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Approximately 70% of treatment failures in nasopharyngeal carcinoma (NPC) patients are attributed to distant metastasis, yet the underlying mechanisms remain unclear. RNA 5-methylcytosine (m5C) is an emerging regulatory modification that controls gene expression and plays a critical role in tumor progression. However, there is little information on the potential roles of RNA m5C modification in NPC metastasis. In this study, we found that the m5C reader Aly/REF export factor (ALYREF) is significantly upregulated in NPC, whereby its high expression is associated with metastasis and poor prognosis. ALYREF overexpression was found to promote tumor metastasis of NPC cells in vitro and in vivo. Mechanistically, m5C-modified NOTCH1 mRNA was identified as a target of ALYREF. Moreover, ALYREF was found to upregulate NOTCH1 expression by enhancing its RNA stability in an m5C modification-dependent manner, thereby promoting the activation of the NOTCH signaling pathway and facilitating NPC metastasis. Overall, our data reveal the crucial role of ALYREF in NPC metastasis and provide a potential therapeutic target for NPC.
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Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Metástasis de la Neoplasia , Estabilidad del ARN , ARN Mensajero , Receptor Notch1 , Humanos , Receptor Notch1/metabolismo , Receptor Notch1/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/metabolismo , Línea Celular Tumoral , ARN Mensajero/metabolismo , ARN Mensajero/genética , Animales , Regulación Neoplásica de la Expresión Génica , Ratones Desnudos , Masculino , Femenino , Ratones , Transducción de Señal , Ratones Endogámicos BALB C , Regulación hacia Arriba/genética , Carcinoma/metabolismo , Carcinoma/genética , Carcinoma/patología , Persona de Mediana EdadRESUMEN
Nasopharyngeal carcinoma (NPC), a squamous cell carcinoma originating in the nasopharynx, is a leading malignancy in south China and other south and east Asia areas. It is frequently associated with Epstein-Barr virus (EBV) infection, while there are also some NPC patients without EBV infection. Here, it is shown that the EBV+ (EBV positive) and EBV- (EBV negative) NPCs contain both shared and distinct genetic abnormalities, among the latter are increased mutations in TP53. To investigate the functional roles of NPC-associated genetic alterations, primary, orthotopic, and genetically defined NPC models were developed in mice, a key tool missed in the field. These models, initiated with gene-edited organoids of normal nasopharyngeal epithelium, faithfully recapitulated the pathological features of human disease. With these models, it is found that Trp53 and Cdkn2a deficiency are crucial for NPC initiation and progression. And latent membrane protein1 (LMP1), an EBV-coding oncoprotein, significantly promoted the distal metastasis. Further, loss of TGFBR2, which is frequently disrupted both in EBV- and EBV+ NPCs, dramatically accelerated the progression and lung metastasis of NPC probably by altering tumor microenvironment. Taken together, this work establishes a platform to dissect the genetic mechanisms underlying NPC pathogenesis and might be of value for future translational studies.
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Photo-assisted uranium extraction from seawater (UES) is regarded as an efficient technique for uranium resource recovery, yet it currently faces many challenges, such as issues like biofouling resistance, low charge separation efficiency, slow carrier transfer, and a lack of active sites. Based on addressing the above challenges, a novel oxygen-deficient Co3O4-x/g-C3N4 p-n heterojunction is developed for efficient photo-assisted uranium extraction from seawater. Relying on the defect-coupling heterojunction synergistic effect, the redistribution of molecular charge density formed the built-in electric field as revealed by DFT calculations, significantly enhancing the separation efficiency of carriers and accelerating their migration rate. Notably, oxygen vacancies served as capture sites for oxygen, effectively promoting the generation of reactive oxygen species (ROS), thereby significantly improving the photo-assisted uranium extraction performance and antibacterial activity. Thus, under simulated sunlight irradiation with no sacrificial reagent added, Co3O4-x/g-C3N4 extracted a high uranium extraction amount of 1.08 mg g-1 from 25 L of natural seawater after 7 days, which is superior to most reported carbon nitride-based photocatalysts. This study elaborates on the important role of surface defects and inerface engineering strategies in enhancing photocatalytic performance, providing a new approach to the development and design of uranium extraction material from seawater.
