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BACKGROUND: It has been proposed that anti-angiogenesis therapy could induce tumor "vascular normalization" and further enhance the efficacy of chemotherapy, radiotherapy, target therapy, and immunotherapy for nearly twenty years. However, the detailed molecular mechanism of this phenomenon is still obscure. METHOD: Overexpression and knockout of CCL28 in human lung adenocarcinoma cell line A549 and murine lung adenocarcinoma cell line LLC, respectively, were utilized to establish mouse models. Single-cell sequencing was performed to analyze the proportion of different cell clusters and metabolic changes in the tumor microenvironment (TME). Immunofluorescence and multiplex immunohistochemistry were conducted in murine tumor tissues and clinical biopsy samples to assess the percentage of pericytes coverage. Primary pericytes were isolated from lung adenocarcinoma tumor tissues using magnetic-activated cell sorting (MACS). These pericytes were then treated with recombinant human CCL28 protein, followed by transwell migration assays and RNA sequencing analysis. Changes in the secretome and metabolome were examined, and verification of retinoic acid metabolism alterations in pericytes was conducted using quantitative real-time PCR, western blotting, and LC-MS technology. Chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) was employed to validate the transcriptional regulatory ability and affinity of RXRα to specific sites at the ANGPT1 promoter. RESULTS: Our study showed that after undergoing anti-angiogenesis treatment, the tumor exhibited a state of ischemia and hypoxia, leading to an upregulation in the expression of CCL28 in hypoxic lung adenocarcinoma cells by the hypoxia-sensitive transcription factor CEBPB. Increased CCL28 could promote tumor vascular normalization through recruiting and metabolic reprogramming pericytes in the tumor microenvironment. Mechanistically, CCL28 modified the retinoic acid (RA) metabolism and increased ANGPT1 expression via RXRα in pericytes, thereby enhancing the stability of endothelial cells. CONCLUSION: We reported the details of the molecular mechanisms of "vascular normalization" after anti-angiogenesis therapy for the first time. Our work might provide a prospective molecular marker for guiding the clinical arrangement of combination therapy between anti-angiogenesis treatment and other therapies.
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Adenocarcinoma del Pulmón , Angiopoyetina 1 , Quimiocinas CC , Neoplasias Pulmonares , Pericitos , Pericitos/metabolismo , Ratones , Humanos , Animales , Angiopoyetina 1/metabolismo , Angiopoyetina 1/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Quimiocinas CC/metabolismo , Quimiocinas CC/genética , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Microambiente Tumoral , Neovascularización Patológica/metabolismo , Línea Celular TumoralRESUMEN
BACKGROUND: Diagnosis and severity assessment of tinnitus are mostly based on the patient's descriptions and subjective questionnaires, which lacks objective means of diagnosis and assessment bases, the accuracy of which fluctuates with the clarity of the patient's description. This complicates the timely modification of treatment strategies or therapeutic music to improve treatment efficacy. NEW METHOD: We employed a novel random convolutional kernel-based method for electrocardiogram (ECG) signal analysis to identify patients' emotional states during Music Tinnitus Sound Therapy (Music-TST) sessions. Then analyzed correlations between emotional changes in different treatment phase and Tinnitus Handicap Inventory (THI) score differences to determine the impact of emotions on tinnitus treatment efficacy. RESULTS: This study revealed a significant correlation between patients' emotion changes during Music-TST and the therapy's effectiveness. Changes in arousal and dominance dimension, were strongly linked to THI variations. These findings highlight the substantial impact of emotional responses on sound therapy's efficacy, offering a new perspective for understanding and optimizing tinnitus treatment. COMPARISON WITH EXISTING METHODS: Compared to existing methods, we proposed an objective indicator to assess the progress of sound therapy, the indicator could also be used to provide feedback to optimize sound therapy music. CONCLUSIONS: This study revealed the critical role of emotion changes in tinnitus sound therapy. By integrating objective ECG-based emotion analysis with traditional subjective scale like THI, we present an innovative approach to assess and potentially optimize therapy effectiveness. This finding could lead to more personalized and effective treatment strategies for tinnitus sound therapy.
