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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.
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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 20-37â (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).
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Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano , Ácidos Graxos , Methylobacterium , Filogenia , RNA Ribossômico 16S , Microbiologia do Solo , RNA Ribossômico 16S/genética , DNA Bacteriano/genética , Ácidos Graxos/análise , Ácidos Graxos/química , Methylobacterium/genética , Methylobacterium/classificação , Methylobacterium/isolamento & purificação , China , Hibridização de Ácido Nucleico , Análise de Sequência de DNA , Fosfolipídeos/análiseRESUMO
Objective To observe the effect of excess oxygen supply for different time periods on the mitochondrial energy metabolism in alveolar epithelial type â ¡ cells. Methods Rat RLE-6TN cells were assigned into a control group (21% O2 for 4 h) and excess oxygen supply groups (95% O2 for 1,2,3,and 4 h,res-pectively).The content of adenosine triphosphate (ATP),the activity of mitochondrial respiratory chain complex V,and the mitochondrial membrane potential were determined by luciferase assay,micro-assay,and fluorescent probe JC-1,respectively.Real-time fluorescence quantitative PCR was employed to determine the mRNA levels of NADH dehydrogenase subunit 1 (ND1),cytochrome b (Cytb),cytochrome C oxidase subunit I (COXI),and adenosine triphosphatase 6 (ATPase6) in the core subunits of mitochondrial respiratory chain complexes â ,â ¢,â £,and â ¤,respectively. Results Compared with the control group,excess oxygen supply for 1,2,3,and 4 h down-regulated the mRNA levels of ND1 (q=24.800,P<0.001;q=13.650,P<0.001;q=9.869,P<0.001;q=20.700,P<0.001),COXI (q=16.750,P<0.001;q=10.120,P<0.001;q=8.476,P<0.001;q=14.060,P<0.001),and ATPase6 (q=22.770,P<0.001;q=15.540,P<0.001;q=12.870,P<0.001;q=18.160,P<0.001).Moreover,excess oxygen supply for 1 h and 4 h decreased the ATPase activity (q=9.435,P<0.001;q=11.230,P<0.001) and ATP content (q=5.615,P=0.007;q=5.029,P=0.005).The excess oxygen supply for 2 h and 3 h did not cause significant changes in ATPase activity (q=0.156,P=0.914;q=3.197,P=0.116) and ATP content (q=0.859,P=0.557;q=1.273,P=0.652).There was no significant difference in mitochondrial membrane potential among the groups (F=0.303,P=0.869). Conclusion Short-term excess oxygen supply down-regulates the expression of the core subunits of mitochondrial respiratory chain complexes and reduces the activity of ATPase,leading to the energy metabolism disorder of alveolar epithelial type â ¡ cells.
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Trifosfato de Adenosina , Metabolismo Energético , Animais , Ratos , Adenosina Trifosfatases , RNA Mensageiro , OxigênioRESUMO
WHAT IS KNOWN AND OBJECTIVE: It is estimated that 60% of children undergoing anaesthesia develop severe preoperative anxiety. The anxiety is associated with adverse reactions. Sedatives such as dexmedetomidine, midazolam, clonidine, ketamine, and melatonin can be used as premedication against preoperative anxiety. However, no consensus has been reached on the choice of pre-anaesthetic sedatives in children before selective surgery. Therefore, the current network meta-analysis (NMA) was carried out to evaluate different sedatives in children aged between 1 and 7 before general anaesthesia for selective surgery. METHODS: Randomized clinical trials (RCTs) were retrieved from Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases from inception to October 22, 2021. Primary outcomes showed satisfactory sedation at parent separation and also at induction or mask acceptance. Secondary outcomes were those related to added benefits and side effects. The present NMA was conducted using the R software. Results of the study were reported as Relative Risk (RR) or Mean Difference (MD) at a 95% credible intervals (CrIs). RESULTS AND DISCUSSION: A total of 48 trials were included in the present study. It was found that the effectiveness of dexmedetomidine, midazolam, clonidine, and ketamine were superior to that of placebo in satisfactory sedation at parent separation and induction or mask acceptance. There was no significant difference between melatonin and placebo in satisfactory sedation at induction or mask acceptance. Dexmedetomidine, ketamine, clonidine, and melatonin were superior to placebo in reducing emergence delirium (ED). In addition, midazolam prolonged the length of stay in the post anaesthesia care unit (PACU) as compared with placebo. Dexmedetomidine caused a significant reduction in systolic blood pressure (SBP) and heart rate (HR). Nevertheless, it was noted that the hemodynamic changes were roughly within safety limits. WHAT IS NEW AND CONCLUSION: It was evident that the studied drugs can provide effective sedation with exception of melatonin and placebo. However, it was found that midazolam, ketamine, and clonidine lead to several side effects. The findings of the present study supported that dexmedetomidine, especially intranasal administration, has potential in the optimal selection of the sedatives for premedication in children. This is because the drug has effective sedation, reduced incidence of ED, side effects, and onset time.
