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Sulforaphane (SFN) exerts anticancer effect on various cancers including gastric cancer. However, the regulatory effect of SFN on programmed death-ligand 1 (PD-L1) and checkpoint blockade therapy in gastric cancer have not been elucidated. Here we demonstrated that SFN suppressed gastric cancer cell growth both in vitro and in vivo study. SFN upregulated PD-L1 expression through activating ΔNP63α in gastric cancer cells. Further, we found that SFN impaired the anticancer effect of anti-PD-L1 monoclonal antibody (α-PD-L1 mab) on gastric cancer cells. These results uncover a novel PD-L1 regulatory mechanism and the double-edged role of SFN in gastric cancer intervention.
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Antígeno B7-H1 , Inibidores de Checkpoint Imunológico , Isotiocianatos , Neoplasias Gástricas , Sulfóxidos , Fatores de Transcrição , Isotiocianatos/farmacologia , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Antígeno B7-H1/metabolismo , Sulfóxidos/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Animais , Camundongos , Linhagem Celular Tumoral , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos NusRESUMO
Zinc finger proteins (ZNFs) play a significant role in the initiation and progression of tumors. Nevertheless, the specific contribution of ZNF610 to lung adenocarcinoma (LUAD) remains poorly understood. This study sought is to elucidate the role of ZNF610 in LUAD. Transcript data of LUAD were obtained from The Cancer Genome Atlas Program (TCGA) database and processed via R program. The expression of ZNF610 was assessed in various cell lines. To compare the proliferative capacity of cells with or without ZNF610 silencing, CCK8, cell colony formation assay, and Celigo label-free cell counting assay were employed. Furthermore, transwell migration and invasion assays were conducted to evaluate the migratory and invasive abilities of the cells. The expression levels of genes and proteins were assessed using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot techniques. In different LUAD cells, the expression level of ZNF610 was found to be significantly higher in LUAD cells compared to MRC-5 and BASE-2B cells. Moreover, the silencing of ZNF610 resulted in a decrease in cell proliferation and migration abilities. Additionally, the apoptosis rate of cells increased upon silencing ZNF610. Notably, the proportion of cells in the G0/G1 phase increased, while the proportion of cells in the S phase decreased following ZNF610 silencing. Finally, ß-catenin and snail were identified as downstream targets of ZNF610 in cells. Our findings suggest that silencing ZNF610 could inhibit LUAD cell proliferation and migration, possibly through the downregulation of ß-catenin and snail.
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Adenocarcinoma de Pulmão , Movimento Celular , Proliferação de Células , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Inativação Gênica , Linhagem Celular Tumoral , ApoptoseRESUMO
Exosomes are nanoscale membrane vesicles actively released by cells and play an important role in the diagnosis of cancer-related diseases. However, it is challenging to efficiently enrich exosomes from extracellular fluids. In this work, we used DNA nanostructures as "nanoweights" during centrifugation to facilitate the enrichment of cancerous exosomes in human serum. Two different DNA tetrahedral nanostructures (DTNs), each carrying a specific aptamer for exosome biomarker recognition, were incubated with clinical samples simultaneously. One DTN triggered the cross-linking of multiple target exosomes and, therefore, enabled low-speed and fast centrifugation for enrichment. The other DTN further narrowed down the target exosome subtype and initiated a hybridization chain reaction (HCR) for sensitive signal amplification. The method enabled the detection of 1.8 × 102 MCF-7-derived exosomes per microliter and 5.6 × 102 HepG2-derived exosomes per microliter, with 1000-fold higher sensitivity than conventional ELISA and 10-fold higher sensitivity than some recently reported fluorescence assays. Besides, the dual-aptamer system simultaneously recognized multiple surface proteins, eliminating the interference risk from free proteins. Thus, this easy-to-operate method can enrich exosomes with excellent specificity and sensitivity and therefore will be appealing in biomedical research and clinical diagnosis.