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Electrocardiografía , Emociones , Musicoterapia , Acúfeno , Acúfeno/terapia , Acúfeno/fisiopatología , Acúfeno/diagnóstico , Humanos , Masculino , Emociones/fisiología , Femenino , Persona de Mediana Edad , Musicoterapia/métodos , Adulto , Resultado del Tratamiento , Anciano , Estimulación Acústica/métodosRESUMEN
The progress of modern medical technology has made artificial heart valve replacement an effective means to treat valvular disease, but the impact of cardiac function on patients after surgery is still a key issue. The purpose of this study was to construct the cirRNA-miRNA-mRNA network after artificial heart valve replacement in valvular disease patients, and to explore the regulatory mechanism related to MAPK1 protein, so as to reveal its potential role in affecting cardiac function. We downloaded cyclic cRNA expression profiles from the GEO database. Use the limma package to identify dec. WGCNA is used to identify key modules of circular rna. The target miRNAs of circular rna and the corresponding target genes of miRNAs were screened by ring intertome and target scan database. GO and KEGG analysis using the DAVID database. The genes associated with iron sag disease were derived from FerrDb database. The overlapping genes were obtained by Wien analysis. Next, the CircrNa-mirNa-mrna network was constructed based on the circRNA-miRNA pair and miRNA-mRNA pair and their cyclic landscape software. This study revealed the changes in the structure and expression of MAPK1 protein in the cirRNA-miRNA-mRNA network after artificial heart valve replacement in valvular disease patients, suggesting the potential role of MAPK1 protein in regulating cardiac function, and laying a foundation for further revealing its mechanism and clinical application.
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Obesity shapes anti-tumor immunity through lipid metabolism; however, the mechanisms underlying how colorectal cancer (CRC) cells utilize lipids to suppress anti-tumor immunity remain unclear. Here, we show that tumor cell-intrinsic ATP6V0A1 drives exogenous cholesterol-induced immunosuppression in CRC. ATP6V0A1 facilitates cholesterol absorption in CRC cells through RAB guanine nucleotide exchange factor 1 (RABGEF1)-dependent endosome maturation, leading to cholesterol accumulation within the endoplasmic reticulum and elevated production of 24-hydroxycholesterol (24-OHC). ATP6V0A1-induced 24-OHC upregulates TGF-ß1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-ß1 into the tumor microenvironment by CRC cells activates the SMAD3 pathway in memory CD8+ T cells, ultimately suppressing their anti-tumor activities. Moreover, we identify daclatasvir, a clinically used anti-hepatitis C virus (HCV) drug, as an ATP6V0A1 inhibitor that can effectively enhance the memory CD8+ T cell activity and suppress tumor growth in CRC. These findings shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.
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Linfocitos T CD8-positivos , Colesterol , Neoplasias Colorrectales , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Humanos , Animales , Colesterol/metabolismo , Ratones , Línea Celular Tumoral , Factor de Crecimiento Transformador beta1/metabolismo , Memoria Inmunológica , ATPasas de Translocación de Protón Vacuolares/metabolismo , Microambiente Tumoral/inmunología , Receptores X del Hígado/metabolismo , Hidroxicolesteroles/metabolismo , Hidroxicolesteroles/farmacología , Pirrolidinas/farmacología , Proteína smad3/metabolismo , Ratones Endogámicos C57BL , Carbamatos/farmacologíaRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent malignancy with a pressing need for improved therapeutic response and prognosis prediction. This study delves into a novel predictive model related to ferroptosis, a regulated cell death mechanism disrupting metabolic processes. RESULTS: Single-cell sequencing data analysis identified subpopulations of HCC cells exhibiting activated ferroptosis and distinct gene expression patterns compared to normal tissues. Utilizing the LASSO-Cox algorithm, we constructed a model with 10 single-cell biomarkers associated with ferroptosis, namely STMN1, S100A10, FABP5, CAPG, RGCC, ENO1, ANXA5, UTRN, CXCR3, and ITM2A. Comprehensive analyses using these biomarkers revealed variations in immune infiltration, tumor mutation burden, drug sensitivity, and biological functional profiles between risk groups. Specific associations were established between particular immune cell subtypes and certain gene expression patterns. Treatment response analyses indicated potential benefits from anti-tumor immune therapy for the low-risk group and chemotherapy advantages for the high-risk group. CONCLUSIONS: The integration of this single-cell level model with clinicopathological features enabled accurate overall survival prediction and effective risk stratification in HCC patients. Our findings illuminate the potential of ferroptosis-related genes in tailoring therapy and prognosis prediction for HCC, offering novel insights into the intricate interplay among ferroptosis, immune response, and HCC progression.
