PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells.

Aberrant cell proliferation is a hallmark of cancer, including glioblastoma (GBM). Here we report that protein arginine methyltransferase (PRMT) 6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells (GSCs), a subpopulation in GBM critical for malignancy. We identified a casein kinase 2 (CK2)-PRMT6-regulator of chromatin condensation 1 (RCC1) signaling axis whose activity is an important contributor to the stem-like properties and tumor biology of GSCs. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation, which promotes PRMT6 methylation of RCC1, which in turn is required for RCC1 association with chromatin and activation of RAN. Disruption of this pathway results in defects in mitosis. EPZ020411, a specific small-molecule inhibitor for PRMT6, suppresses RCC1 arginine methylation and improves the cytotoxic activity of radiotherapy against GSC brain tumor xenografts. This study identifies a CK2α-PRMT6-RCC1 signaling axis that can be therapeutically targeted in the treatment of GBM.

Alterations in microbiota-metabolism-circRNA crosstalk in autism spectrum disorder-like behaviours caused by maternal exposure to glyphosate-based herbicides in mice.

Epidemiological evidence indicates exposure to glyphosate-based herbicides (GBHs) increases the risk for autism spectrum disorder (ASD). The gut microbiota has been found to influence ASD behaviours through the microbiota-gut-brain axis. However, the underlying links between early life GBH exposure and ASD-like phenotypes through the microbiota-gut-brain axis remain unclear. Therefore, we exposed mice to low-dose GBH (0.10, 0.25, 0.50, and 1.00 %) and determined the effects on ASD-like behaviours. Furthermore, three kinds of omics (gut microbiomics, metabolomics, and transcriptomics) were conducted to investigate the effects of GBH exposure on gut microbiota, gut metabolites, and circular RNAs (circRNAs) in the prefrontal cortex (PFC) using a cross-generational mouse model. Behavioural analyses suggested social impairment and repetitive/stereotypic behaviours in the GBH-exposed offspring. Furthermore, maternal exposure to glyphosate significantly altered the ASD-associated gut microbiota of offspring, and ASD-associated gut metabolites were identified. Specifically, we found that alterations in the gut microenvironment may contribute to changes in gut permeability and the blood-brain barrier, which are related to changes in the levels of circRNAs in the PFC. Our results suggest a potential effect of circRNAs through the disruption of the gut-brain interaction, which is an important factor in the pathogenesis of ASD in offspring induced by maternal exposure to GBH.

Impact of pesticides exposure during neurodevelopmental period on autism spectrum disorders - A focus on gut microbiota.

Accumulating evidence indicates exposure to pesticides during the crucial neurodevelopmental period increases susceptibility to many diseases, including the neurodevelopmental disorder known as autism spectrum disorder (ASD). In the last few years, it has been hypothesized that gut microbiota dysbiosis is strongly implicated in the aetiopathogenesis of ASD. Recently, new studies have suggested that the gut microbiota may be involved in the neurological and behavioural defects caused by pesticides, including ASD symptoms. This review highlights the available evidence from recent animal and human studies on the relationship between pesticides that have the potential to disturb intestinal microbiota homeostasis, and ASD symptoms. The mechanisms through which gut microbiota dysbiosis may trigger ASD-like behaviours induced by pesticides exposure during the neurodevelopmental period via the altered production of bacterial metabolites (short chain fatty acids, lipids, retinol, and amino acid) are also described. According to recent research, gut microbiota dysbiosis may be a major contributor to the symptoms of ASD associated with pesticides exposure. However, to determine the detailed mechanism of action of gut microbiota on pesticide-induced ASD behaviours, actual population exposure scenarios from epidemiological studies should be used as the basis for the appropriate exposure pattern and dosage to be used in animal studies.

N-α-Acetyltransferase 10 inhibits invasion and metastasis of oral squamous cell carcinoma via regulating Pirh2-p53 signalling pathway.

N-α-Acetyltransferase 10 (NAA10) was reported to be involved in tumour invasion and metastasis in several of tumours. However, the role and mechanism of NAA10-mediated invasion and metastasis in oral squamous cell carcinoma (OSCC) remains undetermined. Herein, our study showed that NAA10 inhibits cell migration and invasion in vitro and attenuates the xenograft tumorigenesis in nude mice. Mechanistically, we demonstrated that there is a physical interaction between NAA10 and RelA/p65 in OSCC cells, thereby preventing RelA/p65-mediated transcriptional activation of Pirh2. Consequently, inhibition of Pirh2 increased p53 level and suppressed the expression of p53 downstream targets, matrix metalloprotein-2 (MMP-2) and MMP-9. Therefore, NAA10 may function as a tumour metastasis suppressor in the progression of OSCC by targeting Pirh2-p53 axis and might be a prognostic marker as well as a therapeutic target for OSCC.

Naa10p and IKKα interaction regulates EMT in oral squamous cell carcinoma via TGF-ß1/Smad pathway.