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In this paper, we describe Ixeridiumnujiangense, a novel species identified in southwestern Yunnan, China. Two populations have been found along the riverbanks of the Nujiang River in Yongde and Zhenkang Counties. Morphologically, I.nujiangense is most similar to the recently described I.malingheense, but it can be readily distinguished by its mostly divided basal leaves, narrower non-clasping cauline leaves, notably shorter corolla tube, pale brown anthers, and considerably longer beak of achenes.
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The coronary artery constitutes a vital vascular system that sustains cardiac function, with its primary role being the conveyance of indispensable nutrients to the myocardial tissue. When coronary artery disease occurs, it will affect the blood supply of the heart and induce myocardial ischemia. Therefore, it is of great significance to numerically simulate the coronary artery and evaluate its blood supply capacity. In this article, the coronary artery lumped parameter model was derived based on the relationship between circuit system parameters and cardiovascular system parameters, and the blood supply capacity of the coronary artery in healthy and stenosis states was studied. The aortic root pressure calculated by the aortic valve fluid-structure interaction (AV FSI) simulator was employed as the inlet boundary condition. To emulate the physiological phenomenon of sudden pressure drops resulting from an abrupt reduction in blood vessel radius, a head loss model was connected at the coronary artery's entrance. For each coronary artery outlet, the symmetric structured tree model was appended to simulate the terminal impedance of the missing downstream coronary arteries. The particle swarm optimization (PSO) algorithm was used to optimize the blood flow viscous resistance, blood flow inertia, and vascular compliance of the coronary artery model. In the stenosis states, the relative flow and fractional flow reserve (FFR) calculated by numerical simulation corresponded to the published literature data. It was anticipated that the proposed model can be readily adapted for clinical application, serving as a valuable reference for diagnosing and treating patients.
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Algoritmos , Simulación por Computador , Circulación Coronaria , Vasos Coronarios , Modelos Cardiovasculares , Humanos , Vasos Coronarios/fisiología , Circulación Coronaria/fisiología , Hemodinámica , Estenosis Coronaria/fisiopatología , Reserva del Flujo Fraccional Miocárdico/fisiología , Velocidad del Flujo Sanguíneo/fisiología , Presión Sanguínea/fisiología , Enfermedad de la Arteria Coronaria/fisiopatología , Válvula Aórtica/fisiologíaRESUMEN
Introduction: Circadian syndrome (CircS) is proposed as a novel risk cluster based on reduced sleep duration, abdominal obesity, depression, hypertension, dyslipidemia and hyperglycemia. However, the association between CircS and chronic kidney disease (CKD) remains unclear. To investigate the cross-sectional and longitudinal association between CircS and CKD, this study was performed. Methods: A national prospective cohort (China Health and Retirement Longitudinal Study, CHARLS) was used in this study. To define CKD, the estimated glomerular filtration rate (eGFR) was calculated based on the 2012 CKD-EPI creatinine-cystatin C equation. Participants with eGFR <60 mL.min-1/1.73/m2 were diagnosed with CKD. Multivariate binary logistic regression was used to assess the cross-sectional association between CircS and CKD. Subgroup and interactive analyses were performed to determine the interactive effects of covariates. In the sensitivity analysis, the obese population was excluded and another method for calculating the eGFR was used to verify the robustness of previous findings. In addition, participants without CKD at baseline were followed up for four years to investigate the longitudinal relationship between CircS and CKD. Results: A total of 6355 participants were included in this study. In the full model, CircS was positively associated with CKD (OR = 1.28, 95% CI = 1.04-1.59, P < 0.05). As per one increase of CircS components, there was a 1.11-fold (95% CI = 1.04-1.18, P < 0.05) risk of prevalent CKD in the full model. A significant interactive effect of hyperuricemia in the CircS-CKD association (P for interaction < 0.01) was observed. Sensitivity analyses excluding the obese population and using the 2009 CKD-EPI creatinine equation to diagnose CKD supported the positive correlation between CircS and CKD. In the 2011-2015 follow-up cohort, the CircS group had a 2.18-fold risk of incident CKD (95% CI = 1.33-3.58, P < 0.01) in the full model. The OR was 1.29 (95% CI = 1.10-1.51, P < 0.001) with per one increase of CircS components. Conclusion: CircS is a risk factor for CKD and may serve as a predictor of CKD for early identification and intervention.
