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Polypeptides encoded by long noncoding RNAs (lncRNAs) are a novel class of functional molecules. However, whether these hidden polypeptides participate in the TP53 pathway and play a significant biological role is still unclear. Here, we discover that TP53-regulated lncRNAs can encode peptides, two of which are functional in various human cell lines. Using ribosome profiling and RNA-seq approaches in HepG2 cells, we systematically identified more than 300 novel TP53-regulated lncRNAs and further confirmed that 15 of these TP53-regulated lncRNAs encode peptides. Furthermore, several peptides were validated by mass spectrometry. Ten of the novel translational lncRNAs are directly inducible by TP53 in response to DNA damage. We show that the TP53-inducible peptides TP53LC02 and TP53LC04, but not their lncRNAs, can suppress cell proliferation. TP53LC04 peptide also has a function associated with cell proliferation by regulating the cell cycle in response to DNA damage. This study shows that TP53-regulated lncRNAs can encode new functional peptides, leading to the expansion of the TP53 tumor-suppressor network and providing novel potential targets for cancer therapy.
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ARN Largo no Codificante , Proliferación Celular/genética , Humanos , Péptidos/metabolismo , Péptidos/farmacología , ARN Largo no Codificante/metabolismo , Ribosomas/metabolismo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The precise timing of flowering plays a pivotal role in ensuring successful plant reproduction and seed production. This process is intricately governed by complex genetic networks that integrate internal and external signals. This study delved into the regulatory function of microRNA397 (miR397) and its target gene LACCASE-15 (OsLAC15) in modulating flowering traits in rice (Oryza sativa). Overexpression of miR397 led to earlier heading dates, decreased number of leaves on the main stem, and accelerated differentiation of the spikelet meristem. Conversely, overexpression of OsLAC15 resulted in delayed flowering and prolonged vegetative growth. Through biochemical and physiological assays, we uncovered that miR397-OsLAC15 had a profound impact on carbohydrate accumulation and photosynthetic assimilation, consequently enhancing the photosynthetic intensity in miR397-overexpressing rice plants. Notably, we identified that OsLAC15 is at least partially localized within the peroxisome organelle, where it regulates the photorespiration pathway. Moreover, we observed that a high CO2 concentration could rescue the late flowering phenotype in OsLAC15-overexpressing plants. These findings shed valuable insights into the regulatory mechanisms of miR397-OsLAC15 in rice flowering and provided potential strategies for developing crop varieties with early flowering and high-yield traits through genetic breeding.
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Oryza , Oryza/metabolismo , Flores/fisiología , Fitomejoramiento , Hojas de la Planta/genética , Hojas de la Planta/metabolismo , Reproducción , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
Non-coding RNAs (ncRNAs) are emerging as key regulators of various biological processes. Although thousands of ncRNAs have been discovered, the transcriptional mechanisms and networks of the majority of ncRNAs have not been fully investigated. In this study, we updated ChIPBase to version 3.0 (https://rnasysu.com/chipbase3/) to provide the most comprehensive transcriptional regulation atlas of ncRNAs and protein-coding genes (PCGs). ChIPBase has identified â¼151 187 000 regulatory relationships between â¼171 600 genes and â¼3000 regulators by analyzing â¼55 000 ChIP-seq datasets, which represent a 30-fold expansion. Moreover, we de novo identified â¼29 000 motif matrices of transcription factors. In addition, we constructed a novel 'Enhancer' module to predict â¼1 837 200 regulation regions functioning as poised, active or super enhancers under â¼1300 conditions. Importantly, we constructed exhaustive coexpression maps between regulators and their target genes by integrating expression profiles of â¼65 000 normal and â¼15 000 tumor samples. We built a 'Disease' module to obtain an atlas of the disease-associated variations in the regulation regions of genes. We also constructed an 'EpiInter' module to explore potential interactions between epitranscriptome and epigenome. Finally, we designed 'Network' module to provide extensive and gene-centred regulatory networks. ChIPBase will serve as a useful resource to facilitate integrative explorations and expand our understanding of transcriptional regulation.
