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The mTOR inhibitor everolimus has been approved as a sequential or second-line therapy for renal cell carcinoma (RCC). However, the development of drug resistance limits its clinical applications. This study aims to address the challenge of everolimus resistance and provide new insights into the treatment of advanced RCC. Here, the cytotoxicity of the DNA methyltransferase 1 (DNMT1) inhibitor SGI-1027 in inducing cell vacuolation and methuosis is discovered and demonstrated for the first time. Additionally, SGI-1027 exerts synergistic effects with everolimus, as their combination suppresses the growth, migration, and invasion of renal cancer cells. Mechanistically, apoptosis and GSDME-dependent pyroptosis triggered by lysosomal membrane permeability (LMP) are observed. The upregulation of GSDME expression and increased lysosomal activity in renal cancer cells provide a therapeutic window for the combination of these two drugs to treat renal cancer. The combination treatment exhibits effective anti-tumor activity and is well tolerated in a subcutaneous tumor model. Overall, this study validates and reveals the specific cytotoxicity property of SGI-1027 and its potent synergistic effect with everolimus, offering new insights into advanced RCC therapy and everolimus-resistance overcoming.
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BACKGROUND: A comprehensive understanding of the genetic basis of rare diseases and their regulatory mechanisms is essential for human molecular genetics. However, the genetic mutant spectrum of pathogenic genes within the Chinese population remains underrepresented. Here, we reported previously unreported functional ABHD12 variants in two Chinese families and explored the correlation between genetic polymorphisms and phenotypes linked to PHARC syndrome. METHODS: Participants with biallelic pathogenic ABHD12 variants were recruited from the Chinese Deafness Genetics Cohort. These participants underwent whole-genome sequencing. Subsequently, a comprehensive literature review was conducted. RESULTS: Two Han Chinese families were identified, one with a compound heterozygous variant and the other with a novel homozygous variant in ABHD12. Among 65 PHARC patients, including 62 from the literature and 3 from this study, approximately 90% (57 out of 63) exhibited hearing loss, 82% (50 out of 61) had cataracts, 82% (46 out of 56) presented with retinitis pigmentosa, 79% (42 out of 53) experienced polyneuropathy, and 63% (36 out of 57) displayed ataxia. Seventeen different patterns were observed in the five main phenotypes of PHARC syndrome. A total of 33 pathogenic variants were identified in the ABHD12. Compared with other genotypes, individuals with biallelic truncating variants showed a higher incidence of polyneuropathy (p = 0.006), but no statistically significant differences were observed in the incidence of hearing loss, ataxia, retinitis pigmentosa and cataracts. CONCLUSIONS: The diagnosis of PHARC syndrome is challenging because of its genetic heterogeneity. Therefore, exploring novel variants and establishing genotype-phenotype correlations can significantly enhance gene diagnosis and genetic counseling for this complex disease.
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Ataxia , Catarata , Estudios de Asociación Genética , Monoacilglicerol Lipasas , Linaje , Fenotipo , Polineuropatías , Retinitis Pigmentosa , Humanos , Masculino , Femenino , Ataxia/genética , Catarata/genética , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/patología , Polineuropatías/genética , Monoacilglicerol Lipasas/genética , Mutación , Adulto , Niño , Adolescente , GenotipoRESUMEN
Spent phosphor is an important secondary resource for extracting rare earth elements. Microwave absorption properties and enhanced extraction of Eu from blue phosphor by microwave alkali roasting were studied. Dielectric properties of alkali roasting system were measured by resonator perturbation method. Dielectric constant increases linearly from 250 °C until it reaches a peak at 400 °C. The dielectric loss reaches a higher value at 400-550 °C, due to the strong microwave absorption properties of molten alkali and roasted products. Effects of roasting temperature, roasting time and alkali addition amount on Eu leaching were investigated. The phosphor was completely decomposed into Eu2O3, BaCO3 and MgO at 400 °C. The alkaline decomposition process of phosphor is more consistent with diffusion control model with Eα being 28.9 kJ/mol. Effects of the main leaching conditions on Eu leaching were investigated. The leaching kinetic of Eu was in line with diffusion control model with Eα being 5.74 kJ/mol. The leaching rules of rare earths in the mixed phosphor were studied. The results showed that the presence of red and green phosphor affected the recovery of blue phosphor. The optimum process parameters of rare earth recovery in single blue phosphor and mixed phosphor were obtained, and the recovery of Eu were 97.81% and 94.80%, respectively. Microwave alkali roasting promoted the dissociation of phosphor and leaching of rare earths. The results can provide reference for the efficient and selective recovery of rare earths in phosphors.
