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KEY MESSAGE: Sucrose invertase activity is positively related to osmotic and salt stress resistance in peanut. Sucrose invertases (INVs) have important functions in plant growth and response to environmental stresses. However, their biological roles in peanut are still not fully revealed. In this research, we identified 42 AhINV genes in the peanut genome. They were highly conserved and clustered into three groups with 24 segmental duplication events occurred under purifying selection. Transcriptional expression analysis exhibited that they were all ubiquitously expressed, and most of them were up-regulated by osmotic and salt stresses, with AhINV09, AhINV23 and AhINV19 showed the most significant up-regulation. Further physiochemical analysis showed that the resistance of peanut to osmotic and salt stress was positively related to the high sugar content and sucrose invertase activity. Our results provided fundamental information on the structure and evolutionary relationship of INV gene family in peanut and gave theoretical guideline for further functional study of AhINV genes in response to abiotic stress.
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Arachis , Azúcares , Arachis/genética , beta-Fructofuranosidasa/genética , Estrés Salino , SacarosaRESUMEN
RATIONALE AND OBJECTIVES: This study aimed to develop and validate a dual-energy CT (DECT)-based model for preoperative prediction of the number of central lymph node metastases (CLNMs) in clinically node-negative (cN0) papillary thyroid carcinoma (PTC) patients. MATERIALS AND METHODS: Between January 2016 and January 2021, 490 patients who underwent lobectomy or thyroidectomy, CLN dissection, and preoperative DECT examinations were enrolled and randomly allocated into the training (N = 345) and validation cohorts (N = 145). The patients' clinical characteristics and quantitative DECT parameters obtained on primary tumors were collected. Independent predictors of> 5 CLNMs were identified and integrated to construct a DECT-based prediction model, for which the area under the curve (AUC), calibration, and clinical usefulness were assessed. Risk group stratification was performed to distinguish patients with different recurrence risks. RESULTS: More than 5 CLNMs were found in 75 (15.3%) cN0 PTC patients. Age, tumor size, normalized iodine concentration (NIC), normalized effective atomic number (nZeff) and the slope of the spectral Hounsfield unit curve (λHu) in the arterial phase were independently associated with> 5 CLNMs. The DECT-based nomogram that incorporated predictors demonstrated favorable performance in both cohorts (AUC: 0.842 and 0.848) and significantly outperformed the clinical model (AUC: 0.688 and 0.694). The nomogram showed good calibration and added clinical benefit for predicting> 5 CLNMs. The KaplanMeier curves for recurrence-free survival showed that the high- and low-risk groups stratified by the nomogram were significantly different. CONCLUSION: The nomogram based on DECT parameters and clinical factors could facilitate preoperative prediction of the number of CLNMs in cN0 PTC patients.
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Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/diagnóstico por imagen , Cáncer Papilar Tiroideo/cirugía , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/cirugía , Neoplasias de la Tiroides/patología , Metástasis Linfática/diagnóstico por imagen , Metástasis Linfática/patología , Tiroidectomía , Nomogramas , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Ganglios Linfáticos/patologíaRESUMEN
BACKGROUND: Accumulating evidence links the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement to venous thromboembolism (VTE) in non-small cell lung cancer (NSCLC) patients. However, the corresponding mechanisms remain unclear. METHOD: High-throughput sequencing analysis of H3122 human ALK-positive NSCLC cells treated with ALK inhibitor/ dimethyl sulfoxide (DMSO) was performed to identify coagulation-associated differential genes between EML4-ALK fusion protein inhibited cells and control cells. Sequentially, we confirmed its expression in NSCLC patients' tissues and in the plasma of a subcutaneous xenograft mouse model. An inferior vena cava (IVC) ligation model was used to assess clot formation potential. Additionally, pathways involved in tissue factor (TF) regulation were explored in ALK-positive cell lines H3122 and H2228. Statistical significance was determined by Student t-test and one-way ANOVA using SPSS. RESULTS: Sequencing analysis identified a significant downregulation of TF after inhibiting EML4-ALK fusion protein activity in H3122 cells. In clinical NSCLC cases, TF expression was increased especially in ALK-positive