammation-related diseases such as hypertension. However, its specific immunological role in CD4+ T cell activities and related inflammatory diseases remains elusive. Our investigation has uncovered that the deficiency of eEF2K disrupts the survival and proliferation of CD4+ T cells, impairs their ability to secrete cytokines. Notably, this dysregulation leads to heightened production of pro-inflammatory cytokine IL-17, fosters a pro-inflammatory microenvironment in the absence of eEF2K in CD4+ T cells. Furthermore, the absence of eEF2K in CD4+ T cells is linked to increased metabolic activity and mitochondrial bioenergetics. We have shown that eEF2K regulates mitochondrial function and CD4+ T cell activity through the upregulation of the transcription factor, signal transducer and activator of transcription 3 (STAT3). Crucially, the deficiency of eEF2K exacerbates the severity of inflammation-related diseases, including rheumatoid arthritis, multiple sclerosis, and ulcerative colitis. Strikingly, the use of C188-9, a small molecule targeting STAT3, mitigates colitis in a murine immunodeficiency model receiving eEF2K knockout (KO) CD4+ T cells. These findings emphasize the pivotal role of eEF2K in controlling the function and metabolism of CD4+ T cells and its indispensable involvement in inflammation-related diseases. Manipulating eEF2K represents a promising avenue for novel therapeutic approaches in the treatment of inflammation-related disorders.
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Quinasa del Factor 2 de Elongación , Interleucina-17 , Ratones , Animales , Interleucina-17/genética , Quinasa del Factor 2 de Elongación/genética , Quinasa del Factor 2 de Elongación/metabolismo , Linfocitos T CD8-positivos/metabolismo , Inflamación/genética , Linfocitos T CD4-PositivosRESUMEN
Nucleus-accumbens-associated protein-1 (NAC1) is a cancer-related transcriptional factor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and has been appreciated as one of the top potential cancer driver genes. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. Here, we show that NAC1 is a negative regulator of NF-κB signaling, and NAC1 depletion enhances the level of the nuclear NF-κB in human melanoma. Furthermore, the inhibition of NF-κB signaling significantly potentiates the antineoplastic activity of the NAC1 inhibition in both the cultured melanoma cells and xenograft tumors. This study identifies a novel NAC1-NF-κB signaling axis in melanoma, offering a promising new therapeutic option to treat melanoma.
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Nucleus accumbens-associated protein 1 (NAC1), a transcriptional cofactor, has been found to play important roles in regulating regulatory T cells, CD8+ T cells, and antitumor immunity, but little is known about its effects on T-cell memory. In this study, we found that NAC1 expression restricts memory formation of CD4+ T cells during viral infection. Analysis of CD4+ T cells from wild-type (WT) and NAC1-deficient (-/- ) mice showed that NAC1 is essential for T-cell metabolism, including glycolysis and oxidative phosphorylation, and supports CD4+ T-cell survival in vitro. We further demonstrated that a deficiency of NAC1 downregulates glycolysis and correlates with the AMPK-mTOR pathway and causes autophagy defective in CD4+ T cells. Loss of NAC1 reduced the expression of ROCK1 and the phosphorylation and stabilization of BECLIN1. However, a forced expression of ROCK1 in NAC1-/- CD4+ T cells restored autophagy and the activity of the AMPK-mTOR pathway. In animal experiments, adoptively transferred NAC1-/- CD4+ T cells or NAC1-/- mice challenged with VACV showed enhanced formation of VACV-specific CD4+ memory T cells compared to adoptively transferred WT CD4+ T cells or WT mice. This memory T-cell formation enhancement was abrogated by forcing expression of ROCK1. Our study reveals a novel role for NAC1 as a suppressor of CD4+ T-cell memory formation and suggests that targeting NAC1 could be a new approach to promoting memory CD4+ T-cell development, which is critical for an effective immune response against pathogens.
