RESUMEN
The high prevalence of cancer and detrimental side effects associated with many cancer treatments necessitate the search for effective alternative therapies. Natural products are increasingly being recognized and investigated for their potential therapeutic benefits. Scutellaria barbata D. Don (SBD), a plant with potent antitumor properties, has attracted significant interest from oncology researchers. Its primary flavonoid components-scutellarin and luteolin-which have limited oral bioavailability due to poor absorption. This hinders its application for cancer treatment. The gut microbiota, which is considered a metabolic organ, can modulate the biotransformation of compounds, thereby altering their bioavailability and efficacy. In this study, we employed liquid chromatography tandem mass spectrometry (LC-MS/MS 8060) and ion trap-time of flight (LC-MSn-IT-TOF) analysis to investigate the ex vivo metabolism of scutellarin and luteolin by the gut microbiota. Five metabolites and one potential metabolite were identified. We summarized previous studies on their antitumor effects and performed in vitro tumor cell line studies to prove their antitumor activities. The possible key pathway of gut microbiota metabolism in vitro was validated using molecular docking and pure enzyme metabolic experiments. In addition, we explored the antitumor mechanisms of the two components of SBD through network pharmacology, providing a basis for subsequent target identification. These findings expand our understanding of the antitumor mechanisms of SBD. Notably, this study contributes to the existing body of knowledge regarding flavonoid biotransformation by the gut microbiota, highlighting the therapeutic potential of SBD in cancer treatment. Moreover, our results provide a theoretical basis for future in vivo pharmacokinetic studies, aiming to optimize the clinical efficacy of SBD in oncological applications.
Asunto(s)
Apigenina , Microbioma Gastrointestinal , Glucuronatos , Luteolina , Scutellaria , Espectrometría de Masas en Tándem , Microbioma Gastrointestinal/efectos de los fármacos , Luteolina/farmacología , Luteolina/metabolismo , Luteolina/farmacocinética , Scutellaria/química , Apigenina/farmacología , Glucuronatos/metabolismo , Humanos , Espectrometría de Masas en Tándem/métodos , Línea Celular Tumoral , Animales , Simulación del Acoplamiento Molecular , Extractos Vegetales/farmacología , Cromatografía Liquida/métodos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/farmacocinética , Disponibilidad Biológica , Masculino , Biotransformación , Antineoplásicos/farmacología , Antineoplásicos/farmacocinéticaRESUMEN
Liquiritigenin is a natural medicine. However, its inhibitory effect and its potential mechanism on bladder cancer (BCa) remain to be explored. It was found that it could be visualized that the transplanted tumours in the low-dose liquiritigenin -treated group and the high-dose liquiritigenin -treated group were smaller than those in the model group. Liquiritigenin treatment led to alterations in Lachnoclostridium, Escherichia-Shigella, Alistipes and Akkermansia. Non-targeted metabolomics analysis showed that a total of multiple differential metabolites were identified between the model group and the high-dose liquiritigenin-treated group. This provides a new direction and rationale for the antitumour effects of liquiritigenin.
RESUMEN
BACKGROUND: Cognitive impairment (CI) is a common mental health disorder among older adults, and dietary patterns have an impact on cognitive function. However, no systematic researches have constructed anti-inflammatory diet (AID) and protein-enriched diet (PED) to explore their association with CI among older adults in China. METHODS: The data used in this study were obtained from the 2018 waves of the China Longitudinal Health and Longevity Survey (CLHLS). We construct AID, PED, and calculate scores for CI. We use binary logistic regression to explore the relationship between them, and use restrictive cubic splines to determine whether the relationships are non-linear. Subgroup analysis and sensitivity analysis were used to demonstrate the robustness of the results. RESULTS: A total of 8692 participants (mean age is 83.53 years) were included in the analysis. We found that participants with a higher AID (OR = 0.789, 95% confidence interval: 0.740-0.842, p < 0.001) and PED (OR = 0.910, 95% confidence interval: 0.866-0.956, p < 0.001) score showed lower odds of suffering from CI. Besides, the relationship between the two dietary patterns and CI is linear, and the results of subgroup analysis and sensitivity analysis are also significant. CONCLUSION: Higher intakes of AID and PED are associated with a lower risk of CI among older adults, which has important implications for future prevention and control of CI from a dietary and nutritional perspective.