NSCLC tissues. Meanwhile, H3122 and H2228 with high TF expression exhibited shorter plasma clotting time and higher TF activity versus ALK-negative H1299 and A549 in cell culture supernatant. Mice bearing H2228 tumor showed a higher concentration of tumor-derived TF and TF activity in plasma and the highest adjusted IVC clot weights. Limiting EML4-ALK protein phosphorylation downregulated extracellular regulated protein kinases 1/2 (ERK1/2)-activating the protein-1(AP-1) signaling pathway and thus attenuated TF expression. CONCLUSION: EML4-ALK fusion protein may enhance venous thrombogenicity by regulating coagulation factor TF expression. There was potential involvement of the pERK1/2-AP-1 pathway in this process.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Animales , Ratones , Neoplasias Pulmonares/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/uso terapéutico , Tromboplastina/genética , Factor de Transcripción AP-1/uso terapéutico , Proliferación Celular , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/análisis , Proteínas de Fusión Oncogénica/metabolismoRESUMEN
Background: Although computed tomography (CT)-defined emphysema is considered a predictor of lung cancer risk, it is not fully clear whether CT-defined emphysema is associated with the prognosis of lung cancer. We aimed to assess the clinical impact of CT-defined emphysema on the survival of lung cancer. Methods: In the prospective cohort study of nonsmall cell lung cancer (NSCLC), the correlation between CT-defined emphysema and clinical variables was analysed. A multivariable Cox regression model was built to assess the association between CT-defined emphysema and overall survival (OS) for up to 8.8â years. The differences in survival analyses were derived by Kaplan-Meier analysis and log-rank testing. Low attenuation area (LAA%) was defined as the per cent of voxels below -950â HU. Results: 854 patients were included and CT-defined emphysema was present in 300 (35.1%) at diagnosis. Epidermal growth factor receptor (EGFR) wild-type (OR 1.998; p<0.001) and anaplastic lymphoma kinase (ALK) wild-type (OR 2.277; p=0.004) were associated with CT-defined emphysema. CT-defined emphysema remained a significant predictor of prognosis adjusting for age, sex, smoking history, tumour histology and Eastern Cooperative Oncology Group Performance Status (ECOG PS), whether in I-IIIA stage (adjusted hazard ratio (HR) 1.745; p=0.017) or in IIIB-IV stage (adjusted HR 1.291; p=0.022). Stratified analyses showed that OS rate among the driver oncogene groups with different CT-defined emphysema status differed significantly (log-rank p<0.001). Furthermore, patients with centrilobular emphysema (CLE) with LAA% >17% displayed poorer survival than those with LAA% ≤17% (median 432 versus 670â days; HR 1.564; p=0.020). Conclusions: CT-defined emphysema, especially CLE with LAA%>17%, is an independent predictor of NSCLC prognosis. Moreover, prospective studies are needed to further explore this association.
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BACKGROUND: Along with the improvement of lung cancer screening implementation, the identification of interstitial lung abnormality (ILA) is increasing. Currently, there is a limited description of the oncogenic status and ILA subtypes among newly diagnosed non-small cell lung cancer (NSCLC) patients with ILA in the Chinese population. This study aimed to investigate the prevalence, characteristics, oncogenic status and factors associated with overall survival (OS) among NSCLC patients with ILA. METHODS: A total of 765 newly diagnosed NSCLC cases at our hospital were reviewed and ILA was diagnosed according to the criteria of the Fleischner Society. The characteristics, clinical pathological features and OS of NSCLC patients with ILA were retrospectively analyzed. RESULTS: Of the 765 patients included in the study, 101 (13.2%) cases experienced ILA at the time of NSCLC diagnosis. Multivariate analysis revealed that ILA was more likely to be detected in NSCLC patients who were age ≥60 (OR 2.404, p = 0.001), male gender (OR 2.476, p = 0.004), and EGFR wild-type (OR 2.035, p = 0.007). Additionally, according to the multivariate Cox model, the presence of ILA in NSCLC patients was significantly associated with a shorter OS period than those without ILA (751 days vs. 445 days, HR 0.6, p = 0.001). Following analysis, it was determined that OS in patients with usual interstitial pneumonia (UIP) was shorter than in those without UIP (HR 1.82, p = 0.037). CONCLUSION: ILA is a common comorbidity among newly diagnosed NSCLC patients. We found that patients with EGFR wild-type NSCLC were more likely to develop ILA. The presence of ILA, especially UIP, was significantly associated with poor NSCLC prognosis.
