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The Hippo signaling is instrumental in regulating organ size, regeneration, and carcinogenesis. The cytoskeleton emerges as a primary Hippo signaling modulator. Its structural alterations in response to environmental and intrinsic stimuli control Hippo signaling pathway activity. However, the precise mechanisms underlying the cytoskeleton regulation of Hippo signaling are not fully understood. RAP2 GTPase is known to mediate the mechanoresponses of Hippo signaling via activating the core Hippo kinases LATS1/2 through MAP4Ks and MST1/2. Here we show the pivotal role of the reciprocal regulation between RAP2 GTPase and the cytoskeleton in Hippo signaling. RAP2 deletion undermines the responses of the Hippo pathway to external cues tied to RhoA GTPase inhibition and actin cytoskeleton remodeling, such as energy stress and serum deprivation. Notably, RhoA inhibitors and actin disruptors fail to activate LATS1/2 effectively in RAP2-deficient cells. RNA sequencing highlighted differential regulation of both actin and microtubule networks by RAP2 gene deletion. Consistently, Taxol, a microtubule-stabilizing agent, was less effective in activating LATS1/2 and inhibiting cell growth in RAP2 and MAP4K4/6/7 knockout cells. In summary, our findings position RAP2 as a central integrator of cytoskeletal signals for Hippo signaling, which offers new avenues for understanding Hippo regulation and therapeutic interventions in Hippo-impaired cancers.
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Vía de Señalización Hippo , Proteínas Serina-Treonina Quinasas , Transducción de Señal , Animales , Humanos , Ratones , Citoesqueleto/metabolismo , Microtúbulos/metabolismo , Paclitaxel/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas de Unión al GTP rap/metabolismo , Proteínas de Unión al GTP rap/genética , Proteína de Unión al GTP rhoA/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , FosforilaciónRESUMEN
The addition of ceramic fillers is regarded as an effective strategy for enhancing the ionic conductivity of polymer electrolytes. However, particulate fillers typically fail to provide continuous conductive pathways and effective reinforcement. Herein, we report a ceramic nanowire filler with long-range interfacial conductivity and abundant lithium vacancies for a poly(ethylene oxide) (PEO)-based all-solid-state polymer electrolyte. LLZO nanowires (LLZO NWs) with a high aspect ratio are synthesized by combining sol-gel electrospinning and the multi-step process involving pre-oxidation, pre-sintering, and secondary sintering, resulting in a high tensile strength of the composite electrolyte (6.87 MPa). Notably, tantalum-aluminum co-substituted LLZO NWs (TALLZO NWs) release abundant lithium vacancies, further enhancing the Lewis acid-base properties, leading to a rapid ion migration speed (Li+ transfer number = 0.79) and significantly high ionic conductivity (3.80 × 10-4 S cm-1). Due to the synergistic effect of nanostructure modification and heteroatom co-doping, the assembled all-solid-state lithium-sulfur battery exhibits a high initial discharge capacity (776 mA h g-1 at 25 °C), remarkable rate capability, and excellent cycling performance (81% capacity retention after 200 cycles at 0.1C).
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Hypoxic microenvironments are intricately linked to malignant characteristics of glioblastoma multiforme (GBM). Long non-coding ribonucleic acids (lncRNAs) have been reported to be involved in the progression of GBM and closely associated with hypoxia. Nevertheless, the differential expression profiles as well as functional roles of lncRNAs in GBM cells under hypoxic conditions remain largely obscure. We explored the expression profiles of lncRNAs in hypoxic U87 cells as well as T98G cells using sequencing analysis. The effect of differentially expressed lncRNAs (DElncRNAs) was assessed through bioinformatic analysis. Furthermore, the expression of lncRNAs significantly dysregulated in both U87 and T98G cells was further validated using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Relevant cell functional experiments were also conducted. We used predicted RNA-binding proteins (RBPs) to construct an interaction network via the interaction prediction module. U87 and T98G cells showed dysregulation of 1115 and 597 lncRNAs, respectively. Gene Ontology (GO) analysis indicated that altered lncRNA expression was associated with nucleotide-excision repair and cell metabolism in GBM cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed the association between dysregulated lncRNAs and the Hippo signaling pathway under hypoxia. The dysregulation of six selected lncRNAs (ENST00000371192, uc003tnq.3, ENST00000262952, ENST00000609350, ENST00000610036, and NR_046262) was validated by qRT-PCR. Investigation of lncRNA-microRNA (miRNA)-mRNA networks centered on HIF-1α demonstrated cross-talk between the six validated lncRNAs and 16 related miRNAs. Functional experiments showed the significant inhibition of GBM cell proliferation, invasion, and migration by the knockdown of uc003tnq.3 in vitro. Additionally, uc003tnq.3 was used to construct a comprehensive RBP-transcription factor (TF)-miRNA interaction network. The expression of LncRNAs was dysregulated in GBM cells under hypoxic conditions. The identified six lncRNAs might exert important effect on the development of GBM under hypoxic microenvironment.