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Dexmedetomidina , Ketamina , Melatonina , Anestesia Geral/efeitos adversos , Criança , Pré-Escolar , Clonidina , Dexmedetomidina/efeitos adversos , Humanos , Hipnóticos e Sedativos/efeitos adversos , Lactente , Ketamina/efeitos adversos , Midazolam , Metanálise em RedeRESUMO
Objective To explore the effect of overwork (OW) on extracellular matrix of arterial vessel wall in rats. Methods Random number grouping method was employed to assign 18 Sprague-Dawley rats into three groups(n=6):the control group(no special treatment),group OW(forced swimming twice a day for 15 days),and sleep deficiency(SD)+OW group(in addition to forced swimming twice a day,the rats were put on the platforms in water to limit sleep for 15 days).On the 16th day,the abdominal aorta and common carotid artery were collected after blood sampling from heart under deep anesthesia.A part of the abdominal aorta sample was taken for Masson staining of collagen fiber,and Verhoeff-Van Gieson staining was carried out for the elastic fiber of common carotid artery.Image J was employed for the quantitative analysis of collagen fiber and elastic fiber content.The expression of collagen 1(Col-1) protein was quantified by immunohistochemistry and the ultrastructure of vascular matrix was examined by transmission electron microscopy.The other part of the abdominal aorta sample was used to determine the mRNA levels of matrix metalloproteinase(MMP)-1,MMP-2,MMP-9,tissue inhibitor of metalloproteinases-1(TIMP-1),and Col-1 by quantitative real-time polymerase chain reaction. Results Compared with that in control group,the content of collagen fiber in groups OW and SD+OW had no significant change(all P>0.05);the content of elastic fiber in groups OW and SD+OW decreased(all P<0.001) and had no significant difference between each other(P>0.05).The vascular vessel wall of group OW showed slight fiber breakage,while that of group SD+OW presented wormhole-like or spongy fiber fragmentation.The mRNA levels of MMP-1 and MMP-2 in groups OW and SD+OW had no significant difference between each other(P>0.05) but were higher than that in control group(all P<0.001).The mRNA levels of MMP-9 and TIMP-1 had no significant difference among the three groups(all P>0.05).Groups OW and SD+OW had lower mRNA level(all P<0.001) and protein level(all P<0.001) of Col-1 than control group,while the mRNA and protein levels of Col-1 had no significant difference between groups OW and SD+OW(P>0.05). Conclusion OW can reduce the content of Col-1 and elastic fibers in the extracellular matrix of arterial vessels,destroy the elastic lamina of vascular wall,up-regulate the expression of MMP-1 and MMP-2,thereby injuring arterial vessels.
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Metaloproteinase 2 da Matriz , Inibidor Tecidual de Metaloproteinase-1 , Animais , Colágeno Tipo I , Matriz Extracelular/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
OBJECTIVES: To study the demographic features of children with allergic diseases receiving standardized sublingual immunotherapy (SLIT) and the influencing factors for the compliance with SLIT. METHODS: A retrospective analysis was performed on the demographic features and follow-up data of 1 789 children with allergic diseases who received SLIT in Children's Hospital of Jiangxi Province from January 1, 2018 to December 31, 2020. The compliance with SLIT and its influencing factors were analyzed. RESULTS: A total of 1 789 children received SLIT, among whom there were 1 271 boys (71.05%) and 518 girls (28.95%), with an age range of 4-14 years. Among these children, 777 (43.43%) had complete compliance with SLIT and 1 012 (56.57%) withdrew from the treatment within one year. Among the 1 012 children, 354 (34.98%) withdrew from the treatment due to self-conscious inconvenient use, 346 (34.19%) withdrew due to unsatisfactory treatment outcome, 253 (25.00%) stopped the treatment due to the improvement in symptoms, and 59 (5.83%) terminated the treatment due to adverse reactions. Withdrawal was mainly observed within 1-4 months after treatment (74.31%, 752/1 012). Girls tended to have a lower compliance rate than boys, and the children with a single disease had a lower compliance rate than those with multiple diseases (P<0.05). The multivariate analysis showed that compared with boys, girls had an increased risk of withdrawal (OR=0.811, 95%CI: 0.658-0.998, P<0.05), and compared with the children with multiple diseases, the children with a single disease were more likely to withdraw from the treatment (OR=1.313, 95%CI: 1.005-1.715, P<0.05). CONCLUSIONS: Children with allergic diseases tend to have poor compliance with SLIT, which is associated with sex and the number of diseases, and the main reasons for withdrawal are self-conscious inconvenient use and unsatisfactory treatment outcome.
