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Although greenspace exposure has physiological health benefits, there is insufficient research on the threshold effect of health benefits in typical urban landscapes. Here we selected five typical urban landscapes (open greenspace, semi-closed greenspace, closed greenspace, bluespace, grey space) in 15 urban parks in Xiamen, China, and applied the physiological health threshold model to calculate the efficiency threshold and benefit threshold of greenspace exposure by continuously monitoring the changes of two physiological indicators-electroencephalography (EEG) and heart rate (HR). (1) The EEG threshold results show that compared with greenspace exposure, bluespace exposure can reach the physiological health efficiency threshold faster (4-5 min) but does not show an advantage in terms of benefit threshold. The more open the greenspace, the faster it can reach the efficiency threshold (5-6 min), but the higher the canopy density of the (closed) greenspace, the shorter the time to reach the efficiency threshold (8-9 min). (2) The HR threshold shows that bluespace and open greenspace are the fastest to reach the efficiency threshold (1 min), with the remaining greenspace reaching it after 6-7 min. The benefit threshold was reached faster in the bluespace (11 min) than in the greenspace (18-21 min), and the degree of openness of the greenspace has no significant effect on the speed of benefit thresholds. (3) Combining the results of EEG and HR thresholds, it can be seen that bluespace is better at reducing stress, while open greenspace can reach efficiency thresholds more quickly. This study confirms the physiological health threshold model, offering a reference for urban greenspace planning to enhance residents' stress management and health.
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Comprehensive lipid and volatile compound analyses were performed with squids collected from four varied geographical locations to discriminate the regional characteristics. A total of 1442 lipid molecules and 110 volatiles were detected in the squid muscle samples. There were significant differences in the lipid profiles between Argentine squid (Illex argentinus, AGT), North Pacific Ocean squid (Ommastrephes Bartram, NPO), Equatorial squid (Dosidicus gigas, EQ), and Peruvian squid (Dosidicus gigas, PR) muscle. Phosphatidylcholines (14.64%), triacylglycerols (12.42%), and ceramides (10.97%) were the main lipid components. The contents of polyunsaturated fatty acid in phospholipids and in glycerolipids were 30.35-52.05% and 18.11-25.15%, respectively. The volatiles in squids exhibited significant regional variation; 1-pentanol and 1-octanol, 2-ethyl-1-hexanol and terpinen-4-ol, 2,7-ethyl-1-hexanol, 3-methy-1-butanol and 2-propyl-1-pentanol were identified as characteristic flavor compounds in AGT, NPO, EQ, and PR, respectively. Sphingomyelin, phosphatidylserine, phosphatidylethanolamine, and ceramide were strongly correlated with volatiles in squid muscle. Our study is a reference for the lipid nutritional value and flavor compounds of squids.
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Decapodiformes , Cromatografía de Gases y Espectrometría de Masas , Lipidómica , Compuestos Orgánicos Volátiles , Animales , Decapodiformes/química , Compuestos Orgánicos Volátiles/análisis , Océano Pacífico , Lipidómica/métodos , Cromatografía de Gases y Espectrometría de Masas/métodos , Argentina , Perú , Cromatografía Líquida de Alta Presión , Microextracción en Fase Sólida/métodos , Triglicéridos/análisis , Lípidos/análisis , Fosfolípidos/análisis , Músculos/químicaRESUMEN
Excessive levels of nitrate nitrogen (NO3--N) could lead to ecological issues, particularly in the Yarlung Tsangpo River (YTR) region located on the Qinghai Tibet Plateau. Therefore, it is crucial to understand the fate and sources of nitrogen to facilitate pollution mitigation efforts. Herein, multiple isotopes and source resolution models were applied to analyze key transformation processes and quantify the sources of NO3-. The δ15N-NO3- and δ18O-NO3- isotopic compositions in the YTR varied between 1.23 and 13.64 and -7.88-11.19, respectively. The NO3--N concentrations varied from 0.08 to 0.86 mg/L in the dry season and 0.20-1.19 mg/L during the wet season. Nitrification remained the primary process for nitrogen transformation in both seasons. However, the wet season had a widespread effect on increasing nitrate levels, while denitrification had a limited ability to reduce nitrate. The elevated nitrate concentrations during the flood season were caused by increased release of NO3- from manure & sewage (M&S) and chemical fertilizers (CF). Future endeavors should prioritize enhancing management strategies to improve the utilization efficiency of CF and hinder the direct entry of untreated sewage into the water system.