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Regulación de la Expresión Génica , ARN no Traducido , ARN no Traducido/genética , ARN no Traducido/metabolismo , Factores de Transcripción/metabolismo , Redes Reguladoras de GenesRESUMEN
Pheromones could promote hormone secretions and regulate sexual behavior. It was unclear whether multiparous pheromone could induce variations in puberty. The aim was to ascertain whether pheromone in urine of multiparous females induced central precocious puberty (CPP) in juvenile C57BL/6J females. The precocious puberty was examined by vaginal smear, lordosis reaction, HE stain, and ELISA analysis. Results suggested that the first vaginal opening and the first estrus were significantly earlier. The time interval of the first vaginal opening and estrus was significantly shortened. It was interesting that the first estrus was significantly correlated with the first vaginal opening and the time interval of the first estrus. In the first estrus, female lordosis reaction, the number of mature follicles, and the weight of the ovary and uterus significantly increased. The level of luteinizing hormones also significantly increased. Thus, multiparous pheromone can regulate sex hormone to induce CPP in juvenile C57BL/6J females.
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Lordosis , Feromonas , Animales , Femenino , Hormona Luteinizante , Ratones , Ratones Endogámicos C57BL , Feromonas/farmacología , Feromonas/fisiología , Maduración Sexual/fisiologíaRESUMEN
Polydopamine nanoparticles are artificial melanin nanoparticles (MNPs) that show strong antioxidant activity. The effects of MNPs on the neuroprotection of mesenchymal stem cells (MSCs) against hypoxic-ischemic injury and the underlying mechanism have not yet been revealed. In this study, an oxygen-glucose deprivation (OGD)-injured neuron model was used to mimic neuronal hypoxic-ischemic injury in vitro. MSCs pretreated with MNPs and then cocultured with OGD-injured neurons were used to investigate the potential effects of MNPs on the neuroprotection of MSCs and to elucidate the underlying mechanism. After coculturing with MNPs-pretreated MSCs, MSCs, and MNPs in a transwell coculture system, the OGD-injured neurons were rescued by 91.24%, 79.32%, and 59.97%, respectively. Further data demonstrated that MNPs enhanced the neuroprotection against hypoxic-ischemic injury of MSCs by scavenging reactive oxygen species and superoxide and attenuating neuronal apoptosis by deactivating caspase-3, downregulating the expression of proapoptotic Bax proteins, and upregulating the expression of antiapoptotic Bcl-2 proteins. These findings suggest that MNPs enhance the neuroprotective effect of MSCs against hypoxic-ischemic injury by inhibiting apoptosis and upregulating antioxidant defense, which could provide some evidence for the potential application of combined MNPs and MSCs in the therapy for ischemic stroke.
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Células Madre Mesenquimatosas , Nanopartículas , Antioxidantes/metabolismo , Antioxidantes/farmacología , Apoptosis/fisiología , Glucosa/metabolismo , Humanos , Hipoxia/metabolismo , Melaninas/metabolismo , Neuroprotección , Oxígeno/metabolismoRESUMEN
AIMS: This meta-analysis aimed to systematically evaluate the prospective association between advanced glycation end products (AGEs) and major adverse cardiovascular events (MACE). DATA SYNTHESIS: Prospective studies that reported the association of AGEs (measured by skin autofluorescence) with MACE were searched in PubMed and EMBASE from inception up to July 2021. Multivariable-adjusted hazard ratios (HRs) and their respective 95% confidence intervals (CIs) reflecting the risk of MACE associated with AGEs were determined using random-effects meta-analysis. Fourteen articles with sixteen items involving 79,389 participants were included. A significant association was found between AGEs and MACE (pooled HR: 1.54, 95% CI: 1.31-1.81, I2 = 68%). Moreover, AGEs were associated with a significant increase in fatal cardiovascular disease (CVD) (HR: 1.88, 95% CI: 1.30-2.70) and nonfatal CVD (HR: 1.40, 95% CI: 1.12-1.74). The association between AGEs and MACE was also significant in patients with diabetes (HR: 1.88, 95% CI: 1.31-2.69) and kidney disease (HR: 1.50, 95% CI: 1.16-1.94). CONCLUSIONS: This meta-analysis indicates that higher levels of AGEs measured by skin autofluorescence are significantly correlated with a higher pooled risk of MACE, and AGEs are closely related to both nonfatal and fatal cardiovascular events. AGEs are a valuable biomarker for predicting the occurrence of MACE. THE PROSPERO REGISTRATION NUMBER: CRD42021279714.