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Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Exossomos , Neoplasias , Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais/métodos , Centrifugação , DNA/química , Exossomos/química , Humanos , Neoplasias/diagnóstico , Neoplasias/metabolismoRESUMO
PURPOSE: LINC01089 is a newly identified lncRNA and rarely reported in human cancers. Our study aimed to investigate its role in lung cancer. METHODS: YY1, LINC01089, and miR-301b-3p levels in lung cancer tissues and cells were assessed using qRT-PCR. Bioinformatics analysis and luciferase reporter, ChIP, and RIP assays were carried out for determining the relationships among YY1, LINC01089, miR-301b-3p, and HPGD. Gain- and loss-of-function assays were carried out to confirm the impacts of LINC01089 and HPDG in lung cancer cells. CCK-8 assay was used to assess cell proliferation rate, and Transwell assay was applied to measure cell invasion and migration. An in vivo tumor model was applied for validating the role of LINC01089. RESULTS: LINC01089 was decreased in lung cancer tissues and cells, and low LINC01089 level predicted a poor clinical outcome. YY1 directly bound to LINC01089 promoter region and inhibited its transcription. LINC01089 knockdown thwarted the proliferation, invasion, and migration capacity of H1299 and A549 cells and aggravated tumor growth. Specifically, LINC01089 functioned as a competing endogenous RNA of miR-301b-3p to modulate HPGD and thereby affected lung cancer progression. CONCLUSION: Our data revealed that LINC01089, directly suppressed by YY1, inhibited lung cancer progression by targeting the miR-301b-3p/HPGD axis. Graphical abstract 1. LINC01089 expression was downregulated in lung cancer tisuues and cell lines, and low LINC01089 levels predicted a poor clinical outcome. 2. LINC01089 knockdown enhanced proliferation, invasion, and migration of H1299 and A549 cells in vitro and promoted lung cancer cell tumorigenesis and metastasis in vivo. 3. LINC01089, directly suppressed by YY1, functioned as a competing endogenous RNA against miR-301b-3p to increase HPGD expression.
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Neoplasias Pulmonares , MicroRNAs , RNA Longo não Codificante , Humanos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Fator de Transcrição YY1/genética , Fator de Transcrição YY1/metabolismo , RNA Longo não Codificante/genéticaRESUMO
OBJECTIVE: To investigate the effect of Helicobacter pylori (HP) eradication therapy on salivary pepsin concentration in laryngopharyngeal reflux (LPR) patients with HP infection. MATERIALS AND METHODS: A total of 477 patients with suspected LPR were enrolled from June 2020 to September 2021. Reflux symptom index, reflux finding score, the positive rates and disintegrations per minute values of HP infection detected by 14C urea breath test and salivary pepsin concentrations analyzed using enzyme-linked immunosorbent assay were compared in LPR patients and non-LPR patients with or without HP infection. HP-positive patients were treated with HP eradication therapy while HP-negative patients with PPI therapy. RESULTS: The scores of nagging cough (0.88 vs. 0.50, P = 0.035), erythema or hyperemia (1.93 vs. 1.78, P = 0.035) and vocal fold edema (1.04 vs. 0.85, P = 0.025) were higher in the LPR (+) Hp (+) subgroup than in LPR (+) Hp (-) subgroup. The concentrations of salivary pepsin in the Hp (+) subgroup were higher than in the Hp (-) subgroup either in LPR patients (75.24 ng/ml vs. 61.39 ng/ml, P = 0.005) or the non-LPR patients (78.42 ng/ml vs. 48.96 ng/ml, P = 0.024). Compared to baseline (before treatment), scores of nagging cough (0.35 vs. 0.84, P = 0.019) and erythema or hyperemia (1.50 vs. 1.83, P = 0.039) and the concentrations of salivary pepsin (44.35 ng/ml vs. 74.15 ng/ml, P = 0.017) in LPR patients with HP infection decreased after HP treatment; yet, this was not observed for the LPR patients without HP infection treated with PPI only (P > 0.05). CONCLUSION: HP infection may aggravate the symptoms and signs of LPR patients, partly by increasing their salivary pepsin concentration.
