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Repetitive elements (REs) compose â¼50% of the human genome and are normally transcriptionally silenced, although the mechanism has remained elusive. Through an RNAi screen, we identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound H3K9me3-modified nucleosomes at the replication fork and recruited SUV39H1, CRL4, and Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition reactivated REs, leading to DNA replication stress and stimulation of MAVS/STING antiviral pathways and interferon (IFN) signaling in cancer cells to promote decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response. FBXO44 expression inversely correlated with replication stress, antiviral pathways, IFN signaling, and cytotoxic T cell infiltration in human cancers, while a FBXO44-immune gene signature correlated with improved immunotherapy response in cancer patients. FBXO44/SUV39H1 were dispensable in normal cells. Collectively, FBXO44/SUV39H1 are crucial repressors of RE transcription, and their inhibition selectively induces DNA replication stress and viral mimicry in cancer cells.
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Replicación del ADN/genética , Proteínas F-Box/metabolismo , Neoplasias/genética , Secuencias Repetitivas de Ácidos Nucleicos/genética , Adulto , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Roturas del ADN de Doble Cadena , Resistencia a Antineoplásicos , Femenino , Regulación Neoplásica de la Expresión Génica , Histonas/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunidad , Interferones/metabolismo , Lisina/metabolismo , Masculino , Metilación , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Neoplasias/inmunología , Nucleosomas/metabolismo , Transducción de Señal , Transcripción Genética , Resultado del TratamientoRESUMEN
A mesenchymal tumor phenotype associates with immunotherapy resistance, although the mechanism is unclear. Here, we identified FBXO7 as a maintenance regulator of mesenchymal and immune evasion phenotypes of cancer cells. FBXO7 bound and stabilized SIX1 co-transcriptional regulator EYA2, stimulating mesenchymal gene expression and suppressing IFNα/ß, chemokines CXCL9/10, and antigen presentation machinery, driven by AXL extracellular ligand GAS6. Ubiquitin ligase SCFFBXW7 antagonized this pathway by promoting EYA2 degradation. Targeting EYA2 Tyr phosphatase activity decreased mesenchymal phenotypes and enhanced cancer cell immunogenicity, resulting in attenuated tumor growth and metastasis, increased infiltration of cytotoxic T and NK cells, and enhanced anti-PD-1 therapy response in mouse tumor models. FBXO7 expression correlated with mesenchymal and immune-suppressive signatures in patients with cancer. An FBXO7-immune gene signature predicted immunotherapy responses. Collectively, the FBXO7/EYA2-SCFFBXW7 axis maintains mesenchymal and immune evasion phenotypes of cancer cells, providing rationale to evaluate FBXO7/EYA2 inhibitors in combination with immune-based therapies to enhance onco-immunotherapy responses.
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Proteínas F-Box , Proteína 7 que Contiene Repeticiones F-Box-WD , Neoplasias , Animales , Línea Celular Tumoral , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Proteínas de Homeodominio/genética , Humanos , Evasión Inmune , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Neoplasias/genética , Proteínas Nucleares/metabolismo , Fenotipo , Proteínas Tirosina Fosfatasas/genética , Ubiquitina/metabolismoRESUMEN
Glioblastoma (GBM) ranks among the most lethal of human malignancies with GBM stem cells (GSCs) that contribute to tumor growth and therapeutic resistance. Identification and isolation of GSCs continue to be a challenge, as definitive methods to purify these cells for study or targeting are lacking. Here, we leveraged orthogonal in vitro and in vivo phage display biopanning strategies to isolate a single peptide with GSC-specific binding properties. In silico analysis of this peptide led to the isolation of EYA1 (Eyes Absent 1), a tyrosine phosphatase and transcriptional coactivator. Validating the phage discovery methods, EYA1 was preferentially expressed in GSCs compared to differentiated tumor progeny. MYC is a central mediator of GSC maintenance but has been resistant to direct targeting strategies. Based on correlation and colocalization of EYA1 and MYC, we interrogated a possible interaction, revealing binding of EYA1 to MYC and loss of MYC expression upon targeting EYA1. Supporting a functional role for EYA1, targeting EYA1 expression decreased GSC proliferation, migration, and self-renewal in vitro and tumor growth in vivo. Collectively, our results suggest that phage display can identify novel therapeutic targets in stem-like tumor cells and that an EYA1-MYC axis represents a potential therapeutic paradigm for GBM.
