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Rationale: The aryl hydrocarbon receptor (AhR) functions in the regulation of intestinal inflammation, but knowledge of the underlying mechanisms in innate immune cells is limited. Here, we investigated the role of AhR in modulating the functions of macrophages in inflammatory bowel disease pathogenesis. Methods: The cellular composition of intestinal lamina propria CD45+ leukocytes in a dextran sulfate sodium (DSS)-induced mouse colitis model was determined by single-cell RNA sequencing. Macrophage pyroptosis was quantified by analysis of lactate dehydrogenase release, propidium iodide staining, enzyme-linked immunosorbent assay, western blot, and flow cytometry. Differentially expressed genes were confirmed by RNA-seq, RT-qPCR, luciferase assay, chromatin immunoprecipitation, and immunofluorescence staining. Results: AhR deficiency mediated dynamic remodeling of the cellular composition of intestinal lamina propria (LP) CD45+ immune cells in a colitis model, with a significant increase in monocyte-macrophage lineage. Mice with AhR deficiency in myeloid cells developed more severe dextran sulfate sodium induced colitis, with concomitant increased macrophage pyroptosis. Dietary supplementation with an AhR pre-ligand, indole-3-carbinol, conferred protection against colitis while protection failed in mice lacking AhR in myeloid cells. Mechanistically, AhR signaling inhibited macrophage pyroptosis by promoting ornithine decarboxylase 1 (Odc1) transcription, to enhance polyamine biosynthesis. The increased polyamine, particularly spermine, inhibited NLRP3 inflammasome assembly and subsequent pyroptosis by suppressing K+ efflux. AHR expression was positively correlated with ODC1 in intestinal mucosal biopsies from patients with ulcerative colitis. Conclusions: These findings suggest a functional role for the AhR/ODC1/polyamine axis in maintaining intestinal homeostasis, providing potential targets for treatment of inflammatory bowel disease.
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Colitis , Sulfato de Dextran , Macrófagos , Poliaminas , Piroptosis , Receptores de Hidrocarburo de Aril , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genética , Animales , Ratones , Macrófagos/metabolismo , Macrófagos/inmunología , Colitis/metabolismo , Colitis/inducido químicamente , Colitis/patología , Humanos , Poliaminas/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ratones Noqueados , Inflamación/metabolismo , Masculino , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Factores de Transcripción con Motivo Hélice-Asa-Hélice BásicoRESUMEN
BACKGROUND: CXCR6+CD8+T cells have been implicated in the pathogenesis of various liver and autoimmune diseases. However, their involvement in primary biliary cholangitis (PBC) has not been elucidated. METHODS: We used immunohistochemistry and flow cytometry to quantify CXCR6+CD8+T cells in hepatic tissue and peripheral blood samples obtained from CXCR6+CD8+T cells obtained from PBC patients. Then, we performed comprehensive statistical analyses to access the correlation between the abundance of these cells and clinical as well as pathological data across different stages of PBC. RESULTS: Our research revealed that CXCR6+ cell frequencies in CD3+CD8+T cells from PBC patients significantly exceeded that of healthy controls (HCs) (2.24 vs. 0.61%, p < 0.01). A similar pattern emerged for hepatic CXCR6+CD8+T cell counts, which were notably higher in the PBC cohort compared to HCs. Our cohort consisted of 118 PBC patients, categorized into 62 early-stage (E-PBC) and 56 late-stage (L-PBC) cases. Notably, significant disparities existed between these groups in terms of liver enzyme and lipid profile levels (p < 0.05), with no notable differences observed in gender, age, blood counts, cholesterol levels, or autoantibodies (p > 0.05). Intriguingly, the quantity of hepatic CXCR6+CD8+T cells per high power field (HPF) was significantly elevated in both E-PBC and L-PBC patients as opposed to normal liver samples, indicating a substantial increase in these cells across all stages of PBC (p = 0.000). Spearman's rank correlation analysis showed a positive correlation between CXCR6+CD8+T cell counts and serum levels of Alkaline Phosphatase (AKP) and Gamma-Glutamyl Transferase (GGT), ANA, IgG and IgM, while revealing a negligible correlation with Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST). Subsequent findings indicated significant variances in CXCR6+ cell numbers not only among different PBC stages but also across various degrees of inflammation and fibrosis (p ≤ 0.007). In a follow-up study post-Ursodeoxycholic Acid (UDCA) treatment, stark differences were identified in biochemical and immunohistochemical profiles between responder (31 patients) and non-responder (33 patients) groups (p < 0.05). A Wilcoxon rank-sum test further demonstrated a significant difference in the level of hepatic CXCR6+CD8+T cells between these two response groups (p = 0.002). CONCLUSION: CXCR6+CD8+T cells play a vital role in the pathogenesis of PBC, exhibiting correlations with the extent of inflammation, staging of liver fibrosis, and response to pharmacological interventions in PBC patients.