Epithelial-mesenchymal transition (EMT) has been contributed to increase migration and invasion of cancer cells. However, the correlate of Naa10p and IKKα with EMT in oral squamous cell carcinoma (OSCC) is not yet fully understood. In our present study, we found N-α-acetyltransferase 10 protein (Naa10p) and IκB kinase α (IKKα) were abnormally abundant in oral squamous cell carcinoma (OSCC). Bioinformatic results indicate that the expression of Naa10p and IKKα is correlated with TGF-ß1/Smad and EMT-related molecules. The Transwell migration, invasion, qRT-PCR and Western blot assay indicated that Naa10p repressed OSCC cell migration, invasion and EMT, whereas IKKα promoted TGF-ß1-mediated OSCC cell migration, invasion and EMT. Mechanistically, Naa10p inhibited IKKα activation of Smad3 through the interaction with IKKα directly in OSCC cells after TGF-ß1 stimulation. Notably, knockdown of Naa10p reversed the IKKα-induced change in the migration, invasion and EMT-related molecules in OSCC cells after TGF-ß1 stimulation. These findings suggest that Naa10p interacted with IKKα mediates EMT in OSCC cells through TGF-ß1/Smad, a novel pathway for preventing OSCC.

Inverse correlation between Naa10p and Pirh2 expression and the combined prognostic value in oral squamous cell carcinoma patients.

BACKGROUND: This study aims to explore the associations between N-α-acetyltransferase 10 protein (Naa10p) and p53-induced protein with a RING-H2 domain (Pirh2) expression and clinicopathological characteristics in oral squamous cell carcinoma (OSCC). METHODS: Immunohistochemistry was performed to detect Naa10p and Pirh2 levels containing 118 OSCC specimens, and additional analyses were used to determine correlations between Naa10p and Pirh2 expressions, generate survival curves, and perform univariate and multivariate statistical analyses. Further, quantitative real-time PCR (qRT-PCR) and western blot were employed to examine Naa10p and Pirh2 expression level in OSCC patients' samples. We further validated the result using RNAseq data from The Cancer Genome Atlas (TCGA) and mRNA array data from GSE31056 and GSE30784. RESULTS: Naa10p and Pirh2 are overexpression, and the protein level of Naa10p was negatively correlated with that of Pirh2 in OSCC tissues. Multivariate Cox proportional hazard regression analysis showed that positive Naa10p expression and negative Pirh2 expression were both independent good prognostic factors for OSCC patients. Furthermore, the Naa10p-positive/Pirh2-negative group has the best prognosis among all OSCC patients. Results from qRT-PCR showed the higher expression level of Naa10 and lower expression level of Pirh2 in tumor tissues than adjacent normal tissues. TCGA database and data from GSE31056 and GSE30784 showed the similar result. The correlation analysis showed that the mRNA level of Naa10 was negatively correlated that of Pirh2. CONCLUSION: The expression of Naa10p is negatively correlated with that of Pirh2, and positive Naa10p and negative Pirh2 might be independent biomarkers for better OSCC prognoses.

PRL-3 promotes telomere deprotection and chromosomal instability.

Phosphatase of regenerating liver (PRL-3) promotes cell invasiveness, but its role in genomic integrity remains unknown. We report here that shelterin component RAP1 mediates association between PRL-3 and TRF2. In addition, TRF2 and RAP1 assist recruitment of PRL-3 to telomeric DNA. Silencing of PRL-3 in colon cancer cells does not affect telomere integrity or chromosomal stability, but induces reactive oxygen species-dependent DNA damage response and senescence. However, overexpression of PRL-3 in colon cancer cells and primary fibroblasts promotes structural abnormalities of telomeres, telomere deprotection, DNA damage response, chromosomal instability and senescence. Furthermore, PRL-3 dissociates RAP1 and TRF2 from telomeric DNA in vitro and in cells. PRL-3-promoted telomere deprotection, DNA damage response and senescence are counteracted by disruption of PRL-3-RAP1 complex or expression of ectopic TRF2. Examination of clinical samples showed that PRL-3 status positively correlates with telomere deprotection and senescence. PRL-3 transgenic mice exhibit hallmarks of telomere deprotection and senescence and are susceptible to dextran sodium sulfate-induced colon malignancy. Our results uncover a novel role of PRL-3 in tumor development through its adverse impact on telomere homeostasis.

Repressor activator protein 1-promoted colorectal cell migration is associated with the regulation of Vimentin.

Repressor activator protein 1 plays important roles in telomere protection, while repressor activator protein 1 binds to extra-telomeric DNA and exerts the function as a transcriptional regulator. Previous study showed that repressor activator protein 1 regulates the transcriptional activity of nuclear factor-κB, and it was highly expressed in breast cancer tissues; however, the clinical significance of repressor activator protein 1 expression in cancer remains to be elucidated. In this study, we discovered that repressor activator protein 1 was highly expressed in colorectal cancer tissues. High expression of repressor activator protein 1 was significantly correlated with poor prognosis and distant metastasis. Knockdown of repressor activator protein 1 in colorectal cancer cells did not affect cell proliferation or colony formation, but dramatically decreased cell migration and F-actin-enriched membrane protrusions. Microarray screening revealed that Vimentin was downregulated after repressor activator protein 1 knockdown, which was validated by analysis of a colorectal cancer dataset. Furthermore, knockdown of Vimentin attenuated repressor activator protein 1-enhanced cell migration. Thus, our study suggests that repressor activator protein 1 is a prognostic marker and a potential target for colorectal cancer therapy.