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Biomarcadores de Tumor , Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Ferroptosis/genética , Ferroptosis/efectos de los fármacos , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Análisis de la Célula Individual , Medicina de Precisión/métodosRESUMEN
AURKA, also known as Aurora kinase A, is a key molecule involved in the occurrence and progression of cancer. It plays crucial roles in various cellular processes, including cell cycle regulation, mitosis, and chromosome segregation. Dysregulation of AURKA has been implicated in tumorigenesis, promoting cell proliferation, genomic instability, and resistance to apoptosis. In this study, we conducted an extensive bibliometric analysis of research focusing on Aurora-A in the context of cancer by utilizing the Web of Science literature database. Various sophisticated computational tools, such as VOSviewer, Citespace, Biblioshiny R, and Cytoscape, were employed for comprehensive literature analysis and big data mining from January 1998 to September 2023.The primary objectives of our study were multi-fold. Firstly, we aimed to explore the chronological development of AURKA research, uncovering the evolution of scientific understanding over time. Secondly, we investigated shifting trends in research topics, elucidating areas of increasing interest and emerging frontiers. Thirdly, we delved into intricate signaling pathways and protein interaction networks associated with AURKA, providing insights into its complex molecular mechanisms. To further enhance the value of our bibliometric analysis, we conducted a meta-analysis on the prognostic value of AURKA in terms of patient survival. The results were visually presented, offering a comprehensive overview and future perspectives on Aurora-A research in the field of oncology. This study not only contributes to the existing body of knowledge but also provides valuable guidance for researchers, clinicians, and pharmaceutical professionals. By harnessing the power of bibliometrics, our findings offer a deeper understanding of the role of AURKA in cancer and pave the way for innovative research directions and clinical applications.
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Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC.
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Subunidad p19 de la Interleucina-23 , Fosfatidilinositol 3-Quinasas , Receptor de Muerte Celular Programada 1 , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Linfocitos T Citotóxicos , Neoplasias de la Mama Triple Negativas , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/inmunología , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Línea Celular Tumoral , Femenino , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Subunidad p19 de la Interleucina-23/metabolismo , Animales , Ratones , Anticuerpos Monoclonales/farmacologíaRESUMEN
Aim: Azithromycin (AZM) is widely used to treat mycoplasma infection in pregnancy. However, there is no adequate evaluation of its side effect on the placenta. In this study, using human placental syncytiotrophoblasts and a mouse model, we investigated whether AZM use in pregnancy might adversely affect placental function and pregnancy outcome. Results: Transcriptomic analysis of AZM-treated human placental syncytiotrophoblasts showed increased expression of endoplasmic reticulum (ER) stress-related genes and decreased expression of genes for hormone production and growth factor processing. Verification studies showed that AZM increased the abundance of ER stress mediators (phosphorylated eIF2α, activating transcription factor 4 [ATF4], and C/EBP Homologous Protein [CHOP]) and decreased the abundance of enzymes involved in progesterone and estradiol synthesis (STS, CYP11A1, and CYP19A1) and insulin-like growth factor binding protein (IGFBP) cleavage (PAPPA and ADAM12) in human placental syncytiotrophoblasts. Inhibition of ER stress blocked AZM-induced decreases in the expression of CYP19A1, CYP11A1, PAPPA, and ADAM12, suggesting that the inhibition of AZM on those genes' expression was secondary to AZM-induced ER stress. Further mechanism study showed that increased ATF4 in ER stress might repressively interact with C/EBPα to suppress the expression of those genes, including CEBPA itself. Mouse studies showed that AZM administration decreased fetal weights along with increased ER stress mediators and decreased levels of insulin-like growth factor, estrogen, and progesterone in the maternal blood, which could be alleviated by inhibition of ER stress. Innovation and Conclusion: These findings first support the fact that AZM, often used during pregnancy, may affect fetal growth by inhibiting crucial enzymes for estrogen and progesterone synthesis and disrupting crucial proteases for IGFBP cleavage via inducing ER stress in placental syncytiotrophoblasts.