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Tasa de Filtración Glomerular , Insuficiencia Renal Crónica , Humanos , Masculino , Femenino , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/fisiopatología , Persona de Mediana Edad , Estudios de Seguimiento , Anciano , Estudios Transversales , Estudios Longitudinales , Estudios Prospectivos , China/epidemiología , Factores de Riesgo , Envejecimiento/fisiología , Trastornos Cronobiológicos/complicaciones , Trastornos Cronobiológicos/epidemiologíaRESUMEN
Epstein-Barr virus (EBV) is linked to various malignancies and autoimmune diseases, posing a significant global health challenge due to the lack of specific treatments or vaccines. Despite its crucial role in EBV infection in B cells, the mechanisms of the glycoprotein gp42 remain elusive. In this study, we construct an antibody phage library from 100 EBV-positive individuals, leading to the identification of two human monoclonal antibodies, 2B7 and 2C1. These antibodies effectively neutralize EBV infection in vitro and in vivo while preserving gp42's interaction with the human leukocyte antigen class II (HLA-II) receptor. Structural analysis unveils their distinct binding epitopes on gp42, different from the HLA-II binding site. Furthermore, both 2B7 and 2C1 demonstrate potent neutralization of EBV infection in HLA-II-positive epithelial cells, expanding our understanding of gp42's role. Overall, this study introduces two human anti-gp42 antibodies with potential implications for developing EBV vaccines targeting gp42 epitopes, addressing a critical gap in EBV research.
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Anticuerpos Monoclonales , Epítopos , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Humanos , Herpesvirus Humano 4/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Anticuerpos Monoclonales/inmunología , Epítopos/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Ratones , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Proteínas Virales/inmunología , Linfocitos B/inmunologíaRESUMEN
INTRODUCTION: Chronic kidney disease (CKD) is a common risk factor for sarcopenia. However, whether sarcopenia increases the risk of CKD remains unclear. To investigate the longitudinal and causal associations between possible sarcopenia and CKD, this study was performed. METHODS: Possible sarcopenia was defined according to the Asian Working Group for Sarcopenia in 2019. Participants aged ≥ 40 years were recruited from the baseline survey of the China Health and Retirement Longitudinal Study and followed up for four years. Binary logistic regression was used to evaluate the cross-sectional and longitudinal associations between possible sarcopenia, low muscle strength, low physical performance and CKD. Propensity score matching was used to balance the intergroup differences. Subgroup and interactive analyses were adopted to identify potential interactive effects. Mendelian Randomization analysis was used to assess the causal association between appendicular lean mass (ALM) and CKD. RESULTS: After data cleansing, a total of 7296 participants were included in the baseline survey. In the cross-sectional analyses, the odds ratios (ORs) of prevalent CKD were 1.50 (95% CI = 1.23-1.84, p < 0.001) for possible sarcopenia, 1.37 (95% CI = 1.10-1.70, p < 0.01) for low muscle strength and 1.42 (95% CI = 1.16-1.74, p < 0.001) for low physical performance in the full models. No significant interaction effects of covariates were detected (all P for interaction > 0.05). After four years of follow-up, an increased risk of incident CKD was also observed in participants with possible sarcopenia (OR = 1.66, 95% CI = 1.13-2.44, p = 0.010) and low physical performance (OR = 1.69, 95% CI = 1.16-2.45, p = 0.006), but not in participants with low muscle strength (OR = 1.19, 95% CI = 0.75-1.88, p = 0.469). In the Mendelian Randomization analysis, the inverse variance weighted estimator showed that a 1-standard deviation increase of genetically predicted ALM was associated with a lower risk of CKD (OR = 0.92, 95% CI = 0.85-0.99, p = 0.035). All the sensitivity analyses supported the main findings. CONCLUSIONS: Possible sarcopenia is an independent risk factor for CKD and may serve as a predictor of CKD for early identification and intervention.