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Teorema de Bayes , Monitoreo del Ambiente , Nitratos , Ríos , Contaminantes Químicos del Agua , Nitratos/análisis , Ríos/química , Monitoreo del Ambiente/métodos , Contaminantes Químicos del Agua/análisis , Tibet , Estaciones del Año , DesnitrificaciónRESUMEN
Ferroptosis is a type of cell death that is caused by the oxidation of lipids and is dependent on the presence of iron. It was first characterized by Brent R. Stockwell in 2012, and since then, research in the field of ferroptosis has rapidly expanded. The process of ferroptosis-induced cell death is genetically, biochemically, and morphologically distinct from other forms of cellular death, such as apoptosis, necroptosis, and non-programmed cell death. Extensive research has been devoted to comprehending the intricate process of ferroptosis and the various factors that contribute to it. While the majority of these studies have focused on examining the effects of lipid metabolism and mitochondria on ferroptosis, recent findings have highlighted the significant involvement of signaling pathways and associated proteins, including Nrf2, P53, and YAP/TAZ, in this process. This review provides a concise summary of the crucial signaling pathways associated with ferroptosis based on relevant studies. It also elaborates on the drugs that have been employed in recent years to treat ferroptosis-related diseases by targeting the relevant signaling pathways. The established and potential therapeutic targets for ferroptosis-related diseases, such as cancer and ischemic heart disease, are systematically addressed.
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Climate is the most important environmental factor influencing yield during rice growth and development. To investigate the relationships between climate and yield under different crop rotation patterns and planting methods, three typical rotation patterns (vegetable-rice (V), rape-rice (R), and wheat-rice (W)) and two mechanical planting methods (mechanical transplanting (T1) and mechanical direct seeding (T2)) were established. The results showed that compared to the V rotation pattern, the average daily temperature (ADT) during the sowing to heading stage increased under both R and W rotation patterns, which significantly shortened the growth period. Thus, the effective accumulated temperature (EAT), photosynthetic capacity, effective panicle (EP), and spikelet per panicle (SP) under R and W rotation patterns significantly decreased, leading to reductions in grain yield (GY). VT2 had a higher ratio of productive tillers (RPT), relative chlorophyll content (SPAD), leaf area index (LAI), and net photosynthetic rate (Pn) than those of VT1, which significantly increased panicle dry matter accumulation (DMA), resulting in an increase in GY. Although RT2 and WT2 had a higher RPT than those of RT1 and WT1, the GY of RT1 and WT1 decreased due to the significant reductions in EAT and photosynthetic capacity. Principal component analysis (PCA) showed that the comprehensive score for different rotation patterns followed the order of V > R > T with VT2 ranking first. The structural equation model (SEM) showed that EAT and ADT were the most important climate factors affecting yield, with total effects of 0.520 and -0.446, respectively. In conclusion, mechanical direct seeding under vegetable-rice rotation pattern and mechanical transplanting under rape-rice or wheat-rice rotation pattern were the rice-planting methods that optimized the climate resources in southwest China.