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Álcalis , Metales de Tierras Raras , Microondas , Metales de Tierras Raras/química , Álcalis/química , Europio/química , Reciclaje , Fósforo/químicaRESUMEN
Accurate quantification of tumor growth patterns can indicate the development process of the disease. According to the important features of tumor growth rate and expansion, physicians can intervene and diagnose patients more efficiently to improve the cure rate. However, the existing longitudinal growth model can not well analyze the dependence between tumor growth pixels in the long space-time, and fail to effectively fit the nonlinear growth law of tumors. So, we propose the ConvLSTM coordinated longitudinal Transformer (LCTformer) under spatiotemporal features for tumor growth prediction. We design the Adaptive Edge Enhancement Module (AEEM) to learn static spatial features of different size tumors under time series and make the depth model more focused on tumor edge regions. In addition, we propose the Growth Prediction Module (GPM) to characterize the future growth trend of tumors. It consists of a Longitudinal Transformer and ConvLSTM. Based on the adaptive abstract features of current tumors, Longitudinal Transformer explores the dynamic growth patterns between spatiotemporal CT sequences and learns the future morphological features of tumors under the dual views of residual information and sequence motion relationship in parallel. ConvLSTM can better learn the location information of target tumors, and it complements Longitudinal Transformer to jointly predict future imaging of tumors to reduce the loss of growth information. Finally, Channel Enhancement Fusion Module (CEFM) performs the dense fusion of the generated tumor feature images in the channel and spatial dimensions and realizes accurate quantification of the whole tumor growth process. Our model has been strictly trained and tested on the NLST dataset. The average prediction accuracy can reach 88.52% (Dice score), 89.64% (Recall), and 11.06 (RMSE), which can improve the work efficiency of doctors.
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Neoplasias , Humanos , Neoplasias/diagnóstico por imagen , Aprendizaje , Factores de Tiempo , Procesamiento de Imagen Asistido por ComputadorRESUMEN
Prostate-specific antigen (PSA) test is widely used to diagnose early prostate cancer (PCa). Its low sensitivity, especially in the gray zone, usually incurs overtreatment or missed diagnosis. As an emerging tumor marker, exosomes have attracted great interest in non-invasive diagnosis of PCa. However, the quick direct detection of exosomes in serum is still a big challenge for convenient screening of early PCa due to their high-degree heterogeneity and complexity. Here we develop the label-free biosensors based on wafer-scale plasmonic metasurfaces, and establish a flexible spectral methodology of exosomes profiling, which facilitates their identification and quantification in serum. We combine the metasurfaces functionalized by anti-PSA and anti-CD63, respectively, and build a portable immunoassay system to detect serum PSA and exosomes simultaneously within 20 min. Our scheme can discriminate early PCa from benign prostatic hyperplasia with a diagnostic sensitivity of 92.3%, which is much higher that of 58.3% for conventional PSA tests. The receiver operating characteristic analysis in clinical trials demonstrates significant PCa distinguishing capability with an area under the curve up to 99.4%. Our work provides a rapid and powerful approach for precise diagnosis of early PCa, and will inspire more exosomes metasensing studies for other early cancer screening.
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Técnicas Biosensibles , Exosomas , Hiperplasia Prostática , Neoplasias de la Próstata , Masculino , Humanos , Antígeno Prostático Específico , Exosomas/patologíaRESUMEN
Due to the harsh marine environment, the communication cost of multi-ship formation is expensive, but it is often ignored in the existing research. On this basis, this paper proposes a novel distributed anti-windup neural network (NN)-sliding mode formation controller of multi-ships with minimum cost. Firstly, distributed control is applied to devise the formation controller of multi-ships because it is a promising solution for the problem of single point failure. Secondly, the Dijkstra algorithm is introduced to optimize the communication topology, and then an optimized communication topology with minimum cost is used in the distributed formation controller design. Thirdly, to alleviate the influence of input saturation, an anti-windup mechanism is devised by combining an auxiliary design system with sliding mode control and radial basis function neural network method; and then a novel distributed anti-windup neural network-sliding mode formation controller of multi-ships is obtained, which can also handle the problem of nonlinearity, model uncertainty, and time-varying disturbances of ship motion. On the strength of Lyapunov theory, the closed-loop signals are proved to be stable. Multiple comparative simulations are carried out to validate the effectiveness and advantage of the proposed distributed formation controller.