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This study informed researchers about the performance of different level-specific and target-specific model fit indices in the Multilevel Latent Growth Model (MLGM) with unbalanced design. As the use of MLGMs is relatively new in applied research domain, this study helped researchers using specific model fit indices to evaluate MLGMs. Our simulation design factors included three levels of number of groups (50, 100, and 200) and three levels of unbalanced group sizes (5/15, 10/20, and 25/75), based on simulated datasets derived from a correctly specified MLGM. We evaluated the descriptive information of the model fit indices under various simulation conditions. We also conducted ANOVA to calculated the extent to which these fit indices could be influenced by different design factors. Based on the results, we made recommendations for practical and theoretical research about the fit indices. CFI- and TFI-related fit indices performed well in the MLGM and could be trustworthy to use to evaluate model fit under similar conditions found in applied settings. However, RMSEA-related fit indices, SRMR-related fit indices, and chi square-related fit indices varied by the factors included in this study and should be used with caution for evaluating model fit in the MLGM.
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Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of allergic asthma. Here, we have evaluated the anti-inflammatory impact of dimethyl fumarate (DMF) in allergic asthma with more focus on determining its effect on T cell responses in allergic asthma. By utilizing the ovalbumin (OVA)-induced allergic asthma model, we observed that DMF administration reduced the allergic asthma symptoms and IgE levels in the OVA-induced mice model. Histopathological analysis showed that DMF treatment in an OVA-induced animal model eased the inflammation in the nasal and bronchial tissues, with a particular decrease in the infiltration of immune cells. Additionally, RT-qPCR analysis exhibited that treatment of DMF in an OVA-induced model reduced the expression of inflammatory cytokine (IL4, IL13, and IL17) while augmenting anti-inflammatory IL10 and Foxp3 (forkhead box protein 3). Mechanistically, we found that DMF increased the expression of Foxp3 by exacerbating the expression of nuclear factor E2-related factor 2 (Nrf2), and the in-vitro activation of Foxp3+ Tregs leads to an escalated expression of Nrf2. Notably, CD4-specific Nrf2 deletion intensified the allergic asthma symptoms and reduced the in-vitro iTreg differentiation. Meanwhile, DMF failed to exert protective effects on OVA-induced allergic asthma in CD4-specific Nrf2 knock-out mice. Overall, our study illustrates that DMF enhances Nrf2 signaling in T cells to assist the differentiation of Tregs, which could improve the anti-inflammatory immune response in allergic asthma.
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Asma , Dimetilfumarato , Factor 2 Relacionado con NF-E2 , Transducción de Señal , Linfocitos T Reguladores , Animales , Femenino , Ratones , Asma/tratamiento farmacológico , Asma/inmunología , Asma/metabolismo , Citocinas/metabolismo , Dimetilfumarato/farmacología , Dimetilfumarato/uso terapéutico , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 2 Relacionado con NF-E2/metabolismo , Ovalbúmina/inmunología , Transducción de Señal/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismoRESUMEN
The lymphoma incidence rate is on the rise, with invasive forms particularly prone to relapse following conventional treatment, posing a significant threat to human life and wellbeing. Numerous studies have shown that traditional Chinese botanical drug medicine offers promising therapeutic benefits for various malignancies, with previous experimental findings indicating that Celastrus orbiculatus extract effectively combats digestive tract tumors. However, its impact on lymphoma remains unexplored. This study aims to investigate the impact and underlying mechanisms of COE on the proliferation and apoptosis of Burkitt lymphoma cells. We diluted COE in RPMI-1640 medium to create various working concentrations and introduced it to human Burkitt lymphoma Raji and Ramos cells. To evaluate cell viability, we used the CCK-8 assay, and we observed morphological changes using HE staining. We also conducted Annexin V-PI and JC-1 staining experiments to assess apoptosis. By combining the cell cycle experiment with the EDU assay, we gained insights into the effects of COE on DNA replication in lymphoma cells. Using Western blotting, we detected alterations in apoptosis-related proteins. In vivo experiments revealed that following COE intervention, tumor volume decreased, survival time was prolonged, spleen size reduced, and the expression of tumor apoptosis-related proteins changed. Our findings indicate that COE effectively inhibits lymphoma cell proliferation and promotes apoptosis by regulating these apoptosis-related proteins.