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Bacteriófagos , Neoplasias Encefálicas , Glioblastoma , Bacteriófagos/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular , Glioblastoma/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Células Madre Neoplásicas/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/metabolismoRESUMEN
Lung cancer is the leading cause of cancer-related death globally, with non-small-cell lung cancer (NSCLC) being the predominant subtype. Overall survival remains low for NSCLC patients, and novel targets are needed to improve outcome. Raf-1 is a key component of the Ras/Raf/MEK signalling pathway, but its role and downstream targets in NSCLC are not completely understood. Our previous study indicated a possible correlation between Raf-1 levels and ribosomal protein S6 kinase (p70S6K) function. In this study, we aimed to investigate whether p70S6K is a downstream target of Raf-1 in NSCLC. Raf-1 was silenced in NSCLC cell lines by using small hairpin RNA, and Raf-1 and p70S6K protein levels were measured via Western blot. p70S6K was then overexpressed following Raf-1 knock-down; then, cell proliferation, apoptosis and the cell cycle in NSCLC cell lines were examined. Tumour xenografts with NSCLC cells were then transplanted for in vivo study. Tumours were measured and weighed, and Raf-1 and p70S6K expression, cell proliferation and apoptosis were examined in tumour tissues by Western blot, Ki-67 staining and TUNEL staining, respectively. When Raf-1 was silenced, p70S6K protein levels were markedly decreased in the A549 and H1299 NSCLC cell lines. A significant decrease in NSCLC cell proliferation, a profound increase in apoptosis and cell cycle arrest were observed in vitro following Raf-1 knock-down. Overexpression of p70S6K after Raf-1 depletion effectively reversed these effects. Xenograft studies confirmed these results in vivo. In conclusion, Raf-1 targets p70S6K as its downstream effector to regulate NSCLC tumorigenicity, making Raf-1/p70S6K signalling a promising target for NSCLC treatment.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogénicas c-raf/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal , Animales , Apoptosis , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Neoplasias Pulmonares/patología , Ratones Desnudos , Modelos BiológicosRESUMEN
BACKGROUND & AIMS: AT-rich interaction domain 1a (Arid1a), a component of the chromatin remodeling complex, has emerged as a tumor suppressor gene. It is frequently mutated in hepatocellular carcinoma (HCC). However, it remains unknown how Arid1a suppresses HCC development and whether Arid1a deficiency could be exploited for therapy, we aimed to explore these questions. METHODS: The expression of Arid1a in human and mouse HCCs was determined by immunohistochemical (IHC) staining. Gene expression was determined by quantitative PCR, ELISA or western blotting. Arid1a knockdown HCC cell lines were established by lentiviral-based shRNA. Tumor angiogenesis was quantified based on vessel density. The regulation of angiopoietin (Ang2) expression by Arid1a was identified by chromatin immunoprecipitation (ChIP) assay. The tumor promoting function of Arid1a loss was studied with a xenograft model in nude mice and diethylnitrosamine (DEN)-induced HCC in Arid1a conditional knockout mice. The therapeutic values of Ang2 antibody and sorafenib treatment were evaluated both in vitro and in vivo. RESULTS: We demonstrate that Arid1a deficiency, occurring in advanced human HCCs, is associated with increased vessel density. Mechanistically, loss of Arid1a causes aberrant histone H3K27ac deposition at the angiopoietin-2 (Ang2) enhancer and promoter, which eventually leads to ectopic expression of Ang2 and promotes HCC development. Ang2 blockade in Arid1a-deficient HCCs significantly reduces vessel density and tumor progression. Importantly, sorafenib treatment, which suppresses H3K27 acetylation and Ang2 expression, profoundly halts the progression of Arid1a-deficient HCCs. CONCLUSIONS: Arid1a-deficiency activates Ang2-dependent angiogenesis and promotes HCC progression. Loss of Arid1a in HCCs confers sensitivity to Ang2 blockade and sorafenib treatment. LAY SUMMARY: AT-rich interaction domain 1a (Arid1a), is a tumor suppressor gene. Arid1a-deficiency promotes Ang2-dependent angiogenesis leading to hepatocellular carcinoma progression. Arid1a-deficiency also sensitizes tumors to Ang2 blockade by sorafenib treatment.