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BACKGROUND: Necrotizing enterocolitis (NEC) is a life-threatening disease that affects premature infants. However, the role of inflammatory biomarkers in identifying surgical/death NEC without pneumoperitoneum remains elusive. PURPOSE: We aimed to verify the value of platelet-to-lymphocyte ratio (PLR) and the combination of white blood cell (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), neutrophil lymphocyte ratio (NLR), PLR, C reactive protein (CRP) and procalcitonin (PCT) in predicting the severity of NEC, and to construct a model to differ surgically NEC from non-surgically NEC. METHODS: A retrospective analysis was performed on 191 premature infants with NEC. Based on the inclusion and exclusion criteria, 90 infants with Stage II and IIIA NEC were enrolled in this study, including surgical/death NEC (n = 38) and medical NEC (n = 52). The values of inflammatory biomarkers were collected within 24 h of onset. RESULTS: The univariate analysis revealed that the values of WBC (p = 0.040), ANC (p = 0.048), PLR (p = 0.009), CRP (p = 0.016) and PCT (p < 0.01) in surgical/death NEC cohort were significantly higher than medical NEC cohort. Binary multivariate logistic regression analysis indicates that ANC, PLR, CRP, and PCT are capable of distinguishing infants with surgical/death NEC, and the AUC of the regression equation was 0.79 (95% CI 0.64-0.89; sensitivity 0.63; specificity 0.88), suggesting the equation has a good discrimination. IMPLICATIONS FOR PRACTICE AND RESEARCH: Elevated PLR is associated with severe inflammation in surgical/death NEC patients. The prediction modelling of combination of ANC, PLR, CRP and PCT can differentiate surgical/death NEC from infants with medical NEC, which may improve risk awareness and facilitate effective communication between nurses and clinicians. However, multicentre research is needed to verify these findings for better clinical management of NEC.
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Biomarcadores , Proteína C-Reactiva , Enterocolitis Necrotizante , Recien Nacido Prematuro , Humanos , Enterocolitis Necrotizante/cirugía , Enterocolitis Necrotizante/sangre , Enterocolitis Necrotizante/diagnóstico , Estudios Retrospectivos , Recién Nacido , Biomarcadores/sangre , Masculino , Femenino , Proteína C-Reactiva/análisis , Polipéptido alfa Relacionado con Calcitonina/sangre , Neumoperitoneo/sangre , Inflamación/sangre , Recuento de Leucocitos , Enfermedades del Prematuro/cirugía , Enfermedades del Prematuro/sangre , Enfermedades del Prematuro/diagnósticoRESUMEN
Wound infections, especially those caused by pathogenic bacteria, present a considerable public health concern due to associated complications and poor therapeutic outcomes. Herein, we developed antibacterial nanoparticles, namely, PGTP, by coordinating guanidine derivatives with a porphyrin-based sonosensitizer. The synthesized PGTP nanoparticles, characterized by their strong positive charge, effectively disrupted the bacterial biosynthesis process through charge interference, demonstrating efficacy against both Gram-negative and Gram-positive bacteria. Additionally, PGTP nanoparticles generated reactive oxygen species under ultrasound stimulation, resulting in the disruption of biofilm integrity and efficient elimination of pathogens. RNA-seq analysis unveiled the detailed mechanism of wound healing, revealing that PGTP nanoparticles, when coupled with ultrasound, impair bacterial metabolism by interfering with the synthesis and transcription of amino acids. This study presents a novel approach to combatting wound infections through ultrasound-driven charge-interfering therapy, facilitated by advanced antibacterial nanomaterials.