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Proteínas Quinasas Activadas por AMP , Linfocitos T CD8-positivos , Animales , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Linfocitos T CD4-Positivos , Supervivencia Celular , Memoria Inmunológica , Ratones Endogámicos C57BL , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Triptolide (TP) is an important active compound from Tripterygium wilfordii Hook F (TwHF), however, it is greatly limited in clinical practice due to its severe toxicity, especially testicular injury. Melatonin is an endogenous hormone and has beneficial effects on the reproductive system. However, whether triptolide-induced testicular injury can be alleviated by melatonin and the underlying mechanism are not clear. PURPOSE: In this study, we aimed to explore whether triptolide-induced testicular Sertoli cells toxicity can be mitigated by melatonin and the underlying mechanisms involved. METHODS: Cell apoptosis was assessed by flow cytometry, western blot, immunofluorescence and immunohistochemistry. Fluorescent probe Mito-Tracker Red CMXRos was used to observe the mitochondria morphology. Mitochondrial membrane potential and Ca2+ levels were used to investigate mitochondrial function by confocal microscope and flow cytometry. The expression levels of SIRT1/Nrf2 pathway were detected by western blot, immunofluorescence and immunohistochemistry. Small interfering RNA of NRF2 and SIRT1 inhibitor EX527 was used to confirm the role of SIRT1/NRF2 pathway in the mitigation of triptolide-induced Sertoli cell damage by melatonin. Co-Immunoprecipitation assay was used to determine the interaction between SIRT1 and NRF2. RESULTS: Triptolide-induced dysfunction of testicular Sertoli cells was significantly improved by melatonin treatment. Specifically, triptolide-induced oxidative stress damage and changes of mitochondrial morphology, mitochondrial membrane potential, and BTB integrity were alleviated by melatonin. Mechanistically, triptolide inhibited SIRT1 and then reduced the activation of NRF2 pathway via regulating the interaction between SIRT1 and NRF2, thereby downregulating the downstream antioxidant genes, which was reversed by melatonin. Nevertheless, knockdown of NRF2 or inhibition of SIRT1 abolished the protective effect of melatonin. CONCLUSION: Triptolide-induced testicular Sertoli cell damage could be alleviated by melatonin via regulating the crosstalk between SIRT1 and NRF2, which is helpful for developing a new strategy to alleviate triptolide-induced toxicity.
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Melatonina , Fenantrenos , Masculino , Humanos , Células de Sertoli , Melatonina/farmacología , Melatonina/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Sirtuina 1/metabolismo , Estrés Oxidativo , Fenantrenos/farmacologíaRESUMEN
Triple-negative breast cancer (TNBC), characterized by a deficiency in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor2 (HER2), is among the most lethal subtypes of breast cancer (BC). Nevertheless, the molecular determinants that contribute to its malignant phenotypes such as tumor heterogeneity and therapy resistance, remain elusive. In this study, we sought to identify the stemness-associated genes involved in TNBC progression. Using bioinformatics approaches, we found 55 up- and 9 downregulated genes in TNBC. Out of the 55 upregulated genes, a 5 gene-signature (CDK1, EZH2, CCNB1, CCNA2, and AURKA) involved in cell regeneration was positively correlated with the status of tumor hypoxia and clustered with stemness-associated genes, as recognized by Parametric Gene Set Enrichment Analysis (PGSEA). Enhanced infiltration of immunosuppressive cells was also positively correlated with the expression of these five genes. Moreover, our experiments showed that depletion of the transcriptional co-factor nucleus accumbens-associated protein 1 (NAC1), which is highly expressed in TNBC, reduced the expression of these genes. Thus, the five genes signature identified by this study warrants further exploration as a potential new biomarker of TNBC heterogeneity/stemness characterized by high hypoxia, stemness enrichment, and immune-suppressive tumor microenvironment.
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T cells are essential to cell-mediated immunity during bacterial, viral, and fungal infections, and immune-related diseases [...].
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Autoimmune diseases such as rheumatoid arthritis and type 1 diabetes are increasingly common global problems. Concerns about increases in the prevalence of such diseases and the limited efficacy of conventional treatment regimens necessitates new therapies to address these challenges. Autoimmune disease severity and dysbiosis are interconnected. Although probiotics have been established as a therapy to rebalance the microbiome and suppress autoimmune symptoms, these microbes tend to lack a number of advantageous qualities found in non-commensal bacteria. Through attenuation and genetic manipulation, these non-commensal bacteria have been engineered into recombinant forms that offer malleable platforms capable of addressing the immune imbalances found in RA and T1D. Such bacteria have been engineered to express valuable gene products known to suppress autoimmunity such as anti-inflammatory cytokines, autoantigens, and enzymes synthesizing microbial metabolites. This review will highlight current and emerging trends in the field and discuss how they may be used to prevent and control autoimmune diseases.
