Abstract: Natural product curcumin (Cur) and H 2 S-releasing prodrug SH-aspirin (SH-ASA) are potential anticancer agents with diverse mechanisms, but their clinical application prospects are restricted by hydrophobicity and limited efficiency. In this work, we coencapsulated SH-ASA and Cur into methoxy poly(ethylene glycol)-poly (lactide-coglycolide) (mPEG-PLGA) nanoparticles through a modified oil-in-water single-emulsion solvent evaporation process. The prepared SH-ASA/Cur-coloaded mPEG-PLGA nanoparticles had a mean particle size of 122.3±6.8 nm and were monodispersed (polydispersity index =0.179±0.016) in water, with high drug-loading capacity and stability. Intriguingly, by treating with SH-ASA/Cur-coloaded mPEG-PLGA nanoparticles, obvious synergistic anticancer effects on ES-2 and SKOV3 human ovarian carcinoma cells were observed in vitro, and activation of the mitochondrial apoptosis pathway was indicated. Our results demonstrated that SH-ASA/Cur-coloaded mPEG-PLGA nanoparticles could have potential clinical advantages for the treatment of ovarian cancer. Keywords: drug delivery, cancer therapy, ovarian cancer, synergistic effect
Objective. To investigate the clinical characteristics of patients with unstable angina (UA) who received elective percutaneous coronary intervention (PCI) in a traditional Chinese medicine (TCM) hospital and to analyze the related risk factors of periprocedural myocardial injury (PMI). Methods. On the basis of cross-sectional investigation, the case-control method was adopted. We retrospectively collected clinical data of patients with UA who successfully received elective PCI in Beijing Hospital of TCM from February 2017 to February 2019. Based on the occurrence of PMI, the case-control was formed. The influence of related factors on PMI occurrence was analyzed using the logistic multiple regression equation based on the parameters between the comparison groups. Results. 1. Incidence of PMI and related clinical features: Of the 265 UA patients, the incidence of PMI was 26.4%, nearly one quarter (23.4%) had old myocardial infarction, nearly half (45.3%) had previously received coronary intervention. The prevalence of patients with previous hypertension (75.8%), type 2 diabetes (57%), and high-low-density lipoprotein cholesterolemia (69.3%) exceeded 50%, more than 50% of the patients have triple-vessel disease (50.2%). 2. Features of TCM syndrome elements: The main TCM syndromes of the investigated patients are blood stasis syndrome (81.1%) and Qi deficiency syndrome (77.3%), the others include Phlegm turbidity syndrome (53.2%), Yang deficiency syndrome (50.9%), Yin deficiency syndrome (50.1%), Qi stagnation syndrome (30.1%), and coagulated cold syndrome (17.1%). 3. Factors of PMI occurrence: According to the occurrence of PMI, 265 patients were divided into PMI group (n = 70) and non-PMI group (n = 195). The comparison between groups shows that the preoperative SYNTAX score, the number of stents, and the total length of stents of the patients in the PMI group were higher than those in the non-PMI group ( ); the patients in the PMI group treated by Shen-Yuan-Dan (SYD), a Chinese medicine prescription with Qi-supplementing and blood stasis-purging, were significantly lower than those in the non-PMI group ( ). Brought these four factors (preoperative SYNTAX score, number of stents implanted, total length of implanted stents, and treated by SYD) into the binary logistic regression equation, those who were only treated by SYD have statistical significance in the equation as a protective factor (OR 0.327, 95% CI 0.117–0.916, ). Conclusion. Patients with UA who received elective PCI in TCM institutions may have clinical characteristics including multiple accompanying diseases and high stenosis coronary artery, in which the incidence of poor blood glucose control and high rate of three-vessel coronary disease are particularly significant. The TCM syndromes are mainly Qi deficiency and blood stasis syndromes. The decrease of PMI may be attributed to the application of SYD in the real world. This trial is registered at ChiCTR2100043465.