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Antibacterianos , Biopelículas , Nanopartículas , Infección de Heridas , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/uso terapéutico , Infección de Heridas/tratamiento farmacológico , Infección de Heridas/microbiología , Nanopartículas/química , Nanopartículas/uso terapéutico , Biopelículas/efectos de los fármacos , Animales , Ratones , Ondas Ultrasónicas , Especies Reactivas de Oxígeno/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Humanos , Porfirinas/química , Porfirinas/farmacología , Porfirinas/uso terapéutico , Terapia por Ultrasonido/métodos , Bacterias Grampositivas/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacosRESUMEN
Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) patients receiving targeted therapy. However, the mechanism that causes cetuximab resistance, especially microRNA (miRNA) regulation, remains unclear. Growing evidence suggests that miRNAs may act as "nuclear activating miRNAs" for targeting promoter regions or enhancers related to target genes. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, quantitative real-time polymerase chain reaction (qRTâPCR) and fluorescence in situ hybridization (FISH) results provided compelling evidence of miR-451a nuclear enrichment in response to cetuximab treatment. Chromatin isolation via RNA purification, microarray analysis, and bioinformatic analysis revealed that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It has also been demonstrated that the activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Logistic regression analyses of 87 HNSCC samples indicated the significance of miR-451a and KDM7A in the development of cetuximab resistance. These discoveries support the potential of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear-activating miRNAs.
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Cetuximab , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello , MicroARNs , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Cetuximab/farmacología , Resistencia a Antineoplásicos/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Animales , Ratones , Núcleo Celular/metabolismo , Núcleo Celular/genética , Femenino , Ratones DesnudosRESUMEN
Objective: The primary aim of this study is to explore the effects of enteral nutrition support with ultrasound-guided three-lumen gastrojejunal tube insertion on nutritional status in patients with severe neurological diseases. Additionally, we aim to assess the impact of this intervention on the success rate of catheterization and the aspiration rate, to comprehensively evaluate its benefits and optimize patient care. Methods: Between March 2022 and March 2023, 60 patients were recruited and randomly divided into ultrasound-guided and control groups of 30 patients each using the Simple Randomisation method. In the control group, a triple-lumen feeding tube was blindly inserted at the bedside for enteral nutritional therapy, and in the ultrasound-guided group, ultrasound-guided identification of gastric structures for placement of a triple-lumen feeding tube for enteral nutritional support, and both treatments were continued for 2 weeks. The success rate of catheterization, nutritional status, aspiration rate, patient satisfaction, and incidence of complications were compared between the two groups before and after treatment. Results: The difference in the success rate of catheterization between the ultrasound guidance group and control group was not statistically significant (93.33% vs 96.67%, P>0.05). After treatment, TP (70.84±3.54 vs 67.15±4.23), ALB (41.23±3.65 vs 38.22±3.47), and Hb (11.54±0.62 vs 9.35±0.28) levels in the ultrasound guidance group were higher than in the control group (P < .05). The difference in aspiration rate between the ultrasound guidance group and control group was not statistically significant [0.00% (0/30) vs 3.33% (1/30), P > .05]. The patient satisfaction in the ultrasound guidance group was higher than that in the control group (P < .05). The difference in the incidence of complications (stomachache, headache, nausea, and vomiting) between the ultrasound guidance group and control group was not statistically significant (6.67% vs 20.00%, P > .05). Conclusion: Enteral nutrition support with ultrasound-guided three-lumen gastrojejunal tube insertion can improve the success rate of catheterization and nutritional status, reduce aspiration rate, and improve satisfaction in patients with severe neurological diseases. In the future, we need to further investigate the incorporation of ultrasound guidance into standard care protocols for patients with severe neurological disorders requiring enteral nutrition. The indications for ultrasound guidance in nursing should also be expanded. In conclusion, ultrasound-guided insertion should be considered the technique of choice for improving nutritional status in the population of patients with severe neurological disease.