Asunto(s)
Disfunción Cognitiva , Humanos , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/epidemiología , Masculino , Femenino , China/epidemiología , Estudios Transversales , Anciano de 80 o más Años , Anciano , Proteínas en la Dieta/administración & dosificación , Dieta , Factores de Riesgo , Estudios Longitudinales , CogniciónRESUMEN
Background: Appearance anxiety and depression have become common and global public health problems worldwide, especially among adolescents. However, few studies have revealed the mechanisms between them. This study aimed to explore the multiple mediating roles of interpersonal sensitivity and social support between appearance anxiety and depression among medical college students. Methods: With 13 invalid samples excluded, 724 college students participated in our survey and completed questionnaires. The average age of 724 samples was 19.8 ± 2.02 including freshman to senior year and graduate school and above; 31.9% of the participants were male and 68.1% were female. SPSS 25.0 and Hayes' PROCESS macro were used for statistical description, correlation analysis and built multiple mediation models. Results: Appearance anxiety can not only directly affect depression, but also indirectly affect depression through three significant mediating pathways: (1) IS (B = 0.106, 95% CI [0.082-0.132]), which accounted for 49.77% of the total effect, (2) SS (B = 0.018, 95% CI [0.008-0.031]), which accounted for 8.45% of the total effect, and (3) IS and SS (B = 0.008, 95% CI [0.003-0.014]), which accounted for 3.76% of the total effect. And the total mediating effect was 61.97%. Limitations: It is a cross-sectional research method and the causal relationship is unclear. Conclusions: This study found that lower interpersonal sensitivity and higher social support can effectively reduce depression caused by appearance anxiety among college students. The schools and relevant departments should take measures to reduce the interpersonal sensitivity of college students and establish reliable social support, so as to reduce the occurrence of depression.
Asunto(s)
Depresión , Estudiantes de Medicina , Adolescente , Humanos , Masculino , Femenino , Depresión/epidemiología , Universidades , Estudios Transversales , Ansiedad/epidemiologíaRESUMEN
BACKGROUND: Berberine is the main bioactive constituent of Coptis chinensis, a quaternary ammonium alkaloid. While berberine's cardiovascular benefits are well-documented, its impact on thrombosis remains not fully understood. PURPOSE: This study investigates the potential of intestinal microbiota as a novel target for preventing thrombosis, with a focus on berberine, a natural compound known for its effectiveness in managing cardiovascular conditions. METHODS: Intraperitoneal injection of carrageenan induces the secretion of chemical mediators such as histamine and serotonin from mast cells to promote thrombosis. This model can directly and visually observe the progression of thrombosis in a time-dependent manner. Thrombosis was induced by intravenous injection of 1 % carrageenan solution (20 mg/kg) to all mice except the vehicle control group. Quantitative analysis of gut microbiota metabolites through LC/MS. Then, the gut microbiota of mice was analyzed using 16S rRNA sequencing to assess the changes. Finally, the effects of gut microbiota on thrombosis were explored by fecal microbiota transplantation. RESULTS: Our research shows that berberine inhibits thrombosis by altering intestinal microbiota composition and related metabolites. Notably, berberine curtails the biosynthesis of phenylacetylglycine, a thrombosis-promoting coproduct of the host-intestinal microbiota, by promoting phenylacetic acid degradation. This research underscores the significance of phenylacetylglycine as a thrombosis-promoting risk factor, as evidenced by the ability of intraperitoneal phenylacetylglycine injection to reverse berberine's efficacy. Fecal microbiota transplantation experiment confirms the crucial role of intestinal microbiota in thrombus formation. CONCLUSION: Initiating our investigation from the perspective of the gut microbiota, we have, for the first time, unveiled that berberine inhibits thrombus formation by promoting the degradation of phenylacetic acid, consequently suppressing the biosynthesis of PAG. This discovery further substantiates the intricate interplay between the gut microbiota and thrombosis. Our study advances the understanding that intestinal microbiota plays a crucial role in thrombosis development and highlights berberine-mediated intestinal microbiota modulation as a promising therapeutic approach for thrombosis prevention.