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Reasonable nitrogen (N) and potassium (K) application rates can effectively improve fertilizer use efficiency, rice yield and quality. A two-year field experiment was conducted with combined application of three N rates (135, 180, and 225 kg ha-1, denoted as N1-N3) and four K rates (0, 90, 135, and 180 kg ha-1, denoted as K0-K3) using super indica hybrid rice cultivar Yixiangyou (YXY) 2115 to explore the effects of co-application of N and K on rice growth and development. The results indicated that the combined application of N and K had significantly interactive effects on dry matter (DM) accumulation, nutrients absorption, N harvest index (NHI), K harvest index (KHI), spikelets per panicle and most rice quality indexes. The highest total DM accumulation (17998.17-19432.47 kg ha-1) at maturity stage was obtained under N3K2. The effect of co-application of N and K on nutrients absorption and utilization varied between the two years and within each year. The highest total N and K accumulations at maturity stage were observed under N3K1 and N3K2, respectively, while the highest N recovery efficiency (NRE) and K recovery efficiency (KRE) were observed under N1K3. High expression levels of N and K metabolism-related genes in rice grains were observed under N3K2 or N3K3, consistent with N and K uptake. Co-application of N and K increased rice yield significantly and the highest yield (6745.02-7010.27 kg ha-1) was obtained under N2K2. As more N was gradually applied, rice appearance quality improved but milling, cooking and eating quality decreased. Although appropriate application of K could improve rice milling, cooking and eating quality, it reduced appearance quality. The optimal milling, cooking and eating quality were obtained under N1K2, while the best appearance quality was obtained under N3K0. Overall, a combination of 135-210 kg ha-1 N and 115-137 kg ha-1 K application rates was recommended for achieving relatively higher yield and better quality in rice production.
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Complete ammonia oxidation (comammox) bacteria can complete the whole nitrification process independently, which not only challenges the classical two-step nitrification theory but also updates long-held perspective of microbial ecological relationship in nitrification process. Although comammox bacteria have been found in many ecosystems in recent years, there is still a lack of research on the comammox process in rhizosphere of emergent macrophytes in lakeshore zone. Sediment samples were collected in this study from rhizosphere, far-rhizosphere, and non-rhizosphere of emergent macrophytes along the shore of Lake Liangzi, a shallow lake. The diversity of comammox bacteria and amoA gene abundance of comammox bacteria, ammonia-oxidizing archaea (AOA), and ammonia-oxidizing bacteria (AOB) in these samples were measured. The results showed that comammox bacteria widely existed in the rhizosphere of emergent macrophytes and fell into clade A.1, clade A.2, and clade B, and clade A was the predominant community in all sampling sites. The abundance of comammox amoA gene (6.52 × 1062.45 × 108 copies g−1 dry sediment) was higher than that of AOB amoA gene (6.58 × 1043.58 × 106 copies g−1 dry sediment), and four orders of magnitude higher than that of AOA amoA gene (7.24 × 1026.89 × 103 copies g−1 dry sediment), suggesting that the rhizosphere of emergent macrophytes is more favorable for the growth of comammox bacteria than that of AOB and AOA. Our study indicated that the comammox bacteria may play important roles in ammonia-oxidizing processes in all different rhizosphere regions.(AU)
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Humanos , Rizosfera , Microbiología del Suelo , Amoníaco , Lagos/microbiología , Archaea , Oxidación-Reducción , Microbiología , Técnicas Microbiológicas , EcosistemaRESUMEN
BACKGROUND: Neoadjuvant chemoimmunotherapy (NACI) is promising for resectable nonsmall cell lung cancer (NSCLC), but predictive biomarkers are still lacking. The authors aimed to develop a model based on pretreatment parameters to predict major pathological response (MPR) for such an approach. METHODS: The authors enrolled operable NSCLC treated with NACI between March 2020 and May 2023 and then collected baseline clinical-pathology data and routine laboratory examinations before treatment. The efficacy and safety data of this cohort was reported and variables were screened by Logistic and Lasso regression and nomogram was developed. In addition, receiver operating characteristic curves, calibration curves, and decision curve analysis were used to assess its power. Finally, internal cross-validation and external validation was performed to assess the power of the model. RESULTS: In total, 206 eligible patients were recruited in this study and 53.4% (110/206) patients achieved MPR. Using multivariate analysis, the predictive model was constructed by seven variables, prothrombin time (PT), neutrophil percentage (NEUT%), large platelet ratio (P-LCR), eosinophil percentage (EOS%), smoking, pathological type, and programmed death ligand-1 (PD-L1) expression finally. The model had good discrimination, with area under the receiver operating characteristic curve (AUC) of 0.775, 0.746, and 0.835 for all datasets, cross-validation, and external validation, respectively. The calibration curves showed good consistency, and decision curve analysis indicated its potential value in clinical practice. CONCLUSION: This real world study revealed favorable efficacy in operable NSCLC treated with NACI. The proposed model based on multiple clinically accessible parameters could effectively predict MPR probability and could be a powerful tool in personalized medication.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Terapia Neoadyuvante , Nomogramas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Femenino , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Anciano , Inmunoterapia/métodos , Estudios Retrospectivos , Resultado del Tratamiento , Curva ROCRESUMEN