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Carcinoma de Pulmón de Células no Pequeñas , Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Neoplasias Pulmonares , Humanos , Masculino , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/epidemiología , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/epidemiología , Enfermedades Pulmonares Intersticiales/patología , Estudios Retrospectivos , Prevalencia , Detección Precoz del Cáncer , Pronóstico , Pulmón/patología , Receptores ErbBRESUMEN
Guinea pigs are a valuable animal model for studying various diseases, including reproductive diseases. However, techniques for generating embryos via embryo engineering in guinea pigs are limited; for instance, in vitro maturation (IVM) technique is preliminary for guinea pig oocytes. In this study, we aimed to establish and optimize an IVM method for guinea pig oocytes by investigating various factors, such as superovulation induced by different hormones, culture supplementation (e.g., amino acids, hormone, and inhibitors), culture conditions (e.g., oocyte type, culture medium type, and treatment time), and in vivo hCG stimulation. We found that oocytes collected from guinea pigs with superovulation induced by hMG have a higher IVM rate compared to those collected from natural cycling individuals. Moreover, we found that addition of L-cysteine, cystine, and ROS in the culture medium can increase the IVM rate. In addition, we demonstrated that in vivo stimulation with hCG for 3-8 h can further increase the IVM rate. As a result, the overall IVM rate of guinea pig oocytes under our optimized conditions can reach ~69%, and the mature oocytes have high GSH levels and normal morphology. In summary, we established an effective IVM method for guinea pig oocytes by optimizing various factors and conditions, which provides a basis for embryo engineering using guinea pigs as a model.
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Técnicas de Maduración In Vitro de los Oocitos , Oocitos , Femenino , Cobayas , Animales , Técnicas de Maduración In Vitro de los Oocitos/métodos , Oocitos/metabolismo , Oogénesis , Aminoácidos/metabolismo , Cisteína/farmacología , Cisteína/metabolismoRESUMEN
Objectives: To develop and validate a CT-based radiomics nomogram that can provide individualized pretreatment prediction of the response to platinum treatment in small cell lung cancer (SCLC). Materials: A total of 134 SCLC patients who were treated with platinum as a first-line therapy were eligible for this study, including 51 patients with platinum resistance (PR) and 83 patients with platinum sensitivity (PS). The variance threshold, SelectKBest, and least absolute shrinkage and selection operator (LASSO) were applied for feature selection and model construction. The selected texture features were calculated to obtain the radiomics score (Rad-score), and the predictive nomogram model was composed of the Rad-score and the clinical features selected by multivariate analysis. Receiver operating characteristic (ROC) curves, calibration curves, and decision curves were used to assess the performance of the nomogram. Results: The Rad-score was calculated using 10 radiomic features, and the resulting radiomics signature demonstrated good discrimination in both the training set (area under the curve [AUC], 0.727; 95% confidence interval [CI], 0.627-0.809) and the validation set (AUC, 0.723; 95% CI, 0.562-0.799). To improve diagnostic effectiveness, the Rad-score created a novel prediction nomogram by combining CA125 and CA72-4. The radiomics nomogram showed good calibration and discrimination in the training set (AUC, 0.900; 95% CI, 0.844-0.947) and the validation set (AUC, 0.838; 95% CI, 0.534-0.735). The radiomics nomogram proved to be clinically beneficial based on decision curve analysis. Conclusion: We developed and validated a radiomics nomogram model for predicting the response to platinum in SCLC patients. The outcomes of this model can provide useful suggestions for the development of tailored and customized second-line chemotherapy regimens.