Asunto(s)
Berberina , Microbioma Gastrointestinal , Fenilacetatos , Trombosis , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Berberina/farmacología , Berberina/análogos & derivados , Trombosis/prevención & control , Masculino , Ratones , Fenilacetatos/farmacología , Carragenina , Coptis/química , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Trasplante de Microbiota Fecal , ARN Ribosómico 16SRESUMEN
BACKGROUND: Studies have extensively examined the factors contributing to the onset of occupational stress, burnout, and depression. However, the relationship between these variables is limited. OBJECTIVE: This study aimed to explore the association between occupational stress, burnout, and depressive symptoms and to investigate the mediating effect of burnout between occupational stress and depressive symptoms in medical staff. METHODS: A cross-sectional survey was conducted among medical staff in Chongqing, China. The Core Occupational Stress Scale (COSS), Maslach Burnout Inventory: General Survey (MBI-GS), and Patient Health Questionnaire-9 (PHQ-9) were used to assess the status of occupational stress, burnout, and depressive symptoms, respectively. The bootstrapping analyses using SPSS PROCESS macros version 3 were conducted to examine mediating effects. RESULTS: The study conducted on medical staff in Chongqing revealed that the detection rates of occupational stress, occupational burnout, and depressive symptoms were 31.8%, 23.3%, and 30.3%, respectively. Hierarchical regression analysis revealed that occupational stress and burnout accounted for 19.3% (pâ<â0.001) and 18.8% (pâ<â0.001) of the variance in depressive symptoms, respectively. Mediation analysis showed that occupational stress indirectly affected depressive symptoms through the mediating effect of occupational burnout, with a mediation effect value of 0.13 (bootstrap 95% CI: 0.116-0.144) and the mediation effect accounting for 44.8% of the total effect. CONCLUSION: Our results indicated that occupational stress and burnout were predictors of depressive symptoms. Occupational stress had a significant indirect effect on depressive symptoms via burnout. These results suggest that reducing occupational stress and burnout could be effective strategies for preventing depression among medical staff.
Asunto(s)
Agotamiento Profesional , COVID-19 , Depresión , Estrés Laboral , Humanos , Estudios Transversales , China/epidemiología , Masculino , Agotamiento Profesional/psicología , Agotamiento Profesional/epidemiología , Agotamiento Profesional/etiología , Femenino , Depresión/psicología , Depresión/epidemiología , Depresión/etiología , Adulto , COVID-19/psicología , COVID-19/epidemiología , Estrés Laboral/psicología , Estrés Laboral/epidemiología , Encuestas y Cuestionarios , Persona de Mediana Edad , Cuerpo Médico/psicología , Cuerpo Médico/estadística & datos numéricos , SARS-CoV-2RESUMEN
BACKGROUND: According to the World Health Organization, foodborne disease is a significant public health issue. We will choose the best model to predict foodborne disease by comparison, to provide evidence for government policies to prevent foodborne illness. METHODS: The foodborne disease monthly incidence data from June 2017 to April 2022 were obtained from the Chongqing Nan'an District Center for Disease Prevention and Control. Data from June 2017 to June 2021 were used to train the model, and the last 10 months of incidence were used for prediction and validation The incidence was fitted using the seasonal autoregressive integrated moving average (SARIMA) model, Holt-Winters model and Exponential Smoothing (ETS) model. Besides, we used MSE, MAE, RMSE to determine which model fits better. RESULTS: During June 2017 to April 2022, the incidence of foodborne disease showed seasonal changes, the months with the highest incidence are June to November. The optimal model of SARIMA is SARIMA (1,0,0) (1,1,0)12. The MSE, MAE, RMSE of the Holt-Winters model are 8.78, 2.33 and 2.96 respectively, which less than those of the SARIMA and ETS model, and its prediction curve is closer to the true value. The optimal model has good predictive performance. CONCLUSION: Based on the results, Holt-Winters model produces better prediction accuracy of the model.
