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1.
J Hepatol ; 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38759889

RESUMEN

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.

2.
Antonie Van Leeuwenhoek ; 117(1): 83, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38806744

RESUMEN

An aerobic, Gram-stain-negative, motile rod bacterium, designated as SYSU BS000021T, was isolated from a black soil sample in Harbin, Heilongjiang province, China. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the isolate belongs to the genus Methylobacterium, and showed the highest sequence similarity to Methylobacterium segetis KCTC 62267 T (98.51%) and Methylobacterium oxalidis DSM 24028 T (97.79%). Growth occurred at 20-37℃ (optimum, 28 °C), pH 6.0-8.0 (optimum, pH 7.0) and in the presence of 0% (w/v) NaCl. Polar lipids comprised of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unidentified aminolipid and one unidentified polar lipid. The major cellular fatty acids (> 5%) were C18:0 and C18:1 ω7c and/or C18:1 ω6c. The predominant respiratory quinone was Q-10. The genomic G + C content was 68.36% based on the whole genome analysis. The average nucleotide identity (≤ 83.5%) and digital DNA-DNA hybridization (≤ 27.3%) values between strain SYSU BS000021T and other members of the genus Methylobacterium were all lower than the threshold values recommended for distinguishing novel prokaryotic species. Based on the results of phenotypic, chemotaxonomic and phylogenetic analyses, strain SYSU BS000021T represents a novel species of the genus Methylobacterium, for which the name Methylobacterium nigriterrae sp. nov. is proposed. The type strain of the proposed novel species is SYSU BS000021T (= GDMCC 1.3814 T = KCTC 8051 T).


Asunto(s)
Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano , Ácidos Grasos , Methylobacterium , Filogenia , ARN Ribosómico 16S , Microbiología del Suelo , ARN Ribosómico 16S/genética , ADN Bacteriano/genética , Ácidos Grasos/análisis , Ácidos Grasos/química , Methylobacterium/genética , Methylobacterium/clasificación , Methylobacterium/aislamiento & purificación , China , Hibridación de Ácido Nucleico , Análisis de Secuencia de ADN , Fosfolípidos/análisis
3.
Clin Genitourin Cancer ; 22(2): 347-353, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38195301

RESUMEN

BACKGROUND: CD70 is commonly overexpressed in renal cell carcinoma and is minimally expressed in normal human tissue, making it a potential therapeutic target for patients with advanced renal cell carcinoma. The expression frequency of CD70 in metastatic renal cell carcinoma is not well established. MATERIALS AND METHODS: We assessed CD70 immunohistochemistry in 391 primary renal tumors and 72 metastatic renal cell carcinomas on a tissue microarray including 26 sets of paired primary and metastatic tumors. RESULTS: CD70 was frequently overexpressed in clear cell carcinoma, with a significantly lower expression rate in papillary renal cell carcinoma (P < .0001). No expression of CD70 was detected in other types of renal tumors and normal renal parenchyma. In clear cell renal cell carcinoma, CD70 expression was significantly correlated with hypoxia pathway proteins, corroborating with a recent study suggesting that CD70 is a downstream target gene of hypoxia-inducible factor. While higher expression levels were observed in males and non-Caucasians, CD70 expression was not associated with tumor grade, sarcomatoid differentiation, stage, or cancer-specific survival. Further, analysis of 26 paired primary and metastatic tumors from same individuals revealed a concordance rate of 85%. CONCLUSION: Our findings validated CD70 as a promising therapeutic target for patients with metastatic clear cell renal cell carcinoma. The utility of primary tumor tissue as surrogate samples for metastatic clear cell carcinoma awaits future CD70-targeted clinical trials.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Masculino , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Riñón/patología , Hipoxia , Biomarcadores de Tumor , Ligando CD27/metabolismo
4.
Nurse Educ Today ; 142: 106357, 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-39154593

RESUMEN

BACKGROUND: Most nursing managers are not fully aware of second victims and may not be able to provide support. Moreover, there are relatively few training courses for nursing managers about second victims. AIM: To describe the construction and evaluation of a second victim course for nursing managers. DESIGN: A single-group pretest-posttest study design was used. SETTING: A large comprehensive tertiary hospital with over 3000 beds in China. PARTICIPANTS: Forty-nine nursing managers who met the inclusion and exclusion criteria participated in this training. Sixteen clinical frontline nurses who experienced adverse events within three months following the training were also invited. METHODS: The course "Second Victim & Empathy Communication" was developed through a literature review and expert consultation and consisted of 4 unit modules: (1) adverse events & second victims, (2) the recovery trajectory of second victims, (3) second victim supportive resources, and (4) key strategies of empathy communication. A course evaluation questionnaire, an empathy communication questionnaire for nursing managers, a second victim evaluation questionnaire, and an open-ended question were used to measure the feasibility, acceptability and effectiveness of the course. RESULTS: >97.96 % of the nursing managers were satisfied with the course, >97.96 % had learned new knowledge, and >95.92 % had changed their behavior and attitudes toward second victims. Their levels of empathetic communication differed significantly before and after training (t = -2.170, P = 0.035). Among these nursing managers, twenty-six participants provided positive and meaningful feedback and suggestions to the course by answering an open-ended question. A total of 66.6 % to 100 % of second victims were satisfied with the empathetic communication behavior exhibited by nursing managers. CONCLUSION: The second victim training course is feasible and can be used for clinical training to enhance nursing managers' understanding of second victims and enhance their empathetic communication.