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Enfermedades Cardiovasculares , Sistema Cardiovascular , Biomarcadores , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Productos Finales de Glicación Avanzada , Humanos , Estudios Prospectivos , PielRESUMEN
LTR retrotransposons are abundant repetitive elements in the human genome, but their functions remain poorly understood. Here, we report the function and regulatory mechanism of an ERV-9 LTR retrotransposon-derived lncRNA called p53-regulated lncRNA for homologous recombination (HR) repair 1 (PRLH1) in human cells. PRLH1 is highly expressed in p53-mutated hepatocellular carcinoma (HCC) samples and promotes cell proliferation in p53-mutated HCC cells, and its transcription is promoted by NF-Y and suppressed by p53. Mechanistically, PRLH1 specifically binds to an uncharacterized domain of RNF169 through two GCUUCA boxes in its 5' terminal region to form a DNA repair complex that supplants 53BP1 at double-strand break (DSB) sites and then promotes the initiation of HR repair. Notably, PRLH1 is essential for the stabilization of RNF169, acting as an RNA platform to recruit and assemble HR protein factors. This study characterizes PRLH1 as a novel HR-promoting factor and provides new insights into the function and mechanism of LTR retrotransposon-derived lncRNAs.
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Epistasis Genética , Recombinación Homóloga , ARN Largo no Codificante/genética , Retroelementos , Secuencias Repetidas Terminales , Ubiquitina-Proteína Ligasas/genética , Secuencia de Bases , Sitios de Unión , Factor de Unión a CCAAT/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferación Celular , Roturas del ADN de Doble Cadena , Reparación del ADN , Regulación de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Modelos Biológicos , Regiones Promotoras Genéticas , Unión Proteica , Estabilidad Proteica , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/metabolismoRESUMEN
CONTEXT: Endothelin-1(ET-1) has been implicated in coronary artery disease (CAD) and may be associated with coronary artery ectasia (CAE). OBJECTIVE: To clarify the relationship between big ET-1 and isolated CAE. METHODS: We measured big ET-1 with ELISA in 216 patients (CAE, n = 72; CAD, n = 72; normal, n = 72) and evaluated the link with isolated CAE. RESULTS: The level of plasma big ET-1 was significantly higher in patients with isolated CAE (p < 0.001). Big ET-1 was strongly and independently associated with CAE by multivariate analysis (OR 95%CI: 1.026 (1.018-1.034), p = 0.000). CONCLUSIONS: Big ET-1 may be a useful predictor for the presence of isolated CAE.
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Enfermedad de la Arteria Coronaria/diagnóstico , Dilatación Patológica/diagnóstico , Endotelina-1/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Enfermedad de la Arteria Coronaria/sangre , Dilatación Patológica/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las PruebasRESUMEN
OBJECTIVES: To assess the prognostic value of coexisting coronary artery disease (CAD), Markis class, and ectasia ratio for major adverse cardiovascular events in patients with coronary artery ectasia (CAE). METHODS: A total of 512 consecutive patients with angiographically proven CAE were enrolled. Coronary ectasia extent was graded using the Markis class, and ectasia severity was assessed based on the ectasia ratio. Patients were followed up for a median of 34.6 months. RESULTS: In the current study, 76 cases had isolated CAE, while the remaining 436 cases had coexisting CAD (mixture CAE). Males (84.4%) were predominantly affected, and the right coronary artery (55.1%) was most commonly involved. During follow-up, 86 overall major adverse cardiovascular events were diagnosed. Kaplan-Meier analysis failed to reveal any differences between isolated and mixture CAE in both cumulative and event-free survival analyses (p=0.429 and p=0.277, respectively). Moreover, when patients were divided into 4 groups according to Markis class (type I-IV) or 2 groups based on the ectasia ratio (1.5-2.0 and >2.0), there was no significant difference in survival outcomes among the groups (p>0.05). CONCLUSIONS: In this follow-up study with a relatively large sample, the survival rate of patients with CAE appeared to be independent of coexisting CAD and ectasia extent and severity.
