Dopamine Inhibits the Expression of Hepatitis B Virus Surface and e Antigens by Activating the JAK/STAT Pathway and Upregulating Interferon-stimulated Gene 15 Expression.

Background and Aims: Hepatitis B virus (HBV) infection is a major risk factor for cirrhosis and liver cancer, and its treatment continues to be difficult. We previously demonstrated that a dopamine analog inhibited the packaging of pregenomic RNA into capsids. The present study aimed to determine the effect of dopamine on the expressions of hepatitis B virus surface and e antigens (HBsAg and HBeAg, respectively) and to elucidate the underlying mechanism. Methods: We used dopamine-treated HBV-infected HepG2.2.15 and NTCP-G2 cells to monitor HBsAg and HBeAg expression levels. We analyzed interferon-stimulated gene 15 (ISG15) expression in dopamine-treated cells. We knocked down ISG15 and then monitored HBsAg and HBeAg expression levels. We analyzed the expression of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway factors in dopamine-treated cells. We used dopamine hydrochloride-treated adeno-associated virus/HBV-infected mouse model to evaluate HBV DNA, HBsAg, and HBeAg expression. HBV virus was collected from HepAD38.7 cell culture medium. Results: Dopamine inhibited HBsAg and HBeAg expression and upregulated ISG15 expression in HepG2.2.15 and HepG2-NTCP cell lines. ISG15 knockdown increased HBsAg and HBeAg expression in HepG2.2.15 cells. Dopamine-treated cells activated the JAK/STAT pathway, which upregulated ISG15 expression. In the adeno-associated virus-HBV murine infection model, dopamine downregulated HBsAg and HBeAg expression and activated the JAK-STAT/ISG15 axis. Conclusions: Dopamine inhibits the expression of HBsAg and HBeAg by activating the JAK/STAT pathway and upregulating ISG15 expression.

Identification of angiogenesis-related genes signature for predicting survival and its regulatory network in glioblastoma.

Glioblastoma (GBM) is notorious for malignant neovascularization that contributes to undesirable outcome. However, its mechanisms remain unclear. This study aimed to identify prognostic angiogenesis-related genes and the potential regulatory mechanisms in GBM. RNA-sequencing data of 173 GBM patients were obtained from the Cancer Genome Atlas (TCGA) database for screening differentially expressed genes (DEGs), differentially transcription factors (DETFs), and reverse phase protein array (RPPA) chips. Differentially expressed genes from angiogenesis-related gene set were extracted for univariate Cox regression analysis to identify prognostic differentially expressed angiogenesis-related genes (PDEARGs). A risk predicting model was constructed based on 9 PDEARGs, namely MARK1, ITGA5, NMD3, HEY1, COL6A1, DKK3, SERPINA5, NRP1, PLK2, ANXA1, SLIT2, and PDPN. Glioblastoma patients were stratified into high-risk and low-risk groups according to their risk scores. GSEA and GSVA were applied to explore the possible underlying GBM angiogenesis-related pathways. CIBERSORT was employed to identify immune infiltrates in GBM. The Pearson's correlation analysis was performed to evaluate the correlations among DETFs, PDEARGs, immune cells/functions, RPPA chips, and pathways. A regulatory network centered by three PDEARGs (ANXA1, COL6A1, and PDPN) was constructed to show the potential regulatory mechanisms. External cohort of 95 GBM patients by immunohistochemistry (IHC) assay demonstrated that ANXA1, COL6A1, and PDPN were significantly upregulated in tumor tissues of high-risk GBM patients. Single-cell RNA sequencing also validated malignant cells expressed high levels of the ANXA1, COL6A1, PDPN, and key DETF (WWTR1). Our PDEARG-based risk prediction model and regulatory network identified prognostic biomarkers and provided valuable insight into future studies on angiogenesis in GBM.

Prognosis and Immune Landscapes in Glioblastoma Based on Gene-Signature Related to Reactive-Oxygen-Species.