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Meeting the demand for efficient photosensitizers in photodynamic therapy (PDT), a series of iridium(III) complexes decorated with silicane-modified rhodamine (Si-rhodamine) was meticulously designed and synthesized. These complexes demonstrate exceptional PDT potential owing to their strong absorption in the near-infrared (NIR) spectrum, particularly responsive to 808 nm laser stimulation. This feature is pivotal, enabling deep-penetration laser excitation and overcoming depth-related challenges in clinical PDT applications. The molecular structures of these complexes allow for reliable tuning of singlet oxygen generation with NIR excitation, through modification of the cyclometalating ligand. Notably, one of the complexes (4) exhibits a remarkable ROS quantum yield of 0.69. In vivo results underscore the efficacy of 4, showcasing significant tumor regression at depths of up to 8.4 mm. This study introduces a promising paradigm for designing photosensitizers capable of harnessing NIR light effectively for deep PDT applications.
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Fotoquimioterapia , Fármacos Fotosensibilizantes , Silanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fotoquimioterapia/métodos , Iridio/farmacología , Iridio/química , Rodaminas , Línea Celular Tumoral , Rayos InfrarrojosRESUMEN
Hyalectan cleavage may play an important role in extracellular matrix remodeling. However, the proteolytic enzyme responsible for hyalectan degradation for fetal membrane rupture at parturition remains unknown. Here, we reveal that versican (VCAN) is the major hyalectan in the amnion, where its cleavage increases at parturition with spontaneous rupture of membrane. We further reveal that ADAMTS4 is a crucial proteolytic enzyme for VCAN cleavage in the amnion. Inflammatory factors may enhance VCAN cleavage by inducing ADAMTS4 expression and inhibiting ADAMTS4 endocytosis in amnion fibroblasts. In turn, versikine, the VCAN cleavage product, induces inflammatory factors in amnion fibroblasts, thereby forming a feedforward loop between inflammation and VCAN degradation. Mouse studies show that intra-amniotic injection of ADAMTS4 induces preterm birth along with increased VCAN degradation and proinflammatory factors abundance in the fetal membranes. Conclusively, there is enhanced VCAN cleavage by ADAMTS4 in the amnion at parturition, which can be reenforced by inflammation.
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Proteína ADAMTS4 , Amnios , Versicanos , Femenino , Humanos , Recién Nacido , Embarazo , Proteína ADAMTS4/metabolismo , Amnios/metabolismo , Inflamación/metabolismo , Parto/metabolismo , Péptido Hidrolasas/metabolismo , Nacimiento Prematuro/metabolismo , Versicanos/metabolismo , Animales , RatonesRESUMEN
Electrochemically converting nitrate, a widely distributed nitrogen contaminant, into harmless N2 is a feasible and environmentally friendly route to close the anthropogenic nitrogen-based cycle. However, it is currently hindered by sluggish kinetics and low N2 selectivity, as well as scarce attention to reactor configuration. Here, we report a flow-through zero-gap electrochemical reactor that shows a high performance of nitrate reduction with 100% conversion and 80.36% selectivity of desired N2 in the chlorine-free system at 100 mg-N·L-1 NO3- while maintaining a rapid reduction kinetics of 0.07676 min-1. More importantly, the mass transport and current utilization efficiency are significantly improved by shortening the inter-electrode distance, especially in the zero-gap electrocatalytic system where the current efficiency reached 50.15% at 5 mA·cm-2. Detailed characterizations demonstrated that during the electroreduction process, partial Cu(OH)2 on the cathode surface was reconstructed into stable Cu/Cu2O as the active phase for efficient nitrate reduction. In situ characterizations revealed that the highly selective *NO to *N conversion and the N-N coupling step played crucial roles during the selective reduction of NO3- to N2 in the zero-gap electrochemical system. In addition, theoretical calculations demonstrated that improving the key intermediate *N coverage could effectively facilitate the N-N coupling step, thereby promoting N2 selectivity. Moreover, the environmental and economic benefits and long-term stability shown by the treatment of real nitrate-containing wastewater make our proposed electrocatalytic system more attractive for practical applications.