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Angiografía Coronaria/métodos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Estenosis Coronaria/diagnóstico por imagen , Vasos Coronarios/diagnóstico por imagen , Dilatación Patológica/diagnóstico por imagen , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND: It has been shown that alkaline phosphatase (ALP) is a reliable marker for cardiovascular events and mortality. However, there is no data available regarding the association of ALP with isolated coronary artery ectasia (CAE). The aim of the present study was to assess the serum ALP activity in isolated CAE. METHODS: Seventy-nine patients with isolated CAE (59 males; mean age, 52 ± 12 years) and 88 age- and gender-matched normal subjects (73 males; mean age, 52 ± 7 years) were enrolled. Baseline characteristics were recorded in both groups and serum ALP activity were compared between the two groups. RESULTS: Patients with angiography-proved isolated CAE had significantly higher serum ALP activity compared with angiographic normal controls (72.41 ± 29.97 vs. 59.27 ± 14.46, p < 0.001). In the multivariate analysis, increased ALP (OR = 1.037, 95% CI 1.017-1.057, p < 0.001) were independent predictors for the presence of isolated CAE. A cut-off of ≥ 66.5 U/L of ALP activity measured on admission had a 60.8% sensitivity and 75.0% specificity in predicting isolated CAE by receiver operating characteristic (ROC) curve analysis. CONCLUSION: Our data firstly demonstrated that serum ALP activity, a readily available clinical laboratory value, was associated with the presence of isolated CAE.
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Fosfatasa Alcalina/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnóstico , Vasos Coronarios/patología , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/patología , Vasos Coronarios/diagnóstico por imagen , Dilatación Patológica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Curva ROCRESUMEN
Background: Drug-coated balloon (DCB) is a novel approach to avoiding stent-related complications and has proven effective for the treatment of in-stent restenosis (ISR) and small vessels. However, its role in the treatment of de novo lesions in large vessels is less settled. Aims: To estimate the efficacy and safety of drug-coated balloon versus stent in the treatment of de novo lesions in large coronary arteries. Methods: We searched the literature until April 2023. We judged the safety of DCB based on major adverse cardiovascular events (MACEs), cardiac death, all-cause mortality, non-fatal myocardial infarction, target lesion revascularization (TLR), and bleeding event; and efficacy according to late lumen loss (LLL), minimum lumen diameter (MLD). We conducted subgroup analyses according to stent type and whether urgent PCI was required. Results: A total of 10 RCTs were included. Overall, LLL (mean difference (MD) = -0.19, 95 % confidence interval (CI): -0.32 to -0.06, P = 0.003) was lower in the DCB group than in the Stent arm. This effect was consistent in subgroup analysis regardless of stent type and disease type. In terms of safety indicators, there were no significant differences between DCB and stent. The subgroup analyses found that safety indicators showed no significant differences between DCB and drug-eluting stent (DES), but TLR was lower in the DCB than in the bare metal stent (BMS). Moreover, in ST-elevation myocardial infarction (STEMI), safety indicators and LLL showed no significant differences between DCB and DES, but MLD in the DCB was smaller. While in patients with excluded STEMI, MACE and TLR was lower in the DCB compared with the overall stent. Conclusions: DCB could be a promising alternative for treating de novo lesions in large coronary arteries with satisfactory efficacy and low risk, superior to BMS and not inferior to DES, with a trend toward lower late lumen loss.
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A kink-turn (K-turn) is a three-dimensional RNA structure that exists in all three primary phylogenetic domains. In this study, we developed the RIP-PEN-seq method to identify the full-length sequences of RNAs bound by the K-turn binding protein 15.5K and discovered a previously uncharacterized class of RNAs with backward K-turn motifs (bktRNAs) in humans and mice. All bktRNAs share two consensus sequence motifs at their fixed terminal position and have complex folding properties, expression and evolution patterns. We found that a highly conserved bktRNA1 guides the methyltransferase fibrillarin to install RNA methylation of U12 small nuclear RNA in humans. Depletion of bktRNA1 causes global splicing dysregulation of U12-type introns by impairing the recruitment of ZCRB1 to the minor spliceosome. Most bktRNAs regulate the splicing of local introns by interacting with the 15.5K protein. Taken together, our findings characterize a class of small RNAs and uncover another layer of gene expression regulation that involves crosstalk among bktRNAs, RNA splicing and RNA methylation.