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Rinite Alérgica , Imunoterapia Sublingual , Masculino , Animais , Feminino , Humanos , Criança , Pré-Escolar , Adolescente , Estudos Retrospectivos , Pyroglyphidae , Rinite Alérgica/terapia , Resultado do Tratamento , Demografia , AlérgenosRESUMO
Sentinel lymph nodes (SLNs), being the first nodes to receive lymph from a primary tumour and the preferential site of initial tumour metastases, are intensively exposed to the bioactive products of tumour cells and other associated cells. This makes them ideal for studies of the factors that determine selective tissue susceptibility to metastases. We postulate that tumour-induced immune modulation of SLNs facilitates lymph-node metastases by inhibiting the generation of tumour-specific cytotoxic T cells that are active against tumour cells of primary and metastatic melanomas. Immune modulation of the lymph nodes can be reversed by granulocyte/macrophage colony-stimulating factor (GM-CSF), a finding that has implications for the future therapy of lymph-node metastases.
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Metástase Linfática/imunologia , Metástase Linfática/patologia , Neoplasias/imunologia , Neoplasias/patologia , Animais , Movimento Celular , Células Dendríticas/citologia , Células Dendríticas/imunologia , Humanos , Neoplasias/metabolismo , Neoplasias/terapia , Biópsia de Linfonodo SentinelaRESUMO
We present the case of a patient who had experienced a fever of unknown cause for >7 months after surgical treatment for hallux valgus. A patch test revealed a positive reaction to a titanium alloy. All symptoms subsequently disappeared after we removed the implanted titanium screws. Histopathologic examination of the tissue surrounding the screws showed macrophage infiltration in the tissue. For >1 year after removal of the titanium screws, the patient's body temperature remained <37°C. These results support a diagnosis of titanium allergy in our patient. To the best of our knowledge, a long-term fever caused by an allergic reaction to mini-titanium screws of such a small size has not been reported. A review of 16 cases of titanium allergy reported in the published data confirmed that titanium allergy is extremely rare and that the clinical symptoms can vary. Titanium allergy should be suspected when a patient presents with a fever of unknown cause, delayed wound healing, dermatitis, or impaired fracture healing after internal fixation with titanium materials. A patch test for titanium or the lymphocyte transformation test could offer guidance for the clinical diagnosis of titanium allergy. Finally, we recommend that all patients should be asked whether they have a history of an allergy to any metal before surgery.
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Parafusos Ósseos/efeitos adversos , Febre/etiologia , Hallux Valgus/cirurgia , Hipersensibilidade/diagnóstico , Hipersensibilidade/etiologia , Titânio/efeitos adversos , Adolescente , Humanos , MasculinoRESUMO
Knee osteoarthritis (KOA) is characterized by debilitating pain. Electroacupuncture (EA), a traditional Chinese medical therapy, has shown promise in KOA pain management. This study investigated the therapeutic potential of EA in KOA and its impact on limbic system neural plasticity. Sixteen rats were randomly assigned into two groups: EA group and sham-EA group. EA or sham-EA interventions were administered at acupoints ST32 (Futu) and ST36 (Zusanli) for three weeks. Post-intervention resting-state fMRI was scanned, assessing parameters including Amplitude of low frequency fluctuations (ALFF), regional homogeneity (ReHo), functional connectivity (FC) and nodal characterizations of network within limbic system. The results showed that EA was strategically directed towards the limbic system, resulting in discernible alterations in neural activity, FC, and network characteristics. Our findings demonstrate that EA had a significant impact on the limbic system neural plasticity in rats with KOA, presenting a novel nonpharmacological approach for KOA treatment.
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Eletroacupuntura , Osteoartrite do Joelho , Ratos , Animais , Eletroacupuntura/métodos , Osteoartrite do Joelho/terapia , Dor , Manejo da Dor , Sistema LímbicoRESUMO
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.
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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.
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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.