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Vegetation restoration on purple soil (Eutric Leptic Regosols) slopes aiming at reducing soil erosion in the Rainy Zone of Western China has significantly altered soil organic carbon (SOC) storage and distribution. A better understanding of the effects of different vegetation restoration types on SOC dynamics and fractions is critical in devising better policy to protect or enhance SOC stocks to improve soil quality and ecosystem function. In the present study, total, labile, and non-labile organic carbon (TOC, LC, and NLC), and carbon management index (CMI) of Cryptomeria fortunei (CF), mixed C. fortunei and Betula luminifera (MF), Neosinocalamus affinis (NA), and Camellia sinensis (CS) were compared with those of Zea mays field (ZM) on purple soil slopes in the Rainy Zone of Western China in order to develop more effective ways to implement vegetation restoration in the future. Different vegetation restoration types (CF, MF, NA and CS) increased TOC stock by 47.79%-118.31% and NLC stock by 56.61%-129.52% in the 0-50 cm soil layer compared with that of ZM. The direction and magnitude of changes in LC stock and CMI, however, depended strongly on the vegetation restoration type. Compared with ZM, CF had the largest increase of LC stock and CMI, whereas NA had the largest decrease of LC stock and CMI in the 0-50 cm soil layer. The LC:TOC ratio in four reforested species all declined significantly compared with that of ZM (p < 0.01), indicating decreased SOC activity after afforestation. The vegetation type and soil depth together explained more than 90% of the changes of TOC and its fractions in the plantations on purple soil slopes. Our study demonstrates that transforming the ZM into the CS is optimal to achieve the sustainable development goal, whereas transforming the ZM into the NA reduces the SOC activity and availability.
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Ecosistema , Suelo , Carbono/análisis , Secuestro de Carbono , ChinaRESUMEN
ABSTRACT: Heart failure is mainly caused by a decline in the systolic function of the heart. Long noncoding RNAs are related to cardiac diseases. This study aimed to explore the effects of long noncoding RNAs testis development related gene 1 (TDRG1) on the fibrogenesis and inflammatory response of transforming growth factor-beta1 (TGF-ß1)-stimulated human cardiac fibroblasts (HCFs). Levels of proinflammatory cytokines were evaluated by enzyme-linked immunosorbent assay. Reverse-transcription quantitative polymerase chain reaction was applied to reveal the expression levels of TDRG1, miR-605-3p, and tumor necrosis factor receptor superfamily (TNFRSF21). Western blot analysis was prepared to detect protein levels of TNFRSF21 and fibrosis-related genes. Luciferase reporter assay was conducted for confirming the interaction between miR-605-3p and TDRG1/TNFRSF21. We found that TGF-ß1-stimulated HCFs showed high concentrations of proinflammatory cytokines and increased protein levels of fibrosis-related genes, suggesting the dysfunctions of TGF-ß1-stimulated HCFs. In addition, TDRG1 was upregulated in TGF-ß1-stimulated HCFs. We found that interfering with TDRG1 alleviated dysfunctions of TGF-ß1-stimulated HCFs. Moreover, TDRG1 bound with miR-605-3p. MiR-605-3p exerted the antifibrogenic and anti-inflammatory effects in TGF-ß1-treated HCFs. As a target gene of miR-605-3p, TNFRSF21 reversed the antifibrogenic and anti-inflammatory effects of TDRG1 knockdown in TGF-ß1-treated HCFs. Overall, our study confirmed that TDRG1 aggravates fibrogenesis and inflammatory response in TGF-ß1-treated HCFs via the miR-605-3p/TNFRSF21 axis.