Asunto(s)
Enfermedades Transmitidas por los Alimentos , Modelos Estadísticos , Humanos , Estaciones del Año , Incidencia , Predicción , Enfermedades Transmitidas por los Alimentos/epidemiología , China/epidemiologíaRESUMEN
In chronic infections and cancer, T cells are exposed to prolonged antigen stimulation, resulting in loss of function (or exhaustion) and impairment of effective immunological protection. Exhausted T cells are heterogeneous and include early progenitors (Tpex) and terminally exhausted cells (Tex). Here, we used bulk and single-cell transcriptomics to analyze expression of transposable elements (TEs) in subpopulations of mouse and human CD8+ tumor-infiltrating T lymphocytes (TILs). We show that in mice, members of the virus-like murine VL30 TE family (mostly intact, evolutionary young ERV1s) are strongly repressed in terminally exhausted CD8+ T cells in both tumor and viral models of exhaustion. Tpex expression of these VL30s, which are mainly intergenic and transcribed independently of their closest gene neighbors, was driven by Fli1, a transcription factor involved in progression from Tpex to Tex. Immune checkpoint blockade (ICB) in both mice and patients with cancer increased TE expression (including VL30 in mice), demonstrating that TEs may be applicable as ICB response biomarkers. We conclude that expression of TEs is tightly regulated in TILs during establishment of exhaustion and reprogramming by ICB. Analyses of TE expression on single cells and bulk populations open opportunities for understanding immune cell identity and heterogeneity, as well as for defining cellular gene expression signatures and disease biomarkers.
Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Animales , Ratones , Humanos , Elementos Transponibles de ADN/genética , Agotamiento de Células T , BiomarcadoresRESUMEN
Occupational stress, cumulative fatigue, and work-related musculoskeletal disorders (WMSDs) are major concerns in the field of occupational health. Previous studies on occupational health focused on key industries, such as medical care, while there were few related studies on Information Technology (IT) industry. Our study explored the factors influencing occupational stress, cumulative fatigue, and musculoskeletal disorders in the IT industry. We collected 1363 IT workers' valid questionnaires, of which 73.1% of participants were technicians in Chongqing, 2021. The core occupational stress scale (COSS), self-diagnosis checklist for the assessment of workers' accumulated fatigue and Chinese musculoskeletal disorders questionnaire were used to measure the occupational stress, cumulative fatigue, and musculoskeletal disorders of the respondents. Logistic regressions were used to explore the correlated factors affecting these indicators. The results showed that the prevalence of occupational stress, cumulative fatigue, and musculoskeletal disorders was 50.4%, 47%, and 72.3%, respectively. Working in the current position for 3-10 years was a common increased risk for all three indicators. Insomnia was associated with an increased risk of cumulative fatigue (Odds Ratio, OR = 2.156, p < 0.001) and musculoskeletal disorders (OR = 1.878, p < 0.001). Cumulative fatigue was also associated with an increased risk of having WMSDs (OR = 3.207, p < 0.001). According to our findings, occupational factors, such as long working years, overtime work, and personal lifestyle, are highly related to the occurrence of occupational stress, cumulative fatigue, and musculoskeletal disorders for IT industry workers. More attention should be paid to women and those with long working hours in the IT industry.
RESUMEN
Sleep disorders, which are prominent problems among college students, may be associated with skipping breakfast. Therefore, we aimed to explore the role of sleep chronotypes and depressive symptoms as mediators in the relationship between breakfast frequency and sleep quality. A cross-sectional survey enrolling random samples of 712 college students was conducted by the Questionnaire Star online platform. Statistical description and correlation analysis were performed by SPSS 25.0, and a chain mediation test was performed by model 6 in PROCESS 3.5. The result of the article demonstrated that breakfast frequency can affect sleep quality through two mediating pathways: â sleep chronotypes, with a mediating effect of 32%; and â¡ depressive symptoms, with a mediating effect of 52.4%. However, the chain mediating effects of sleep chronotypes and depressive symptoms was not significant, and neither was the direct effect of breakfast frequency on sleep quality. Breakfast frequency can indirectly affect sleep quality by adjusting sleep chronotypes and depressive symptoms. Regular breakfast can increase morning and intermediate sleep chronotypes, reduce depressive symptoms, and thus improve sleep quality.