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Nitratos , Aguas Residuales , Nitratos/química , Electrodos , Nitrógeno/análisis , Nitrógeno/química , CinéticaRESUMEN
Metastatic disease, a leading and lethal indication of deaths associated with tumors, results from the dissemination of metastatic tumor cells from the site of primary origin to a distant organ. Dispersion of metastatic cells during the development of tumors at distant organs leads to failure to comply with conventional treatments, ultimately instigating abrupt tissue homeostasis and organ failure. Increasing evidence indicates that the tumor microenvironment (TME) is a crucial factor in cancer progression and the process of metastatic tumor development at secondary sites. TME comprises several factors contributing to the initiation and progression of the metastatic cascade. Among these, various cell types in TME, such as mesenchymal stem cells (MSCs), lymphatic endothelial cells (LECs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), T cells, and tumor-associated macrophages (TAMs), are significant players participating in cancer metastasis. Besides, various other factors, such as extracellular matrix (ECM), gut microbiota, circadian rhythm, and hypoxia, also shape the TME and impact the metastatic cascade. A thorough understanding of the functions of TME components in tumor progression and metastasis is necessary to discover new therapeutic strategies targeting the metastatic tumor cells and TME. Therefore, we reviewed these pivotal TME components and highlighted the background knowledge on how these cell types and disrupted components of TME influence the metastatic cascade and establish the premetastatic niche. This review will help researchers identify these altered components' molecular patterns and design an optimized, targeted therapy to treat solid tumors and restrict metastatic cascade.
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Células Supresoras de Origen Mieloide , Neoplasias , Humanos , Células Endoteliales/patología , Neoplasias/patología , Microambiente Tumoral , Células Supresoras de Origen Mieloide/patologíaRESUMEN
Previous studies did not provide substantial evidence for long-term immune persistence after the hepatitis B vaccine (HepB) in preterm birth (PTB) children. Consequently, there is ongoing controversy surrounding the booster immunization strategy for these children. Therefore, we conducted a retrospective cohort study to evaluate the disparities in immune persistence between PTB children and full-term children. A total of 1027 participants were enrolled in this study, including 505 PTB children in the exposure group and 522 full-term children in the control group. The negative rate of hepatitis B surface antibody (HBsAb) in the PTB group was significantly lower than that in the control group (47.9% vs. 41.4%, p = .035). The risk of HBsAb-negative in the exposure group was 1.5 times higher than that in the control group (adjusted odds ratio [aOR] = 1.5, 95% confidence interval [CI]: 1.1-2.0). The geometric mean concentration (GMC) of HBsAb was much lower for participants in the exposure group compared to participants in the control group (9.3 vs. 12.4 mIU/mL, p = .029). Subgroup analysis showed that the very preterm infants (gestational age <32 weeks) and the preterm low birth weight infants (birth weight <2000 g) had relatively low GMC levels of 3.2 mIU/mL (95% CI: 0.9-11.1) and 7.9 mIU/mL (95% CI: 4.2-14.8), respectively. Our findings demonstrated that PTB had a significant impact on the long-term persistence of HBsAb after HepB vaccination. The very preterm infants (gestational age <32 weeks) and the preterm low birth weight infants (birth weight <2000 g) may be special populations that should be given priority for HepB booster vaccination.