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Inhibidores de la Angiogénesis/farmacología , Angiopoyetina 2/metabolismo , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neovascularización Patológica/tratamiento farmacológico , Proteínas Nucleares , Sorafenib/farmacología , Factores de Transcripción , Animales , Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/metabolismo , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Estadificación de Neoplasias , Proteínas Nucleares/deficiencia , Proteínas Nucleares/metabolismo , Factores de Transcripción/deficiencia , Factores de Transcripción/metabolismoRESUMEN
Length of hospital stay (LOS) of asthma can be a reflection of the disease burden faced by patients, and it is also sensitive to air pollution. This study aims at estimating and validating the effects of air pollution and readmission on the LOS for those who have asthma, considering their readmission history, minimum temperature, and threshold effects of air pollutants. In addition, sex, age, and season were also constructed for stratification to achieve more precise and specific results. The results show that no significant effects of PM2.5 and NO2 on LOS were observed in any of the patients, but there were significant effects of PM2.5 and NO2 on LOS when a stratifying subgroup analysis was performed. The effect of PM10 on LOS was found to be lower than that of PM2.5 and higher than that of NO2 . SO2 did not have a significant effect on LOS for patients with asthma in our study. Our study confirmed that the adverse effects of air pollutants (such as PM10 ) on LOS for patients with asthma existed; in addition, these effects vary for different stratifications. We measured the effects of air pollutants on the LOS for patients with asthma, and this study offers policy makers quantitative evidence that can support relevant policies for health care resource management and ambient air pollutants control.
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OBJECTIVE: This study aimed to determine whether a search index could provide insight into trends in asthma admission in China. An Internet search index is a powerful tool to monitor and predict epidemic outbreaks. However, whether using an internet search index can significantly improve asthma admissions forecasts remains unknown. The long-term goal is to develop a surveillance system to help early detection and interventions for asthma and to avoid asthma health care resource shortages in advance. METHODS: In this study, we used a search index combined with air pollution data, weather data, and historical admissions data to forecast asthma admissions using machine learning. RESULTS: Results demonstrated that the best area under the curve in the test set that can be achieved is 0.832, using all predictors mentioned earlier. CONCLUSION: A search index is a powerful predictor in asthma admissions forecast, and a recent search index can reflect current asthma admissions with a lag-effect to a certain extent. The addition of a real-time, easily accessible search index improves forecasting capabilities and demonstrates the predictive potential of search index.