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Tuberculosis (TB) is a major fatal infectious disease globally, exhibiting high morbidity rates and impacting public health and other socio-economic factors. However, some individuals are resistant to TB infection and are referred to as "Resisters". Resisters remain uninfected even after exposure to high load of Mycobacterium tuberculosis (Mtb). To delineate this further, this study aimed to investigate the factors and mechanisms influencing the Mtb resistance phenotype. We assayed the phagocytic capacity of peripheral blood mononuclear cells (PBMCs) collected from Resisters, patients with latent TB infection (LTBI), and patients with active TB (ATB), following infection with fluorescent Mycobacterium bovis Bacillus Calmette-Guérin (BCG). Phagocytosis was stronger in PBMCs from ATB patients, and comparable in LTBI patients and Resisters. Subsequently, phagocytes were isolated and subjected to whole transcriptome sequencing and small RNA sequencing to analyze transcriptional expression profiles and identify potential targets associated with the resistance phenotype. The results revealed that a total of 277 mRNAs, 589 long non-coding RNAs, 523 circular RNAs, and 35 microRNAs were differentially expressed in Resisters and LTBI patients. Further, the endogenous competitive RNA (ceRNA) network was constructed from differentially expressed genes after screening. Bioinformatics, statistical analysis, and quantitative real-time polymerase chain reaction were used for the identification and validation of potential crucial targets in the ceRNA network. As a result, we obtained a ceRNA network that contributes to the resistance phenotype. TCONS_00034796-F3, ENST00000629441-DDX43, hsa-ATAD3A_0003-CYP17A1, and XR_932996.2-CERS1 may be crucial association pairs for resistance to TB infection. Overall, this study demonstrated that the phagocytic capacity of PBMCs was not a determinant of the resistance phenotype and that some non-coding RNAs could be involved in the natural resistance to TB infection through a ceRNA mechanism.
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Leucocitos Mononucleares , MicroARNs , Mycobacterium tuberculosis , Fagocitos , Fagocitosis , Tuberculosis , Humanos , Fagocitos/metabolismo , Fagocitos/inmunología , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/inmunología , Tuberculosis/genética , Tuberculosis/microbiología , Tuberculosis/inmunología , Fagocitosis/genética , MicroARNs/genética , MicroARNs/metabolismo , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Masculino , Adulto , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Femenino , Transcriptoma/genética , Tuberculosis Latente/genética , Tuberculosis Latente/inmunología , Tuberculosis Latente/microbiología , Resistencia a la Enfermedad/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Mycobacterium bovis/inmunología , Persona de Mediana Edad , Biología Computacional/métodos , Adulto Joven , ARN Endógeno CompetitivoRESUMEN
BACKGROUND: Vitamin D may help to alleviate asthma exacerbation because of its anti-inflammation effect, but the evidence is inconsistent in childhood asthma. MiRNAs are important mediators in asthma pathogenesis and also excellent non-invasive biomarkers. We hypothesized that circulating miRNAs are associated with asthma exacerbation and modified by vitamin D levels. METHODS: We sequenced baseline serum miRNAs from 461 participants in the Childhood Asthma Management Program (CAMP). Logistic regression was used to associate miRNA expression with asthma exacerbation through interaction analysis first and then stratified by vitamin D insufficient and sufficient groups. Microarray from lymphoblastoid B-cells (LCLs) treated by vitamin D or sham of 43 subjects in CAMP were used for validation in vitro. The function of miRNAs was associated with gene modules by weighted gene co-expression network analysis (WGCNA). RESULTS: We identified eleven miRNAs associated with asthma exacerbation with vitamin D effect modification. Of which, five were significant in vitamin D insufficient group and nine were significant in vitamin D sufficient group. Six miRNAs, including hsa-miR-143-3p, hsa-miR-192-5p, hsa-miR-151a-5p, hsa-miR-24-3p, hsa-miR-22-3p and hsa-miR-451a were significantly associated with gene modules of immune-related functions, implying miRNAs may mediate vitamin D effect on asthma exacerbation through immune pathways. In addition, hsa-miR-143-3p and hsa-miR-451a are potential predictors of childhood asthma exacerbation at different vitamin D levels. CONCLUSIONS: miRNAs are potential mediators of asthma exacerbation and their effects are directly impacted by vitamin D levels.