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The application of carbides in catalysis, batteries, aerospace fields, etc. has been continuously expanded and deepened, which is attributed to the diversified physicochemical properties of carbides via a tune-up of their morphology, composition, and microstructure. The emergence of MAX phases and high entropy carbides with unparalleled application potential undoubtedly further stimulates the research upsurge of carbides. The traditional pyrometallurgical or hydrometallurgical synthesis of carbides inevitably faces the shortcomings of complex process, unacceptable energy consumption, extreme environmental pollution, and beyond. The molten salt electrolysis synthesis method with the superiorities of straightforward route, high efficiency, and environmental friendliness has demonstrated its validity in the synthesis of various carbides, which naturally initiates more research. In particular, the process can achieve CO2 capture while synthesizing carbides based on the excellent CO2 capture capability of some molten salts, which is of great significance for carbon neutralization. In this paper, the synthesis mechanism of carbide by molten salt electrolysis, the process of CO2 capture and carbides conversion, the latest research progress in the synthesis of binary, ternary, multi-component, and composite carbides are reviewed. Finally, the challenges, development perspectives, and research directions of electrolysis synthesis of carbides in molten salts are featured.
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For the past three years, COVID-19 has become an increasing global health issue. Adaptive immune cells, especially T cells, have been extensively investigated in regard to SARS-CoV-2 infection. However, human health and T cell responses are also impacted by many other pathogens and chronic diseases. We have summarized T cell performance during SARS-CoV-2 coinfection with other viruses, bacteria, and parasites. Furthermore, we distinguished if those altered T cell statuses under coinfection would affect their clinical outcomes, such as symptom severity and hospitalization demand. T cell alteration in diabetes, asthma, and hypertension patients with SARS-CoV-2 infection was also investigated in our study. We have summarized whether changes in T cell response influence the clinical outcome during comorbidities.
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Immunotherapy has led to impressive advances in the treatment of autoimmune and pro-inflammatory disorders; yet, its clinical outcomes remain limited by a variety of factors including the pro-inflammatory microenvironment (IME). Discovering effective immunomodulatory agents, and the mechanisms by which they control disease, will lead to innovative strategies for enhancing the effectiveness of current immunotherapeutic approaches. We have metabolically engineered an attenuated bacterial strain (i.e., Brucella melitensis 16M ∆vjbR, Bm∆vjbR::tnaA) to produce indole, a tryptophan metabolite that controls the fate and function of regulatory T (Treg) cells. We demonstrated that treatment with Bm∆vjbR::tnaA polarized macrophages (Mφ) which produced anti-inflammatory cytokines (e.g., IL-10) and promoted Treg function; moreover, when combined with adoptive cell transfer (ACT) of Treg cells, a single treatment with our engineered bacterial strain dramatically reduced the incidence and score of autoimmune arthritis and decreased joint damage. These findings show how a metabolically engineered bacterium can constitute a powerful vehicle for improving the efficacy of immunotherapy, defeating autoimmunity, and reducing inflammation by remodeling the IME and augmenting Treg cell function.
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Autoinmunidad , Microbioma Gastrointestinal , Humanos , Inflamación , Citocinas/metabolismo , Linfocitos T Reguladores , Bacterias/metabolismoRESUMEN
Purpose: For patients with symptomatic middle cerebral artery (MCA) atherosclerotic stenosis, identifying the potential stroke mechanisms may contribute to secondary prevention. The purpose of the study is to explore the relationship between stroke mechanisms and the characteristics of culprit plaques in patients with atherosclerotic ischemic stroke in the M1 segment of the middle cerebral artery (MCA) based on high-resolution vessel wall imaging (HR-VWI). Methods: We recruited 61 patients with acute ischemic stroke due to MCA atherosclerotic stenosis from Shenzhen Bao'an District People's Hospital. According to prespecified criteria based on infarct topography and magnetic resonance angiography, possible stroke mechanisms were divided into parent artery atherosclerosis occluding penetrating artery (P), artery-to-artery embolism (A), hypoperfusion (H), and mixed mechanisms (M). The correlation between the characteristics of MCA M1 culprit plaque and different stroke mechanisms was analyzed using HR-VWI. The indicators included plaque surface irregularity, T1 hyperintensity, location, plaque burden (PB), remodeling index (RI), enhancement rate, and stenosis rate. Results: Parental artery atherosclerosis occluding penetrating artery was the most common mechanism (37.7%). The proposed criteria showed substantial to excellent interrater reproducibility (κ, 0.728; 0.593-0.863). Compared with the P group, the surface irregularity, T1 hyperintensity, and obvious enhancement of the culprit plaque in the A group were more common (p < 0.0125). Compared with the other stroke mechanisms, positive remodeling of culprit plaques was more common (p < 0.0125), the RI was greater (p < 0.05), and the PB was the smallest (p < 0.05) in the P group. The enhancement ratio (ER) was smaller in the P group (p < 0.05). Compared with the A group, T1 hyperintensity of the culprit plaque was more common in the H group (p < 0.0125), and the stenosis rate was greater (p < 0.05). After adjustment for clinical demographic factors in the binary logistic regression analysis, the enhancement level (odds ratio [OR] 0.213, 95% CI (0.05-0.91), p = 0.037) and PB of culprit plaque (OR 0, 95% CI (0-0.477), p = 0.034) were negatively associated with P groups. Conclusion: The culprit plaque characteristics of patients with symptomatic MCA atherosclerotic in different stroke mechanisms may be evaluated using HR-VWI. The plaque characteristics of different stroke mechanisms may have clinical value for the selection of treatment strategies and prevention of stroke recurrence. Clinical trial registration: Identifier: ChiCTR1900028533.