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BACKGROUND: The roles of carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA21-1) and neuron-specific enolase (NSE) in metastases occurrence and poor diagnosis in specific histological classifications of lung cancer need further exploring. In this study, we investigated relationship between elevated levels of three biomarkers of CEA, CYFRA21-1 and NSE (individually and in combination) and metastasis, survival status and prognosis in lung cancer patients. METHODS: Eight hundred and sixty eight lung cancer patients including adenocarcinoma (ADC, N = 445), squamous cell carcinoma (SCC, N = 215), small cell lung cancer (SCLC, N = 159) and other types (N = 49) were categorized into negative, moderate and high groups according to serum levels of biomarkers, and were then categorized into negative, single, double and triple groups according to any positive combination of three biomarkers. The cutoff values of three biomarkers for groupings were developed on the training group (N = 432) and verified in a validation group (N = 436). Clinical and laboratory characteristics were then assessed for correlation with occurrence of metastasis, survival status and prognosis between the two groups. Further correlation analyses were also conducted by different subtypes (ADC, SCC and SCLC) and tumor stages (I + II, III and IV) of lung cancers. RESULTS: The consistent results between training and validation group confirmed the rationality of grouping methods. CYFRA21-1 levels had stronger association with metastases and survival status than CEA and NSE in all lung cancer patients. When stratified by subtypes, these significances only existed in ADC patients for CYFRA21-1. Cox regression analyses showed that CYFRA21-1 and NSE were independent prognostic factors for lung cancer patients. However, only CYFRA21-1 was an independent prognostic factor in ADC and SCLC patients subtypes. Cox-regression results also indicated that CYFRA21-1 could act as independent prognostic factor in different stages (I + II, III and IV) of lung cancer. CONCLUSION: CYFRA21-1 was more important in metastasis occurrence and in predicting poor prognosis in lung cancer patients than CEA, NSE and positive numbers of biomarkers.
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Antígenos de Neoplasias/sangre , Antígeno Carcinoembrionario/sangre , Queratina-19/sangre , Neoplasias Pulmonares/diagnóstico , Fosfopiruvato Hidratasa/sangre , Biomarcadores de Tumor/sangre , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/clasificación , Masculino , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
The extracellular-regulated kinase (ERK) 1/2, as a member of the mitogen-activated protein kinase family, plays a crucial role in the development of cancer. However, little is known about the prognostic value of ERK1/2 and phosphorylated ERK1/2 (p-ERK1/2) in non-small cell lung cancer (NSCLC). Thus, we investigated their prognostic values and analyzed the associations between their expressions and clinicopathological features in NSCLC patients. We examined ERK1/2 and p-ERK1/2 expressions via immunohistochemistry in 183 NSCLC samples. The prognostic significances of protein expression were evaluated with univariate and multivariate survival analysis. Of the specimens, 44.8 and 44.3 % revealed positive staining for ERK1/2 and p-ERK1/2, respectively. There were 24.6 % specimens with both ERK1/2 and p-ERK1/2-positive expression. The results showed p-ERK1/2-positive expression was an independent prognostic factor for poor overall survival (OS) in NSCLC patients on both univariate analysis (p < 0.0001) and multivariate analysis (p = 0.0000). Meanwhile, the positive expression of both proteins was also associated with poor OS (p = 0.002). With respect to clinicopathological features, the tumor differentiation was significantly associated with the positivity of ERK1/2, p-ERK1/2, and both proteins, while histological type was only related to ERK1/2. However, there were no significant differences between the expressions and other clinical features, such as gender, age, smoking, tumor-node-metastasis (TNM) stage, lymph node metastasis, and treatments. The p-ERK1/2-positive expression was associated with adverse outcomes, and the positive expression of both ERK1/2 and p-ERK1/2 proteins was also related to poor OS. Therefore, the positivity of p-ERK1/2 expression may serve as a vital biomarker in the development of NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Proteína Quinasa 3 Activada por Mitógenos/biosíntesis , Pronóstico , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Persona de Mediana Edad , Proteína Quinasa 3 Activada por Mitógenos/genética , Estadificación de Neoplasias , FosforilaciónRESUMEN
BACKGROUND: Genetic alterations could be responsible lung cancer, the leading cause of worldwide cancer death. METHODS: This study investigated gene mutations in a Han Chinese family of lung cancer using the whole genome exome sequencing and subsequent Sanger sequencing validation and then confirmed alteration of prominin 1(PROM1) and cyclic AMP-response element binding protein-regulated transcription co-activator2 (CRTC2) in blood samples of 343 sporadic lung cancer patients vs. 280 healthy controls as well as in 200 pairs of lung cancer and the corresponding normal tissues using PCR-restriction fragment length polymorphism and directed DNA sequencing of PCR products. RESULTS: The data showed PROM1 (p. S281R) and CRTC2 (p. R379C) mutations, in 5 and 2 cases of these 343 sporadic lung cancer patients, respectively. Notably, these mutations were absent in the healthy controls. Furthermore, in the 200 lung cancer and the matched normal tissues, PROM1 mutation occurred in 3 patients (i.e., one squamous cell carcinoma and two adenocarcinomas) with a mutation frequency of 1.5%, while CRTC2 mutation occurred in 5 patients (two squamous cell carcinomas and three adenocarcinomas) with a mutation frequency of 2.5%. CONCLUSIONS: The data from the current study demonstrated novel PROM1 and CRTC2 mutations, which could promote lung cancer development.