Asunto(s)
Depresión , Calidad del Sueño , Humanos , Depresión/epidemiología , Depresión/diagnóstico , Cronotipo , Desayuno , Estudios Transversales , Sueño , Encuestas y Cuestionarios , EstudiantesRESUMEN
Oncogenesis often implicates epigenetic alterations, including derepression of transposable elements (TEs) and defects in alternative splicing. Here, we explore the possibility that noncanonical splice junctions between exons and TEs represent a source of tumor-specific antigens. We show that mouse normal tissues and tumor cell lines express wide but distinct ranges of mRNA junctions between exons and TEs, some of which are tumor specific. Immunopeptidome analyses in tumor cell lines identified peptides derived from exon-TE splicing junctions associated to MHC-I molecules. Exon-TE junction-derived peptides were immunogenic in tumor-bearing mice. Both prophylactic and therapeutic vaccinations with junction-derived peptides delayed tumor growth in vivo. Inactivation of the TE-silencing histone 3-lysine 9 methyltransferase Setdb1 caused overexpression of new immunogenic junctions in tumor cells. Our results identify exon-TE splicing junctions as epigenetically controlled, immunogenic, and protective tumor antigens in mice, opening possibilities for tumor targeting and vaccination in patients with cancer.
Asunto(s)
Antígenos de Neoplasias , Elementos Transponibles de ADN , Animales , Ratones , Elementos Transponibles de ADN/genética , Antígenos de Neoplasias/genética , Exones/genética , ARN Mensajero , Línea Celular TumoralRESUMEN
Background: Depressive symptoms (DS) can erode physical and mental health; social support (SS) is considered a buffer for DS and a promoter for improving coping and recovery abilities. However, there is almost no research on the mediating role of negative coping (NC) in SS and DS, especially among firefighters. Methods: A cross-sectional survey was conducted among firefighters in Chongqing, China, and the valid data of 407 firefighters were collected through questionnaires distributed on the WeChat platform in 2020. Statistical Product and Service Solutions (SPSS) 26.0 is used for descriptive statistics and correlation analysis. Structural equation modeling was adopted to analyze the association among SS, NC, and DS. The mediation effect is also evaluated. Results: Firefighters' detection rate of DS is 23.3%, and when they receive more SS were less likely to develop DS. NC was positively correlated with DS (ß = 0.54, p < 0.001) after controlling for SS. Besides, the results of structural equation modeling showed that NC partially mediates the relationship between SS and DS (standard error = 0.039, indirect effects = 0.109, 95% confidence interval: 0.047-0.200 p < 0.001). Conclusion: NC has a partial indirect effect between SS and DS among firefighters. SS could not only affect DS directly but also indirect work on it by affecting NC. This discovery will be a novel and meaningful part of the research on the firefighter population.
