5-Methylcytosine-Related Long Noncoding RNAs Are Potential Biomarkers to Predict Overall Survival and Regulate Tumor-Immune Environment in Patients with Bladder Cancer.

The role of 5-methylcytosine-related long noncoding RNAs (m5C-lncRNAs) in bladder cancer (BLCA) remains unclear. Here, we aim to study the prognostic value, gene expression characteristics, and correlation between the m5C-lncRNA risk model and the tumor microenvironment, immune infiltration, and tumor mutations in BLCA. After collecting BLCA patient RNA sequence transcriptome data, clinical information and mutation data from the Cancer Genome Atlas (TCGA) database, 17 m5C-related lncRNAs independently correlated with OS were obtained by Lasso and multivariate Cox regression analysis, and a risk model was constructed. Univariate Cox, multivariate Cox regression analysis, and the C-index curve proved that the risk model was a significant independent prognostic indicator for patients with BLCA. ESTIMATE and CIBERSORT indicated that the higher the number of immune cells and stromal cells in TME, the higher the prognostic risk. We found that in the low-risk group, the expression levels of immune cells that predicted a good prognosis were higher, including plasma cells, regulatory T cells, and CD 8 T cells. There is a negative correlation between TMB and risk score. The TMB of the low-risk group is significantly higher than that of the high-risk group. In conclusion, the m5C-related risk model is crucial to predict the prognosis of patients with BLCA.

Developing Smart Nanoparticles Responsive to the Tumor Micro-Environment for Enhanced Synergism of Thermo-Chemotherapy With PA/MR Bimodal Imaging.

With the development of nanotechnology, a theranostics nanoplatform can have broad applications in multimodal image-guided combination treatment in cancer precision medicine. To overcome the limitations of a single diagnostic imaging mode and a single chemotherapeutic approach, we intend to combat tumor growth and provide therapeutic interventions by integrating multimodal imaging capabilities and effective combination therapies on an advanced platform. So, we have constructed IO@MnO2@DOX (IMD) hybrid nanoparticles composed of superparamagnetic iron oxide (IO), manganese dioxide (MnO2), and doxorubicin (DOX). The nano-platform could achieve efficient T2-T1 magnetic resonance (MR) imaging, switchable photoacoustic (PA) imaging, and tumor microenvironment (TME)-responsive DOX release and achieve enhanced synergism of magnetic hyperthermia and chemotherapy with PA/MR bimodal imaging. The results show that IMD has excellent heating properties when exposed to an alternating magnetic field (AMF). Therefore, it can be used as an inducer for tumor synergism therapy with chemotherapy and hyperthermia. In the TME, the IMD nanoparticle was degraded, accompanied by DOX release. Moreover, in vivo experimental results show that the smart nanoparticles had excellent T2-T1 MR and PA imaging capabilities and an excellent synergistic effect of magnetic hyperthermia and chemotherapy. IMD nanoparticles could significantly inhibit tumor growth in tumor-bearing mice with negligible side effects. In conclusion, smart IMD nanoparticles have the potential for tumor diagnosis and growth inhibition as integrated diagnostic nanoprobes.

Uterine artery embolization, surgery and high intensity focused ultrasound in the treatment of uterine fibroids: a network meta-analysis.

BACKGROUND: To systematic review the safety and effectiveness between uterine artery embolization (UAE), surgery and high intensity focused ultrasound (HIFU) in the treatment of uterine fibroids. METHODS: The PubMed, EMbase, The Cochrane Library, Web of Science, Wanfang Data, and CNKI were electronically searched to collect relevant studies on comparing the safety and effectiveness of UAE, surgery and HIFU in the treatment of uterine fibroids from January 2000 to August 2019. After two reviewers independently screened the literature, extracted the data and evaluated the risk of bias of included studies, network meta-analysis was performed by ADDIS 1.16.8 and Stata 14 software. RESULTS: A total of 11 studies (22 articles) involving 3,646 patients were included. Compared with surgery, UAE and HIFU patients had higher quality of life (1-year follow-up) improvement, and UAE was higher than HIFU. Network meta-analysis show that patients treated with HIFU had the lowest incidence of major complications within 1 year, followed by UAE, and the highest surgery. Patients treated with HIFU and UAE have shorter hospital stays and quicker recovery time than surgery. The rate of further intervention after surgery treatment might be lower than that of UAE and HIFU. CONCLUSIONS: UAE has the highest quality of life improvement (1-year follow-up) for uterine fibroids. HIFU and UAE are safer with shorter hospital stays and quicker recovery time compared with surgery. However, both UAE and HIFU have the risks of re-treatment. However, limited by the number and quality of included studies, the above conclusions need to be verified through more high-quality studies.