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MicroARNs , Miocardio , ARN Largo no Codificante , Receptores del Factor de Necrosis Tumoral , Antiinflamatorios/farmacología , Proliferación Celular , Fibroblastos/patología , Fibrosis , Humanos , MicroARNs/metabolismo , Miocardio/citología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Identification of effective therapies for colorectal cancer (CRC) remains an urgent medical need, especially for the microsatellite-stable (MSS) phenotype. In the current study, a combination of fruquintinib plus anti-PD-1 for MSS CRC therapy was investigated. First, a case of advanced MSS CRC was reported. After failure of multiline therapy, the patient finally achieved rapid response after receiving fruquintinib plus anti-PD-1 treatment. Then the effect of fruquintinib plus anti-PD-1 was verified using a murine syngeneic model of CT26 cells (MSS). The results showed that cotreatment significantly inhibited tumor growth and promote survival time for tumor-bearing mice compared with the single drug alone. In addition, fruquintinib/anti-PD-1 cotreatment decreased angiogenesis, enhanced normalization of the vascular structure, and alleviated tumor hypoxia. Moreover, the combination therapy reprogrammed the immune microenvironment by enhancing chemotactic factor release, increasing CD8+ T cell infiltration and activation, decreasing ration of regulatory T cells, and promoting M1/M2 ratio of macrophage. Finally, the enhanced antitumor effect of fruquintinib/anti-PD-1 cotreatment was significantly reversed in CD8 knockout mice compared with that in the wild-type mice. Our study indicated that combination of fruquintinib and anti-PD-1 could synergistically suppress CRC progression and altered the tumor microenvironment in favor of antitumor immune responses.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzofuranos/farmacología , Neoplasias Colorrectales/terapia , Quinazolinas/farmacología , Microambiente Tumoral/efectos de los fármacos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzofuranos/uso terapéutico , Antígenos CD8/genética , Línea Celular Tumoral/trasplante , Quimioterapia Adyuvante/métodos , Colectomía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Ratones , Ratones Noqueados , Inestabilidad de Microsatélites , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Quinazolinas/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Resultado del Tratamiento , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Adulto JovenRESUMEN
Substantial evidence highlighted the critical role of long non-coding RNAs (lncRNA) in driving hepatocarcinogenesis. We hypothesized that functional variants in genome-wide association studies (GWASs) associated loci might alter the expression levels of lncRNAs and contribute to the development of hepatocellular carcinoma (HCC). Here, we prioritized potentially cis-expression quantitative trait loci-based single nucleotide polymorphism (SNP)-lncRNA association together with the physical interaction by the analyses from Hi-C data in GWAS loci of chronic hepatitis B and HCC. Subsequently, by leveraging two-stage case-control study (1738 hepatitis B [HBV]) related HCC cases and 1988 HBV persistent carriers) and biological assays, we identified that rs2647046 was significantly associated with HCC risk (odds ratio = 1.26, 95% CI = 1.11 to 1.43, P = 4.14 × 10-4). Luciferase reporter assays and electrophoretic mobility shift assays showed that rs2647046 A allele significantly increased transcriptional activity via influencing transcript factor binding affinity. Allele-specific chromosome conformation capture assays revealed that enhancer with rs2647046 interacted with the HLA-DQB1-AS1 promoter to allele-specifically influence its expression by CTCF-mediated long-range loop. Cell proliferation assays indicated that HLA-DQB1-AS1 is a potential oncogene in HCC. Our study showed HLA-DQB1-AS1 regulated by a causal SNP in a long-range interaction manner conferred the susceptibility to HCC, suggesting an important mechanism of modulating lncRNA expression for risk-associated SNPs in the etiology of HCC.