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Helicobacter pylori , Hiperemia , Refluxo Laringofaríngeo , Tosse , Humanos , Refluxo Laringofaríngeo/complicações , Refluxo Laringofaríngeo/diagnóstico , Refluxo Laringofaríngeo/tratamento farmacológico , Pepsina A , Saliva , UreiaRESUMO
The concentration of butyric acid in the intestine increased with the increase in the content of fermentable dietary fibre; however, the potential physiological impact of a high dose of butyric acid on fish has not been sufficiently studied. The aim of this study was to investigate the effect of two dosages of butyric acid on the growth and health of the liver and intestine of the largemouth bass (Micropterus salmoides). Sodium butyrate (SB) was added to the diet at 0 g/kg (CON), 2 g/kg (SB2), and 20 g/kg (SB20), and the juvenile largemouth bass were fed to apparent satiation for 56 days. No significant difference was observed in the specific growth rate or hepatosomatic index among the groups (P > 0.05). The concentration of ß-hydroxybutyric acid in the liver, the activities of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, and the concentrations of triglyceride and total cholesterol in serum increased significantly in the SB20 group compared to the CON group (P < 0.05). The relative expression of fas, acc, il1b, nfkb, and tnfa in the liver of the SB20 groups was also significantly higher than that of the CON group (P < 0.05). The above indicators in the group SB2 had similar change tendencies. The expression of nfkb and il1b in the intestine of both the SB2 and SB20 groups was significantly downregulated compared with that in the CON group (P < 0.05). The size of hepatocytes was enlarged, and the intracellular lipid droplets and the degree of hepatic fibrosis were increased in the SB20 group compared to the CON group. There was no significant difference in intestinal morphology among the groups. The above results indicated that neither 2 g/kg nor 20 g/kg SB had a positive effect on the growth of largemouth bass, while a high dosage of SB induced liver fat accumulation and fibrosis.
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In a study on the anti-nutritional effect of dietary fiber, it was noticed that a high-pectin diet (PEC diet) caused growth retardation, hepatic cholestasis, steatosis, fibrosis, and enteritis accompanied by decreased glycocholic acid (GCA) in Pelteobagrus fulvidraco. This study was conducted to investigate the potential alleviating effects of supplementation with GCA. A PEC diet and a diet supplemented with 0.6 g kg-1 GCA based on the PEC diet (named the GCA diet) were formulated and randomly fed to juvenile Pelteobagrus fulvidraco. Compared to fish that were fed the PEC diet for 7 days, the GCA content in liver increased significantly in fish fed the GCA diet, the incidence of abnormal liver color, gallbladder somatic index (GBSI), total bile acid concentration in serum and liver, and the expression of arnesoid X receptor gene (fxr) upregulated and genes involved in bile acid (BA) synthesis and uptake in liver decreased significantly. After 56 days, the SGR, the expression of fxr and genes involved in BA synthesis and transportation in the liver, the serum content of total bilirubin, total protein, and globulin were significantly higher, while the hepatosomatic index, GBSI, liver lipid and collagen content, and the incidence of distal intestine tissue damage were lower in fish fed the GCA diet than in those fed the PEC diet. These results suggested that GCA improved growth performance and alleviated hepatic cholestasis and tissue damage to the liver and intestine induced by a high-pectin diet, which might occur through activating FXR.
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To reveal the impact of dietary fiber (DF) on the bile acid (BA) profiles of fish, yellow catfish (Pelteobagrus fulvidraco) were fed a diet containing 300 g kg-1 dextrin (CON diet, control) or pectin (a type of soluble DF, PEC diet) for 7 days, and then the BA profiles were analyzed by UHPLC-MS/MS. A total of 26 individuals of BAs were detected in the fish body, with 8, 10, 14, and 22 individuals of BAs detected in the liver, serum, bile, and hindgut digesta, respectively. The conjugated BAs (CBAs) of fish were dominated by taurine CBAs (TCBAs). The concentrations of free BAs (FBAs) and the value of FBAs/CBAs in the bile of fish fed the PEC diet were nearly 5 and 7 times higher, respectively than those in fish fed the CON diet. The value of glycine CBAs/TCBAs in the liver, serum and bile of fish fed the PEC diet was significantly lower, and in the hindgut digesta was higher than that of fish fed the CON diet (P < 0.05). These results suggested that dietary pectin greatly changed the BA profiles of Pelteobagrus fulvidraco, attributed to inhibition of reabsorption of BAs. Therefore, attention should be paid to the impact on BA homeostasis when replacing fishmeal with DF-rich plant ingredients in the fish diet.