Development and Validation of a Radiomics Nomogram for Predicting Clinically Significant Prostate Cancer in PI-RADS 3 Lesions.

PURPOSE: To develop and validate a radiomics nomogram for the prediction of clinically significant prostate cancer (CsPCa) in Prostate Imaging-Reporting and Data System (PI-RADS) category 3 lesions. METHODS: We retrospectively enrolled 306 patients within PI-RADS 3 lesion from January 2015 to July 2020 in institution 1; the enrolled patients were randomly divided into the training group (n = 199) and test group (n = 107). Radiomics features were extracted from T2-weighted imaging (T2WI), apparent diffusion coefficient (ADC) imaging, and dynamic contrast-enhanced (DCE) imaging. Synthetic minority oversampling technique (SMOTE) was used to address the class imbalance. The ANOVA and least absolute shrinkage and selection operator (LASSO) regression model were used for feature selection and radiomics signature building. Then, a radiomics score (Rad-score) was acquired. Combined with serum prostate-specific antigen density (PSAD) level, a multivariate logistic regression analysis was used to construct a radiomics nomogram. Receiver operating characteristic (ROC) curve analysis was used to evaluate radiomics signature and nomogram. The radiomics nomogram calibration and clinical usefulness were estimated through calibration curve and decision curve analysis (DCA). External validation was assessed, and the independent validation cohort contained 65 patients within PI-RADS 3 lesion from January 2020 to July 2021 in institution 2. RESULTS: A total of 75 (24.5%) and 16 (24.6%) patients had CsPCa in institution 1 and 2, respectively. The radiomics signature with SMOTE augmentation method had a higher area under the ROC curve (AUC) [0.840 (95% CI, 0.776-0.904)] than that without SMOTE method [0.730 (95% CI, 0.624-0.836), p = 0.08] in the test group and significantly increased in the external validation group [0.834 (95% CI, 0.709-0.959) vs. 0.718 (95% CI, 0.562-0.874), p = 0.017]. The radiomics nomogram showed good discrimination and calibration, with an AUC of 0.939 (95% CI, 0.913-0.965), 0.884 (95% CI, 0.831-0.937), and 0.907 (95% CI, 0.814-1) in the training, test, and external validation groups, respectively. The DCA demonstrated the clinical usefulness of radiomics nomogram. CONCLUSION: The radiomics nomogram that incorporates the MRI-based radiomics signature and PSAD can be conveniently used to individually predict CsPCa in patients within PI-RADS 3 lesion.

Direct Interaction of Daxx and Androgen Receptor Is Required for Their Regulatory Activity in Cholesterol Biosynthesis.

INTRODUCTION: Homeostasis of cholesterol is crucial for cellular function, and dysregulated cholesterol biosynthesis is a metabolic event that can lead to hepatic and cardiovascular abnormalities. OBJECTIVE: The aim of this study was to investigate the effects and mechanisms of domain-associated protein (Daxx) and androgen receptor (AR) on intracellular cholesterol synthesis. METHODS: HepG2 cells were transfected with pCDNA3.1(+)/Daxx plasmid or treated with testosterone propionate to observe the effects of Daxx and AR on intracellular cholesterol levels. Co-immunoprecipitation experiments were performed to identify the interaction between Daxx and AR and to explore the regulatory effects of this interaction on cholesterol synthesis. RESULTS: Our experiments showed that AR promoted cholesterol synthesis and accumulation by activating sterol-regulatory element-binding protein isoform 2. AR-induced cholesterol synthesis was inhibited by Daxx; however, the expression of AR was not affected. Further studies demonstrated the existence of direct binding between Daxx and AR and this interaction was required to suppress AR activity. CONCLUSIONS: The Daxx-mediated antagonism of AR depicts a more complete picture as to how Daxx regulates intracellular cholesterol level and provides a new target for treatment of atherosclerosis.