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Empalme del ARN , ARN , Humanos , Animales , Ratones , Filogenia , Empalme del ARN/genética , ARN/genética , Empalmosomas/genética , Empalmosomas/metabolismo , Intrones/genéticaRESUMEN
Viruses are obligate intracellular parasites that rely on cell surface receptor molecules to complete the first step of invading host cells. The experimental method for virus receptor screening is time-consuming, and receptor molecules have been identified for less than half of known viruses. This study collected known human viruses and their receptor molecules. Through bioinformatics analysis, common characteristics of virus receptor molecules (including sequence, expression, mutation, etc.) were obtained to study why these membrane proteins are more likely to become virus receptors. An in-depth analysis of the cataloged virus receptors revealed several noteworthy findings. Compared to other membrane proteins, human virus receptors generally exhibited higher expression levels and lower sequence conservation. These receptors were found in multiple tissues, with certain tissues and cell types displaying significantly higher expression levels. While most receptor molecules showed noticeable age-related variations in expression across different tissues, only a limited number of them exhibited gender-related differences in specific tissues. Interestingly, in contrast to normal tissues, virus receptors showed significant dysregulation in various types of tumors, particularly those associated with dsRNA and retrovirus receptors. Finally, GateView, a multi-omics platform, was established to analyze the gene features of virus receptors in human normal tissues and tumors. Serving as a valuable resource, it enables the exploration of common patterns among virus receptors and the investigation of virus tropism across different tissues, population preferences, virus pathogenicity, and oncolytic virus mechanisms.
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Neoplasias , Receptores Virales , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/virología , Receptores Virales/genética , Receptores Virales/metabolismo , Biología Computacional/métodos , MultiómicaRESUMEN
2'-O-methylation (Nm) is one of the most abundant RNA epigenetic modifications and plays a vital role in the post-transcriptional regulation of gene expression. Current Nm mapping approaches are normally limited to highly abundant RNAs and have significant technical hurdles in mRNAs or relatively rare non-coding RNAs (ncRNAs). Here, we developed a new method for enriching Nm sites by using RNA exoribonuclease and periodate oxidation reactivity to eliminate 2'-hydroxylated (2'-OH) nucleosides, coupled with sequencing (Nm-REP-seq). We revealed several novel classes of Nm-containing ncRNAs as well as mRNAs in humans, mice, and drosophila. We found that some novel Nm sites are present at fixed positions in different tRNAs and are potential substrates of fibrillarin (FBL) methyltransferase mediated by snoRNAs. Importantly, we discovered, for the first time, that Nm located at the 3'-end of various types of ncRNAs and fragments derived from them. Our approach precisely redefines the genome-wide distribution of Nm and provides new technologies for functional studies of Nm-mediated gene regulation.
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Exorribonucleasas , ARN no Traducido , Humanos , Animales , Ratones , Exorribonucleasas/genética , Exorribonucleasas/metabolismo , Metilación , ARN no Traducido/genética , Secuencia de Bases , ARN Nucleolar Pequeño/metabolismo , ARN Mensajero/genéticaRESUMEN
Background: Heart failure (HF) is the most common outcome of cardiovascular disease, and an increasing number of patients with heart failure die from noncardiac causes, such as cancer. Epidemiological data suggest that ischemic cardiomyopathy-induced HF (ischemic HF) may be associated with an increased incidence of cancer. This study aimed to investigate the possible mechanisms of the association between ischemic HF and cancer, as well as potential therapeutic targets. Methods: Weighted gene co-expression network analysis was performed to analyze the correlations between phenotypes and gene modules using immune cells as phenotypes. Differential analysis was then performed to screen differentially expressed genes (DEGs) in ischemic HF and normal control samples. The macrophage-related Brown module was identified as the key module, and immune-related DEGs were obtained by taking the intersection of the Brown module, DEGs, and immune-related genes using a Venn diagram. DDX58 was identified as the key gene using a protein-protein interaction network and expression analyses and validated using immunohistochemistry. Kaplan-Meier survival analysis was performed to analyze the correlation between DDX58 expression and tumor prognosis. Spearman correlation analysis was performed to assess the correlation between DDX58 expression and immune cell infiltration. Results: DDX58 was identified as a key immune-related gene associated with ischemic HF and was highly expressed in most cancer types. The survival analysis revealed a significant negative correlation between high DDX58 expression and prognosis in multiple tumor types. Moreover, DDX58 expression was significantly associated with immune cell infiltration and immune checkpoint gene expression in many cancer types. Conclusion: DDX58 is a key immune-related gene in ischemic HF and may play a crucial role in the relationship between ischemic HF and cancer. Pan-cancer analysis suggests that DDX58 is a promising clinical prognostic marker for most cancers and may be a therapeutic target for cancer patients and ischemic HF patients at an increased risk of cancer.