RESUMEN
Breast cancer is composed of distinct subgroups, triple-negative breast cancer (TNBC), human epidermal growth factor receptor-2 (HER2), luminal A, and luminal B, which are associated with different prognosis. MEP50 is the main partner of the arginine methyltransferase PRMT5 required for its enzymatic activity. Here, we examined MEP50 expression in the different breast cancer subgroups from the transcriptomic data obtained on human breast cancer samples and on normal breast tissues in two cohorts (Curie, n = 141; The Cancer Genome Atlas-TCGA, n = 788). We observed higher levels of MEP50 mRNA in TNBC (Curie, n = 41; TCGA, n = 106) compared to the other breast cancer subgroups and normal breast tissues. Using an online KM-plotter database, which allows survival analyses in a larger number of breast cancer patients, we found that high MEP50 mRNA levels were associated with a more favorable recurrence-free survival (RFS) in TNBC (n = 953, p = 1.2 × 10-4) and luminal B (n = 1353, p = 0.013) tumors, whereas high PRMT5 mRNA levels were associated with worse RFS in these two subgroups (TNBC: n = 442, p = 1.0 × 10-4; luminal B: n = 566, p = 6.8 × 10-3). We next determined the expression and the subcellular localization of MEP50 protein by immunohistochemistry (IHC) in our Curie cohort of breast cancer (n = 94) and normal tissues (n = 7) using a validated MEP50 antibody. MEP50 was more expressed in breast tumors compared to normal breast tissues (p = 0.02). MEP50 was more localized to the cytosol in breast cancer cells compared to normal breast tissue (p = 4 × 10-4), and was more found at the plasma membrane in normal tissues compared to breast tumors (p = 0.01). We also evaluated PRMT5 activity by IHC in our Curie cohort using a validated antibody (H4R3me2s) detecting histone H4 symmetrically dimethylated on Arg3. High levels of H4R3me2s were found in normal breast tissues, whereas the lowest levels of H4R3me2s were observed in TNBC and HER2 breast cancer subgroups. Altogether, our study reports the expression of the PRMT5 cofactor (MEP50) and substrate (H4R3me2s) in breast cancer and highlights the association of PRMT5 and MEP50 mRNA with prognosis in luminal B and TNBC breast cancer subgroups and certain TNBC subtypes.
RESUMEN
INTRODUCTION: Chongqing is among the areas with the highest rubella incidence rates in China. This study aimed to analyze the temporal distribution characteristics of rubella and establish a forecasting model in Chongqing, which could provide a tool for decision-making in the early warning system for the health sector. METHODOLOGY: The rubella monthly incidence data from 2004 to 2019 were obtained from the Chongqing Center of Disease and Control. The incidence from 2004 to June 2019 was fitted using the seasonal autoregressive integrated moving average (SARIMA) model and the back-propagation neural network (BPNN) model, and the data from July to December 2019 was used for validation. RESULTS: A total of 30,083 rubella cases were reported in this study, with a significantly higher average annual incidence before the nationwide introduction of rubella-containing vaccine (RCV). The peak of rubella notification was from April to June annually. Both SARIMA and BPNN models were capable of predicting the expected incidence of rubella. However, the linear SARIMA model fits and predicts better than the nonlinear BPNN model. CONCLUSIONS: Based on the results, rubella incidence in Chongqing has an obvious seasonal trend, and SARIMA (2,1,1) × (1,1,1) 12 model can predict the incidence of rubella well. The SARIMA model is a feasible tool for producing reliable rubella forecasts in Chongqing.
Asunto(s)
Modelos Estadísticos , Rubéola (Sarampión Alemán) , China/epidemiología , Humanos , Incidencia , Redes Neurales de la Computación , Rubéola (Sarampión Alemán)/epidemiología , Rubéola (Sarampión Alemán)/prevención & control , Estaciones del Año , Factores de TiempoRESUMEN
Objective: To investigate associations between visceral adiposity index (VAI) and cardiovascular and cerebrovascular diseases (CCDs) in the American population from 1999 to 2018. Methods: Data from the National Health and Nutrition Examination Survey (1998-2018) were analyzed in this study. Specifically, VAI scores were calculated using sex-specific equations that incorporate body mass index, waist circumference (WC), high-density lipoprotein (HDL), triglycerides (TG), and cholesterol. Weighted logistic regression analysis was conducted to assess the relationship between VAI tertile and increased risk of CCDs. Restricted cubic splines were used to evaluate the non-linear relationship between VAI and CCDs, such as heart failure, angina, heart attack, stroke, hypertension, and coronary heart disease. Sensitivity analysis was conducted, using VAI quartiles as independent variables. Results: A total of 22,622 subjects aged over 20 years were included. In the fully adjusted model after controlling for covariates, the third VAI tertile was more strongly associated with CCDs than the first VAI tertile, with odds ratio (OR) and 95% confidence interval (95% CI) values for angina of 2.86, 1.68-4.85; heart attack, 1.75, 1.14-2.69; stroke, 2.01, 1.23-3.26; hypertension, 2.28, 1.86-2.78; and coronary heart disease, 1.78, 1.32-2.41; but there was no significant association with heart failure (p > 0.05). Restricted cubic splines revealed parabolic relationships between VAI score and angina (p for non-linear = 0.03), coronary heart disease (p for non-linear = 0.01), and hypertension (p for non-linear < 0.001). Sensitivity analysis indicated that the fourth VAI quartile was more strongly associated with an increased risk of angina (OR = 2.92, 95% CI, 1.49-5.69), hypertension (OR = 2.37, 95% CI, 1.90-2.97), heart attack (OR = 1.77, 95% CI, 1.09-2.88), and coronary heart disease (OR = 1.89, 95% CI, 1.24-2.86) than the first VAI quartile. VAI had superior predictive power for prevalent CCDs than other independent indicators (p < 0.05). Conclusion: Visceral adiposity index score is positively correlated with angina, heart attack, stroke, hypertension, and coronary heart disease, but not heart failure, and the relationships between VAI score and angina, hypertension, and coronary heart disease are non-linear.