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Análisis de la Aleatorización Mendeliana , Insuficiencia Renal Crónica , Sarcopenia , Humanos , Sarcopenia/epidemiología , Insuficiencia Renal Crónica/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Estudios de Seguimiento , Anciano , Estudios Transversales , Estudios Longitudinales , China/epidemiología , Fuerza Muscular , Factores de Riesgo , AdultoRESUMEN
BACKGROUND: Alzheimer's Disease (AD) is the most prevalent type of dementia. The early change of gut microbiota is a potential biomarker for preclinical AD patients. OBJECTIVE: The study aimed to explore changes in gut microbiota characteristics in preclinical AD patients, including those with Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI), and detect the correlation between gut microbiota characteristics and cognitive performances. METHODS: This study included 117 participants [33 MCI, 54 SCD, and 30 Healthy Controls (HC)]. We collected fresh fecal samples and blood samples from all participants and evaluated their cognitive performance. We analyzed the diversity and structure of gut microbiota in all participants through qPCR, screened characteristic microbial species through machine learning models, and explored the correlations between these species and cognitive performances and serum indicators. RESULTS: Compared to the healthy controls, the structure of gut microbiota in MCI and SCD patients was significantly different. The three characteristic microorganisms, including Bacteroides ovatus, Bifidobacterium adolescentis, and Roseburia inulinivorans, were screened based on the best classification model (HC and MCI) having intergroup differences. Bifidobacterium adolescentis is associated with better performance in multiple cognitive scores and several serum indicators. Roseburia inulinivorans showed negative correlations with the scores of the Functional Activities Questionnaire (FAQ). CONCLUSION: The gut microbiota in patients with preclinical AD has significantly changed in terms of composition and richness. Correlations have been discovered between changes in characteristic species and cognitive performances. Gut microbiota alterations have shown promise in affecting AD pathology and cognitive deficit.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/fisiología , Enfermedad de Alzheimer/microbiología , Femenino , Masculino , Estudios Transversales , Anciano , Disfunción Cognitiva/microbiología , Heces/microbiología , Persona de Mediana EdadRESUMEN
OBJECTIVE: Face memory impairment significantly affects social interactions and daily functioning in individuals with mild cognitive impairment (MCI). While deficits in recognizing familiar faces among individuals with MCI have been reported, their ability to learn and recognize unfamiliar faces remains unclear. This study examined the behavioral performance and event-related potentials (ERPs) of unfamiliar face memorization and recognition in MCI. METHODS: Fifteen individuals with MCI and 15 healthy controls learned and recognized 90 unfamiliar neutral faces. Their performance accuracy and cortical ERPs were compared between the two groups across the learning and recognition phases. RESULTS: Individuals with MCI had lower accuracy in identifying newly learned faces than healthy controls. Moreover, individuals with MCI had reduced occipitotemporal N170 and central vertex positive potential responses during both the learning and recognition phases, suggesting impaired initial face processing and attentional resources allocation. Also, individuals with MCI had reduced central N200 and frontal P300 responses during the recognition phase, suggesting impaired later-stage face recognition and attention engagement. CONCLUSION: These findings provide neurobehavioral evidence for impaired learning and recognition of unfamiliar faces in individuals with MCI. SIGNIFICANCE: Individuals with MCI may have face memory deficits in both early-stage face processing and later-stage recognition .
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Disfunción Cognitiva , Reconocimiento Facial , Humanos , Reconocimiento en Psicología/fisiología , Potenciales Evocados/fisiología , Aprendizaje , Reconocimiento Facial/fisiología , Disfunción Cognitiva/diagnóstico , Reconocimiento Visual de Modelos/fisiologíaRESUMEN
In this paper, we describe a new species, Melanoserispenghuana, from Mt. Jiaozi Xueshan located in North-central Yunnan, China. Despite its morphological similarities to M.likiangensis, M.penghuana exhibits distinct differences in leaf texture, shape of terminal lobes, indumentum of leaves, peduncles, and involucres, as well as the length of the achenes. Additionally, the conservation status of this species is classified as Vulnerable through data analysis from two field surveys.