Glioblastoma (GBM) is the most malignant and aggressive primary brain tumor and is highly resistant to current therapeutic strategies. Previous studies have demonstrated that reactive oxygen species (ROS) play an important role in the regulation of signal transduction and immunosuppressive environment in GBM. To further study the role of ROS in prognosis, tumor micro-environment (TME) and immunotherapeutic response in GBM, an ROS-related nine-gene signature was constructed using the Lasso-Cox regression method and validated using three other datasets in our research, based on the hallmark ROS-pathway-related gene sets and the Cancer Genome Atlas GBM dataset. Differences in prognosis, TME scores, immune cell infiltration, immune checkpoint expression levels, and drug sensitivity between high-risk and low-risk subgroups were analyzed using R software. Collectively, our research uncovered a novel ROS-related prognostic model for primary GBM, which could prove to be a potential tool for clinical diagnosis of GBM, and help assess the immune and molecular characteristics of ROS in the tumorigenesis and immunosuppression of GBM. Our research also revealed that the expressions of ROS-related genes-HSPB1, LSP1, and PTX3-were closely related to the cell markers of tumor-associated macrophages (TAMs) and M2 macrophages validated by quantitative RT-PCR, suggesting them could be potential targets of immunotherapy for GBM.

Diagnostic Potential of microRNAs in Extracellular Vesicles Derived from Bronchoalveolar Lavage Fluid for Pneumonia-A Preliminary Report.

Current clinical needs require the development and use of rapid and effective diagnostic indicators to accelerate the identification of pneumonia and the process of microbiological diagnosis. MicroRNAs (miRNAs) in extracellular vesicles (EVs) have become attractive candidates for novel biomarkers to evaluate the presence and progress of many diseases. We assessed their performance as biomarkers of pneumonia. Patients were divided into the pneumonia group (with pneumonia) and the control group (without pneumonia). We identified and compared two upregulated miRNAs in EVs derived from bronchoalveolar lavage fluid (BALF-EVs) between the two groups (PmiR-17-5p = 0.009; PmiR-193a-5p = 0.031). Interestingly, in cell-debris pellets and EVs-free supernatants derived from bronchoalveolar lavage fluid (BALF-cell-debris pellets and BALF-EVs-free supernatants), total plasma, and EVs derived from plasma (plasma-EVs), the expression of miR-17-5p and miR-193a-5p showed no difference between pneumonia group and control group. In vitro experiments revealed that miR-17-5p and miR-193a-5p were strikingly upregulated in EVs derived from macrophages stimulated by lipopolysaccharide. MiR-17-5p (area under the curve, AUC: 0.753) and miR-193a-5p (AUC: 0.692) in BALF-EVs are not inferior to procalcitonin (AUC: 0.685) in the diagnosis of pneumonia. Furthermore, miR-17-5p and miR-193a-5p in BALF-EVs had a significantly higher specificity compared to procalcitonin and could be served as a potential diagnostic marker. MiR-17-5p and miR-193a-5p in EVs may be involved in lung inflammation by influencing the forkhead box O (FoxO) signaling pathway and protein processing in endoplasmic reticulum. This study is one of the few studies which focused on the potential diagnostic role of miRNAs in BALF-EVs for pneumonia and the possibility to use them as new biomarkers for a rapid and early diagnosis.

A biodegradable "Nano-donut" for magnetic resonance imaging and enhanced chemo/photothermal/chemodynamic therapy through responsive catalysis in tumor microenvironment.

Prussian blue (PB) is a safe photothermal agent for tumor therapy, yet poor photothermal effect and single therapeutic function severely restrict its further clinical applications. Herein, a biodegradable "Nano-donut" (CMPB-MoS2-PEG) is fabricated for magnetic resonance (MR) imaging and enhanced photothermal therapy (PTT)/ chemodynamic therapy (CDT)/chemotherapy through responsive catalysis in tumor microenvironment (TME). The "Nano-donut" is organically composed of Cu/Mn ions doped-PB and MoS2. The porous donut structure of CMPB-MoS2-PEG endows them as a carrier for delivery of doxorubicin hydrochloride (DOX) to tumor site. The framework of Nano-donut specifically decomposes in TME due to the reaction between Fe2+/Fe3+ and H2O2. The multivalent elements (Cu/Fe/Mn ions) decrease the bandgap and then enhance CDT by synergistically catalyzing H2O2 into toxic ·OH. Meanwhile, the Mn4+ also reacts with H2O2 to generate O2, improving the hypoxia of TME and enhancing the chemotherapy effect of released DOX. The MoS2 mingles in the PB, which significantly enhances photothermal conversion efficiency (η) effect of PB from 16.02% to 38.0%. In addition, Fe3+ as T2-weighted MR imaging agent can achieve MR imaging-guided therapy. The data clearly shows Nano-donut/DOX nanocomposites (NCs) have a remarkable inhibition for cancer cells and excellent biological safety in tumor treatment.

Accurately Controlled Delivery of Temozolomide by Biocompatible UiO-66-NH2 Through Ultrasound to Enhance the Antitumor Efficacy and Attenuate the Toxicity for Treatment of Malignant Glioma.