<div>Abstract<p>Glioma stem cells (GSC) are a subpopulation of tumor cells with special abilities to proliferate and differentiate in gliomas. They are one of the main causes of tumor recurrence, especially under hypoxic conditions. Although long noncoding RNAs (lncRNA) are known to be involved in numerous biological processes and are implied in the occurrence of certain diseases, their role in tumor development and progression remains poorly understood. Here we explored the mechanisms by which lncRNA derived from hypoxic GSCs (H-GSC) cause glioma progression. Isolation and identification of the Linc01060 gene, the exosomes containing them, and the proteins from tumor cells regulating the gene allowed for studying the effects of Linc01060 on proliferation and glycometabolism. H-GSC exerted their effects by transferring exosomes to glioma cells, resulting in a significant increase in Linc01060 levels. Mechanistically, Linc01060 directly interacted with the transcription factor myeloid zinc finger 1 (MZF1) and enhanced its stability. Linc01060 facilitated nuclear translocation of MZF1 and promoted MZF1-mediated c-Myc transcriptional activities. In addition, c-Myc enhanced the accumulation of the hypoxia-inducible factor-1 alpha (HIF1α) at the posttranscriptional level. HIF1α bound the hormone response elements of the Linc01060 promoter, upregulating the transcription of Linc01060 gene. Clinically, Linc01060 was upregulated in glioma and was significantly correlated with tumor grade and poor clinical prognosis. Overall, these data show that secretion of Linc01060-containing exosomes from H-GSCs activates prooncogenic signaling pathways in glioma cells to promote disease progression.</p>Significance:<p>These findings suggest that inhibition of Linc01060-containing exosomes or targeting the Linc01060/MZF1/c-Myc/HIF1α axis may be an effective therapeutic strategy in glioma.</p></div>
Abstract Background Patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) have an increased risk of disease exacerbation and decreased survival. We aimed to develop and validate a non‐invasive nomogram for predicting COPD associated with severe PH and a prognostic nomogram for patients with COPD and concurrent PH (COPD–PH). Methods This study included 535 patients with COPD–PH from six hospitals. A multivariate logistic regression analysis was used to analyse the risk factors for severe PH in patients with COPD and a multivariate Cox regression was used for the prognostic factors of COPD–PH. Performance was assessed using calibration, the area under the receiver operating characteristic curve and decision analysis curves. Kaplan–Meier curves were used for a survival analysis. The nomograms were developed as online network software. Results Tricuspid regurgitation velocity, right ventricular diameter, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), the red blood cell count, New York Heart Association functional class and sex were non‐invasive independent variables of severe PH in patients with COPD. These variables were used to construct a risk assessment nomogram with good discrimination. NT‐proBNP, mean pulmonary arterial pressure, partial pressure of arterial oxygen, the platelet count and albumin were independent prognostic factors for COPD–PH and were used to create a predictive nomogram of overall survival rates. Conclusions The proposed nomograms based on a large sample size of patients with COPD–PH could be used as non‐invasive clinical tools to enhance the risk assessment of severe PH in patients with COPD and for the prognosis of COPD–PH. Additionally, the online network has the potential to provide artificial intelligence‐assisted diagnosis and treatment. Highlights A multicentre study with a large sample of chronic obstructive pulmonary disease (COPD) patients diagnosed with PH through right heart catheterisation. A non‐invasive online clinical tool for assessing severe pulmonary hypertension (PH) in COPD. The first risk assessment tool was established for Chinese patients with COPD–PH.
Transarterial chemoembolization (TACE) has been widely introduced to treat hepatocellular carcinoma (HCC) especially for unresectable patients for decades. However, TACE evokes an angiogenic response due to the secretion of vascular endothelial growth factor (VEGF), resulting in the formation of new blood vessels and eventually tumor recurrence. Thus, we aimed to develop regorafenib (REGO)-loaded poly (lactide-co-glycolide) (PLGA) microspheres that enabled localized and sustained drug delivery to limit proangiogenic responses following TACE in HCC treatment. REGO-loaded PLGA microspheres were prepared using the emulsion-solvent evaporation/extraction method, in which DMF was selected as an organic phase co-solvent. Accordingly, we optimized the proportion of DMF, which the optimal ratio to DCM was 1:9 (v/v). After preparation, the microspheres provided high drug loading capacity of 28.6%, high loading efficiency of 91.5%, and the average particle size of 149 µm for TACE. IR spectra and XRD were applied to confirming sufficient REGO entrapment. The in vitro release profiles demonstrated sustained drug release of microspheres for more than 30 d To confirm the role of REGO-loaded microspheres in TACE, the cell cytotoxic activity on HepG2 cells and anti-angiogenic effects in HUVECs Tube-formation assay were studied in combination with miriplatin. Moreover, the microspheres indicated the potential of antagonizing miriplatin resistance of HepG2 cells in vitro. Pharmacokinetics preliminary studies exhibited that REGO could be sustainably released from microspheres for more than 30 d after TACE in vivo. In vivo anti-tumor efficacy was further determined in HepG2 xenograft tumor mouse model, demonstrating that REGO microspheres could improve the antitumor efficacy of miriplatin remarkably compared with miriplatin monotherapy. In conclusion, the obtained REGO microspheres demonstrated promising therapeutic effects against HCC when combined with TACE.