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Asma , MicroARN Circulante , MicroARNs , Humanos , MicroARNs/metabolismo , MicroARN Circulante/genética , Perfilación de la Expresión Génica , Asma/diagnóstico , Asma/genética , Vitamina DRESUMEN
Tumor metastasis is a spatial and temporal process that starts with remodeling to generate a proper premetastatic niche in a distant tissue. Infiltration of immunosuppressive macrophages is one of the notable characteristics in the premetastatic niche, which is a fundamental requirement for primary tumor metastasis. Here, we demonstrated that small extracellular vesicles (sEV) carrying RAB21 homed to lung macrophages and interacted with integrin-ß1 on macrophages. ABHD12 expression was high in lung metastatic tumors and was mostly expressed by macrophages. Head and neck squamous cell carcinoma (HNSCC)-derived sEVs carrying ABHD12-polarized macrophages toward an immunosuppressive phenotype, driving premetastatic niche formation, which facilitated lung metastasis. ABHD12 additionally upregulated S1PR1 by activating the AKT-FoxO1 pathway in macrophages, and significantly enhanced antitumor responses were observed in tumor models treated with agents targeting both S1PR1 and PD-1. Collectively, our study suggests that RAB21+ABHD12+ sEVs derived from HNSCC cells contribute to the formation of the immunosuppressive microenvironment in the premetastatic niche and are a potential therapeutic target for enhancing the antitumor efficacy of anti-PD-1 therapy.
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Vesículas Extracelulares , Neoplasias de Cabeza y Cuello , Neoplasias Pulmonares , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Pulmón/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Macrófagos/patología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Microambiente Tumoral , Proteínas de Unión al GTP rab/genética , Monoacilglicerol LipasasRESUMEN
BACKGROUND: Recombinant human growth hormone (rhGH) therapy is beneficial for children with Prader-Willi syndrome (PWS) in improving short stature and metabolism, but the effect of early rhGH treatment on respiratory and sleep parameters for PWS children under three years old remains elusive. Thus, this study aimed to investigate the impact of rhGH treatment on sleep-related breathing disorders (SRBDs) for toddlers with PWS. METHODS: A total of 17 age-matched PWS patients receiving rhGH treatment (rhGH group) and 17 control individuals not receiving rhGH treatment (non-rhGH group) were recruited for this study between October 2018 and January 2023. Data related to polysomnography-polygraphy (PSG) and serum levels of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) were collected. RESULTS: The mean age in the rhGH group was 20.76 ± 9.22 months, which was comparable to that of the non-rhGH group (25.23 ± 13.81 months). The demographic and anthropometric parameters were similar across the two groups after 52 weeks of treatment. Administration of rhGH to toddlers did not exert adverse effects on the obstructive apnea-hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), mean percutaneous oxygen saturation (SpO2), lowest SpO2, duration when SpO2 is lower than 90%, or proportion of the patients with SpO2 lower than 90%. Furthermore, the increased IGF-1 z-score and IGFBP-3 level did not worsen SRBDs. CONCLUSION: Treatment with rhGH for 52 weeks on young toddlers with PWS showed no deleterious effects on SRBDs. This shed more light on the importance of initiating rhGH therapy early in PWS patients.
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Hormona de Crecimiento Humana , Síndrome de Prader-Willi , Humanos , Preescolar , Lactante , Hormona de Crecimiento Humana/uso terapéutico , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina , Factor I del Crecimiento Similar a la Insulina , Síndrome de Prader-Willi/complicaciones , Síndrome de Prader-Willi/tratamiento farmacológico , Estudios Retrospectivos , SueñoRESUMEN
As an efficient and cost-effective adsorbent, biochar has been widely used in the adsorption and removal of dyes. In this study, a simple NaOH-modified biochar with the pyrolysis temperature of 300 °C (NaCBC300) was synthesized, characterized, and investigated for the adsorption performances and mechanisms of methylene blue (MB). NaCBC300 exhibited excellent MB adsorption performance with maximum removal efficiency and adsorption capacity of 99.98% and 290.71 mg g-1, which were three and four times higher than biochar without modification, respectively. This might be attributed to the increased content of -OH and the formation of irregular flakes after NaOH modification. The Freundlich isotherm suggested multilayer adsorption between NaCBC300 and MB. Spectroscopic characterizations demonstrated that multiple mechanisms including π-π interaction, H-bonding, and pore-filling were involved in the adsorption. According to density functional theory (DFT) calculations, electrostatic interaction between NaCBC300 and MB was verified. The highest possibility of the attraction between NaCBC300 and MB was between -COOH in NaCBC300 and R-N(CH3)2 in MB. This work improved our understanding of the mechanism for MB adsorption by modified biochar and provided practical and theoretical guidance for adsorbent preparation with high adsorption ability for dyes.