RESUMEN
Tumor-infiltrating CD8 + T cells progressively lose functionality and fail to reject tumors. The underlying mechanism and re-programing induced by checkpoint blockers are incompletely understood. We show here that genetic ablation or pharmacological inhibition of histone lysine methyltransferase Suv39h1 delays tumor growth and potentiates tumor rejection by anti-PD-1. In the absence of Suv39h1, anti-PD-1 induces alternative activation pathways allowing survival and differentiation of IFNγ and Granzyme B producing effector cells that express negative checkpoint molecules, but do not reach final exhaustion. Their transcriptional program correlates with that of melanoma patients responding to immune-checkpoint blockade and identifies the emergence of cytolytic-effector tumor-infiltrating lymphocytes as a biomarker of clinical response. Anti-PD-1 favors chromatin opening in loci linked to T-cell activation, memory and pluripotency, but in the absence of Suv39h1, cells acquire accessibility in cytolytic effector loci. Overall, Suv39h1 inhibition enhances anti-tumor immune responses, alone or combined with anti-PD-1, suggesting that Suv39h1 is an "epigenetic checkpoint" for tumor immunity.
Asunto(s)
Linfocitos T CD8-positivos , Melanoma , Metiltransferasas , Receptor de Muerte Celular Programada 1 , Proteínas Represoras , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Epigénesis Genética , Humanos , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Melanoma/genética , Melanoma/inmunología , Melanoma/terapia , Metiltransferasas/antagonistas & inhibidores , Metiltransferasas/genética , Metiltransferasas/inmunología , Metiltransferasas/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
Influenza is a global serious public health threat. Seasonal influenza among children in Chongqing has been a heavy health burden. To date, few studies have examined the spatial and temporal characteristics of influenza. This research sheds new light on correlating them with influenza outbreaks with data of over 5 years (2014-2018). All cluster outbreaks among preschool and school-age children reported in Chongqing were collected through the Public Health Emergency Management Information System. The demographical, epidemiological, and clinical data of the cases were analyzed. From 2014 to 2018, a total of 111 preschool- and school-based influenza-like illness outbreaks involving 3,549 cases were identified. Several clinical symptoms that were analyzed in this study showed significant contrast between influenza A and B. Spatial autocorrelation analysis over the 5-year data detected Xiushan district being the most likely cluster. The exploration of the spatial distribution and clinical characteristics of influenza cluster of children in Chongqing could help the effective implementation of health policies. Future studies should be conducted to monitor the outbreaks of influenza among children.
Asunto(s)
Gripe Humana , Niño , Preescolar , China/epidemiología , Brotes de Enfermedades , Predicción , Humanos , Gripe Humana/epidemiología , Instituciones AcadémicasRESUMEN
Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. PRMT1 depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. PRMT1 enzymatic activity is also required to stimulate the canonical Wnt pathway. Type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients as well as erlotinib, an EGFR inhibitor. Therefore, targeting PRMT1 in combination with these chemotherapies may improve existing treatments for TNBC patients.