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Antígenos CD/genética , Carcinoma de Células Escamosas/genética , Glicoproteínas/genética , Neoplasias Pulmonares/genética , Péptidos/genética , Factores de Transcripción/genética , Antígeno AC133 , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Carcinoma de Células Escamosas/patología , Exoma/genética , Femenino , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
Accumulating evidence supports that genetic factors are another risk factors for lung cancer. Previously, we used whole exome sequencing with sanger sequencing to search for genetic-related mutations in one of four individuals from a pedigree with lung cancer history. Then, we used PCR-RFLP and direct-sequence in the sample size of 318 individuals with lung cancer (cases) and 272 controls. Recently, we detected two new genes including CRTC2 (CREB regulated transcription coactivator 2) and PROM1(human prominin-1,CD133). We investigated the CRTC2 mutation and PROM1 mutation of surgically resected NSCLC tissues (n=200). The presence or absence of CRTC2 and PROM1 mutation was analyzed by direct sequencing. The expression of CRTC2 and PROM1 was studied by western blot and immunohistochemical analysis of the lung cancer tissues which had the mutation of the two genes(cases), the samples without mutations(controls) and the normal lung tissue(controls). CRTC2 and PROM1 mutations in 5 NSCLC tissues and 3 NSCLC tissues out of the samples were identified. The positive results were closely correlated with clinicopathological features, such as male gender, adenocarcinoma, smoker status, and older age (≥55). We found that the CRTC2 and PROM1 expression were significantly higher in tissues of NSCLS with mutations than that without mutations and the normal lung tissue. The results imply that the high expression of CRTC2 and PROM1 may play an important role in the development and hereditary of NSCLC.
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Antígenos CD/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Glicoproteínas/metabolismo , Neoplasias Pulmonares/metabolismo , Péptidos/metabolismo , Factores de Transcripción/metabolismo , Antígeno AC133 , Anciano , Antígenos CD/genética , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Análisis Mutacional de ADN , Femenino , Expresión Génica , Glicoproteínas/genética , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Estadificación de Neoplasias , Péptidos/genética , Factores de Riesgo , Factores de Transcripción/genéticaRESUMEN
Long noncoding RNAs (lncRNAs) have been demonstrated to participate in neuroblastoma cisplatin resistance and tumorigenesis. LncRNA LINC00460 was previously reported to play a critical regulatory role in many cancer development. Nevertheless, its role in modulating neuroblastoma cisplatin resistance has not been explored till now. Cisplatin-resistant neuroblastoma cell lines were established by exposing neuroblastoma cell lines to progressively increasing concentrations of cisplatin for 6 months. LINC00460, microRNA (miR)-149-5p, and delta-like ligand 1 (DLL1) mRNA expression was measured through RT-qPCR. The protein levels of DLL1, epithelial-to-mesenchymal transition (EMT) markers, and the Notch signaling-related molecules were measured via western blotting. The IC50 value for cisplatin, cell growth, metastasis and apoptosis were analyzed in cisplatin-resistant neuroblastoma cells. The binding between LINC00460 (or DLL1) and miR-149-5p was validated through dual-luciferase reporter assay. The murine xenograft model was established to perform in vivo assays. LINC00460 and DLL1 levels were elevated, while miR-149-5p level was reduced in cisplatin-resistant neuroblastoma cells. LINC00460 depletion attenuated IC50 values for cisplatin, weakened cell growth, metastasis, and EMT, and enhanced apoptosis in cisplatin-resistant neuroblastoma cells. Mechanically, LINC00460 sponged miR-338-3p to increase DLL1 level, thereby activating Notch signaling pathway. DLL1 overexpression antagonized LINC00460 silencing-induced suppression on neuroblastoma cell cisplatin resistance and malignant behaviors, while such effects were further reversed by treatment with DAPT, the inhibitor of Notch pathway. Additionally, LINC00460 knockdown further augmented cisplatin-induced impairment on tumor growth in vivo. LINC00460 contributes to neuroblastoma cisplatin resistance and tumorigenesis through miR-149-5p/DLL1/Notch pathway, providing new directions to improve the therapeutic efficacy of chemotherapy drugs applied in patients with neuroblastoma.