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The combination of immunotherapy and chemotherapy to ablate tumors has attracted substantial attention due to the ability to simultaneously elicit antitumor immune responses and trigger direct tumor cell death. However, conventional combinational strategies mainly focus on the employment of drug carriers to deliver immunomodulators, chemotherapeutics, or their combinations, always suffering from complicated preparation and carrier-relevant side effects. Here, the fabrication of bacterial flagellum-drug nanoconjugates (FDNCs) for carrier-free immunochemotherapy is described. FDNCs are simply prepared by attaching chemotherapeutics to amine residues of flagellin through an acid-sensitive and traceless cis-aconityl linker. By virtue of native nanofibrous structure and immunogenicity, bacterial flagella not only show long-term tumor retention and highly efficient cell internalization, but also provoke robust systemic antitumor immune responses. Meanwhile, conjugated chemotherapeutics exhibit an acid-mediated release profile and durable intratumoral exposure, which can induce potent tumor cell inhibition via direct killing. More importantly, this combination is able to augment immunoactivation effects associated with chemotherapy-enabled immunogenic tumor cell death to further enhance antitumor efficacy. By leveraging the innate response of the immune system to pathogens, the conjugation of therapeutic agents with self-adjuvant bacterial flagella provides an alternative approach to develop carrier-free nanotherapeutics for tumor immunochemotherapy.
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Nanoconjugados , Neoplasias , Humanos , Nanoconjugados/química , Portadores de Fármacos/química , Neoplasias/tratamiento farmacológico , Adyuvantes Inmunológicos , Flagelos , Inmunoterapia , Línea Celular TumoralRESUMEN
Although immunotherapy can prolong survival in some patients with head and neck squamous cell carcinoma (HNSCC), the response rate remains low. Clarification of the critical mechanisms regulating CD8+ T-cell infiltration and dysfunction in the tumor microenvironment could help maximize the benefit of immunotherapy for treating HNSCC. Here, we performed spatial transcriptomic analysis of HNSCC specimens with differing immune infiltration and single-cell RNA sequencing of five pairs of tumor and adjacent tissues, revealing specific cancer-associated fibroblast (CAF) subsets related to CD8+ T-cell infiltration restriction and dysfunction. These CAFs exhibited high expression of CXCLs (CXCL9, CXCL10, and CXCL12) and MHC-I and enrichment of galectin-9 (Gal9). The proportion of MHC-IhiGal9+ CAFs was inversely correlated with abundance of a TCF1+GZMK+ subset of CD8+ T cells. Gal9 on CAFs induced CD8+ T-cell dysfunction and decreased the proportion of tumor-infiltrating TCF1+CD8+ T cells. Collectively, the identification of MHC-IhiGal9+ CAFs advances the understanding of the precise role of CAFs in cancer immune evasion and paves the way for more effective immunotherapy for HNSCC. SIGNIFICANCE: Spatial analysis identifies IFN-induced MHC-IhiGal9+ CAFs that form a trap for CD8+ T cells, providing insights into the complex networks in the tumor microenvironment that regulate T-cell infiltration and function.