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Although low-dose computed tomography screening improves lung cancer survival in at-risk groups, inequality remains in lung cancer diagnosis due to limited access to and high costs of medical imaging infrastructure. We designed a needleless and imaging-free platform, termed PATROL (point-of-care aerosolizable nanosensors with tumor-responsive oligonucleotide barcodes), to reduce resource disparities for early detection of lung cancer. PATROL formulates a set of DNA-barcoded, activity-based nanosensors (ABNs) into an inhalable format. Lung cancer-associated proteases selectively cleave the ABNs, releasing synthetic DNA reporters that are eventually excreted via the urine. The urinary signatures of barcoded nanosensors are quantified within 20 min at room temperature using a multiplexable paper-based lateral flow assay. PATROL detects early-stage tumors in an autochthonous lung adenocarcinoma mouse model with high sensitivity and specificity. Tailoring the library of ABNs may enable not only the modular PATROL platform to lower the resource threshold for lung cancer early detection tools but also the rapid detection of chronic pulmonary disorders and infections.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Animales , Ratones , Sistemas de Atención de Punto , Neoplasias Pulmonares/diagnóstico , Modelos Animales de Enfermedad , ADNRESUMEN
Flexible quasi-solid-state sodium ion batteries featuring their low-cost, high safety and excellent mechanical strength have attracted widespread interest in the field of wearable electronic devices. However, the development of such batteries faces great challenges including the construction of interfacial compatible flexible electrode materials and addressing the high safety demands of electrolyte. Here selenium-vacancies regulated bimetallic selenide heterojunctions anchored on waste cotton cloth-derived flexible carbon cloth (FCC) with robust interfacial C-Se-Co/Fe chemical bonds as a flexible anode material (CCFSF) is proposed by ultrafast microwave pyrolysis method. Rich selenium vacancies and CoSe2 /FeSe2-x heterostructures are synchronously formed that can significantly improve ionic and electronic diffusion kinetics. Additionally, a uniform carbon layer coating on the surface of Se-deficient heterostructures endows it with outstanding structural stability. The flexible cathode (PB@FCC) is also fabricated by directly growing Prussian blue nanoparticles on the FCC. Furthermore, an advanced flexible quasi-solid-state Na-ion pouch cell is assembled by coupling CCFSF anode, PB@FCC cathode with P(VDF-HFP)-based gel polymer electrolyte. The full cell not only demonstrates excellent energy storage performance but also robust mechanical flexibility and safety. The present work offers an effective avenue to achieve high safety flexible energy storage device, promoting the development of flexible wearable electronic devices.
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Melanoseriskangdingensis, a new species native to western Sichuan, China, is firstly described and illustrated, and its conservation status is also assessed. It bears resemblance to M.macrantha and M.bracteata in terms of morphology; however, there are distinguishing characteristics in terms of their leaf structure, presence of bracts, hairiness of involucre, number of florets, and length of both stamen tube and achene's beak.
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Myocardial infarction (MI) is a major cause of death and disability worldwide, but current treatments are limited by their invasiveness, side effects, and lack of efficacy. Novel drug targets for MI prevention are urgently needed. In this study, we used Mendelian randomization to identify potential therapeutic targets for MI using plasma protein quantitative trait loci as exposure variables and MI as the outcome variable. We further validated our findings using reverse causation analysis, Bayesian co-localization analysis, and external datasets. We also constructed a protein-protein interaction network to explore the relationships between the identified proteins and known MI targets. Our analysis revealed 2 proteins, LPA and APOA5, as potential drug targets for MI, with causal effects on MI risk confirmed by multiple lines of evidence. LPA and APOA5 are involved in lipid metabolism and interact with target proteins of current MI medications. We also found 4 other proteins, IL1RN, FN1, NT5C, and SEMA3C, that may have potential as drug targets but require further confirmation. Our study demonstrates the utility of Mendelian randomization and protein quantitative trait loci in discovering novel drug targets for complex diseases such as MI. It provides insights into the underlying mechanisms of MI pathology and treatment.
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Análisis de la Aleatorización Mendeliana , Infarto del Miocardio , Humanos , Teorema de Bayes , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/genética , Mapas de Interacción de Proteínas , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido SimpleRESUMEN
Background: Depression and the increased risk of sarcopenia are prevalent among the elderly population. However, the causal associations between these factors remain unclear. To investigate the potential association between depression and the risk of sarcopenia in older adults, this study was performed. Methods: In the baseline survey, a total of 14,258 individuals aged 40 and above from the China Health and Retirement Longitudinal Study (2015) participated. We initially described the baseline prevalence of the disease. Then, logistic regression and restricted cubic spline (RCS) regression were conducted to assess the relationship between depression and sarcopenia. Subgroup analysis was performed to validate the robustness of the findings. Additionally, we conducted Mendelian randomization analysis using the inverse variance weighting estimator to assess the causal relationship between depression and sarcopenia. Furthermore, we adopted six methods, including MR-Egger, simple median, weighted median, maximum likelihood, robust adjusted profile score (RAPS), and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO), for sensitivity analyses. Results: Depression patients exhibited higher risks of sarcopenia in all five models adjusting for different covariates (P < 0.05). The RCS analysis demonstrated a linear relationship between depression and sarcopenia (P < 0.05). In the subgroup analysis, increased risk was observed among participants aged 60-70, married or cohabiting individuals, non-smokers, non-drinkers, those with less than 8 h of sleep, BMI below 24, and individuals with hypertension (all P < 0.05). Mendelian randomization results revealed that genetically proxied depression led to a reduction in appendicular skeletal muscle mass (all P < 0.05). Conclusion: Our study provides observational and causal evidences that depression can lead to sarcopenia. This finding emphasizes the importance of timely identification and management of depression, as well as implementing targeted educational programs as part of comprehensive strategies to prevent sarcopenia.