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Proteínas de Unión al Calcio , Cisplatino , Resistencia a Antineoplásicos , MicroARNs , Neuroblastoma , ARN Largo no Codificante , Receptores Notch , Transducción de Señal , Cisplatino/farmacología , MicroARNs/genética , Neuroblastoma/genética , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/metabolismo , Humanos , Animales , Resistencia a Antineoplásicos/efectos de los fármacos , ARN Largo no Codificante/genética , Línea Celular Tumoral , Receptores Notch/metabolismo , Receptores Notch/genética , Transducción de Señal/efectos de los fármacos , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Ratones , Ratones Desnudos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Proliferación Celular/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones Endogámicos BALB CRESUMEN
Urethral stricture (US) is a challenging problem in urology and its pathogenesis of US is closely related to the fibrotic process. Previous evidence has indicated the downregulation of microRNA (miR)-486 in injured urethral specimens of rats. This study aimed to explore the effects of miR-486-overexpressed bone marrow mesenchymal stem cells (BMSCs) on US. BMSCs were identified by detecting their multipotency and surface antigens. Lentivirus virus expressing miR-486 was transduced into rat BMSCs to overexpress miR-486. Transforming growth factor (TGF)-ß1 induced fibrotic phenotypes in urethral fibroblasts (UFs) and rat models. Western blotting showed protein levels of collagen I/III and collagen type XIII alpha 1 chain (Col13a1). Real time quantitative polymerase chain reaction was utilized for messenger RNA level evaluation. Hematoxylin-eosin, Masson's trichrome, and Von Willebrand Factor staining were conducted for histopathological analysis. Immunofluorescence staining was employed for detecting alpha smooth muscle actin (α-SMA) expression. Luciferase reporter assay verified the interaction between miR-486 and Col13a1. The results showed that miR-486-overexpressed BMSCs suppressed collagen I/III and α-SMA expression in TGF-ß1-stimulated UFs. miR-486-overexpressed BMSCs alleviated urethral fibrosis, collagen deposition, and epithelial injury in the urethral tissue of US rats. miR-486 targeted and negatively regulated Col13a1 in US rats. In conclusion, overexpression of miR-486 in BMSCs targets Col13a1 and attenuates urethral fibrosis in TGF-ß1-triggered UFs and US rats.