Abstract Isocitrate dehydrogenase 1 ( IDH1 ) mutations are discovered in most grade Ⅱ gliomas (71%-78%), grade Ⅲ gliomas (62%-78%) and secondary glioblastomas (88%), and have received lots of attention in recent years. However, the tumor-promoting role of wildtype IDH1 still need to be further investigated. In this article, we found wildtype IDH1 mRNA and protein levels were both elevated in glioma by using bioinformatic analysis, Besides, IDH1 mutation reduced the expression of wildtype IDH1 in U87-R132H cell line. Furthermore, the expression of wildtype IDH1 also increased along with the increase of clinical grades of glioma. Cell function and signaling pathways enrichment analyses were enriched in metabolic processes, phosphatase complex, TCA, DNA replication, p53 signaling pathway, Notch signaling pathway, et al. Single-cell sequencing analysis revealed that high expression of wildtype IDH1 correlated with cell cycle, metastasis, EMT, proliferation, invasion, stemness, and DNA damage. Besides, wildtype IDH1 promoted GBM cell viability, migration, and radioresistance in vitro. Wildtype IDH1 was significantly relevant with diagnosis, prognosis, and survival probability of glioma patients. Therefore, wildtype IDH1 could be an underlying target for glioma therapy.
PurposeWe aim to interrogate the role of positron emission tomography (PET) image discretization parameters on the prognostic value of radiomic features in patients with oropharyngeal cancer.ApproachA prospective clinical trial (NCT01908504) enrolled patients with oropharyngeal squamous cell carcinoma (N=69; mixed HPV status) undergoing definitive radiotherapy and evaluated intra-treatment 18fluorodeoxyglucose PET as a potential imaging biomarker of early metabolic response. The primary tumor volume was manually segmented by a radiation oncologist on PET/CT images acquired two weeks into treatment (20 Gy). From this, 54 radiomic texture features were extracted. Two image discretization techniques—fixed bin number (FBN) and fixed bin size (FBS)—were considered to evaluate systematic changes in the bin number ({32, 64, 128, 256} gray levels) and bin size ({0.10, 0.15, 0.22, 0.25} bin-widths). For each discretization-specific radiomic feature space, an LASSO-regularized logistic regression model was independently trained to predict residual and/or recurrent disease. The model training was based on Monte Carlo cross-validation with a 20% testing hold-out, 50 permutations, and minor-class up-sampling to account for imbalanced outcomes data. Performance differences among the discretization-specific models were quantified via receiver operating characteristic curve analysis. A final parameter-optimized logistic regression model was developed by incorporating different settings parameterizations into the same model.ResultsFBN outperformed FBS in predicting residual and/or recurrent disease. The four FBN models achieved AUC values of 0.63, 0.61, 0.65, and 0.62 for 32, 64, 128, and 256 gray levels, respectively. By contrast, the average AUC of the four FBS models was 0.53. The parameter-optimized model, comprising features joint entropy (FBN = 64) and information measure correlation 1 (FBN = 128), achieved an AUC of 0.70. Kaplan–Meier analyses identified these features to be associated with disease-free survival (p=0.0158 and p=0.0180, respectively; log-rank test).ConclusionsOur findings suggest that the prognostic value of individual radiomic features may depend on feature-specific discretization parameter settings.
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