Background: Previous findings indicate that stress has a profound influence on suicide behavior, but the potential mediating and moderating mechanisms are unknown between uncertainty stress and suicide behavior. The present study, therefore, examined the relationship between uncertainty stress and suicide behavior, the mediating effect of depressive symptoms, and the moderating effect of family relationship in a sample of university students in China. Methods: 1828 university students were assessed anonymously by using the Uncertainty Stress Scale, Center for Epidemiologic Studies Depression Scale, Brief Suicidal Scale, and Family Relationship Scale between May to June in 2021. SPSS 26.0 was used for descriptive statistics and Spearman correlation analysis. PROCESS 3.5 was used to calculate the significance of the mediating and moderating effects of the variables. Results: Moderated mediation model analyses showed that: (a) depressive symptoms partially mediated the link between uncertainty stress and suicide behavior (indirect effect = 0.14, 95%bootstrap CI = 0.10, 0.19). The indirect effect of the depressive symptoms accounted for 67.12% of the total variance in suicide behavior. (b) The indirect association between uncertainty stress and suicide behavior was moderated by family relationship. Specifically, the paths from uncertainty stress to depressive symptoms (interact effect = -0.06, P<0.001) and depressive symptoms to suicide behavior (interact effect = -0.08, P<0.01) were weakened in the context of higher family relationship. Conclusion: Depressive symptoms play a crucial role in bridging uncertainty stress and suicide behavior, while the family relationship can buffer the mediation impact of depressive symptoms. These findings significantly contribute to the prevention and intervention of suicide in Chinese university students.
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Complete ammonia oxidation (comammox) bacteria can complete the whole nitrification process independently, which not only challenges the classical two-step nitrification theory but also updates long-held perspective of microbial ecological relationship in nitrification process. Although comammox bacteria have been found in many ecosystems in recent years, there is still a lack of research on the comammox process in rhizosphere of emergent macrophytes in lakeshore zone. Sediment samples were collected in this study from rhizosphere, far-rhizosphere, and non-rhizosphere of emergent macrophytes along the shore of Lake Liangzi, a shallow lake. The diversity of comammox bacteria and amoA gene abundance of comammox bacteria, ammonia-oxidizing archaea (AOA), and ammonia-oxidizing bacteria (AOB) in these samples were measured. The results showed that comammox bacteria widely existed in the rhizosphere of emergent macrophytes and fell into clade A.1, clade A.2, and clade B, and clade A was the predominant community in all sampling sites. The abundance of comammox amoA gene (6.52 × 106-2.45 × 108 copies g-1 dry sediment) was higher than that of AOB amoA gene (6.58 × 104-3.58 × 106 copies g-1 dry sediment), and four orders of magnitude higher than that of AOA amoA gene (7.24 × 102-6.89 × 103 copies g-1 dry sediment), suggesting that the rhizosphere of emergent macrophytes is more favorable for the growth of comammox bacteria than that of AOB and AOA. Our study indicated that the comammox bacteria may play important roles in ammonia-oxidizing processes in all different rhizosphere regions.
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Amoníaco , Archaea , Archaea/genética , Rizosfera , Ecosistema , Lagos/microbiología , Oxidación-Reducción , Filogenia , Bacterias , Microbiología del SueloRESUMEN
Various cellular stress conditions trigger mitochondrial DNA (mtDNA) release from mitochondria into the cytosol. The released mtDNA is sensed by the cGAS-MITA/STING pathway, resulting in the induced expression of type I interferon and other effector genes. These processes contribute to the innate immune response to viral infection and other stress factors. The deregulation of these processes causes autoimmune diseases, inflammatory metabolic disorders and cancer. Therefore, the cGAS-MITA/STING pathway is a potential target for intervention in infectious, inflammatory and autoimmune diseases as well as cancer. In this review, we focus on the mechanisms underlying the mtDNA-triggered activation of the cGAS-MITA/STING pathway, the effects of the pathway under various physiological and pathological conditions, and advances in the development of drugs that target cGAS and MITA/STING.