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INTRODUCTION: The platelet to white blood cell ratio (PWR) has been reported to be a prognostic factor for some diseases, such as subarachnoid hemorrhage. However, the association between the PWR and chronic kidney disease (CKD) remains unknown. To investigate the cross-sectional and longitudinal association between the PWR and CKD, this study was performed. METHODS: This study used datasets from a national prospective cohort in China (China Health and Retirement Longitudinal Study). A retrospective cohort from 2011 to 2015 was constructed. The PWR was stratified as a categorical variable according to tertiles (T1-T3 groups). CKD was defined as an estimated glomerular filtration rate < 60 mL min-1/1.73/m2. Univariate and multivariate logistic regressions and restricted cubic spline regression were adopted to assess the linear and non-linear association between the PWR and CKD. Propensity score matching was used to balance the discrepancies between covariates. Subgroup and interactive analyses were performed to explore potential interactive effects of covariates. Missing values were interpolated using random forest. The PWR was also stratified according to the median and quartiles as sensitivity analyses. RESULTS: A total of 8600 participants were included in this study. In the full model, the odds ratios (ORs) of prevalent CKD were 0.78 (95% CI = 0.62-0.97, p < 0.05) for the T2 group and 0.59 (95% CI = 0.46-0.76, p < 0.001) for the T3 group. There were significant interactive effects of marital status and smoking in the PWR-CKD association (both p for interaction < 0.05). An L-shaped, non-linear association was detected between the PWR and prevalent CKD in the overall population, participants ≥ 60 years, and females subgroups (all p for non-linear < 0.05). All sensitivity analyses supported the negative association between the PWR and prevalent CKD. In the 2011-2015 follow-up cohort, the ORs of incident CKD were 0.73 (95% CI = 0.49-1.08, p > 0.05) and 0.31 (95% CI = 0.18-0.51, p < 0.001) for the T2 and T3 groups, respectively, in the full model. CONCLUSIONS: A high PWR is associated with a reduced risk of prevalent and incident CKD. The PWR may serve as a predictor for CKD, facilitating the early identification and intervention of kidney function decline.
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BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer with a high incidence in Southern China and Southeast Asia. Patients with remote metastasis and recurrent NPC have poor prognosis. Thus, a better understanding of NPC pathogenesis may identify novel therapies to address the unmet clinical needs. METHODS: H3K27ac ChIP-seq and HiChIP was applied to understand the enhancer landscapes and the chromosome interactions. Whole genome sequencing was conducted to analyze the relationship between genomic variations and epigenetic dysregulation. CRISPRi and JQ1 treatment were used to evaluate the transcriptional regulation of SOX2 SEs. Colony formation assay, survival analysis and in vivo subcutaneous patient-derived xenograft assays were applied to explore the function and clinical relevance of SOX2 in NPC. FINDINGS: We globally mapped the enhancer landscapes and generated NPC enhancer connectomes, linking NPC specific enhancers and SEs. We found five overlapped genes, including SOX2, among super-enhancer regulated genes, survival related genes and NPC essential genes. The mRNA expression of SOX2 was repressed when applying CRISPRi targeting different SOX2 SEs or JQ1 treatment. Next, we identified a genetic variation (Chr3:181422197, G > A) in SOX2 SE which is correlated with higher expression of SOX2 and poor survival. In addition, SOX2 was highly expressed in NPC and is correlated with short survival in patients with NPC. Knock-down of SOX2 suppressed tumor growth in vitro and in vivo. INTERPRETATION: Our study demonstrated the super-enhancer landscape with chromosome interactions and identified super-enhancer driven SOX2 promotes tumorigenesis, suggesting that SOX2 is a potential therapeutic target for patients with NPC. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
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Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Recurrencia Local de Neoplasia/genética , Análisis de Supervivencia , Cromatina/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proliferación Celular , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismoRESUMEN