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Comparing the responses of closely related species to environmental changes is an efficient method to explore adaptive divergence, for a better understanding of the adaptive evolution of marine species under rapidly changing climates. Oysters are keystone species thrive in intertidal and estuarine areas where frequent environmental disturbance occurs including fluctuant salinity. The evolutionary divergence of two sister species of sympatric estuarine oysters, Crassostrea hongkongensis and Crassostrea ariakensis, in response to euryhaline habitats on phenotypes and gene expression, and the relative contribution of species effect, environment effect, and their interaction to the divergence were explored. After a 2-month outplanting at high- and low-salinity locations in the same estuary, the high growth rate, percent survival, and high tolerance indicated by physiological parameters suggested that the fitness of C. ariakensis was higher under high-salinity conditions and that of C. hongkongensis was higher under low-salinity conditions. Moreover, a transcriptomic analysis showed the two species exhibited differentiated transcriptional expression in high- and low-salinity habitats, largely caused by the species effect. Several of the important pathways enriched in divergent genes between species were also salinity-responsive pathways. Specifically, the pyruvate and taurine metabolism pathway and several solute carriers may contribute to the hyperosmotic adaptation of C. ariakensis, and some solute carriers may contribute to the hypoosmotic adaptation of C. hongkongensis. Our findings provide insights into the phenotypic and molecular mechanisms underlying salinity adaptation in marine mollusks, which will facilitate the assessment of the adaptive capacity of marine species in the context of climate change and will also provide practical information for marine resource conservation and aquaculture.
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Background: Invasion and metastasis led to poor prognosis and death of clear cell renal cell carcinoma (ccRCC) patients. The deoxynucleotidyl transferase terminal interacting protein 1 (DNTTIP1) was reported to promote multiple tumor progression. However, there is no research about DNTTIP1 in ccRCC. Methods: Kaplan-Meier survival analysis, multivariate analysis demonstrated the prognostic indicator in overall survival (OS) and disease-free survival (DFS) of ccRCC with DNTTIP1 expression in the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC). Receiver operator characteristic (ROC) curve analyzed diagnostic ability of DNTTIP1 in TCGA-KIRC and validation dataset. The quantitative real-time polymerase chain reaction (qRT-PCR) detected the DNTTIP1 expression in renal cancer tissues, and the Office of Cancer Clinical Proteomics Research (CPTAC) verified the protein expression of DNTTIP1. Moreover, nomogram predicted the role of DNTTIP1 in ccRCC patient. Single-sample Gene Set Enrichment Analysis (SsGSEA) and GSEA evaluated the pathogenesis role of DNTTIP1 in TCGA-KIRC. Results: DNTTIP1 expression was higher in ccRCC tumor tissues. High expression of DNTTIP1 was associated with poor OS (HR = 1.618, P < 0.0001), and poor DFS (HR = 1.789, P < 0.0001). SsGSEA and GSEA showed DNTTIP1 was associated with hypoxia, epithelial-mesenchymal transition (EMT), angiogenesis, G2M checkpoint. DNTTIP1 had a positive correlation with EMT biomarkers in ccRCC, and might be an effective target for ccRCC. Conclusion: This study provided that higher expression of DNTTIP1 predicted poor prognosis in ccRCC, and DNTTIP1 might be a novel detection biomarker and therapeutic target of tumor malignant in the future.