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Enfermedades Autoinmunes , Neoplasias , Humanos , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Transducción de Señal , Inmunidad Innata , Nucleotidiltransferasas/metabolismo , Mitocondrias/metabolismo , Enfermedades Autoinmunes/patología , Neoplasias/patologíaRESUMEN
Recurrent glioma treatment is challenging due to molecular heterogeneity and treatment resistance commonly observed in these tumors. Researchers are actively pursuing new therapeutic strategies. Oncolytic viruses have emerged as a promising option. Oncolytic viruses selectively replicate within tumor cells, destroying them and stimulating the immune system for an enhanced anticancer response. Among Oncolytic viruses investigated for recurrent gliomas, oncolytic herpes simplex virus and oncolytic adenovirus show notable potential. Genetic modifications play a crucial role in optimizing their therapeutic efficacy. Different generations of replicative conditioned oncolytic human adenovirus and oncolytic HSV have been developed, incorporating specific modifications to enhance tumor selectivity, replication efficiency, and immune activation. This review article summarizes these genetic modifications, offering insights into the underlying mechanisms of Oncolytic viruses' therapy. It also aims to identify strategies for further enhancing the therapeutic benefits of Oncolytic viruses. However, it is important to acknowledge that additional research and clinical trials are necessary to establish the safety, efficacy, and optimal utilization of Oncolytic viruses in treating recurrent glioblastoma.
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Infecciones por Adenoviridae , Glioma , Virus Oncolíticos , Humanos , Simplexvirus/genética , Adenoviridae/genética , Recurrencia Local de Neoplasia/terapia , Glioma/terapia , Virus Oncolíticos/genéticaRESUMEN
The water environment of large reservoirs is fragility due to effects from hydrological regulation of damming and anthropogenic inputs. As a critical path to quantify the natural chemical weathering and assess environmental risks, solute chemistry of river has been widely focused on. However, the complexed hydrological conditions of large reservoir affect the chemical compositions, and the significance of solute vertical geochemistry as an indicator of chemical weathering and water quality health remains explore. Therefore, the Three Gorges Reservoir (TGR) was selected as a typical study area, which is the world's largest hydropower project and subject to frequent water quality problems. Then, the chemical compositions in stratified water were determined. Ca2+ (52.8 ± 4.3 mg/L) and HCO3- (180.9 ± 8.9 mg/L) were the most abundant ions among cations and anions, respectively. Incremental mean concentration of total major ions followed with the increase of riverine depth and flow direction. An improved inversion model was used to quantify the source contribution, which weathering of dolomite (34%) and calcite (38%) contributed the most to total cations, and the influences of agriculture and sewage discharge were limited. Additional contributions of evaporite and pyrite oxidation were found in analysis of deeper water samples, which also results in 2%-67% difference in estimated CO2 release flux using data from different depth, indicating additional information about sulfuric acid driven weathering was contained. Finally, the water quality of the reservoir was assessed for irrigation and non-carcinogenic risks. Results showed the stratified water of TGR can be used as a good water source of irrigation. However, NO3- (5.1 ± 1.1 mg/L) may have a potential non-carcinogenic risk to children, especially in surface water. To sum up, this study provided an indispensable supplement to the water chemistry archives in the TGR basin, serving as theoretical references for environmental management of large reservoirs.