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Elementos sin Sentido (Genética)/genética , Carcinoma Hepatocelular/genética , Elementos de Facilitación Genéticos , Cadenas beta de HLA-DQ/metabolismo , Neoplasias Hepáticas/genética , Regiones Promotoras Genéticas , ARN Largo no Codificante/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Cadenas beta de HLA-DQ/genética , Humanos , Neoplasias Hepáticas/patología , Polimorfismo de Nucleótido Simple , Sitios de Carácter CuantitativoRESUMEN
BACKGROUND: Esophageal cancer is the sixth leading cause of cancer-related mortality worldwide, which is partially due to limited progress of therapy. Apatinib, an inhibitor of VEGFR2, has a promising antitumor effect on malignancies. However, the underlying mechanism of its antitumor effect on esophageal cancer remains poorly understood. MATERIALS AND METHODS: Eighteen pairs of frozen esophageal cancer and their para-cancer samples and 25 paraffin specimens from advanced esophageal cancer patients treated with cisplatin-based regimen were collected. The effects of apatinib on cell growth, cell apoptosis, cell cycle and invasion/migration of esophageal cancer cells were assessed. Bioinformatics, luciferase reporter, immunoprecipitation and immunofluorescence assays were conducted for mechanic investigation. Quantitative RT-PCR, western blotting and immunohistochemistry were used to measure the expression of functional genes. Xenograft tumor growth of mice was performed. RESULTS: We found that VEGFR2 was highly expressed in esophageal cancer and associated with poor efficacy of cisplatin-based treatment. Apatinib displayed profound actions against tumor cell growth of human esophageal cancer via promoting cell apoptosis and cell cycle arrest. Also, apatinib displayed the inhibitory effects on cell migration and invasion. Moreover, apatinib strongly suppressed the growth of esophageal cancer xenografts in mice. The effects of apatinib on esophageal cancer were partially dependent on its block of the VEGFR2/Akt/ß-catenin pathway. Specifically, apatinib induced the degradation of ß-catenin and decreased its transcriptional activity through Akt/GSK-3ß repression. Further in vitro and in vivo studies revealed that low dose apatinib had a synergistic antitumor effect with cisplatin on esophageal cancer. CONCLUSION: Our study indicates that apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer by deactivating the Akt/ß-catenin pathway. These findings provide a theoretical foundation for using apatinib as an effective therapeutic drug for esophageal cancer.
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LESSONS LEARNED: Patients with metastatic colorectal cancer with good performance status or no liver metastasis could benefit from apatinib.Circulating tumor DNA abundance may be a predictor in serial monitoring of tumor load. BACKGROUND: Apatinib, an oral vascular endothelial growth factor (VEGF) receptor-2 inhibitor, has been approved as third-line treatment for metastatic gastric cancer in China. The aim of this study was to evaluate the efficacy and safety of apatinib, in the treatment of patients with refractory metastatic colorectal cancer after failure of two or more lines of chemotherapy. METHODS: In this open-label, single-arm, phase II study, patients with histological documentation of adenocarcinoma of the colon or rectum were eligible if they had received at least two prior regimens of standard therapies including fluoropyrimidine, oxaliplatin, and irinotecan. These patients were treated with apatinib in a daily dose of 500 mg, p.o., in the third-line or higher setting. Capture sequencing was dynamically performed to identify somatic variants in circulating tumor DNA (ctDNA) with a panel of 1,021 cancer-related genes. The primary endpoint was progression-free survival (PFS) and the tumor response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Interim analysis was applied as predefined. RESULTS: From June 1, 2016 to December 31, 2017, 26 patients were enrolled. The median PFS of the whole group was 3.9 months (95% confidence interval [CI]: 2.1-5.9). The median overall survival (OS) was 7.9 months (95% CI: 4.6-10.1+). Patients with performance status (PS) 0-1 had longer PFS than those with PS 2 (4.17 months vs. 1.93 months, p = .0014). Patients without liver metastasis also had longer PFS than those who had live metastasis (5.87 months vs. 3.33 months, p = .0274). The common side effects of apatinib were hypertension, hand-foot syndrome, proteinuria, and diarrhea. The incidence of grade 3-4 hypertension, hand-foot syndrome, proteinuria, and diarrhea was 76.92%, 11.54%, 73.08%, and 23.08%, respectively. All of the patients received dose reduction because of adverse effect. Results of capture sequencing showed APC, TP53, and KRAS were most frequently mutant genes. ctDNA abundance increased before the radiographic assessment in ten patients. CONCLUSION: Apatinib monotherapy showed promising efficiency for patients with refractory colorectal cancer, especially in patients with PS 0-1 or no liver metastasis. ctDNA abundance may be a predictor in serial monitoring of tumor load.