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Liver cancer is a kind of malignant tumor with poor sensitivity to chemotherapy. It is urgent to investigate approaches to improve the outcome of chemotherapy. KDM5A has been reported to be an oncogene in various cancers and is associated with drug resistance. However, the functions of KDM5A in chemotherapeutic sensitivity of liver cancer not been well illustrated. In this study, we found that KDM5A was upregulated in liver cancer tissue and cell lines. KDM5A knockdown using a gene interference strategy suppressed the growth of liver cancer in vitro and in vivo. CPI-455, a pharmacological inactivation of KDM5A enhanced the cytotoxicity of cisplatin (CDDP) in liver cells. CPI-455 and CDDP cotreatment resulted in apoptosis and mitochondrial dysfunction. We also found that knockdown or inactivation of KDM5A resulted in the downregulation of ROCK1, an oncogene regulating the activation of the PTEN/AKT signaling pathway. In particular, overexpression of ROCK1 or SF1670, a pharmacological inhibitor of PTEN, alleviated the cytotoxicity of CPI-455 and CDDP cotreatment. In HCCLM3 xenografts, CPI-455 and CDDP cotreatment dramatically inhibited the growth of xenograft tumor compared to CPI-455 or CDDP treatment alone. In conclusion, this study suggested that targeting the inactivation of KDM5A is an efficient strategy to enhance the chemosensitivity of liver cancer cells to CDDP by modulating the ROCK1/PTEN/AKT signaling pathway.
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Neoplasias Hepáticas , Proteínas Proto-Oncogénicas c-akt , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Transducción de Señal , Apoptosis , Neoplasias Hepáticas/tratamiento farmacológico , Resistencia a Antineoplásicos , Proteína 2 de Unión a Retinoblastoma/metabolismo , Quinasas Asociadas a rho/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismoRESUMEN
Koumine, an alkaloid, exerts therapeutic effects against rheumatoid arthritis (RA), and thus may have a potential application in novel treatment strategies against this disease. Herein, we investigated the regulatory effect of koumine on Th cell polarization using a "pyramid" structure model to elucidate the mechanism underlying its therapeutic effect on RA. The third layer of the model comprises the cytokine secretion layer, in which the effects of koumine on the balance of Th-related cytokines were investigated in mice with collagen-induced arthritis (CIA). Koumine showed significant therapeutic effects and reversed the imbalance of Th1/Th2 and Th17/Treg cytokines. In the Th cell polarization layer, the effects of koumine on the relative numbers of Th cell subsets in splenocytes of rats with CIA were examined. Koumine attenuated both of the increased Th1/Th2 and Th17/Treg subset ratios accompanied with its therapeutic effects. Finally, the primary cultured splenocytes from BALB/c mice were used to further investigate the effect of koumine on Th cell activation by evaluating cell proliferation induced by concanavalin A (Con A), lipopolysaccharides (LPS) and phytohemagglutinin (PHA). Koumine inhibited the cell proliferation responses and its effects on proliferation induced by Con A and PHA were greater than those by LPS, showing the relatively selective inhibition on the proliferation of Th cells. Our results suggest that koumine might restore the homeostasis of the network system with Th subsets and cytokines by inhibiting the activation of T cells, subsequently regulating the polarization of Th subsets and the downstream imbalance of pro/anti-inflammatory cytokines in RA.