BACKGROUND: Glioma is the most common and malignant primary brain tumour in adults and has a dismal prognosis. Temozolomide (TMZ) is the only clinical first-line chemotherapy drug for malignant glioma up to present. Due to poor aqueous solubility and toxic effects, TMZ is still inefficient and limited for clinical glioma treatment. METHODS: UiO-66-NH2 nanoparticle is a zirconium-based framework, constructed by Zr and 2-amino-1,4-benzenedicarboxylic acid (BDC-NH2) with octahedral microporous structure, which can be decomposed by the body into an ionic form to discharge. We prepared the nanoscale metal-organic framework (MOF) of UiO-66-NH2 to load TMZ for therapy of malignant glioma, TMZ is released from UiO-66-NH2 through a porous structure. The ultrasound accelerates its porous percolation and promotes the rapid dissolution of TMZ through low-frequency oscillations and cavitation effect. The biological safety and antitumor efficacy were evaluated both in vitro and in vivo. RESULTS: The prepared TMZ@MOF exhibited excellent biocompatibility and biosafety due to minimal drug leakage without ultrasound intervention. We further used the flank model of glioblastoma to verify the in vivo therapeutic effect. TMZ@UiO-66-NH2 nanocomposites could be well delivered to the tumour tissue, which led to local enrichment of the TMZ concentration. Furthermore, TMZ@UiO-66-NH2 nanocomposites under ultrasound demonstrated much more efficient inhibition for tumor growth than TMZ@UiO-66-NH2 nanocomposites and TMZ alone. Meanwhile, the bone marrow suppression side effects of TMZ were significantly reduced by TMZ@UiO-66-NH2 nanocomposites. CONCLUSION: In this work, TMZ@UiO-66-NH2 nanocomposites with ultrasound mediation could effectively improve the killing effect of malignant glioma and decrease TMZ-induced toxicity in normal tissues, demonstrating great potential for the delivery of TMZ in the clinical treatment of malignant gliomas.

[Effect of Huangqin Decoction on pyroptosis pathway of NLRP3/caspase-1 in mice with ulcerative colitis].

To explore the effect of Huangqin Decoction on ulcerative colitis(UC) pyroptosis, and to explain the mechanism of pyroptosis based on NOD-like receptor thermoprotein domain 3(NLRP3)/cysteine proteinase 1(caspase-1) pathway. The animal model of UC induced with 3% dextran sodium sulfate(DSS) was established. The experimental animals were divided into control group, model group, low-dose(4.55 g·kg~(-1)), medium-dose(9.1 g·kg~(-1)) and high-dose(18.2 g·kg~(-1)) Huangqin Decoction groups and salazosulfapyridine group(0.45 g·kg~(-1)). While modeling, intragastric administration was given for 7 consecutive days. On the 8 th day, the mice were euthanized, the colon length was collected, and the histopathological changes were observed by HE staining. The content of interleukin-18(IL-18) was observed by ELISA. The content of lactatedehydrogenase(LDH)was determined by microplate method. TUNEL assay kit was used to detect the cell death. The immunohistochemical staining was used to detect the expressions of NLRP3 and apoptosis-associated speck-like protein containing a CARD(ASC). Western blot was used to detect the expressions of interleukin-1ß(IL-1ß), caspase-1 and gasdermin D(GSDMD).The experimental study showed that compared with normal group, the LDH content, TUNEL positive staining, inflammatory factors(IL-18, IL-1ß), and proteins associated with pyroptosis were significantly increased(P<0.05). Compared with model control group, the LDH content, TUNEL positive staining, inflammatory factors(IL-18, IL-1ß), and proteins associated with pyroptosis were decreased, and these results were more significant in high-dose groups(P<0.05). The results of HE staining showed that Huangqin Decoction could improve the pathological changes of colon. Huangqin Decoction could inhibit UC cell pyroptosis, and the mechanism may be closely related to NLRP3/caspase-1 signaling pathway.

Facile Interfacial Synthesis of Densely Spiky Gold Nano-Chestnuts With Full Spectral Absorption for Photothermal Therapy.