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Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Piridinas/uso terapéutico , Adulto , Anciano , Neoplasias Colorrectales/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Terapia Recuperativa , Tasa de SupervivenciaRESUMEN
BACKGROUND: Tumor-infiltrating immune cells (TIICs) are highly relevant to clinical outcome of glioma. However, previous studies cannot account for the diverse functions that make up the immune response in malignant transformation (MT) from low-grade glioma (LGG) to high-grade glioma (HGG). METHODS: Transcriptome level, genomic profiles and its relationship with clinical practice were obtained from TCGA and CGGA database. The "Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT)" algorithm was used to estimate the fraction of 22 immune cell types. We divided the TCGA and CGGA set into an experiment set (n = 174) and a validation set (n = 74) by random number table method. Univariate and multivariate analyses were performed to evaluate the 22 TIICs' value for MT in LGG. ROC curve was plotted to calculate area under curve (AUC) and cut-off value. RESULTS: Heterogeneity between TIICs exists in both intra- and inter-groups. Several TIICs are notably associated with tumor grade, molecular subtypes and survival. T follicular helper (TFH) cells, activated NK Cells and M0 macrophages were screened out to be independent predictors for MT in LGG and formed an immune risk score (IRS) (AUC = 0.732, p < 0.001, 95% CI 0.657-0.808 cut-off value = 0.191). In addition, the IRS model was validated by validation group, Immunohistochemistry (IHC) and functional enrichment analyses. CONCLUSIONS: The proposed IRS model provides promising novel signatures for predicting MT from LGG to HGG and may bring a better design of glioma immunotherapy studies in years to come.
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BACKGROUND: Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) has been proven to be involved in various human cancers; however, the function of PLOD3 in gastric cancer (GC) remains unclear. In this study, the role of PLOD3 in GC was evaluated. METHODS: The expression of PLOD3 in GC tissues and normal tissues was predicted by The Cancer Genome Atlas (TCGA). The kmplot online tool was performed to evaluate the impact of PLOD3 expression on GC patients' survival. Real-time PCR was conducted to verify PLOD3 expression in our own clinical samples and GC cells. The Cell Counting Kit-8 and the colony formation assay were used to detect GC cell proliferation ability. RESULTS: PLOD3 was upregulated in human GC tissues (compared to adjacent normal tissues, p < 0.001) and GC cells. High expression of PLOD3 was significantly correlated with larger tumor size (p = 0.007) and poor prognosis. Inhibition of PLOD3 could suppress cell proliferation in GC. CONCLUSIONS: These results revealed that PLOD3 may promote the progression of GC.
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Regulación Neoplásica de la Expresión Génica , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/genética , Neoplasias Gástricas/genética , Regulación hacia Arriba , Línea Celular Tumoral , Proliferación Celular/genética , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/metabolismo , Pronóstico , Interferencia de ARN , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Cetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients' response in order to maximize the benefit. METHODS: In this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed. RESULTS: Patients carrying SMAD4 mutations (SMAD4mut, n = 8) or NF1 mutations (NF1mut, n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4wt, n = 25) (P = 0.0081) or wildtype NF1 (NF1wt, n = 29) (P = 0.0028), respectively. None of the SMAD4mut or NF1mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4mut and NF1mut showed the shortest PFS among all the patients. CONCLUSIONS: Our results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Mutación , Neurofibromina 1/genética , Proteína Smad4/genética , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
OBJECTIVE: To investigate the effects and mechanisms of hydroxytyrosol (HT) during the pathogenesis of myocardial ischemia reperfusion (I/R) in rat hearts. METHODS: The rats were randomized into five groups: sham group, I/R group, HT+I/R group, HT+LY294002+I/R group, and LY+I/R group. Myocardial infarct size, markers of oxidative stress, extent of myocardial apoptosis, echocardiographically assessed cardiac function, and expression of Akt and GSK 3ß were measured in each group. RESULTS: Prereperfusion administration of HT was associated with a significantly smaller area of myocardial infarction and remarkably decreased level of myocardial apoptosis and necrosis, as evidenced by a lower apoptotic index, reduced cleaved caspase-3, and the serum activities of lactate dehydrogenase and creatinine kinase MB. Moreover, HT also attenuated the impairment of cardiac systolic function. However, cotreatment with LY294002 and HT completely abolished the above cardioprotective effects of HT. A subsequent mechanistic study revealed that the cardioprotective effects of HT during the process of I/R of the myocardium were dependent on the activation of the Akt/GSK3ß pathway. CONCLUSION: Pretreatment with HT may have antiapoptotic and cardioprotective effects against myocardial I/R injury, and these effects seem to be related to the activation of the Akt/GSK3ß pathway in the myocardium.