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Monitoreo del Ambiente , Contaminantes Químicos del Agua , Niño , Humanos , Monitoreo del Ambiente/métodos , Calidad del Agua , Ríos/química , Tiempo (Meteorología) , Cationes/análisis , Contaminantes Químicos del Agua/análisis , ChinaRESUMEN
This study examined the longitudinal associations of various executive function components with subsequent psychiatric problems in Chinese school-age children. Data from 1,639 children (44.36% girls) ages 6-13 years were drawn from the Children School Functions and Brain Development project. Executive function components were assessed by the cancellation test, the Corsi test, and the Wisconsin Card Sorting Test. Psychiatric problems were determined by parent report. All assessments were administered twice, separated by a 1-year interval. Cross-lagged panel models showed that cognitive flexibility and general psychiatric problems (general p) mutually predicted each other. Worse inhibitory control at baseline significantly predicted more externalizing problems 1 year later, regardless of age, while externalizing problems did not significantly predict inhibitory control 1 year later. Working memory at baseline did not significantly predict internalizing problems and vice versa. These findings demonstrate that better inhibitory control may help to prevent or reduce externalizing problems in Chinese school-age children and that higher cognitive flexibility may help to mitigate general psychiatric problems. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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Trastornos de la Conducta Infantil , Función Ejecutiva , Femenino , Humanos , Niño , Masculino , Estudios Longitudinales , Trastornos de la Conducta Infantil/psicología , Memoria a Corto PlazoRESUMEN
Mitochondria play essential roles in cancer cell adaptation to hypoxia, but the underlying mechanisms remain elusive. Through mitochondrial proteomic profiling, we here find that the prolyl hydroxylase EglN1 (PHD2) accumulates on mitochondria under hypoxia. EglN1 substrate-binding region in the ß2ß3 loop is responsible for its mitochondrial translocation and contributes to breast tumor growth. Furthermore, we identify AMP-activated protein kinase alpha (AMPKα) as an EglN1 substrate on mitochondria. The EglN1-AMPKα interaction is essential for their mutual mitochondrial translocation. After EglN1 prolyl-hydroxylates AMPKα under normoxia, they rapidly dissociate following prolyl-hydroxylation, leading to their immediate release from mitochondria. In contrast, hypoxia results in constant EglN1-AMPKα interaction and their accumulation on mitochondria, leading to the formation of a Ca2+ /calmodulin-dependent protein kinase 2 (CaMKK2)-EglN1-AMPKα complex to activate AMPKα phosphorylation, ensuring metabolic homeostasis and breast tumor growth. Our findings identify EglN1 as an oxygen-sensitive metabolic checkpoint signaling hypoxic stress to mitochondria through its ß2ß3 loop region, suggesting a potential therapeutic target for breast cancer.
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Proteínas Quinasas Activadas por AMP , Neoplasias de la Mama , Femenino , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Hipoxia , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Mitocondrias/metabolismo , ProteómicaRESUMEN
PURPOSE: To analyze the characteristics and prognostic values of Anaplastic Lymphoma Kinase (ALK) fusion gene partner, gene subtype and abundance in tumor tissues of advanced Non Small Cell Lung Cancer (NSCLC) patients with positive ALK fusion gene and to explore the best treatment mode of ALK-Tyrosine Kinase Inhibitors(TKIs). METHODS: Cases of advanced NSCLC patients with ALK positive confirmed by both Next Generation Sequencing (NGS) and immunohistochemistry were retrospectively collected. The relationships of Overall Survival (OS)/Progression Free Survival (PFS) between different mutation subtypes, mutation abundance, clinicopathological features were analyzed. OS/PFS between different treatment mode of ALK inhibitors were compared. RESULTS: Fifty-eight patients were enrolled. There were diverse fusion partners. Five subtypes of Echinoderm Microtubule-associated protein-Like 4 gene (EML4)-ALK fusion mutation were detected: V1,V2,V3,V5 and V7. The mutation abundance ranged from 0.13 to 27.77%, with a median of 5.34%. The abundance of V2 and V5 was higher than V1 and V3 respectively. There was no difference in OS between the low abundance group(≤ 5.34%) and the high abundance group(>5.34%) (P = 0.434). PFS of second-generation ALK inhibitors as first-line treatment was longer than that of Crizotinib as first-line (P<0.001). Never smokers had longer OS than current smokers(P = 0.001). CONCLUSIONS: There are differences in abundance between different fusion partners and subtypes in advanced NSCLC with positive ALK. OS is not associated with subtypes, mutation abundance and first line treatment option of either generation of ALK inhibitors. Smoking is a poor prognostic factor.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Estudios Retrospectivos , Crizotinib/uso terapéutico , Mutación , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
N6-methyladenosine (m6A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and Wilms' tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the underlying regulatory mechanisms remain elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3). We find that METTL3a is required for the METTL3-WTAP interaction, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is essential for the METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A deposition, and METTL3a mediates mammalian target of rapamycin (mTOR) activation via m6A-mediated suppression of TMEM127 expression. Moreover, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component of MTC, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer.