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Hepatitis B , Fenilbutiratos , Nacimiento Prematuro , Niño , Femenino , Humanos , Lactante , Recién Nacido , Peso al Nacer , Estudios de Seguimiento , Hepatitis B/epidemiología , Hepatitis B/prevención & control , Anticuerpos contra la Hepatitis B , Antígenos de Superficie de la Hepatitis B , Vacunas contra Hepatitis B , Recien Nacido Prematuro , Nacimiento Prematuro/epidemiología , Estudios Retrospectivos , VacunaciónRESUMEN
Targeting tumor-infiltrating regulatory T cells (Tregs) is an efficient way to evoke an anti-tumor immune response. However, how Tregs maintain their fragility and stability remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. On the contrary, the decreased IFITM3 expression in STAT1-deficient Tregs indicates that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of tumor-infiltrating Tregs in the tumor model. Overall, our study demonstrates that the perturbation of tumor-infiltrating Tregs through the IFNγ-IFITM3-STAT1 feedback loop is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy.
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Neoplasias , Linfocitos T Reguladores , Humanos , Retroalimentación , Neoplasias/genética , Neoplasias/terapia , Citocinas/metabolismo , Factores de Transcripción Forkhead/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Unión al ARN/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) is a highly malignant tumor with a global prevalence. In addition to the existing clinical guidelines, the effectiveness of anlotinib and Aurora-A inhibitors in treating HCC has also been demonstrated. However, Anlotinib, as an anti-angiogenesis therapy, has shown significant benefits in clinical trials but is limited by its single-agent treatment and the development of drug resistance. Aurora-A inhibitors are currently being tested in clinical trials but have limited efficacy. Combination therapy may offer clear advantages over monotherapy in this context. METHODS: In this study, we used HCC cell lines to investigate whether the combination of the two drugs could enhance their individual strengths and mitigate their weaknesses, thereby providing greater clinical benefits both in vitro and in vivo. RESULTS: Our findings confirmed that the Aurora-A inhibitor alisertib and anlotinib exhibited a time-dose-dependent inhibitory effect on HCC cells. In vitro cytological experiments demonstrated that the combination of the two drugs synergistically inhibited cell proliferation, invasion, and metastasis, while promoting cell apoptosis. Furthermore, we identified the underlying molecular mechanism by which the combination of the Aurora-A inhibitor alisertib and anlotinib inhibited HCC through the inhibition of the NF-ĸB signaling pathway. CONCLUSIONS: In summary, we have demonstrated the effectiveness of combining anlotinib with an Aurora-A inhibitor, which expands the potential applications of anlotinib in the clinical treatment of HCC in the future.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Quinolinas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Indoles/farmacología , Indoles/uso terapéutico , Quinolinas/farmacología , Quinolinas/uso terapéutico , Apoptosis , Proliferación Celular , Línea Celular TumoralRESUMEN
Salmonella including drug-resistant strains are major foodborne pathogens causing serious illness and pose a great threat to the prevention and control for food safety. Phages can naturally defect the bacterium, is considered as a new and promising biological antimicrobial agent in the post-antibiotic era. A poultry facility in Wuhan, China provided wastewater samples from which a collection of 29 phages were isolated and purified. A broad host spectrum phage ISTP3, which capable of infecting all tested Salmonella, including drug-resistant Salmonella enterica, were examined. Additionally, the effectiveness of this phage ISTP3 in reducing drug-resistant S. enterica was assessed in diverse food samples. Transmission electron microscopy (TEM) and whole genome sequencing demonstrated that ISTP3 was found to belong to family Ackermannviridae. The one-step growth experiment and assays of stability demonstrated that ISTP3 exhibited short periods of inactivity before replicating, produced a significant number of viral progeny during infection, and remained high stable under varying pH and temperature conditions. We evaluated the efficacy of phage ISTP3 against drug-resistant Salmonella on chicken breast and lettuce samples at different temperatures. When applying phage ISTP3 in food matrices, the drug resistant Salmonella count significantly reduced at 4°C and 25°C at an MOI of 100 or 1,000 within a timescale of 12 h. Overall, the results, such as broad host ranges, strictly lytic lifestyles, absence of lysogenic related genes, toxin genes, or virulence genes in the genome, demonstrate that the application of phage ISTP3 as a biocontrol agent has promising potential for preventing and controlling drug-resistant S. typhimurium in the context of food safety, processing, and production.