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Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/metabolismo , Alcohol Feniletílico/análogos & derivados , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Modelos Animales de Enfermedad , Masculino , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Alcohol Feniletílico/uso terapéutico , RatasRESUMEN
BACKGROUND: Circulating cell-free mtDNA (ccf-mtDNA) is presumably derived from injured tissue or cells in the body and has been suggested to be a potential biomarker in several diseases. In the present study, we investigated whether ccf-mtDNA levels could serve as a biomarker of diabetic patients without Coronary Heart Disease (CHD) and correlate with their incidence to develop CHD. METHODS: Ccf-mtDNA levels in plasma and the traditional CHD risk factors were determined in 50 type 2 diabetes (DM) with CHD and 50 DM without CHD patients and 50 age- and sex-matched healthy controls. MtDNA levels were assessed by measuring the NADH dehydrogenase 1 gene using quantitative real-time PCR. ROC curve analyses of plasma mtDNA in DM with or without CHD were also determined. Multivariate logistic regression analyses were conducted to determine the correlation between the mtDNA levels and traditional CHD risk factors. RESULTS: The plasma ccf-mtDNA levels and CRP were significantly elevated in DM compared with healthy controls, and a consistent increase of mtDNA in diabetes with CHD compared to those without CHD. The area under the ROC curves of mtDNA in DM patients versus DM patients with CHD and healthy controls was 0.843 and 0.898, respectively. Correlation analyses showed that the mtDNA levels were significantly correlated with that of C-reactive protein (CRP) in patients with CHD. CONCLUSIONS: Ccf-mtDNA was elevated in type 2 diabetes with CHD and correlated with CRP levels. Both may be considered a prognostic biomarker of CHD development.
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Enfermedad Coronaria/etiología , ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/etiología , NADH Deshidrogenasa/genética , Anciano , Área Bajo la Curva , Estudios de Casos y Controles , Enfermedad Coronaria/sangre , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/genética , ADN Mitocondrial/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/diagnóstico , Angiopatías Diabéticas/genética , Femenino , Marcadores Genéticos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Curva ROC , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Riesgo , Regulación hacia ArribaRESUMEN
CONTEXT: Paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium dichloride) is highly toxic and accounts for a large proportion of the herbicide poisonings seen in clinic. The major cause of mortality is respiratory failure. The p38 mitogen-activated protein kinase (MAPK) signal transduction pathway coordinates various cellular stress responses that have been shown to participate in the pathogenesis of PQ-induced lung injury. OBJECTIVE: To evaluate the effect of the specific p38 MAPK inhibitor SB203580 on PQ-induced lung injury and cytokine secretion. METHODS: In groups of 24, rats were treated with PQ, PQ and SB203580 (SB + PQ), SB203580 alone (SB) or normal saline (control group). Six rats from each group were euthanized at 1, 3, 5 or 7 d. Pathology of lung specimens was scored through hematoxylin and eosin staining. Edema in the lung was quantified from wet-to-dry weight ratios. p38 and p-p38MAPK proteins were measured via electrochemiluminescent Western blots. tumor necrosis factor (TNF)-alpha and interleukin-1 beta (IL-1ß) concentrations in lung specimens and bronchoalveolar lavage fluid (BALF) were quantified via enzyme-linked immunosorbent assay. RESULTS: The mortality rate of the SB + PQ group (16.7%) was significantly lower than that of the PQ group (33.3%; p < 0.05). The PQ group had significantly higher pulmonary histology scores, wet-to-dry weight ratios and phosphorylated p-p38 MAPK levels, as well as higher IL-1ß and TNF-alpha levels in BALF and lung tissues, that did the SB + PQ and control groups (p < 0.05, all). CONCLUSION: The data suggest that the p38 MAPK signaling pathway has an important role in regulating the production of IL-1ß and TNF-alpha in PQ-induced lung injury in rats.