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The high demand and extensive exploitation of uranium resources resulted in the ubiquity and high detection levels of uranium mineral-related substances in various environment media in China. The potential adverse effects of uranium mineral-related substances on environment and human health have received extensive attention. Therefore, we reviewed the occurrence and spatial distribution of uranium mineral-related substances in various basins and environmental media in China to obtain an overall understanding. We collected information from over 70 papers reporting the occurrence and distribution of uranium mineral-related substances in multiple environments and 183 articles on the genesis of uranium deposits in China from 2001 to 2021. Then the occurrence of uranium mineral-related substances and corresponding correlation in different basins, environmental media and depth ranges were compared in detail. And this review assessed the uranium mineral-related pollution in China based on various environmental quality standards of China, EPA and WHO, and proposed the priority uranium mineral-related heavy metals and radioactive substances based on cluster analysis. This review showed that there were obvious differences in the occurrence characteristics of various uranium mineral-related substances in different environmental media, especially in the surrounding environment of sandstone type and hard rock type uranium deposits. These results will guide us to tackle the challenge of uranium mineral-related pollution in China. The correlation analysis of uranium mineral-related pollutants in different environmental media and the identification of priority pollutants will also provide instructions for us to control uranium mineral-related pollution. Finally, we put forward a series of urgent and practical suggestions on risk management and control of uranium mining according to the current situation of uranium mining environment in China, which is of guiding significance for the realization of "green uranium mining".
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Contaminantes Radiactivos del Suelo , Uranio , China , Monitoreo del Ambiente/métodos , Humanos , Minerales/análisis , Minería , Uranio/toxicidadRESUMEN
Carbothermal reduction of cathode materials is an effective method to selectively extract lithium carbonate, both mechanical activation and microwave heating can enhance thermal reduction of mixed electrode materials. However, the mechanism of enhanced lithium extraction has not been fully revealed. This study attempts to uncover the synergistic strengthening mechanisms of mechanical activation-microwave reduction from the aspects of material structure, dielectric properties, reduction kinetics and lithium recovery rate. Mechanical activation induces amorphization and structural defects. The enhanced dielectric properties of materials and the induced hotspots/arc plasmas are also responsible for the enhancement of the reduction reaction. The average dissociation activation energy in the activated sample is 18.0 kJ·mol-1, which is 20.3 kJ·mol-1 lower than that of unactivated sample. The model-free method reveals that the carbothermic reduction process can be divided into three stages: (I) initial stage (α < 0.4(0.6)): the activation energy gradually decreases with the formation of strong microwave acceptor-reduction products; (II) transitional stage (0.4(0.6) < α < 0.7): the increase in mass transfer resistance leads to gradual increase in activation energy. Mechanical activation shortens the transitional reaction stage; (III) later reaction stage (α > 0.7), the decrease in activation energy may be attributed to the enhanced microwave absorption and CO reduction. The model-fitting method reveals that after mechanical activation, the reaction kinetic changes from reaction-order model to Ginstling-Brounshtein diffusion model. The optimized lithium extraction process parameters were: activation 300 rpm for 1.5 h, reduction temperature 550 °C. The research results can provide theoretical support for the enhanced extraction of cathode materials.
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The typical microstructure of the laser melting deposition (LMD) additive-manufactured Ti-6.5Al-3.5Mo-1.5Zr-0.3Si alloy (TC11) contains the heat-affected bands (HABs), the narrow bands (NBs) and the melting pools (MPs) that formed due to the reheating and superheating effects during the layer-by-layer manufacturing process. Characterization results indicated that the coarse primary α lath (αp) and transformed ß (ßt) structures were located in the HABs, while the fine basketweave structure was formed inside the MPs. The rapid modifications of microstructure and tensile properties of the LMD-TC11 via electropulsing treatment (EPT) were investigated. The initial heterogeneous microstructure transformed into a complete basketweave structure and the HABs vanished after EPT. Thus, a more homogeneous microstructure was achieved in the EPT sample. The ultrafast microstructural changes were mainly attributed to the solid state phase transformation during electropulsing. The tensile properties of the sample were basically stable, except that the yield strength decreased as EPT voltage increased. This study suggests that EPT could be a promising method to modify the microstructure and mechanical properties of the additive-manufactured alloys in a very short time.
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East Asia has an abundant resource of fragrant japonica rice that is gaining increasing interest among both consumers and producers. However, genomic resources and in particular complete genome sequences currently available for the breeding of fragrant japonica rice are still scarce. Here, integrating Nanopore long-read sequencing, Illumina short-read sequencing, and Hi-C methods, we presented a high-quality chromosome-level genome assembly (~378.78 Mb) for a new fragrant japonica cultivar 'Changxianggeng 1813', with 31,671 predicated protein-coding genes. Based on the annotated genome sequence, we demonstrated that it was the badh2-E2 type of deletion (a 7-bp deletion in the second exon) that caused fragrance in 'Changxianggeng 1813'. Comparative genomic analyses revealed that multiple gene families involved in the abiotic stress response were expanded in the 'Changxianggeng 1813' genome, which further supported the previous finding that no generalized loss of abiotic stress tolerance associated with the fragrance phenotype. Although the 'Changxianggeng 1813' genome showed high genomic synteny with the genome of the non-fragrant japonica rice cultivar Nipponbare, a total of 289,970 single nucleotide polymorphisms (SNPs), 96,093 small insertion-deletion polymorphisms (InDels), and 8690 large structure variants (SVs, >1000 bp) were identified between them. Together, these genomic resources will be valuable for elucidating the mechanisms underlying economically important traits and have wide-ranging implications for genomics-assisted breeding in fragrant japonica rice.