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Glioblastoma is the most lethal primary brain tumor with glioblastoma stem cells (GSCs) atop a cellular hierarchy. GSCs often reside in a perivascular niche, where they receive maintenance cues from endothelial cells, but the role of heterogeneous endothelial cell populations remains unresolved. Here, we show that lymphatic endothelial-like cells (LECs), while previously unrecognized in brain parenchyma, are present in glioblastomas and promote growth of CCR7-positive GSCs through CCL21 secretion. Disruption of CCL21-CCR7 paracrine communication between LECs and GSCs inhibited GSC proliferation and growth. LEC-derived CCL21 induced KAT5-mediated acetylation of HMGCS1 on K273 in GSCs to enhance HMGCS1 protein stability. HMGCS1 promoted cholesterol synthesis in GSCs, favorable for tumor growth. Expression of the CCL21-CCR7 axis correlated with KAT5 expression and HMGCS1K273 acetylation in glioblastoma specimens, informing patient outcome. Collectively, glioblastomas contain previously unrecognized LECs that promote the molecular crosstalk between endothelial and tumor cells, offering potentially alternative therapeutic strategies.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/terapia , Citocinas/metabolismo , Células Endoteliales/metabolismo , Receptores CCR7/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proliferación Celular , Colesterol/metabolismoRESUMEN
BACKGROUND: Early stage lung adenocarcinomas manifested as ground-glass nodules (GGNs) are increasingly being detected, but screening and diagnosis for GGN-featured lung adenocarcinomas in different risk populations reach no agreement. OBJECTIVES: To analyze the clinical, pathological, imaging and genetic features of GGN-featured lung adenocarcinomas on high-resolution computed tomography (HRCT) in different risk groups. METHODS: Include patients with GGNs on HRCT surgically diagnosed as lung adenocarcinoma in the West China Hospital, Sichuan University from 2009 to 2021, and their clinical, pathological, imaging and gene sequencing data. RESULTS: According to Chinese Expert Consensus on Screening and Management of Lung Cancer, 1,800 patients with GGN-featured lung adenocarcinoma, 545 males (incl. 269 smokers) and 1,255 females (incl. 16 smokers), were divided into high-risk (509) and non-high-risk (1,291) groups. Among them, 1,095 were detected via physical examination. The mean age at diagnosis was 54.78 (23-84) and the mean time from detection to diagnosis was 9.59 months. There were more males than females in the high-risk group [288 (56.58%) vs 221 (43.42%)], just the opposite in the non-high-risk group [1,034 (80.09%) vs 257 (19.91%)] (both P < 0.001). No statistical difference was found in GGN detection way (P > 0.05). The frequency of invasive adenocarcinoma was higher in the high-risk group, while those of precursor lesions and minimally invasive adenocarcinoma were higher in the non-high-risk group (all P < 0.001). The preoperative follow-up time in the non-high-risk group was shorter (P < 0.05). A total of 711 gene mutations were observed in 473 patients with a ratio of non-high-risk to high-risk of 494:217. The incidence of EGFR mutation was not statistically significant (P = 0.824), while those of TP53 and KRAS mutations were higher in the high-risk group (P < 0.05). CONCLUSIONS: GGN-featured lung adenocarcinoma is dominated by non-high-risk female patients. Shorter preoperative follow-up in the non-high-risk group and no statistical difference in GGN detection way suggests the existing screening criteria for high-risk population may not suit GGN-featured lung cancer. In addition, the incidences of KRAS and TP53 mutations are higher in the high-risk group.
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Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Masculino , Humanos , Femenino , Proteínas Proto-Oncogénicas p21(ras) , Adenocarcinoma del Pulmón/diagnóstico por imagen , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/genética , Adenocarcinoma/patología , Tomografía Computarizada por Rayos X/métodos , Estudios RetrospectivosRESUMEN
Crystallographically, noncentrosymmetricity (NCS) is an essential precondition and foundation of achieving nonlinear optical (NLO), pyroelectric, ferroelectric, and piezoelectric materials. Herein, structurally, octahedral [SmCl6]3- is substituted by the acentric tetrahedral polyanion [CdBr4]2-, which is employed as a templating agent to induce centrosymmetric (CS)-to-NCS transformation based on the new CS supramolecule [Cd5P2][SmCl6]Cl (1), thereby providing the NCS supramolecule [Cd4P2][CdBr4] (2). Meanwhile, this replacement further results in the host 2D ∞2[Cd5P2]4+ layers converting to yield the twisted 3D ∞3[Cd4P2]2+ framework, which promotes the growth of bulk crystals. Additionally, phase 2 possesses well-balanced NLO properties, enabling considerable second-harmonic generation (SHG) responses (0.8-2.7 × AgGaS2) in broadband spectra, the thermal expansion anisotropy (2.30) together with suitable band gap (2.37 eV) primarily leading to the favorable laser-induced damage threshold (3.33 × AgGaS2), broad transparent window, and sufficient calculated birefringence (0.0433) for phase-matching ability. Furthermore, the first polyanion substitution of the supramolecule plays the role of templating agent to realize the CS-to-NCS transformation, which offers an effective method to rationally design promising NCS-based functional materials.