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Lesión Pulmonar Aguda/patología , Paraquat/toxicidad , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Animales , Líquido del Lavado Bronquioalveolar , Ensayo de Inmunoadsorción Enzimática , Imidazoles/farmacología , Interleucina-1beta/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Fosforilación , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
OBJECTIVE: To describe a case with acute myocardial infarction caused by gastric carcinoma-associated thrombotic thrombocytopenic purpura. CLINICAL PRESENTATION AND INTERVENTION: A 79-year-old man was admitted with abdominal pain and pyrexia. He later developed cardiac complications and microangiopathy that indicated worsening progression. Manifold evidence confirmed the diagnosis of myocardial infarction caused by thrombotic thrombocytopenic purpura. The patient was treated mainly with plasma transfusion incorporated with steroids. CONCLUSION: This case should remind physicians to consider microangiopathy as a differential diagnosis in patients with unexplained cardiac symptoms or atypical presentation. Early diagnosis and treatment are helpful in decreasing the sequelae of this syndrome.
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Infarto del Miocardio/diagnóstico , Infarto del Miocardio/etiología , Púrpura Trombocitopénica Trombótica/complicaciones , Neoplasias Gástricas/complicaciones , Enfermedad Aguda , Anciano , Humanos , MasculinoRESUMEN
Decorating Zn anodes with functionalized polymers is considered as an effective strategy to inhibit dendrite growth. However, this normally brings extra interfacial resistance rendering slow reaction kinetics of Zn2+ . Herein, a poly(2-vinylpyridine) (P2VP) coating with modulated coordination strength and ion conductivity for dendrite-free Zn anode is reported. The P2VP coating favors a high electrolyte wettability and rapid Zn2+ migration speed (Zn2+ transfer number, tZn 2+ = 0.58). Electrostatic potential calculation shows that P2VP mildly coordinates with Zn2+ (adsorption energy = -0.94 eV), which promotes a preferential deposition of Zn along the (002) crystal plane. Notably, the use of partially (26%) quaternized P2VP (q-P2VP) further reduces the interfacial resistance to 126 Ω, leading to a high ion migration speed (tZn 2+ = 0.78) and a considerably low nucleation overpotential (18 mV). As a result of the synergistic effect of mild coordination and partial electrolysis, the overpotential of the q-P2VP-decorated Zn anode retains at a considerably low level (≈46 mV) over 1000 h at a high current density of 10 mA cm-2 . The assembled (NH4 )2 V6 O16 ·1.5H2 O || glass fiber || q-P2VP-Zn full cell reveals a lower average capacity decay rate of only 0.018% per cycle within 500 cycles at 1 A g-1 .
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BACKGROUND AND OBJECTIVES: Microvascular decompression (MVD) is the primary surgical intervention for trigeminal neuralgia (TN), with Teflon being the most conventional decompressing material. However, Teflon has been associated with adhesion and granulomas after MVD, which closely correlated with the recurrence of TN. Therefore, we developed a new technique to prevent direct contact between Teflon and nerve. The purpose of this study is to compare the efficacy of MVD using the gelatin sponge (GS) insertion technique with that of Teflon inserted alone in treating primary TN. METHODS: We retrospectively analyzed the medical records and the follow-up data of 734 patients with unilateral primary TN who underwent MVD at our center from January 2014 to December 2019. After exclusions, we identified 313 cases of GS-inserted MVD and 347 cases of traditional MVD. The follow-up exceeded 3 years. RESULTS: The operating time of the GS-inserted group was longer than that of the Teflon group (109.38 ± 14.77 vs 103.53 ± 16.02 minutes, P < .001). There was no difference between 2 groups in immediate surgical outcomes and postoperative complications. The yearly recurrence rate for GS-inserted MVD was lower at first (1.0%), second (1.2%), and third (1.2%) years after surgery, compared with its counterpart of Teflon group (3.7%, 2.9%, and 1.7% respectively). The first-year recurrence rate (P = .031) and total recurrence rate in 3 years (P = .013) was significantly lower in the GS-inserted group than Teflon group. Kaplan-Meier survival analysis demonstrated better outcomes in GS-inserted MVD groups (P = .020). CONCLUSION: The application of the GS insertion technique in MVD reduced first-year postoperative recurrence of TN, with similar complications rates compared with traditional MVD.