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Ácidos e Sais Biliares , Peixes-Gato , Pectinas/administração & dosagem , Animais , Ácidos e Sais Biliares/análise , Dieta/veterinária , Fígado , Espectrometria de Massas em Tandem , TaurinaRESUMO
PURPOSE: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease with synovitis as pathological changes. The immune microenvironment of RA promotes metabolic reprogramming of immune cells and stromal cells, which leads to dysfunction and imbalance of immune homeostasis. Cell metabolism undergoes the switch from a static regulatory state to a highly metabolic active state, which changes the redox-sensitive signaling pathway and also leads to the accumulation of metabolic intermediates, which in turn can act as signaling molecules and further aggravate the inflammatory response. The reprogramming of immunometabolism affects the function of immune cells and is crucial to the pathogenesis of RA. In addition, mitochondrial dysfunction plays a key role in glycolytic reprogramming in RA. These metabolic changes may be potential therapeutic targets for RA. Therefore, we reviewed the metabolic reprogramming of RA immune cells and fibroblast-like synovium cells (FLS) and its relationship with mitochondrial dysfunction. METHODS: A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning immunometabolic reprogramming, mitochondrial dysfunction, and rheumatoid arthritis. RESULTS: This article reviews the metabolic reprogramming of immune cells and fibroblast-like synoviocytes in RA and their relationship to mitochondrial disfunction, as well as the key pro-inflammatory pathways associated with metabolic reprogramming and chemotherapy as a potential future therapeutic strategy for RA.
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Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Animais , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Transdução de Sinais , Sinoviócitos/imunologia , Sinoviócitos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Correction for 'Optical and electrical effects of plasmonic nanoparticles in high-efficiency hybrid solar cells' by Wei-Fei Fu et al., Phys. Chem. Chem. Phys., 2013, 15, 17105-17111, DOI: 10.1039/C3CP52723A.
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OBJECTIVE: To explore the impact of maternal sex chromosome aneuploidies (SCAs) and copy number variation (CNV) on false-positive results of non-invasive prenatal screening (NIPS) for predicting foetal SCAs. METHODS: In total, 22 844 pregnant women were recruited to undergo NIPS. Pregnant women with high-risk of SCAs underwent prenatal diagnosis and maternal copy number variation sequencing (CNV-seq). RESULTS: Among 117 women with high-risk of SCAs, 72 accepted prenatal diagnosis, 86 accepted maternal CNV-seq, and 21 had maternal sex chromosome abnormalities. The abnormality rate was significantly higher than women at low-risk of SCAs (24.42% vs 3.51%). Using a novel parameter cffDNA (ChrX)/cffDNA, when the ratio was greater than 2, all foetuses had normal karyotype, and 75.0% (6/8) had abnormal maternal chromosome X. If the ratio was less than or equal to 2, only 10% (4/40) of the mothers had chromosome X CNV alterations, while 33.3% (13/40) of their foetuses had sex chromosomes CNV abnormalities. CONCLUSIONS: Approximately 25% of pregnant women with SCAs predicted by NIPS had sex chromosome abnormalities as determined by CNV-seq. The ratio of cffDNA (ChrX)/cffDNA can tentatively distinguish the maternal or foetal origin of abnormal cell-free DNA. In a reanalysis of previous NIPS data, false-positive results caused by maternal CNV might be elucidated.