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Fibroblastos Asociados al Cáncer , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Linfocitos T CD8-positivos , Perfilación de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Microambiente Tumoral/genéticaRESUMEN
Malignant melanoma (MM) frequently occurs in the skin or mucosa, whereas malignant melanoma of unknown primary (MUP) is diagnosed in patients with lymph nodes or visceral organs as the site of origin, where it is challenging to detect the primary lesion by comprehensive examination. MUP is possibly related to the spontaneous regression of the primary lesion. In addition, primary hepatic melanoma (PHM) usually refers to the primary MM occurring in the liver, with no typical primary lesions and no manifestations of tumor metastasis. A 61-year-old male patient with liver as the site of origin was diagnosed with MM by Melan-A, HMB-45, and S-100 immunohistochemistry staining of liver biopsy tissue. Based on a comprehensive examination, no basis was found for melanoma in sites such as the skin, mucosa, five sense organs, brain, digestive tract, respiratory tract, or genitalia, and the patient was subsequently diagnosed with MUP. MMs require a comprehensive inspection, beginning with the liver, to search for the primary lesion; if the primary lesion is not found, the possibility of PHM or MUP should be considered.
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BACKGROUND: The unique expression pattern endows oncofetal genes with great value in cancer diagnosis and treatment. However, only a few oncofetal genes are available for clinical use and the underlying mechanisms that drives the fetal-like reprogramming of cancer cells remain largely unknown. METHODS: Microarray assays and bioinformatic analyses were employed to screen for potential oncofetal long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC). The expression levels of MIR4435-2HG, NOP58 ribonucleoprotein (NOP58), insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) and stem markers were detected by quantitative polymerase chain reaction. The 2'-O-methylation (2'-O-Me) status of rRNA were detected through reverse transcription at low dNTP concentrations followed by PCR. The regulation of MIR4435-2HG by IGF2BP1 was explored by RNA immunoprecipitation (RIP), methylated RIP (MeRIP) and dual-luciferase assays. The interaction between MIR4435-2HG and NOP58 was investigated by RNA Pulldown, RIP and protein stability assays. In vitro and in vivo function assays were performed to detect the roles of MIR4435-2HG/NOP58 in HCC. RESULTS: MIR4435-2HG was an oncofetal lncRNA associated with poor prognosis in HCC. Functional experiments showed that overexpression of MIR4435-2HG remarkably enhanced the stem-cell properties of HCC cells, promoting tumorigenesis in vitro and in vivo. Mechanically, MIR4435-2HG directly bound NOP58 and IGF2BP1. IGF2BP1 upregulated MIR4435-2HG expression in HCC through N6-methyladenosine (m6A) modification. Moreover, MIR4435-2HG protected NOP58 from degradation, which raised rRNA 2'-O-Me levels and promoted internal ribosome entry site (IRES)-dependent translation of oncogenes. CONCLUSIONS: This study identified an oncofetal lncRNA MIR4435-2HG, characterized the role of MIR4435-2HG/NOP58 in stemness maintenance and proliferation of HCC cells, and confirmed m6A as a 'driver' that reactivated MR4435-2HG expression in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , ARN Largo no Codificante/genética , Metilación , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Regulación Neoplásica de la Expresión Génica , Proliferación Celular/genéticaRESUMEN
A postpartum female in her mid-20s presented with atypical symptoms of postdural puncture headache. However, on initial presentation, the patient reported no headache. Primary symptoms of acute, severe interscapular pain and upper extremity radiculopathy at the time of epidural placement were observed. The absence of a positional headache and the severity of pain at presentation prompted MRI analysis to establish a clinical diagnosis.MRI findings revealed a significant cerebrospinal fluid (CSF) leak causing a mass effect on the cervicothoracic spinal cord and severe stenosis at the cauda equina. An epidural blood patch (EBP) was considered; however, it was postulated that the narrow epidural space would not be sufficient to accommodate the volume associated with an EBP. She was managed conservatively until subsequent imaging revealed CSF resorption. She received an epidural blood patch on day 7. Thereafter, her symptoms improved, allowing her to nurse her infant and be discharged home.