The gold nanostructure is regarded as the most promising photothermal agent due to its strong localized surface plasma resonance (LSPR) effect. In particular, the gold nanostructures with sharp spikes on the surface have higher optical signal enhancement, owing to the sharp tips drastically enhancing the intense nanoantenna effect. However, current approaches for the synthesis of spiky gold nanostructures are either costly, complicated, or uncontrollable. Herein, we report a novel strategy to synthesize gold nano-chestnuts (SGNCs) with sharp spikes as an excellent photothermal agent. The SGNCs were prepared by a facile one-pot interfacial synthetic method, and their controllable preparation mechanism was acquired. The SGNCs exhibited ideal full-spectrum absorption and showed excellent photothermal effect. They have a photothermal conversion efficiency (η) as high as 52.9%, which is much higher than traditional photothermal agents. The in vitro and in vivo results show that the SGNCs could efficiently ablate the tumor cells. Thus, the SGNCs have great potential in photothermal therapy applied in malignant tumors.

A novel lncRNA-LINC01116 regulates tumorigenesis of glioma by targeting VEGFA.

Brain glioma is the most common malignant tumor of the central nervous system, and one of the leading causes of death in patients with intracranial tumors. The clinical outcome of glioma is usually poor due to abundant vascularity, fast growth and susceptibility of invasion to normal brain tissues. Our microarray study showed that lncRNA-LINC01116 was significantly upregulated in glioma tissues and played an important role in cell proliferation, cycle, migration, invasion and angiogenesis. In addition, vascular endothelial growth factor (VEGFA) may be the major target genes in the downstream of lncRNA-LINC01116. Dual luciferase assay showed that LINC01116 and VEGFA both contained a miR-31-5p binding site, and LINC01116 could regulate the expression of VEGFA through competitive absorption of miR-31-5p. RNA immunoprecipitation indicated that LINC01116 and VEGFA were present in the miR-31-5p-RISC complex, and biotinylated miR-31-5p pull-down assay suggested that there was a competitive relationship between LINC01116 and VEGFA to bind with miR-31-5p. Collectively, our study has identified a novel lncRNA-LINC01116 and clarified the role and mechanism of LINC01116 in the tumorigenesis of glioma. LINC01116 may prove to be a potential target for the clinical diagnosis and treatment of glioma.

Biodegradable hollow manganese/cobalt oxide nanoparticles for tumor theranostics.

This article describes the fabrication of hollow manganese/cobalt oxide nanoparticles (MCO NPs) with a tunable size through a redox reaction and the Kirkendall effect for cancer imaging and drug delivery. MCO-70 NPs (with an average size of 70 nm) can act as glutathione (GSH)-responsive contrast agents for dual T1/T2-weighted magnetic resonance imaging (MRI). The degradation of MCO NPs by GSH led to the enhancement of their T1 and T2 signals by 2.24- and 3.43-fold compared with those of MCO NPs before degradation, respectively. Antitumor agents such as doxorubicin (Dox) could be encapsulated inside the cavity of the hollow MCO NPs (MCO-70-Dox) and be released in the presence of GSH. The MCO-70-Dox NPs showed good tumor growth inhibition effects in vitro and in vivo, and can be promising drug delivery vehicles and MRI contrast agents for tumor diagnosis and reporting drug release.

Differential Expression of Circular RNAs in Glioblastoma Multiforme and Its Correlation with Prognosis.

OBJECTIVE: The present study aimed to explore the expression profiles of circular RNAs (circRNAs) in glioblastoma multiforme (GBM) in an attempt to identify potential core genes in the pathogenesis of this tumor. METHODS: Differentially expressed circRNAs were screened between tumor tissues from five GBM patients and five normal brain samples using Illumina Hiseq. Bioinformatics analysis was used to analyze their potential function. CircBRAF was further detected in different WHO grades glioma tissues and normal brain tissues. Kaplan-Meier curves and multivariate Cox's analysis were used to analyze the association between circBRAF expression level and prognosis of glioma patients. RESULTS: A total of 1411 differentially expressed circRNAs were identified in GBM patients including 206 upregulated circRNAs and 1205 downregulated circRNAs. Differential expression of circRNAs was closely associated with the biological process and molecular function. The downregulated circRNAs were mainly associated with ErbB and Neurotrophin signaling pathways. Moreover, the expression level of circBRAF in normal brain tissues was significantly higher than that in glioma tissues (P<.001). CircBRAF was significantly lower in glioma patients with high pathological grade (WHO III & IV) than those with low grade (WHO I & II) (P<.001). Cox analysis revealed that high circBRAF expression was an independent biomarker for predicting good progression-free survival and overall survival in glioma patients (HR=0.413, 95% CI 0.201-0.849; HR=0.299, 95% CI 0.135-0.661; respectively). CONCLUSION: The present study identified a profile of dysregulated circRNAs in GBM. Bioinformatics analysis showed that dysregulated circRNAs might be associated with tumorigenesis and development of GBM. In addition, circBRAF could severe as a biomarker for predicting pathological grade and prognosis in glioma patients.