5.
iScience ; 27(7): 110385, 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39092177

RESUMEN

Oxygen therapy is widely used in clinical practice; however, prolonged hyperoxia exposure may result in hyperoxic acute lung injury (HALI). In this study, we investigated the role of FAM134B in hyperoxia-induced apoptosis, cell proliferation, and epithelial-to-mesenchymal transition (EMT) using RLE-6TN cells and rat lungs. We also studied the effect of CeO2-NPs on RLE-6TN cells and lungs following hyperoxia exposure. FAM134B was inhibited in RLE-6TN cells and rat lungs following hyperoxia exposure. Overexpressing FAM134B promoted cell proliferation, and reduced EMT and apoptosis following hyperoxia exposure. FAM134B activation increased ER-phagy, decreased apoptosis, improved lung structure damage, and decreased collagen fiber deposition to limit lung injury. These effects could be reversed by PI3K/AKT pathway inhibitor LY294002. Additionally, CeO2-NPs protected RLE-6TN cells and lung damage following hyperoxia exposure by ameliorating impaired ER-phagy. Therefore, FAM134B restoration is a potential therapeutic target for the HALI. Moreover, CeO2-NPs can be used for the treatment of HALI.

6.
Clin Transl Med ; 14(3): e1594, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38426403

RESUMEN

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common malignant endocrine tumour, and its incidence and prevalence are increasing considerably. Cellular heterogeneity in the tumour microenvironment is important for PTC prognosis. Spatial transcriptomics is a powerful technique for cellular heterogeneity study. METHODS: In conjunction with a clinical pathologist identification method, spatial transcriptomics was employed to characterise the spatial location and RNA profiles of PTC-associated cells within the tissue sections. The spatial RNA-clinical signature genes for each cell type were extracted and applied to outlining the distribution regions of specific cells on the entire section. The cellular heterogeneity of each cell type was further revealed by ContourPlot analysis, monocle analysis, trajectory analysis, ligand-receptor analysis and Gene Ontology enrichment analysis. RESULTS: The spatial distribution region of tumour cells, typical and atypical follicular cells (FCs and AFCs) and immune cells were accurately and comprehensively identified in all five PTC tissue sections. AFCs were identified as a transitional state between FCs and tumour cells, exhibiting a higher resemblance to the latter. Three tumour foci were shared among all patients out of the 13 observed. Notably, tumour foci No. 2 displayed elevated expression levels of genes associated with lower relapse-free survival in PTC patients. We discovered key ligand-receptor interactions, including LAMB3-ITGA2, FN1-ITGA3 and FN1-SDC4, involved in the transition of PTC cells from FCs to AFCs and eventually to tumour cells. High expression of these patterns correlated with reduced relapse-free survival. In the tumour immune microenvironment, reduced interaction between myeloid-derived TGFB1 and TGFBR1 in tumour focus No. 2 contributed to tumourigenesis and increased heterogeneity. The spatial RNA-clinical analysis method developed here revealed prognosis-associated cellular heterogeneity in the PTC microenvironment. CONCLUSIONS: The occurrence of tumour foci No. 2 and three enhanced ligand-receptor interactions in the AFC area/tumour foci reduced the relapse-free survival of PTC patients, potentially leading to improved prognostic strategies and targeted therapies for PTC patients.


Asunto(s)
Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/metabolismo , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Ligandos , Microambiente Tumoral/genética , Recurrencia Local de Neoplasia , Perfilación de la Expresión Génica , Pronóstico , ARN
7.
Nat Commun ; 15(1): 2936, 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38580644

RESUMEN

Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.


Asunto(s)
Enfermedades Autoinmunes , Colangitis , Cirrosis Hepática Biliar , Ratones , Animales , Cirrosis Hepática Biliar/terapia , Inmunoterapia Adoptiva , Receptor de Muerte Celular Programada 1 , Linfocitos T CD8-positivos , Colangitis/terapia , Enfermedades Autoinmunes/genética
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