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Oryza , Cromosomas , Genoma de Planta , Genómica , Odorantes , Oryza/genética , Fitomejoramiento , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors of the urinary system. Distant metastasis is the leading cause of poor prognosis in ccRCC. However, ccRCC is found poorly responsitive to radiotherapy and chemotherapy. Effective therapeutic strategies for its metastasis remain scarce. We analyzed clinical samples and public database, for differential expression of SLC27A2 and further explored its relationship with clinical prognosis. Biochemistry and functional experiments were carried out to study the potential mechanisms of SLC27A2, CDK3, and EMT. SLC27A2 was significantly downregulated in clinical specimens and renal cancer cell lines and predicted poor prognosis. We found that specific upregulation of SLC27A2 could significantly inhibited the proliferation, migration, and invasion of renal cancer cell lines. SLC27A2 could also influence the Epithelial-mesenchymal transition (EMT) signaling pathway, linked to the progression and metastasis of renal cancer. Using whole transcriptome sequencing of SLC27A2, CDK3 was identified as a regulatory SLC27A2 target. In terms of mechanism, SLC27A2 may further inhibit the epithelial-to-mesenchymal transition by negatively regulating CDK3. Our work suggests that functional inhibition of SLC27A2-CDK3-EMT axis may be an attractive therapeutic target for metastasis of ccRCC.
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In this work, nanoscale hydroxyapatite (HAP)-modified ZIF-67 composite, HAP/ZIF-67, with abundant functional groups for uranium(VI) binding was synthesized via a facile ultrasound-assisted synthesis method. The prepared HAP/ZIF-67 was characterized by XRD, SEM, TEM, BET, FT-IR and XPS techniques, and was applied to eliminate uranium(VI) from aqueous solutions under various conditions, i.e., pH, coexisting ions, temperature and contact time. The results indicate that the abundant Co-OH, -CN- and -NH- binding groups originating from the ZIF-67 and the Ca-OH and PO43- derived from loaded nanoscale HAP synergistically endowed HAP/ZIF-67 with the excellent U(VI) adsorption capacity of 453.1 mg/g, which is 2.55 and 1.78 times that of pristine HAP and ZIF-67. HAP/ZIF-67 showed high adsorption selectivity toward U(VI), and the U(VI) elimination efficiency for real wastewater by HAP/ZIF-67 reached 97.29%. The adsorption kinetics and isotherms were well simulated by the pseudo-second-order model and Langmuir isotherm model, respectively, suggesting that U(VI) adsorption was an endothermic monolayer chemisorption process. The adsorption mechanism of U (VI) by HAP/ZIF-67 was dominated by surface complexation process. This work is expected to provide an effective strategy for developing HAP-modified MOFs absorbent to be used for the highly efficient elimination of radionuclides from wastewater.
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Uranio , Adsorción , Durapatita , Cinética , Espectroscopía Infrarroja por Transformada de Fourier , Aguas ResidualesRESUMEN
Lysophosphatidylcholine (LPC), as the main active component of oxidized low-density lipoproteins (ox-LDLs), has significant effects in cerebrovascular disease. However, the complex mechanism by which LPC functions in brain microvascular endothelial cells (BMECs) is not clearly understood. In this study, BMECs were transfected with G protein-coupled receptor 4 (GPR4) siRNA or an NLRP3-overexpression plasmid, and GPR4 expression was identified by RT-qPCR and western blotting; IL-1ß, IL-18, and IL-33 levels were evaluated by ELISA. Apoptosis was monitored by flow cytometry and Hoechst staining, while Caspase 3, ASC, NLRP3, and GPR4 protein expression were examined by western blotting. Our results showed that LPC significantly increased the levels of inflammatory cytokines (IL-1ß, IL-18, and IL-33) and markedly induced apoptosis and NLRP3 inflammasome activation in BMECs. Moreover, LPC notably upregulated GPR4 in BMECs, and knockdown of GPR4 significantly attenuated the effects of LPC in BMECs. Above all, we also proved that LPC induced apoptosis and inflammatory injury in BMECs by causing GPR4 to activate NLRP3 inflammasomes. Therefore, GPR4-mediated activation of NLRP3 inflammasomes might be the underlying mechanism by which LPC promotes the progression of cerebrovascular disease. In summary we found that LPC is an important pathogenic factor in cerebrovascular disease, and can induce GPR4 to active NLRP3 inflammasomes.