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Neoplasias de la Mama , Proteínas de Ciclo Celular , Metiltransferasas , Factores de Empalme de ARN , Humanos , Proteínas de Ciclo Celular/genética , Transformación Celular Neoplásica , Citoplasma , Metiltransferasas/genética , ARN , Factores de Empalme de ARN/genética , Neoplasias de la Mama/patología , Progresión de la EnfermedadRESUMEN
Estrogen receptor α (ERα) is an important driver and therapeutic target in approximately 70% of breast cancers. How ERα drives breast carcinogenesis is not fully understood. In this study, we show that ERα is a negative regulator of type I interferon (IFN) response, which is critical for breast carcinogenesis. Activation of ERα by its natural ligand estradiol inhibits IFN-ß-induced transcription of downstream IFN-stimulated genes (ISGs), whereas deficiency of ERα or stimulation with its antagonist fulvestrant has opposite effects. Mechanistically, ERα inhibits type I IFN response by two distinct mechanisms. ERα induces expression of the histone 2A variant H2A.Z, which restricts engagement of the IFN-stimulated gene factor 3 (ISGF3) complex at the ISG promoters. ERα also interacts with STAT2, which leads to disruption of the ISGF3 complex. These two events mutually lead to transcriptional inhibition of ISGs induced by type I IFNs. In a xenograft mouse tumor model, fulvestrant enhances the ability of IFN-ß to suppress ERα+ breast tumor growth. Consistently, clinical data suggests that ERα+ breast cancer patients with higher levels of ISGs exhibit an increased survival rate. Our findings suggest that ERα inhibits type I IFN response via two distinct mechanisms to promote breast cancer.
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Background: Gastric cancer (GC) ranks as the fifth most prevalent malignancy and the second leading cause of oncologic mortality globally. Despite staging guidelines and standard treatment protocols, significant heterogeneity exists in patient survival and response to therapy for GC. Thus, an increasing number of research have examined prognostic models recently for screening high-risk GC patients. Methods: We studied DEGs between GC tissues and adjacent non-tumor tissues in GEO and TCGA datasets. Then the candidate DEGs were further screened in TCGA cohort through univariate Cox regression analyses. Following this, LASSO regression was utilized to generate prognostic model of DEGs. We used the ROC curve, Kaplan-Meier curve, and risk score plot to evaluate the signature's performance and prognostic power. ESTIMATE, xCell, and TIDE algorithm were used to explore the relationship between the risk score and immune landscape relationship. As a final step, nomogram was developed in this study, utilizing both clinical characteristics and a prognostic model. Results: There were 3211 DEGs in TCGA, 2371 DEGs in GSE54129, 627 DEGs in GSE66229, and 329 DEGs in GSE64951 selected as candidate genes and intersected with to obtain DEGs. In total, the 208 DEGs were further screened in TCGA cohort through univariate Cox regression analyses. Following this, LASSO regression was utilized to generate prognostic model of 6 DEGs. External validation showed favorable predictive efficacy. We studied interaction between risk models, immunoscores, and immune cell infiltrate based on six-gene signature. The high-risk group exhibited significantly elevated ESTIMATE score, immunescore, and stromal score relative to low-risk group. The proportions of CD4+ memory T cells, CD8+ naive T cells, common lymphoid progenitor, plasmacytoid dentritic cell, gamma delta T cell, and B cell plasma were significantly enriched in low-risk group. According to TIDE, the TIDE scores, exclusion scores and dysfunction scores for low-risk group were lower than those for high-risk group. As a final step, nomogram was developed in this study, utilizing both clinical characteristics and a prognostic model. Conclusion: In conclusion, we discovered a 6 gene signature to forecast GC patients' OS. This risk signature proves to be a valuable clinical predictive tool for guiding clinical practice.