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Carcinoma de Células Renais , Neoplasias Renais , Masculino , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Rim/patologia , Hipóxia , Biomarcadores Tumorais , Ligante CD27/metabolismoRESUMO
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.
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Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Ligantes , Microambiente Tumoral/genética , Recidiva Local de Neoplasia , Perfilação da Expressão Gênica , Prognóstico , RNARESUMO
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.
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Doenças Autoimunes , Colangite , Cirrose Hepática Biliar , Camundongos , Animais , Cirrose Hepática Biliar/terapia , Imunoterapia Adotiva , Receptor de Morte Celular Programada 1 , Linfócitos T CD8-Positivos , Colangite/terapia , Doenças Autoimunes/genéticaRESUMO
OBJECTIVE: To study the effects of Astragaloside (AST) on PC12 cells injury and APP expression induced by dexamethasone (DEX) and beta-amyloid protein 25-35 (Abeta(25-35). METHODS: Logarithmic growth phase of the PC12 cells were seeded in culture plates. DEX 5 micromol/L and Abeta(25-35) 1 micromol/L were used to induce PC12 cells injury. MTT assay was used to detect the PC12 cells activity. RT-PCR was used to detect the APP, alpha-secretase and beta-secretase mRNA level of PC12 cells. Western bloting was used to detect APP protein expression of PC12 cells. RESULTS: MTT results showed that, DEX and Abeta(35-35) co-application could significantly decrease PC12 cells activity (P5 < 0.01). AST (10.20 mg/L) and Ginsenoside Rg1 (16 micromol/L) could increase PC12 cells activity. RT-PCR analysis showed that DEX and Abeta(25-35) co-application could significantly increase the beta-secretase mRNA levels and APP770, lower alpha-secretase mRNA levels. AST (10.20 mg/L) and Rg1 could decrease the elevated APP770, beta-secretase mRNA levels and increase the alpha-secretase mRNA level of PCl2 cells. Western bloting analysis result showed that AST (10.20 mg/L) and Rg1 could decrease the APP expression of PC12 cells induced by DEX and Abeta(25-35). CONCLUSION: AST has protective effects on PC12 cell injury induced by DEX and Abeta(25-35). The mechanism may be associated with decreasing the beta-secretase mRNA levels and APP expression, increasing the alpha-secretase mRNA levels.
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Peptídeos beta-Amiloides/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/metabolismo , Astrágalo/química , Sobrevivência Celular/efeitos dos fármacos , Dexametasona/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Saponinas/farmacologia , Triterpenos/farmacologia , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/toxicidade , Precursor de Proteína beta-Amiloide/genética , Animais , Dexametasona/toxicidade , Medicamentos de Ervas Chinesas/farmacologia , Ginsenosídeos/farmacologia , Células PC12 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The objective of the study was to determine the effect of landing surface on plantar kinetics during a half-squat landing. Twenty male elite paratroopers with formal parachute landing training and over 2 years of parachute jumping experience were recruited. The subjects wore parachuting boots in which pressure sensing insoles were placed. Each subject was instructed to jump off a platform with a height of 60 cm, and land on either a hard or soft surface in a half-squat posture. Outcome measures were maximal plantar pressure, time to maximal plantar pressure (T-MPP), and pressure-time integral (PTI) upon landing on 10 plantar regions. Compared to a soft surface, hard surface produced higher maximal plantar pressure in the 1(st) to 4(th) metatarsal and mid-foot regions, but lower maximal plantar pressure in the 5(th) metatarsal region. Shorter T- MPP was found during hard surface landing in the 1(st) and 2(nd) metatarsal and medial rear foot. Landing on a hard surface landing resulted in a lower PTI than a soft surface in the 1(st)phalangeal region. For Chinese paratroopers, specific foot prosthesis should be designed to protect the1(st) to 4(th)metatarsal region for hard surface landing, and the 1(st)phalangeal and 5(th)metatarsal region for soft surface landing. Key PointsUnderstanding plantar kinetics during the half-squat landing used by Chinese paratroopers can assist in the design of protective footwear.Compared to landing on a soft surface, a hard surface produced higher maximal plantar pressure in the 1(st) to 4(th) metatarsal and mid-foot regions, but lower maximal plantar pressure in the 5(th) metatarsal region.A shorter time to maximal plantar pressure was found during a hard surface landing in the 1(st) and 2(nd) metatarsals and medial rear foot.Landing on a hard surface resulted in a lower pressure-time integral than landing on a soft surface in the 1(st) phalangeal region.For Chinese paratroopers, specific foot prosthesis should be designed to protect the 1(st) to 4(th) metatarsal region for a hard surface landing, and the 1(st) phalangeal and 5(th) metatarsal region for a soft surface landing.