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Ácidos Nucleicos Livres/genética , Cromossomos Humanos X/genética , Variações do Número de Cópias de DNA/genética , Síndrome de Klinefelter/diagnóstico , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/diagnóstico , Transtornos dos Cromossomos Sexuais/diagnóstico , Trissomia/diagnóstico , Síndrome de Turner/diagnóstico , Cariótipo XYY/diagnóstico , Amniocentese , Aneuploidia , Ácidos Nucleicos Livres/análise , Reações Falso-Positivas , Feminino , Humanos , Masculino , Teste Pré-Natal não Invasivo , Aberrações dos Cromossomos SexuaisRESUMO
BACKGROUND: Few data are available on the association between postoperative serum uric acid (SUA) level and poor survival in patients undergoing coronary artery bypass grafting (CABG). We evaluated the relationship between postoperative SUA and major adverse cardiac and cerebrovascular events (MACCE) among patients undergoing CABG. METHODS: This study used data from 1614 consecutive patients undergoing CAGB at Fuwai Hospital (Beijing, China) from 2011 to 2015. Patients were stratified into statistical quartiles of postoperative SUA (between 6 and 18 hours after cardiac surgery): less than 203.7, 203.7 to 254.1, 254.1 to 316.6, and ≥316.6 µmol/L. The association of postoperative SUA with MACCE (ie, death, myocardial infarction [MI], stroke, or repeat revascularization) and the composite endpoint of mortality/MI were assessed. RESULTS: Patients had a mean age of 60.3 ± 8.4 years, and 79.3% were male. During mean follow-up of 2.5 ± 0.7 years, MACCE occurred in 201 (12.5%) patients. In separate multivariable regression models, postoperative SUA level was positively associated with in-hospital MACCE (highest vs lowest SUA quartile: odds ratio [OR]: 2.40; 95% confidence interval [CI]: 1.29, 4.48; P = .006) and in-hospital composite endpoint of mortality/MI (OR: 2.88; 95% CI: 1.45, 5.72; P = .003), respectively. And elevated postoperative SUA level was independently associated with MACCE (Hazard ratio [HR]: 1.70; 95% CI: 1.12, 2.57; P = .01) and the composite endpoint of mortality/MI (HR: 2.42; 95% CI: 1.32, 4.43; P = .004) respectively within 3 years after CABG. CONCLUSIONS: Elevated postoperative SUA level is associated with poor clinical outcomes after CABG. Patients with high postoperative SUA levels after CABG might require to be closely monitored.
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Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Ácido Úrico/sangue , Idoso , Biomarcadores/sangue , Doença da Artéria Coronariana/mortalidade , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Complicações Pós-Operatórias/etiologia , Período Pós-Operatório , Prognóstico , Reoperação/estatística & dados numéricos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Taxa de SobrevidaRESUMO
BACKGROUND: The diversity of avian eggshell colour plays important biological roles in ensuring successful reproduction. Eggshell colour is also an important trait in poultry, but the mechanisms underlying it are poorly understood in ducks. This study aimed to provide insights into the mechanism of blue-green eggshell colour generation. RESULTS: Here, white-shelled ducks (HBR) and blue-green-shelled ducks (HQR) were selected from Putian black ducks, and white-shelled ducks (BBR) were selected from Putian white ducks. Transcriptional changes in the shell gland were analysed using RNA-sequencing on the Illumina HiSeq 2500. Twenty-seven individual cDNA libraries were sequenced and generated an average of 7.35 million reads per library; 70.6% were mapped to the duck reference genome, yielding an average of 13,794 genes detected, which accounted for approximately 86.39% of all 15,967 annotated duck genes. A total of 899 differentially expressed genes (DEGs) were detected between the HQR and BBR groups, and 373 DEGs were detected between the HQR and HBR groups. We analysed the DEGs in the HQR-vs-BBR and HQR-vs-HBR comparisons. None of these DEGs were directly involved in the eggshell pigmentation process in HQR-vs-HBR, while UDP-glucuronosyltransferase 2A2 (UGT2A2) and UDP-glucuronosyltransferase 1-1-like (UGT1-1-like), which participate in biliverdin breakdown, were two of the DEGs in HQR-vs-BBR. In the RT-qPCR results, delta-aminolevulinic acid synthase 1 (ALAS1) and EPRS glutamyl-prolyl-tRNA synthetase were significantly upregulated in the HBR group compared with the HQR and BBR groups (P < 0.05). Haem oxygenase (HMOX1) was significantly downregulated in BBR compared with HQR and HBR (P < 0.05). Biliverdin reductase A (BLVRA), GUSB glucuronidase beta, cytochrome c-type haem lyase, protohaem IX farnesyltransferase and UGT2A2 were significantly upregulated in HBR and BBR compared with HQR (P < 0.05). CONCLUSIONS: We conducted a comparative transcriptome analysis of the shell glands of Putian white ducks and Putian black ducks. None of the differentially regulated pathways were directly involved in the eggshell pigmentation process in the HQR-vs-HBR comparison, while 2 DEGs related to biliverdin breakdown were found in HQR-vs-BBR. Based on the RT-qPCR results, we can speculate that both HQR and HBR can produce biliverdin, but HBR cannot accumulate it. Compared with HQR, BBR produced less biliverdin and did not accumulate it.