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Objective: The aim of this study was to evaluate the effectiveness and safety of rescue therapy, a therapy in which rescue devices such as balloon angioplasty, Apollo stent, Wingspan stent, Solitaire stent, or other self-expanding stents are used after the failure of mechanical thrombectomy (MT) and to determine the most effective rescue measure for acute basilar artery occlusion (BAO) after the failure of MT. Methods: For this study, we recruited patients from the BASILAR registry. All participants were divided into three groups: the recanalized with rescue therapy group, the recanalized without rescue therapy group, and the non-recanalized group. Clinical outcomes at 90 days and 1 year were compared. The association of rescue measures with favorable outcomes (modified Rankin Scale [mRS] score of 0-3) in patients achieving successful recanalization via rescue therapy was estimated using multivariate logistic regression analyses. Results: Among the participants, recanalization failure was found in 112 patients and successful recanalization in 473 patients, with 218 patients receiving rescue therapy and 255 patients without rescue therapy. Of these, 111 (43.5%) patients in the recanalized without rescue therapy group, 65 (29.8%) patients in the recanalized with rescue therapy group, and nine (8.0%) patients in the non-recanalized group achieved favorable outcomes at 90 days. Both the recanalization with rescue therapy and the recanalization without rescue therapy groups were associated with favorable outcomes at 90 days and 1 year compared with the non-recanalized group. Moreover, in patients receiving rescue therapy, Wingspan stents, Apollo stents, and balloon angioplasty were associated with higher rates of favorable outcomes at 90 days and 1 year than Solitaire stents. Conclusion: Whether rescue therapy is administered or not, recanalization leads to favorable outcomes in patients with acute BAO. For acute BAO after MT failure, balloon angioplasty, Wingspan stenting, and Apollo stenting could be considered effective and safe rescue options but not Solitaire stenting.
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The CREB1 gene encodes an exceptionally pleiotropic transcription factor that frequently dysregulated in human cancers. CREB1 can regulate tumor cell status of proliferation and/or migration; however, the molecular basis for this switch involvement in cell plasticity has not fully been understood yet. Here, we first show that knocking out CREB1 triggers a remarkable effect of epithelial-mesenchymal transition (EMT) and leads to the occurrence of inhibited proliferation and enhanced motility in HCT116 colorectal cancer cells. By monitoring 45 cellular signaling pathway activities, we find that multiple growth-related pathways decline significantly while inflammatory pathways including NF-κB are largely upregulated in comparing between the CREB1 wild-type and knocked out cells. Mechanistically, cells with CREB1 knocked out show downregulation of MYC as a result of impaired CREB1-dependent transcription of the oncogenic lncRNA CCAT1. Interestingly, the unbalanced competition between the coactivator CBP/p300 for CREB1 and p65 leads to the activation of the NF-κB pathway in cells with CREB1 disrupted, which induces an obvious EMT phenotype of the cancer cells. Taken together, these studies identify previously unknown mechanisms of CREB1 in CRC cell plasticity via regulating lncRNA CCAT1 and NF-κB pathways, providing a critical insight into a combined strategy for CREB1-targeted tumor therapies.
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Plasticidad de la Célula , Neoplasias Colorrectales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , FN-kappa B , ARN Largo no Codificante , Línea Celular Tumoral , Movimiento Celular/genética , Plasticidad de la Célula/genética , Plasticidad de la Célula/fisiología , Proliferación Celular/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/fisiopatología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/fisiología , Regulación Neoplásica de la Expresión Génica , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Some in vitro studies have identified an antithrombotic effect of polysaccharides from Laminaria japonica, but this activity remains to be confirmed in vivo. In this study a polysaccharide fraction termed PLG was extracted from L. japonica in the Beibu Gulf in Guangxi, China, and its antithrombotic effects explored in rat models of carotid and venous thrombosis. Its anticoagulation and antiplatelet properties were assessed by measuring the prothrombin time (PT), activated partial thromboplastin time (APTT) and ADP-induced platelet aggregation rate (Agg(max)). Its effects on bleeding time were measured using the tail transection method. It was found that pretreatment with an intraperitoneal injection of PLG at 2.5 or 5.0 mg/kg significantly prolonged the occlusion time in the carotid thrombosis model, and a dose of 5.0 mg/kg reduced the thrombus weight in the venous thrombosis model. Pretreatment with PLG (5.0 mg/kg) increased the APTT and decreased the ADP-induced platelet Agg(max). Neither dose of PLG significantly prolonged the bleeding time compared with the control group. In an in vitro anticoagulation assay using human plasma, PLG at 57.14, 28.57 and 28.57 µg/mL inhibited APTT and PT in a concentration-dependent manner. The results show that PLG possesses antithrombotic activity in a rat model, and that it may prove to be clinically useful in humans.