Role of Hydrogen Sulfide in Chronic Diseases.

In the past, hydrogen sulfide (H2S) was considered as a poisonous gas or waste of the body. Later, researchers found that H2S-producing enzymes exist in mammals. Moreover, their findings indicated that endogenous H2S was associated with the occurrence of many diseases. Therefore, endogenous H2S is able to participate in the regulation of physiological and pathological functions of the body as a gas signaling molecule. In this review, we summarize the regulation mechanism of endogenous H2S on the body, such as proliferation, apoptosis, migration, angiogenesis, as well as vasodilation/vasoconstriction. Furthermore, we also analyze the relationship between H2S and some chronic diseases, including hypoxic pulmonary hypertension, myocardial infarction, ischemic perfusion kidney injury, diabetes, and chronic intestinal diseases. Finally, we discuss dietary restriction and drugs that target for H2S. Hence, H2S is expected to become a potential target for treatment of these chronic diseases.

Identification of the C-terminal domain of Daxx acts as a potential regulator of intracellular cholesterol synthesis in HepG2 cells.

Daxx is a highly conserved nuclear transcriptional factor, which has been implicated in many nuclear processes including transcription and cell cycle regulation. Our previous study demonstrated Daxx also plays a role in regulation of intracellular cholesterol content. Daxx contains several domains that are essential for interaction with a growing number of proteins. To delineate the underlying mechanism of hypocholesterolemic activity of Daxx, we constructed a set of plasmids which can be used to overexpress different fragments of Daxx and transfected to HepG2 cells. We found that the C- terminal region Daxx626-740 clearly reduced intracellular cholesterol levels and inhibited the expression of SREBPs and SCAP. In GST pull-down experiments and Double immunofluorescence assays, Daxx626-740 was demonstrated to bind directly to androgen receptor (AR). Our findings suggest that the interaction of Daxx626-740 and AR abolishes the AR-mediated activation of SCAP/SREBPs pathway, which suppresses the de novo cholesterol synthesis. Thus, C-terminal domain of Daxx acts as a potential regulator of intracellular cholesterol content in HepG2 cells.

Subcellular localization of DAXX influence ox-LDL induced apoptosis in macrophages.

Here we aimed to evaluate the effects of DAXX subcellular localization on ox-LDL induced macrophages apoptosis. Cytoplasmic localization vector DAXX-W621A and nuclear localization vector DAXX-S667A were constructed by point mutation in DAXX. Blank vector, full length DAXX, DAXX-W621A, DAXX-S667A was transfect into RAW264.7 cells, respectively. Then the cells were incubated with 100 mg/ml ox-LDL for 48 h. Immunofluorescent assay was used to assay the localization of DAXX. MTT and Flow cytometry was used to determine cellular viability and apoptosis. RT-PCR and Western blot were used to analyze the expression levels. A significantly increased expression of DAXX was found in transfected cells of DAXX. The content of DAXX in nucleus was significantly increased in DAXX(S667A), and DAXX was significantly increased in cytoplasm of DAXX(W621A). Besides, we found DAXX was mainly expressed in nucleus with a low-level expression in cytoplasm through immunofluorescence. However in DAXX(W621A) group, the DAXX began to transferred to cytoplasm, which exhibited significant florescence. After treated with ox-LDL, the cytoactive of DAXX-W621A exhibited significantly decreased level when compared DAXX group. However, after added inhibitor LMB, the inhibition was relieved. The cell viability was also significantly increased in DAXX-S667A group. The results of apoptosis rates were similar in each group. Furthermore, we found the expression of ASK1 and JNK was also consistent with the apoptosis rates. Cytoplasmic localization of DAXX can increase injury sensitivity of ox-LDL on cells, and nuclear localization can antagonise the effect of ox-LDL. Besides, it is certified ox-LDL induced apoptosis is mainly through ASK1-JNK pathway.