Analysis on therapeutic outcomes and prognostic factors of intracranial ependymoma: a report of 49 clinical cases in a single center.

Although intracranial ependymoma is relatively rare, it is often associated with great clinical aggressiveness and poor overall survival. There are controversies over factors affecting the prognosis of the disease. The aim of this retrospective study was to evaluate factors that may affect the therapeutic outcome and prognosis of intracranial ependymoma by reviewing the medical records of 49 patients who were surgically treated in our hospital between 2001 and 2014. Univariate and multivariate analyses were performed to identify prognostic variables relative to patient and tumor characteristics, and treatment modalities. All 49 patients (24 men and 25 women; mean age 27.6 years) underwent surgical resection, of whom 14 patients also underwent postoperative radiotherapy. Local recurrence was found in 15 (48.8 %) patients, and 22 (51.2 %) patients died during the follow-up periods. The 5-year recurrence rate was 65 % and the survival rate was 51 %. The results of statistical analysis suggested that preoperative extraventricular drainage and surgical resection extent were prognostic factors related to progression-free survival, and that age, surgical resection extent and histological grade were closely associated with survival. Interestingly, there was a significant correlation between the symptom of hydrocephalus and age (P = 0.010), and patients with a better clinical status (KPS ≥ 80) were significantly associated with a lower WHO grade (P = 0.007). In conclusion, we confirmed that surgical resection extent was the major independent factor affecting both recurrence and survival of patients with intracranial ependymoma, while age and WHO grade were prognostic factors affecting survival but not recurrence.

An integrative analysis of treatment, outcomes and prognostic factors for primary spinal anaplastic ependymomas.

The aim of this study was to elucidate the role of treatment modalities in primary spinal anaplastic ependymomas (PSAE) and identify promising prognostic factors. PSAE are rare tumors of the central nervous system with poorly understood clinical characteristics and treatment outcomes. We reviewed the literature in PubMed, Web of Science and Scopus databases to identify patients with PSAE. Multivariate Cox proportional hazards analysis and univariate Kaplan-Meier analysis were performed on the PSAE patients and overall survival (OS) and progression-free survival (PFS) were assessed to evaluate the clinical outcomes. Of the 40 patients with PSAE, the tumors were mostly intramedullary (n=19; 47.5%) and frequently involved the thoracic cord (n=25; 62.5%). Eighteen patients suffered recurrence during the follow-up with a median PFS of 24 months. The 1, 2, and 5year OS rates of the PSAE patients were 91.5%, 82.1%, and 63.1%, respectively. Gross total resection (GTR) was independently associated with prolonged PFS (hazard ratio [HR] 0.11; p=0.004) and OS (HR 0.11; p=0.003) in the multivariate analysis. Adjuvant radiotherapy also conferred improved PFS (HR 0.15; p=0.008) and OS (HR 0.16; p=0.022). Age, sex, tumor location and chemotherapy did not influence the outcomes in this group. The results of our study suggest that GTR and adjuvant radiotherapy are strong prognostic indicators in patients with PSAE and the role of chemotherapy is yet to be defined.

Unilateral multilevel interlaminar fenestration: a minimally invasive approach for cervical intramedullary lesions.

The traditional approach for cervical intramedullary lesions is laminectomy, but the procedure may result in spinal instability and spinal deformity. Unilateral multilevel interlaminar fenestration (UMIF) is an alternative minimally invasive approach that may have great advantages in preserving spinal stability. However its use in cervical intramedullary lesions is rare, and the indications, safety and limitations of this approach for cervical intramedullary lesions are still under investigation. We report five patients (three males, two females, age range 12-46 years) who were treated between 2010 and 2011 for cervical intramedullary lesions. The lesions included three ependymomas, one astrocytoma and one ependymal cyst, and the locations of the lesions were at the medulla-T2, C4-T1, C5-C7, C4-C7 and C6-C7. All of these lesions were completely removed through UMIF, and all patients had stable or improved neurological status after surgery. No recurrences or spinal deformities were detected during the follow-up period which ranged from 24 to 35 months (mean=27.4 months). UMIF is a feasible approach for selected cervical intramedullary lesions. This approach allows complete resection of multilevel lesions without increasing the risk of injury to the spinal cord, and minimizing the risk of postoperative spinal instability. The indications for and limitations of UMIF are discussed.