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Artritis Experimental , Artritis Reumatoide , Ratones , Ratas , Animales , Lipopolisacáridos/farmacología , Artritis Reumatoide/tratamiento farmacológico , Artritis Experimental/tratamiento farmacológico , Células Th17 , Linfocitos T Reguladores , Citocinas/farmacologíaRESUMEN
Cystic fibrosis (CF) is a life-threatening autosomal-recessive disease caused by mutations in a single gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). CF effects multiple organs, and lung disease is the primary cause of mortality. The median age at death from CF is in the early forties. CF was one of the first diseases to be considered for gene therapy, and efforts focused on treating CF lung disease began shortly after the CFTR gene was identified in 1989. However, despite the quickly established proof-of-concept for CFTR gene transfer in vitro and in clinical trials in 1990s, to date, 36 CF gene therapy clinical trials involving â¼600 patients with CF have yet to achieve their desired outcomes. The long journey to pursue gene therapy as a cure for CF encountered more difficulties than originally anticipated, but immense progress has been made in the past decade in the developments of next generation airway transduction viral vectors and CF animal models that reproduced human CF disease phenotypes. In this review, we look back at the history for the lessons learned from previous clinical trials and summarize the recent advances in the research for CF gene therapy, including the emerging CRISPR-based gene editing strategies. We also discuss the airway transduction vectors, large animal CF models, the complexity of CF pathogenesis and heterogeneity of CFTR expression in airway epithelium, which are the major challenges to the implementation of a successful CF gene therapy, and highlight the future opportunities and prospects.
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To investigate the solid-state forms of koumine hydrochloride (KMY), solid form screening was performed, and one amorphous form and five crystalline forms (forms A, B, C, D, and E) were identified by powder X-ray diffraction. Form A was the dominant crystal product, and its crystal structure and packing pattern were determined by single-crystal X-ray diffraction. The crystals displayed an orthorhombic crystal system and symmetry of space group P212121 with Z' = 1. The amorphous form transformed to form A at 105-120 °C or 75% RH, while forms B, C, D, and E could only be intermediate phases and readily transformed to form A at room temperature. Therefore, the phase transformations of KMY solid-state forms were established. The properties of the amorphous form and form A were further elucidated by applying vibrational spectroscopy, moisture sorption analysis, and thermal analysis. Accordingly, form A, the KMY anhydrate, was found to be the thermodynamically stable form with low hygroscopicity under ambient conditions. These characteristics are crucial in the manufacture and storage of active pharmaceutical ingredients.
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Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells which are abnormally accumulated during the differentiation of myeloid cells. Immunosuppression is the main functional feature of MDSCs, which inhibit T cell activity in the tumor microenvironment (TME) and promote tumoral immune escape. The main principle for immunotherapy is to modulate, restore, and remodel the plasticity and potential of immune system to have an effective anti-tumor response. In the TME, MDSCs are major obstacles to cancer immunotherapy through reducing the anti-tumor efficacy and making tumor cells more resistant to immunotherapy. Therefore, targeting MDSCs treatment becomes the priority of relevant studies and provides new immunotherapeutic strategy for cancer treatment. In this review, we mainly discuss the functions and mechanisms of MDSCs as well as their functional changes in the TME. Further, we review therapeutic effects of immunotherapy against MDSCs and potential breakthroughs regarding immunotherapy targeting MDSCs and immune checkpoint blockade (ICB) immunotherapy.
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Células Supresoras de Origen Mieloide , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Escape del Tumor , Microambiente TumoralRESUMEN
The polarization of macrophages often leads to severe calcification and necrosis in aged atherosclerotic plaques, which eventually leads to poor prognosis of ischaemic cardiovascular and cerebrovascular diseases. More reliable diagnostic methods are urgently needed to discover therapeutic targets of macrophage polarization in aged atherosclerotic plaques. Metabolomics of aged plaques (n = 20) and macrophage polarization transcriptomes (n = 30) were integrated to identify metabolic therapeutic targets of macrophage polarization associated with aged plaque. Finally, metabolic inhibitors were used to verify the reliability of the target genes. Integrated multiomics analysis revealed that 6 metabolic pathways (including 21 genes) regulate macrophage polarization in aged atherosclerosis. Targeted treatment of macrophage polarization with metabolic inhibitors can effectively reduce the adverse risk of aged atherosclerosis. The combination of transcriptomics and metabolomics approaches can identify effective therapeutic targets for macrophage polarization in arteriosclerosis.