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Proteínas Aviárias/genética , Patos/genética , Casca de Ovo/metabolismo , Pigmentação/genética , Análise de Sequência de RNA/métodos , Animais , Cor , Patos/classificação , Casca de Ovo/química , Perfilação da Expressão Gênica/métodos , Anotação de Sequência Molecular , Fenótipo , Transdução de Sinais/genética , Transcriptoma/genéticaRESUMO
Increasing evidence indicates that the expressions of messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs) undergo a frequent and aberrant change in carcinogenesis and cancer development. But some research was carried out on mRNA-lncRNA signatures for prediction of hepatocellular carcinoma (HCC) prognosis. We aimed to establish an mRNA-lncRNA signature to improve the ability to predict HCC patients' survival. The subjects from the cancer genome atlas (TCGA) data set were randomly divided into two parts: training data set (n = 246) and testing data set (n = 124). Using computational methods, we selected eight gene signatures (five mRNAs and three lncRNAs) to generate the risk score model, which were significantly correlated with overall survival of patients with HCC in both training and testing data set. The signature had the ability to classify the patients in training data set into a high-risk group and low-risk group with significantly different overall survival (hazard ratio = 4.157, 95% confidence interval = 2.648-6.526, P < 0.001). The prognostic value was further validated in testing data set and the entire data set. Further analysis revealed that this signature was independent of tumor stage. In addition, Gene Set Enrichment Analysis suggested that high risk score group was associated with cell proliferation and division related pathways. Finally, we developed a well-performed nomogram integrating the prognostic signature and other clinical information to predict 3- and 5-year overall survival. In conclusion, the prognostic mRNAs and lncRNAs identified in our study indicate their potential role in HCC biogenesis. The risk score model based on the mRNA-lncRNA may be an efficient classification tool to evaluate the prognosis of patients' with HCC.
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Endocrine therapy is one of the main treatments for estrogen receptor-positive breast cancers. Tamoxifen is the most commonly used drug for endocrine therapy. However, primary or acquired tamoxifen resistance occurs in a large proportion of breast cancer patients, leading to therapeutic failure. We found that the combination of tamoxifen and ACT001, a nuclear factor-κB (NF-κB) signaling pathway inhibitor, effectively inhibited the proliferation of both tamoxifen-sensitive and tamoxifen-resistant cells. The tamoxifen-resistant cell line MCF7R/LCC9 showed active NF-κB signaling and high apoptosis-related gene transcription, especially for antiapoptotic genes, which could be diminished by treatment with ACT001. These results demonstrate that ACT001 can prevent and reverse tamoxifen resistance by inhibiting NF-κB activation.
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BACKGROUND: Brachydactyly type A1 (BDA1, OMIM 112500) is a rare inherited malformation characterized primarily by shortness or absence of middle bones of fingers and toes. It is the first recorded disorder of the autosomal dominant Mendelian trait. Indian hedgehog (IHH) gene is closely associated with BDA1, which was firstly mapped and identified in Chinese families in 2000. Previous studies have demonstrated that BDA1-related mutant IHH proteins affected interactions with its receptors and impaired IHH signaling. However, how the altered signaling pathway affects downstream transcriptional regulation remains unclear. RESULTS: Based on the mouse C3H10T1/2 cell model for IHH signaling activation, two recombinant human IHH-N proteins, including a wild type protein (WT, amino acid residues 28-202) and a mutant protein (MT, p.E95k), were analyzed. We identified 347, 47 and 4 Gli1 binding sites in the corresponding WT, MT and control group by chromatin immunoprecipitation and the overlapping of these three sets was poor. The putative cis regulated genes in WT group were enriched in sensory perception and G-protein coupled receptor-signaling pathway. On the other hand, putative cis regulated genes were enriched in Runx2-related pathways in MT group. Differentially expressed genes in WT and MT groups indicated that the alteration of mutant IHH signaling involved cell-cell signaling and cellular migration. Cellular assay of migration and proliferation validated that the mutant IHH signaling impaired these two cellular functions. CONCLUSIONS: In this study, we performed integrated genome-wide analyses to characterize differences of IHH/Gli1 downstream regulation between wild type IHH signaling and the E95K mutant signaling. Based on the cell model, our results demonstrated that the E95K mutant signaling altered Gli1-DNA binding pattern, impaired downstream gene expressions, and leaded to weakened cellular proliferation and migration. This study may help to deepen the understanding of pathogenesis of BDA1 and the role of IHH signaling in chondrogenesis.