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Fibrinolíticos/farmacología , Laminaria/química , Polisacáridos/farmacología , Trombosis/prevención & control , Animales , Arterias Carótidas/patología , China , Femenino , Humanos , Masculino , Tiempo de Tromboplastina Parcial , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Tiempo de Protrombina , Ratas Sprague-Dawley , Trombosis/tratamiento farmacológico , Trombosis de la Vena/tratamiento farmacológicoRESUMEN
ABSTRACT: Coronary slow flow phenomenon (CSFP) is a coronary artery disease in which coronary angiography shows no obvious stenosis, but there is a delay in blood flow perfusion. The etiopathogenic mechanisms of CSFP are still unclear. The aim of the present study was to investigate the role of clinical characteristics in patients with CSFP, and to provide a reference for exploring the potential mechanisms of CSFP. Patients with angiographically normal epicardial arteries were enrolled (145 patients with CSFP and 145 normal controls). Collected clinical information and laboratory indexes, which measured by peripheral venous blood samples before coronary angiography. Logistic regression analysis was performed for statistical analysis. The present study found 19 clinical and laboratory indexes with statistical differences between the two groups in univariate analysis. Multivariate analysis showed that monocyte count, haemoglobin, serum creatinine and globulin were independent predictors of CSFP. Moreover, the monocyte count, haemoglobin, creatinine and globulin levels were significantly higher in the CSFP patients than the controls, with positive associations between these parameters and the extent of CSFP. In addition, ROC analysis showed the diagnostic value of the above indexes for CSFP.
Asunto(s)
Enfermedad de la Arteria Coronaria/fisiopatología , Vasos Coronarios/fisiopatología , Fenómeno de no Reflujo/epidemiología , Fenómeno de no Reflujo/fisiopatología , Anciano , Estudios de Casos y Controles , Angiografía Coronaria/métodos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Circulación Coronaria/fisiología , Creatinina/sangre , Femenino , Globulinas/metabolismo , Hemoglobinas/análisis , Humanos , Recuento de Leucocitos/métodos , Masculino , Persona de Mediana Edad , Monocitos/citología , Fenómeno de no Reflujo/sangre , Fenómeno de no Reflujo/diagnóstico por imagen , Estudios RetrospectivosRESUMEN
OBJECTIVE: We aimed to explore the cardiovascular characteristics of patients who were initially diagnosed with breast cancer. METHODS: A total of 600 patients who were diagnosed with primary breast cancer were included in this retrospective study. The data of fasting blood glucose, total cholesterol, total triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, lipoprotein (a) (LP (a)) and serum uric acid were collected. Univariate analysis was used to evaluate the cardiovascular risk factors (CVRFs) in patients with breast cancer. The arteriosclerotic cardiovascular disease (ASCVD) risk assessment was performed. Multivariate analysis was used to identify the factors that influenced axillary lymph node metastasis (ALNM). RESULTS: Compared with the premenopausal group, the prevalence of overweight/obesity (47.6% vs. 35.2%), diabetes (12.8% vs. 4.3%) and hypertension (49.7% vs. 26.3%) were significantly increased in the postmenopausal group (p < 0.05). Comparisons of rural patients and urban patients showed that there were significant differences in the diagnostic age (49.94 ± 9.92 vs. 52.59 ± 11.13) in the rural patients was notably younger in comparison with the urban patients (p < 0.05). However, the number of menopausal patients (44.3% vs. 53.3%) in the rural group were decreased in comparison with the urban group (p < 0.05). In ASCVD risk stratification, the proportion of low-risk patients (56.4% vs. 90.8%), medium-risk patients (20.6% vs 0.3%) and high-risk patients (19.3% vs. 6.6%) were significantly different between the postmenopausal group and premenopausal group (p < 0.05). Residence (OR 0.735; 95% CI 0.516-1.046; p = 0.087), the number of children (OR 1.250; 95% CI 0.990-1.578; p = 0.061) and LP (a) of ≥ 500 mg/L (OR 0.603; 95% CI 0.342-1.063; p = 0.080) were independent influencing factors of ALNM. CONCLUSION: Postmenopausal patients have more CVRFs and higher risks of ASCVD than premenopausal patients initially diagnosed with breast cancer. There was a correlation between CVRFs and ALNM in patients with breast cancer.