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Aterosclerosis , Placa Aterosclerótica , Anciano , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Aterosclerosis/metabolismo , Humanos , Macrófagos/metabolismo , Metabolómica , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Reproducibilidad de los Resultados , TranscriptomaRESUMEN
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and is an enormous burden on both patients and society. There is an urgent need for effective alternative therapeutic strategies for the treatment of DN, as medical treatment is currently limited. The anti-inflammatory, antioxidative, anti-apoptotic, and anti-fibrosis properties of curcumin, a polyphenol curcuminoid, have been demonstrated in research on diabetic nephropathy. The clinical and preclinical trials and mechanisms by which curcumin affects DN have been discussed in this review. A deeper understanding of the pharmacological effects of curcumin on diabetic nephropathy may provide new therapies to improve the development and occurrence of diabetic nephropathy.
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Curcumina , Diabetes Mellitus , Nefropatías Diabéticas , Antiinflamatorios/farmacología , Curcumina/farmacología , Curcumina/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Diarilheptanoides , Humanos , Polifenoles/farmacología , Polifenoles/uso terapéuticoRESUMEN
Clear cell renal carcinoma (CCRC) is the most common type of renal carcinoma. We hope to find out the potential key genes playing important roles in CCRC genesis and progression by analysing the recent expression profiling by array from 2014 to 2016. In order to find out the differentially expressed genes (DEGs) between CCRC and normal renal tissue. Gene Ontology (GO) and Kyoto Encyclopedia of Genes, and Genomes (KEGG) pathway enrichment were carried out by the Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8. Protein-Protein Interaction (PPI) Networks Functional Enrichment Analysis of these DEGs was analyzed using the Search Tool for Recurring Instances of Neighbouring Genes (STRING). The results were then visualized by the software Cytoscape. The authors also used the online tool of Kaplan-Meier plotter survival analysis to assess the significance of the top ten genes in the prognosis of CCRC. A total of 192 DEGs were identified and the top ten key genes were picked out by the software Cytoscape. FN1, CXCR4, LOX, and PLG were then further screened out based on the overall survival analysis; SLC12A1 and LOX were screened out after the recurrence-free survival analysis. LOX was finally believed to be the most reliable prognostic factor since it has prognostic value for both overall survival and recurrence-free survival analysis. Our analysis suggests that LOX is the most reliable prognostic factor for CCRC patients. Key Words: Renal clear cell carcinoma, Microarray datasets, Bioinformatics approach, Prognostic factor, LOX.
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Carcinoma de Células Renales , Neoplasias Renales , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/genética , Biología Computacional/métodos , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Neoplasias Renales/genética , Masculino , Recurrencia Local de Neoplasia , PronósticoRESUMEN
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature cells derived from bone marrow that play critical immunosuppressive functions in the tumor microenvironment (TME), promoting cancer progression. According to base length, Non-coding RNAs (ncRNAs) are mainly divided into: microRNAs (miRNAs), lncRNAs, snRNAs and CircRNAs. Both miRNA and lncRNA are transcribed by RNA polymerase II, and they play an important role in gene expression under both physiological and pathological conditions. The increasing data have shown that MiRNAs/LncRNAs regulate MDSCs within TME, becoming one of potential breakthrough points at the investigation and treatment of cancer. Therefore, we summarize how miRNAs/lncRNAs mediate the differentiation, expansion and immunosuppressive function of tumor MDSCs in TME. We will then focus on the regulatory mechanisms of exosomal MicroRNAs/LncRNAs on tumor MDSCs. Finally, we will discuss how the interaction of miRNAs/lncRNAs modulates tumor MDSCs.