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Braquidactilia/genética , Proteínas Hedgehog/genética , Mutação , Transcrição Gênica/genética , Proteína GLI1 em Dedos de Zinco/genética , Braquidactilia/patologia , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Transdução de Sinais/genéticaRESUMO
Developing high-performance battery systems requires the optimization of every battery component, from electrodes and electrolyte to binder systems. However, the conventional strategy to fabricate battery electrodes by casting a mixture of active materials, a nonconductive polymer binder, and a conductive additive onto a metal foil current collector usually leads to electronic or ionic bottlenecks and poor contacts due to the randomly distributed conductive phases. When high-capacity electrode materials are employed, the high stress generated during electrochemical reactions disrupts the mechanical integrity of traditional binder systems, resulting in decreased cycle life of batteries. Thus, it is critical to design novel binder systems that can provide robust, low-resistance, and continuous internal pathways to connect all regions of the electrode. In this Account, we review recent progress on material and structural design of novel binder systems. Nonconductive polymers with rich carboxylic groups have been adopted as binders to stabilize ultrahigh-capacity inorganic electrodes that experience large volume or structural change during charge/discharge, due to their strong binding capability to active particles. To enhance the energy density of batteries, different strategies have been adopted to design multifunctional binder systems based on conductive polymers because they can play dual functions of both polymeric binders and conductive additives. We first present that multifunctional binder systems have been designed by tailoring the molecular structures of conductive polymers. Different functional groups are introduced to the polymeric backbone to enable multiple functionalities, allowing separated optimization of the mechanical and swelling properties of the binders without detrimental effect on electronic property. We then describe the design of multifunctional binder systems via rationally controlling their nano- and molecular structures, developing the conductive polymer gel binders with 3D framework nanostructures. These gel binders provide multiple functions owing to their structure derived properties. The gel framework facilitates both electronic and ionic transport owing to the continuous pathways for electrons and hierarchical pores for ion diffusion. The polymer coating formed on every particle acts as surface modification and prevents particle aggregation. The mechanically strong and ductile gel framework also sustains long-term stability of electrodes. In addition, the structures and properties of gel binders can be facilely tuned. We further introduce the development of multifunctional binders by hybridizing conductive polymers with other functional materials. Meanwhile mechanistic understanding on the roles that novel binders play in the electrochemical processes of batteries is also reviewed to reveal general design rules for future binder systems. We conclude with perspectives on their future development with novel multifunctionalities involved. Highly efficient binder systems with well-tailored molecular and nanostructures are critical to reach the entire volume of the battery and maximize energy use for high-energy and high-power lithium batteries. We hope this Account promotes further efforts toward synthetic control, fundamental investigation, and application exploration of multifunctional binder materials.