RESUMEN
The quality and yield of cashmere closely affect the economic benefits of cashmere goat farming. Studies have shown that controlling light can have an important impact on cashmere but can also affect the concentration of harmful gases. In order to explore the impact of a short photoperiod on the growth of cashmere and harmful gases in goat houses, 130 female (non-pregnant) Shanbei white cashmere goats, aged 4-5 years with similar body weights, were randomly divided into a control group and a treatment group, with 65 goats in each group. The dietary nutrition levels of the experimental goats were the same, and completely natural light was used in the control group; the light control group received light for 7 h every day (9:30-16:30), and the rest of the time (16:30-9:30 the next day) they did not receive light. The light control treatment was carried out in a control house, and the gas content was analyzed. It was found that a shortened period of light exposure could increase the annual average cashmere production by 34.5%. The content of each gas has a certain functional relationship with the measurement time period, but at the same time, we found that the content of NH3 also changes seasonally. In summary, the use of shortened light periods when raising cashmere goats can significantly increase cashmere production and quality, but at the same time, it will increase the concentration of harmful gases in the goat barn, and ventilation should be increased to ensure the health of the goats and the air quality in the barn.
RESUMEN
Anthropogenic activities pose a more significant threat to the environment than natural phenomena by contaminating the environment with heavy metals. Cadmium (Cd), a highly poisonous heavy metal, has a protracted biological half-life and threatens food safety. Plant roots absorb Cd due to its high bioavailability through apoplastic and symplastic pathways and translocate it to shoots through the xylem with the help of transporters and then to the edible parts via the phloem. The uptake and accumulation of Cd in plants pose deleterious effects on plant physiological and biochemical processes, which alter the morphology of vegetative and reproductive parts. In vegetative parts, Cd stunts root and shoot growth, photosynthetic activities, stomatal conductance, and overall plant biomass. Plants' male reproductive parts are more prone to Cd toxicity than female reproductive parts, ultimately affecting their grain/fruit production and survival. To alleviate/avoid/tolerate Cd toxicity, plants activate several defense mechanisms, including enzymatic and non-enzymatic antioxidants, Cd-tolerant gene up-regulations, and phytohormonal secretion. Additionally, plants tolerate Cd through chelating and sequestering as part of the intracellular defensive mechanism with the help of phytochelatins and metallothionein proteins, which help mitigate the harmful effects of Cd. The knowledge on the impact of Cd on plant vegetative and reproductive parts and the plants' physiological and biochemical responses can help selection of the most effective Cd-mitigating/avoiding/tolerating strategy to manage Cd toxicity in plants.
Asunto(s)
Metales Pesados , Contaminantes del Suelo , Cadmio/metabolismo , Biodegradación Ambiental , Metales Pesados/metabolismo , Plantas/metabolismo , Fotosíntesis , Raíces de Plantas/metabolismo , Contaminantes del Suelo/metabolismoRESUMEN
It is important to describe lineages before they go extinct, as we can only protect what we know. This is especially important in the case of microendemic species likely to be relict populations, such as Hynobius salamanders in southern China. Here, we unexpectedly sampled Hynobius individuals in Fujian province, China, and then worked on determining their taxonomic status. We describe Hynobius bambusicolus sp. nov. based on molecular and morphological data. The lineage is deeply divergent and clusters with the other southern Chinese Hynobius species based on the concatenated mtDNA gene fragments (>1500 bp), being the sister group to H. amjiensis based on the COI gene fragment, despite their geographic distance. In terms of morphology, the species can be identified through discrete characters enabling identification in the field by eye, an unusual convenience in Hynobius species. In addition, we noted some interesting life history traits in the species, such as vocalization and cannibalism. The species is likely to be incredibly rare, over a massively restricted distribution, fitting the definition of Critically Endangered following several lines of criteria and categories of the IUCN Red List of Threatened Species.