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Resection of brain tumors frequently causes injury to the surrounding brain tissue that exacerbates cerebral edema by activating an inflammatory cascade. Although corticosteroids are often utilized peri-operatively to alleviate the symptoms associated with brain edema, they increase operative morbidities and suppress the efficacy of immunotherapy. Thus, novel approaches to minimize cerebral edema caused by neurosurgical procedures will have significant utility in the management of patients with brain tumors. We have studied the role of the receptor for advanced glycation end products (RAGE) and its ligands on inflammatory responses to neurosurgical injury in mice and humans. Blood-brain barrier (BBB) integrity and neuroinflammation were characterized by Nanostring, flow cytometry, qPCR, and immunoblotting of WT and RAGE knockout mice brains subjected to surgical brain injury (SBI). Human tumor tissue and fluid collected from the resection cavity of patients undergoing craniotomy were also analyzed by single-cell RNA sequencing and ELISA. Genetic ablation of RAGE significantly abrogated neuroinflammation and BBB disruption in the murine SBI model. The inflammatory responses to SBI were associated with infiltration of S100A9-expressing myeloid-derived cells into the brain. Local release of pro-inflammatory S100A9 was confirmed in patients following tumor resection. RAGE and S100A9 inhibitors were as effective as dexamethasone in attenuating neuroinflammation. However, unlike dexamethasone and S100A9 inhibitor, RAGE inhibition did not diminish the efficacy of anti-PD-1 immunotherapy in glioma-bearing mice. These observations confirm the role of the RAGE axis in surgically induced neuroinflammation and provide an alternative therapeutic option to dexamethasone in managing post-operative cerebral edema.
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Antiinflamatorios , Edema Encefálico , Neoplasias Encefálicas , Receptor para Productos Finales de Glicación Avanzada , Animales , Antiinflamatorios/farmacología , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/etiología , Lesiones Encefálicas/complicaciones , Neoplasias Encefálicas/cirugía , Dexametasona/uso terapéutico , Modelos Animales de Enfermedad , Humanos , Ratones , Ratas , Ratas Sprague-Dawley , Receptor para Productos Finales de Glicación Avanzada/antagonistas & inhibidoresRESUMEN
Gelsemium elegans (G. elegans) Benth., recognized as a toxic plant, has been used as traditional Chinese medicine for the treatment of neuropathic pain and cancer for many years. In the present study, we aim to obtain the anti-tumor effects of alkaloids of G. elegans and their active components in hepatocellular carcinoma (HCC) and the potential mechanism was also further investigated. We demonstrated that sempervirine induced HCC cells apoptosis and the apoptosis was associated with cell cycle arrest during the G1 phase, up-regulation of p53 and down-regulation of cyclin D1, cyclin B1 and CDK2. Furthermore, sempervirine inhibited HCC tumor growth and enhances the anti-tumor effect of sorafenib in vivo. In addition, inactivation of Wnt/ß-catenin pathway was found to be involved in sempervirine-induced HCC proliferation. The present study demonstrated that alkaloids of G. elegans were a valuable source of active compounds with anti-tumor activity. Our findings justified that the active compound sempervirine inhibited proliferation and induced apoptosis in HCC by regulating Wnt/ß-catenin pathway.
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Koumine (KME) is an active alkaloid extracted from Gelsemium elegans, and its diverse bioactivities have been studied for decades. However, KME exhibits poor solubility and low oral bioavailability, which hampers its potential therapeutic exploitation. This work aimed to develop optimized inclusion complexes to improve the bioavailability of KME. The KME/hydroxypropyl-ß-cyclodextrin (KME/HP-ß-CD) inclusion complexes were prepared by the solvent evaporation method and later optimized using the Box-Behnken design. The optimal KME/HP-ß-CD was characterized by scanning electron microscopy, Fourier transforms infrared spectroscopy, differential scanning calorimetry, and nuclear magnetic resonance spectroscopy. The physicochemical characterization results revealed that the crystalline state of KME was transformed into an amorphous form, forming KME/HP-ß-CD inclusion complexes. Compared with KME, the solubility and in vitro release rate of KME/HP-ß-CD was significantly enhanced by 52.34- and 1.3-fold, respectively. Further research was performed to investigate the intestinal absorption characteristics and in vivo bioavailability in rats. The optimal KME/HP-ß-CD showed enhanced absorptive permeability and relative bioavailability increased more than two-fold compared to that of raw KME. These results indicate that the optimal KME/HP-ß-CD can be used as an effective drug carrier to improve the solubility, intestinal absorption, and bioavailability of KME.