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Conductive polymers have attracted significant interest over the past few decades because they synergize the advantageous features of conventional polymeric materials and organic conductors. With rationally designed nanostructures, conductive polymers can further exhibit exceptional mechanical, electrical, and optical properties because of their confined dimensions at the nanoscale level. Among various nanostructured conductive polymers, conductive polymer gels (CPGs) with synthetically tunable hierarchical 3D network structures show great potential for a wide range of applications, such as bioelectronics, and energy storage/conversion devices owing to their structural features. CPGs retain the properties of nanosized conductive polymers during the assembly of the nanobuilding blocks into a monolithic macroscopic structure while generating structure-derived features from the highly cross-linked network. In this Account, we review our recent progress on the synthesis, properties, and novel applications of dopant cross-linked CPGs. We first describe the synthetic strategies, in which molecules with multiple functional groups are adopted as cross-linkers to cross-link conductive polymer chains into a 3D molecular network. These cross-linking molecules also act as dopants to improve the electrical conductivity of the gel network. The microstructure and physical/chemical properties of CPGs can be tuned by controlling the synthetic conditions such as species of monomers and cross-linkers, reaction temperature, and solvents. By incorporating other functional polymers or particles into the CPG matrix, hybrid gels have been synthesized with tailored structures. These hybrid gel materials retain the functionalities from each component, as well as enable synergic effects to improve mechanical and electrical properties of CPGs. We then introduce the unique structure-derived properties of the CPGs. The network facilitates both electronic and ionic transport owing to the continuous pathways for electrons and hierarchical pores for ion diffusion. CPGs also provide high surface area and solvent compatibility, similar to natural gels. With these improved properties, CPGs have been explored to enable novel conceptual devices in diverse applications from smart electronics and ultrasensitive biosensors, to energy storage and conversion devices. CPGs have also been adopted for developing hybrid materials with multifunctionalities, such as stimuli responsiveness, self-healing properties, and super-repellency to liquid. With synthetically tunable physical/chemical properties, CPGs emerge as a unique material platform to develop novel multifunctional materials that have the potential to impact electronics, energy, and environmental technologies. We hope that this Account promotes further efforts toward synthetic control, fundamental investigation, and application exploration of CPGs.
RESUMO
Controlling architecture of electrode composites is of particular importance to optimize both electronic and ionic conduction within the entire electrode and improve the dispersion of active particles, thus achieving the best energy delivery from a battery. Electrodes based on conventional binder systems that consist of carbon additives and nonconductive binder polymers suffer from aggregation of particles and poor physical connections, leading to decreased effective electronic and ionic conductivities. Here we developed a three-dimensional (3D) nanostructured hybrid inorganic-gel framework electrode by in situ polymerization of conductive polymer gel onto commercial lithium iron phosphate particles. This framework electrode exhibits greatly improved rate and cyclic performance because the highly conductive and hierarchically porous network of the hybrid gel framework promotes both electronic and ionic transport. In addition, both inorganic and organic components are uniformly distributed within the electrode because the polymer coating prevents active particles from aggregation, enabling full access to each particle. The robust framework further provides mechanical strength to support active electrode materials and improves the long-term electrochemical stability. The multifunctional conductive gel framework can be generalized for other high-capacity inorganic electrode materials to enable high-performance lithium ion batteries.
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BACKGROUND AND OBJECTIVE: Transilluminated powered phlebectomy using the TriVex system is a new procedure for minimally invasive varicose vein surgery. We used the TriVex system for the removal of benign superficial subcutaneous soft tissue masses, and we also achieved satisfactory clinical effects. The objective of this study was to explore the feasibility, benefits, and technique-related complications of using the TriVex system for the removal of benign superficial masses as a novel and minimally invasive surgical technique. METHOD: Between January 2010 and August 2016, 452 patients with benign superficial soft tissue masses underwent surgical removal of masses using the TriVex II system in our department. The surgical complications, postoperative cosmetic outcome, and personal satisfaction were reviewed at a mean follow-up of 24 months. RESULTS: The TriVex procedure was successfully completed in all patients using only local tumescent anesthesia without any technical problem and serious complications. The mean operation duration was 8.5 minutes, and the average blood loss was 5 mL. Surgical complications were observed in 69 cases (15.3%) of subcutaneous ecchymosis, 34 cases (7.5%) of skin perforation, 14 cases (3.1%) of subcutaneous hematoma, 13 cases (2.9%) of wound infection, and 7 cases (1.5%) of induration of operation area. Eleven patients (2.4%) showed recurrence during the follow-up and were cured by reoperation by the TriVex system. Overall, the majority of patients (N = 436, 96.5%) were very satisfied or satisfied with the outcome. CONCLUSION: The TriVex procedure for the removal of benign superficial masses is simple, safe, and effective with advantages of short operation time, small incisions, and good cosmetic outcome, which is predicted as a new minimally invasive surgery of superficial masses.