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Apoptosis/efectos de los fármacos , Encéfalo/irrigación sanguínea , Endotelio Vascular/efectos de los fármacos , Inflamasomas/efectos de los fármacos , Lisofosfatidilcolinas/farmacología , Microvasos/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Receptores Acoplados a Proteínas G/metabolismo , Encéfalo/efectos de los fármacos , Línea Celular , HumanosRESUMEN
The effect of preoperative Double-J (DJ) ureteral stenting before flexible ureterorenoscopy (FURS) in the treatment for urinary stones was evaluated. We retrospectively enrolled 306 consecutive patients who underwent FURS from Jan. 2014 to Dec. 2017. All the patients were classified into two groups according to whether they had DJ ureteral stenting before FURS. Baseline characteristics (age, sex, stone location, stone size, surgical success rate, operation time, stone-free rate of the first day after surgery, stone-free rate of the first month after surgery, total complication rate) were compared using Chi-square test for categorical variables and Kruskal-Wallis test for continuous variables. In total, 306 patients were included in this study. The group of DJ stenting before FURS included 203 (66.3%) patients, and non-DJ stenting before FURS was observed in 103 (33.7%) patients. The group of DJ stenting before FURS was significantly associated with a shorter operation time (53.8 vs. 59.3 min, P<0.001), a higher stone-free rate of the first day after surgery (69.0% vs. 51.5%, P=0.003). However, statistical significant differences were not found in the age, sex, stone location, stone size, surgical success rate, stone-free rate of the first month after surgery (89.2% vs. 81.6%, P=0.065) and total complication rate (5.4% vs. 9.7%, P=0.161) between the two groups. Preoperative DJ ureteral stenting before FURS could reduce the operation time and increase stone-free rate of the first day after surgery. However, it might not benefit the stone-free rate of the first month after surgery and reduce the complication rate. Preoperative DJ stenting should be not routinely performed.
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Complicaciones Posoperatorias/epidemiología , Ureteroscopía/métodos , Cálculos Urinarios/cirugía , Cateterismo Urinario/métodos , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Periodo Preoperatorio , Ureteroscopía/efectos adversos , Cateterismo Urinario/efectos adversos , Cateterismo Urinario/instrumentación , Catéteres Urinarios/efectos adversos , Catéteres Urinarios/normasRESUMEN
Invasion and metastasis are the main causes of poor prognosis in patients with clear cell renal cell carcinoma (ccRCC). The homeodomain interacting protein kinases (HIPKs) can regulate cell proliferation and apoptosis. Little is known about the prognostic role of HIPKs in ccRCC. Here we use Kaplan-Meier survival analysis and multivariate analysis to analyze the correlation of overall survival (OS) and disease-free survival (DFS). ROC curves analyzed the relationship between clinicopathological parameters and HIPK3 expression in ccRCC. Univariate analysis and multivariate analysis confirmed that the expression of HIPK3 was associated with OS (HR, 0.701; P=0.041) and DFS (HR, 0.630; P=0.012). Low HIPK3 expression was a poor prognostic factor and HIPK3 expression was significantly down-regulated in ccRCC cancer tissues when compared with normal renal tissues. In vitro cell results also confirmed that HIPK3 over-expression could inhibit tumor growth and malignant characteristics. The results indicate that low expression of HIPK3 in ccRCC tissues is significantly associated with poor survival rates in tumor patients, and HIPK3 may be used as a valuable biomarker and inhibitor of ccRCC.