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BACKGROUND: T cell-mediated antitumor immunity has a vital role in cancer prevention and treatment; however, the immune-suppressive tumor microenvironment (TME) constitutes a significant contributor to immune evasion that weakens antitumor immunity. Here, we explore the relationship between nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB (broad-complex, Tramtrack, bric a brac)/POZ (Poxvirus, and Zinc finger) gene family, and the TME. METHODS: Adoptive cell transfer (ACT) of mouse or human tumor antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) was tested in an immunocompetent or immunodeficient mouse model of melanoma with or without expression of NAC1. The effects of NAC1 expression on immune evasion in tumor cells were assessed in vitro and in vivo. CRISPR/Cas9, glycolysis analysis, retroviral transduction, quantitative real-time PCR, flow cytometric analysis, immunoblotting, database analyses were used to screen the downstream target and underlying mechanism of NAC1 in tumor cells. RESULTS: Tumorous expression of NAC1 negatively impacts the CTL-mediated antitumor immunity via lactate dehydrogenase A (LDHA)-mediated suppressive TME. NAC1 positively regulated the expression of LDHA at the transcriptional level, which led to higher accumulation of lactic acid in the TME. This inhibited the cytokine production and induced exhaustion and apoptosis of CTLs, impairing their cell-killing ability. In the immunocompetent and immunodeficient mice, NAC1 depleted melanoma tumors grew significantly slower and had an elevated infiltration of tumor Ag-specific CTLs following ACT, compared with the control groups. CONCLUSIONS: Tumor expression of NAC1 contributes substantially to immune evasion through its regulatory role in LDHA expression and lactic acid production. Thus, therapeutic targeting of NAC1 warrants further exploration as a potential strategy to reinforce cancer immunotherapy, such as the ACT of CTLs.
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Evasión Inmune , Lactato Deshidrogenasa 5 , Melanoma , Proteínas del Tejido Nervioso , Proteínas Represoras , Animales , Antígenos de Neoplasias , Citocinas , Humanos , Lactato Deshidrogenasa 5/metabolismo , Ácido Láctico , Melanoma/inmunología , Ratones , Ratones SCID , Proteínas de Neoplasias , Proteínas del Tejido Nervioso/genética , Proteínas Represoras/genética , Microambiente TumoralRESUMEN
Quantified inflammatory biomarkers are effective clinical strategy for correct and reasonable drug treatment. In the study, a triple lateral flow immunoassay (triple LFIA) had firstly been developed for specific and simultaneous detection of three pivotal inflammatory biomarkers (PCT, CRP and SAA) via biotin-streptavidin-phycoerythrin signal amplification system in one strip. The developed triple LFIA adopted phycoerythrin (PE) as chromophore to eliminate auto-fluorescence interference from plasma biomolecules and anti-PE mAb as single control line to reduce the nonspecific adsorption, which featured particular advantages in high sensitivity and specificity in a large range of analyte concentrations with the LODs of 0.106 ng/mL for PCT, 0.345 µg/mL for CRP and 3.112 µg/mL SAA, respectively. And the linear quantitative detection ranges were from 0.106 to 100 ng/mL, from 0.345 to 200 µg/mL, and from 3.112 to 200 µg/mL, respectively. Compared to commercial chemiluminescence immunoassay method, the correlations for tested PCT, CRP and SAA in 108 clinical samples were 0.989, 0.987 and 0.988, respectively. In summary, we had proposed a rapid and accurate plasma detection to measure inflammation factors, which facilitated the clinical value to achieve precise treatment.