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Dolor Agudo , Cauda Equina , Cefalea Pospunción de la Duramadre , Femenino , Lactante , Humanos , Cefalea Pospunción de la Duramadre/terapia , Cefalea/etiología , Parche de Sangre Epidural , Pérdida de Líquido CefalorraquídeoRESUMEN
The occurrence of unexplained fertilization failure can have profound psychological and financial consequences for couples struggling with infertility, and its pathogenesis remains unclear. Increasing evidence highlights genetic basis of unexplained fertilization failure occurrence. Here, we identified one novel homozygous nonsense mutation (c.949A>T), one novel homozygous missense mutation (c.1346C>T), and three reported homozygous mutations (c.585G>C, c.1006_1007insTA, c.1221G>A) in six unrelated probands, showing similar manifestations of unexplained fertilization failure. This finding expands the spectrum of WEE2 mutations, highlighting the critical role of WEE2 in fertilization process, and provides a basis for the prognostic value of testing for WEE2 mutations in primary infertile couples with unexplained fertilization failure.
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Infertilidad Femenina , Femenino , Humanos , Fertilización , Fertilización In Vitro , Infertilidad Femenina/genética , Mutación , Mutación Missense , Insuficiencia del TratamientoRESUMEN
The past decade has witnessed a great leap forward in bacteria-based living agents, including imageable probes, diagnostic reagents, and therapeutics, by virtue of their unique characteristics, such as genetic manipulation, rapid proliferation, colonization capability, and disease site targeting specificity. However, successful translation of bacterial bioagents to clinical applications remains challenging, due largely to their inherent susceptibility to environmental insults, unavoidable toxic side effects, and limited accumulation at the sites of interest. Cell surface components, which play critical roles in shaping bacterial behaviors, provide an opportunity to chemically modify bacteria and introduce different exogenous functions that are naturally unachievable. With the help of surface modification, a wide range of functionalized bacteria have been prepared over the past years and exhibit great potential in various biomedical applications. In this article, we mainly review the synthesis, functionalization, and biomedical applications of surface-modified bacteria. We first introduce the approaches of chemical modification based on the bacterial surface structure and then highlight several advanced functions achieved by modifying specific components on the surface. We also summarize the advantages as well as limitations of surface chemically modified bacteria in the applications of bioimaging, diagnosis, and therapy and further discuss the current challenges and possible solutions in the future. This work will inspire innovative design thinking for the development of chemical strategies for preparing next-generation biomedical bacterial agents.
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Bacterias , Microorganismos Modificados GenéticamenteRESUMEN
Patients preparing for their renewal fertility treatments with embryos frozen before coronavirus disease 2019 (COVID-19) infection do not need to be concerned about the potential impact of COVID-19 infection on oocyte quality and embryonic development. However, many women are still hesitant to undergo frozen embryo transfer (FET) due to fear of the detrimental effect of COVID-19 infection on endometrial receptivity and embryo implantation. The objective was to explore whether COVID-19 infection after oocyte retrieval is related to an increased risk of adverse pregnancy outcomes in a cohort of Chinese women undergoing FET. A retrospective cohort study was conducted among 300 infertile women undergoing FET with embryos frozen before COVID-19 infection. Women were categorized into noninfection, infection before FET, or infection after FET groups. Multivariable logistic regression was performed to assess the association of COVID-19 infection with clinical pregnancy outcomes, including biochemical pregnancy, clinical pregnancy, and early miscarriage. The implantation rates for patients in the group with infection before FET (29.14%) and the group with infection after FET (30.38%) were not significantly lower than those in the noninfection group (31.03%). The rate of biochemical pregnancy (54.55% vs. 52.27%, p = 0.750; 43.14% vs. 52.27%, p = 0.209) was not significantly different among the three groups. Although the clinical pregnancy rate showed a declining trend from 45.45% in the noninfection group to 38.27% in the group with infection after FET, this result was not statistically significant. The early miscarriage rate was similar in the group with infection before FET and the group with infection after FET compared with that in the noninfection group (3.64% vs. 5.68%, p = 0.496; 6.86% vs. 5.68%, p = 0.739). After adjusting for potential confounders, the biochemical pregnancy rate, clinical pregnancy rate, and early miscarriage rate were not significantly different for patients with infection before or after FET compared with patients without infection. This research indicated that COVID-19 infection after oocyte retrieval with embryos frozen before infection did not cause any detrimental effect on endometrial receptivity for embryo implantation.