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Purpose: Metagenomic next-generation sequencing(mNGS) is a novel molecular diagnostic technique. For nucleic acid extraction methods, both whole-cell DNA (wcDNA) and cell-free DNA (cfDNA) are widely applied with the sample of bronchoalveolar lavage fluid (BALF). We aim to evaluate the clinical value of mNGS with cfDNA and mNGS with wcDNA for the detection of BALF pathogens in non-neutropenic pulmonary aspergillosis. Methods: mNGS with BALF-cfDNA, BALF-wcDNA and conventional microbiological tests (CMTs) were performed in suspected non-neutropenic pulmonary aspergillosis. The diagnostic value of different assays for pulmonary aspergillosis was compared. Results: BALF-mNGS (cfDNA, wcDNA) outperformed CMTs in terms of microorganisms detection. Receiver operating characteristic (ROC) analysis indicated BALF-mNGS (cfDNA, wcDNA) was superior to culture and BALF-GM. Combination diagnosis of either positive for BALF-mNGS (cfDNA, wcDNA) or CMTs is more sensitive than CMTs alone in the diagnosis of pulmonary aspergillosis (BALF-cfDNA+CMTs/BALF-wcDNA+CMTs vs. CMTs: ROC analysis: 0.813 vs.0.66, P=0.0142/0.796 vs.0.66, P=0.0244; Sensitivity: 89.47% vs. 47.37%, P=0.008/84.21% vs. 47.37%, P=0.016). BALF-cfDNA showed a significantly greater reads per million (RPM) than BALF-wcDNA. The area under the ROC curve (AUC) for RPM of Aspergillus detected by BALF-cfDNA, used to predict "True positive" pulmonary aspergillosis patients, was 0.779, with a cut-off value greater than 4.5. Conclusion: We propose that the incorporation of BALF-mNGS (cfDNA, wcDNA) with CMTs improves diagnostic precision in the identification of non-neutropenic pulmonary aspergillosis when compared to CMTs alone. BALF-cfDNA outperforms BALF-wcDNA in clinical value.
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Líquido del Lavado Bronquioalveolar , Ácidos Nucleicos Libres de Células , ADN de Hongos , Secuenciación de Nucleótidos de Alto Rendimiento , Metagenómica , Aspergilosis Pulmonar , Curva ROC , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Líquido del Lavado Bronquioalveolar/microbiología , Aspergilosis Pulmonar/diagnóstico , Metagenómica/métodos , Masculino , Femenino , ADN de Hongos/genética , ADN de Hongos/aislamiento & purificación , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular/métodos , Anciano , Sensibilidad y Especificidad , AdultoRESUMEN
Recent studies have implicated a crucial role of Hippo signaling in cell fate determination by biomechanical signals. Here we show that mechanical loading triggers the activation of a Hippo-PKCζ-NFκB pathway in chondrocytes, resulting in the expression of NFκB target genes associated with inflammation and matrix degradation. Mechanistically, mechanical loading activates an atypical PKC, PKCζ, which phosphorylates NFκB p65 at Serine 536, stimulating its transcriptional activation. This mechanosensitive activation of PKCζ and NFκB p65 is impeded in cells with gene deletion or chemical inhibition of Hippo core kinases LATS1/2, signifying an essential role of Hippo signaling in this mechanotransduction. A PKC inhibitor AEB-071 or PKCζ knockdown prevents p65 Serine 536 phosphorylation. Our study uncovers that the interplay of the Hippo signaling, PKCζ, and NFκB in response to mechanical loading serves as a therapeutic target for knee osteoarthritis and other conditions resulting from mechanical overloading or Hippo signaling deficiencies.