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Carcinoma de Células Renales/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Renales/genética , Proteínas Serina-Treonina Quinasas/genética , Apoptosis/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular/genética , Supervivencia sin Enfermedad , Regulación hacia Abajo , Femenino , Técnicas de Sustitución del Gen , Humanos , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Estimación de Kaplan-Meier , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Proteínas Serina-Treonina Quinasas/metabolismo , Tasa de SupervivenciaRESUMEN
Inflammation status are especially for tumor growth, and microRNAs (miRNAs) confirmed to participate in cancer occurrence and progression. However, the role of miR-483-5p and the relation with inflammation have not been elucidated in renal cell cancer (RCC). In this study, we intended to explore miR-483-5p expression and the relationship of inflammation status in clear cell renal cell cancer (ccRCC). Using microarray and qRT-PCR (Quantitative Real-time Polymerase Chain Reaction), we investigated the miR-483-5p expression in plasma and ccRCC cancer tissues. Then, we analyzed the correlation of miR-483-5p with clinicopathological parameters and inflammation status in ccRCC. Receiver operator characteristic (ROC) curves analysis was used to analyze the discrimination efficiency of miR-483-5p. in vitro experiments explored the biological role of miR-483-5p in renal cancer cells. miR-483-5p expression was upregulated in plasma of 5 patients with microarray and 12 patients with qRT-PCR in ccRCC at day 7 postoperatively. In addition, low expression of miR-483-5p was found in 58 ccRCC cancer tissues when compared with non-cancerous tissues. miR-483-5p could sufficiently discriminate ccRCC with the area under the curve (AUC) of 0.739 (P < .0001) from normal tissues. Higher expression of miR-483-5p was positively related to lower tumor stage and higher relative expression of miR-483-5p was inversely related to neutrophil-to-lymphocyte ratio (NLR) (P = .03) and lymphocyte-to-monocyte ratio (LMR) (P = .026). Overexpression of miR-483-5p lead to reverse epithelial-mesenchymal transition (EMT) process, restrain cell proliferation and metastasis of renal cancer cells. Our findings suggest that miR-483-5p expression is negatively correlation with inflammation status and may be a potential plasma biomarker for ccRCC.
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Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Regulación hacia Abajo/genética , Inflamación/genética , Neoplasias Renales/genética , Neoplasias Renales/patología , MicroARNs/genética , Carcinoma de Células Renales/sangre , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/sangre , MicroARNs/sangre , Estadificación de Neoplasias , Nefrectomía , Regulación hacia Arriba/genéticaRESUMEN
PURPOSE: Prostate cancer (PCa) is the third most common cancer in men and the second leading cause of cancer-related death in men. DLX1 belongs to the DLX homeobox family and exhibits antitumor activity in many kinds of tumors. MicroRNAs (miRNAs) play important roles in the progression of cancer. However, whether miRNAs affect the development of PCa by targeting DLX1 has not been determined. In this study, we aimed to investigate the role of miR-489-3p in the regulation of DLX1 expression and PCa progression and to provide a potential therapeutic target for PCa treatment. METHODS AND MATERIALS: The Cancer Genome Atlas database was used to analyze the divergent expression of DLX1 in carcinomas and adjacent normal tissues. The expression level of DLX1 in malignant and normal prostate cells was also measured using RT-qPCR and Western blotting. A dual-luciferase reporter assay was performed to determine whether miR-489-3p directly targets DLX1. We transfected 22Rv1 and DU145 cells with miR-489-3p mimics to overexpress miR-489-3p and then evaluated its effect on cellular function. MTT, EdU, colony formation and cell cycle assays were used to evaluate cell growth. JC-1 and ROS assays with flow cytometry were performed to indirectly analyze apoptosis. Transwell assays were conducted to investigate metastasis. RESULTS: The expression level of DLX1 was upregulated in both PCa tissues and cell lines. MiR-489-3p directly targeted DLX1 and downregulated its expression. Overexpression of miR-489-3p significantly suppressed cell growth. MiR-489-3p induced apoptosis through mitochondrial function impairment. Overexpression of miR-489-3p also inhibited cell migration and invasion. DLX1 overexpression reversed the above effects induced by miR-489-3p. CONCLUSION: We identified the involvement of the miR-489-3p/DLX1 pathway in PCa for the first time. In this pathway, miR-489-3p acts as a tumor suppressor by negatively regulating the expression of DLX1. MiR-489-3p may be a potential therapeutic target for PCa treatment.