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Objective: To identify risk factors for postoperative sore throat (POST) after general anesthesia in oral and maxillOfacial surgery. Material and Methods: This study is a retrospective cohort design study. We enrolled patients with oral and maxillofacial surgery who underwent endotracheal intubation under general anesthesia in the Stomatology Hospital, Zhejiang University School Of Medicine between April 2020 and April 2021. They were divided into the POST group and the without POST group. The distribution Of various characteristics in the two groups was firstly analyzed. Then, logistic regression analysis was performed to explore the independent predictors for POST occurrence. Following this, logistic regression and random forest models were constructed and their performance was evaluated to predict POST occurrence. Results: A total of 891 participants were enrolled in the study. Female gender and cough during extubation were significantly associated with increased POST occurrence in multivariate analysis (all P <0.05). Stratified logistic regression analysis results showed that the female gender was an independent predictor for POST occurrence in the 4≤age≤14 and 14
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Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.
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Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Humanos , Masculino , Androgênios/metabolismo , Linhagem Celular Tumoral , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Transdução de SinaisRESUMO
AIM: This study explored the associations of personal, disease, family, and social factors with quality of life (QoL) in patients with two common types of chronic mental illness (CMI) living in Kaohsiung City, Taiwan. METHODS: Using a convenience sample and a cross-sectional design, 714 patients (50.1% male, 49.9% female) with CMI (72.1% schizophrenia and 27.9% affective disorder) and their caregivers were recruited. Demographic information was collected via the following questionnaires: 12-Item Short-Form Health Survey (SF-12), five-item Brief Symptom Rating Scale (BSRS-5), Caregiver Burden Scale, and Clinical Global Impressions (CGI-S) Scale. Pearson correlations and hierarchical regression analyses were used to predict QoL. RESULTS: Disease factors accounted for 17-50% of the change in variance. Predictors of low mental subscale scores included the following: high psychological distress and high family burden as well as a history of suicide attempts, negative caregiver attitudes, and living away from home. Disease factors also explained the greatest variance in the physical subscales. Predictors of low physical subscale scores included the following: high psychological distress, age, unemployment, a history of suicide attempts, high family burden, and living alone. CONCLUSIONS: Disease factors were the most important predictors of QoL in patients with CMI. Family factors were more important than social factors on the mental subscales. Differential relationships were also found for the other two dimensions. Together, these results indicate that a wide range of factors improve the QoL in patients with CMI.
Assuntos
Transtornos Mentais/psicologia , Qualidade de Vida , Adolescente , Adulto , Idoso , Análise de Variância , Cuidadores , Efeitos Psicossociais da Doença , Estudos Transversais , Demografia , Feminino , Humanos , Classificação Internacional de Doenças , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/reabilitação , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Análise de Regressão , Psicologia do Esquizofrênico , Comportamento Social , Meio Social , Taiwan/epidemiologia , Resultado do Tratamento , População Urbana , Adulto JovemRESUMO
Loss-of-function mutations in genes encoding the Krebs cycle enzymes Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) induce accumulation of fumarate and succinate, respectively and predispose patients to hereditary cancer syndromes including the development of aggressive renal cell carcinoma (RCC). Fumarate and succinate competitively inhibit αKG-dependent dioxygenases, including Lysine-specific demethylase 4A/B (KDM4A/B), leading to suppression of the homologous recombination (HR) DNA repair pathway. In this study, we have developed new syngeneic Fh1- and Sdhb-deficient murine models of RCC, which demonstrate the expected accumulation of fumarate and succinate, alterations in the transcriptomic and methylation profile, and an increase in unresolved DNA double-strand breaks (DSBs). The efficacy of poly ADP-ribose polymerase inhibitors (PARPis) and temozolomide (TMZ), alone and in combination, was evaluated both in vitro and in vivo. Combination treatment with PARPi and TMZ results in marked in vitro cytotoxicity in Fh1- and Sdhb-deficient cells. In vivo, treatment with standard dosing of the PARP inhibitor BGB-290 and low-dose TMZ significantly inhibits tumor growth without a significant increase in toxicity. These findings provide the basis for a novel therapeutic strategy exploiting HR deficiency in FH and SDH-deficient RCC with combined PARP inhibition and low-dose alkylating chemotherapy.