BACKGROUND: FLT-PET/CT can accurately identify and locate functional bone marrow (FBM) with hematopoietic capability, the FBM were divided into two levels as FBM1 (strongest hemopoietic ability region)and FBM2 (moderate hemopoietic ability region) via FLT-PET/CT. The purpose of this study was to explore the relationship between dose-volume parameters of pelvic FBM and hematologic toxicity (HT) during radiotherapy with or without concurrent chemotherapy for uterine cervical/endometrial cancer. METHODS: From December 2016 to September 2021, ninety-seven uterine cervical/endometrial cancer patients received intensity-modulated radiation therapy were prospectively recruited in this single-arm, prospective, phase II trial. Blood counts were reviewed weekly during radiotherapy. Single- and multifactor regression methods were used to analyze the relationships between dose-volume parameters of FBM1/2 and grade ≥ 2 HT. ROC curves were used to determine the cutoff values for the dose-volume parameters of FBM1/2. RESULTS: The incidence of grade ≥ 2 leukopenia, neutropenia, thrombocytopenia and anemia in patients during radiotherapy was 63.9%, 45.4%, 19.6% and 38.8% respectively, and the median occurrence time was the 29th, 42th, 35th and 31th day, respectively. Multivariate regression analysis showed that the Dmax of FBM1 was significantly related to grade ≥ 2 leukopenia (OR = 1.277 95% CI 1.067-1.528, P = 0.008), Dmean of FBM2 was significantly related to grade ≥ 2 thrombocytopenia (OR = 1.262 95% CI 1.066-1.494, P = 0.007), and V10 of FBM1 was significantly related to grade ≥ 2 anemia (OR = 1.198 95% CI 1.003-1.431, P = 0.046). The incidence of grade ≥ 2 leukopenia for patients with FBM1 Dmax < 53 Gy was lower than that for patients with FBM1 Dmax ≥ 53 Gy (53.4% vs. 95.8%, P < 0.001). The incidence of grade ≥ 2 thrombocytopenia in patients with FBM2 Dmean < 33 Gy was lower than that in patients with FBM2 Dmean ≥ 33 Gy (0 vs. 28.4%, P < 0.001). The incidence of grade ≥ 2 anemia for patients with FBM1 V10 < 95% was lower than that in patients with FBM1 V10 ≥ 95% (24.4% vs. 57.1%, P = 0.003). CONCLUSIONS: Grade ≥ 2 HT usually occurs in the 4th week of radiotherapy for patients with uterine cervical/endometrial cancer. The Dmax and V10 of FBM1 and the Dmean of FBM2 were significantly associated with the occurrence of grade ≥ 2 HT. The recommended optimal dose constraints were FBM1 Dmax < 53 Gy, V10 < 95%, and FBM2 Dmean <33 Gy.
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Anemia , Neoplasias Endometriales , Leucopenia , Radioterapia de Intensidad Modulada , Trombocitopenia , Neoplasias del Cuello Uterino , Femenino , Humanos , Anemia/complicaciones , Anemia/tratamiento farmacológico , Médula Ósea , Quimioradioterapia/efectos adversos , Cisplatino/efectos adversos , Leucopenia/etiología , Tomografía Computarizada por Tomografía de Emisión de Positrones/efectos adversos , Estudios Prospectivos , Dosificación Radioterapéutica , Radioterapia de Intensidad Modulada/efectos adversos , Trombocitopenia/inducido químicamente , Trombocitopenia/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapiaRESUMEN
Epstein-Barr virus (EBV) is associated with various malignancies and infects >90% of the global population. EBV latent proteins are expressed in numerous EBV-associated cancers and contribute to carcinogenesis, making them critical therapeutic targets for these cancers. Thus, this study aims to develop mRNA-based therapeutic vaccines that express the T-cell-epitope-rich domain of truncated latent proteins of EBV, including truncatedlatent membrane protein 2A (Trunc-LMP2A), truncated EBV nuclear antigen 1 (Trunc-EBNA1), and Trunc-EBNA3A. The vaccines effectively activate both cellular and humoral immunity in mice and show promising results in suppressing tumor progression and improving survival time in tumor-bearing mice. Furthermore, it is observed that the truncated forms of the antigens, Trunc-LMP2A, Trunc-EBNA1, and Trunc-EBNA3A, are more effective than full-length antigens in activating antigen-specific immune responses. In summary, the findings demonstrate the effectiveness of mRNA-based therapeutic vaccines targeting the T-cell-epitope-rich domain of EBV latent proteins and providing new treatment options for EBV-associated cancers.