Expression of CD147 and matrix metalloproteinase-11 in colorectal cancer and their relationship to clinicopathological features.

BACKGROUND: This study aimed to investigate the expression of CD147 and MMP-11 in human colorectal cancer (CRC) and to evaluate their clinical significance. METHODS: Real-time polymerase chain reaction was used to evaluate CD147 and MMP-11 mRNA level in 56 pairs of fresh CRC samples matched with adjacent normal mucosa. The protein expression of CD147 and MMP-11 in CRC specimens and corresponding normal colorectal mucosa were evaluated by immunohistochemistry on CRC tissue microarrays. Expression and co-localization of these two proteins in human colorectal cancer tissue were also evaluated by laser scanning confocal microscopy. Furthermore, their correlations with clinicopathological factors and overall survival after surgery were evaluated. RESULTS: Both CD147 and MMP-11 were demonstrated to be over-expressed at mRNA level (P < 0.001, both) and protein level (P < 0.001, both) in CRC tissue than paired normal mucosa. Spearman rank test showed a positive correlation between these two proteins (P = 0.025). Immunofluorescence double staining confirmed the co-localization of CD147 and MMP-11 in paraffin-embedded tissues of CRC patients. Expression of CD147 and MMP-11 were both correlated with CRC lymph node metastasis (P = 0.021 and P = 0.031, respectively), distant metastasis (P < 0.001 and P = 0.013, respectively) and TNM stage (P = 0.006 and P = 0.049, respectively). Univariate survival analysis showed that both CD147 and MMP11 expression was significantly associated with shorter survival time (P = 0.001 and P = 0.009, respectively). Additionally, in multivariate analysis, both CD147 and MMP-11 were proved to be independent prognostic factors (P = 0.009, 0.028, respectively). CONCLUSIONS: These results indicated that both CD147 and MMP-11 may be involved in the progression of colorectal cancer, and they are potential prognostic factors and might become new therapeutic targets for CRC patients.

[Research on medical instrument information integration technology based on IHE PCD].

Integrating medical instruments with medical information systems becomes more and more important in healthcare industry. To make medical instruments without standard communication interface possess the capability of interoperating and sharing information with medical information systems, we developed a medical instrument integration gateway based on Integrating the Healthcare Enterprise Patient Care Device (IHE PCD) integration profiles in this research. The core component is an integration engine which is implemented according to integration profiles and Health Level Seven (HL7) messages defined in IHE PCD. Working with instrument specific Javascripts, the engine transforms medical instrument data into HL7 ORU message. This research enables medical instruments to interoperate and exchange medical data with information systems in a standardized way, and is valuable for medical instrument integration, especially for traditional instruments.

Study on the Road Performance and Compaction Characteristics of Fiber-Reinforced High-RAP Plant-Mixed Hot Recycled Asphalt Mixtures.

Recycled asphalt pavement (RAP) mixtures are widely adopted due to their significant economic and social benefits from utilizing pavement recycling materials. This study incorporates basalt fibers (BF) and polyester fibers (PF) into plant-mixed hot recycled asphalt mixtures to analyze their enhancement effects on the high-temperature, low-temperature, and fatigue performance at different RAP content levels. Additionally, the study investigates the impact of fiber and RAP additions on the compaction characteristics of the mixtures using gyratory compaction tests, aiming to increase the RAP content of plant-mixed hot recycled asphalt mixtures. Experimental results demonstrate that at 30% and 50% RAP content levels, basalt fibers exhibit more pronounced enhancement effects on the performance of recycled asphalt mixtures compared to polyester fibers. Incorporating basalt fibers increases the fracture energy of recycled asphalt mixtures by 8.63% and 13.9%, and improves fatigue life by 154% and 135%, respectively. Moreover, the addition of both types of fibers increases compaction difficulty, with polyester fibers showing a more significant influence on the compaction energy index (CEI).

Dural puncture epidural with 25-G spinal needles versus conventional epidural technique for labor analgesia: A systematic review of randomized controlled trials.

BACKGROUND: Dural mater is punctured by using a spinal needle without drugs administrated into intrathecal space directly in dural puncture epidural (DPE) analgesia. OBJECTIVE: This study aimed to summarize the evidence of benefits and risks of DPE analgesia with 25-G spinal needles for labor pain relief. METHODS: DPE analgesia with EP analgesia for labor pain relief were systematically searched. The Embase, MEDLINE, Cochrane Central Register of Controlled Trials, Scopus and Web of Science databases were systematically searched till 6th November 2022 to find out randomized controlled trials (RCTs) comparing DPE (using 25-G spinal needles) with conventional epidural (EP) analgesia. The risk of bias was assessed with the Cochrane tool. Risk ratio, mean difference, and 95% confidence intervals were calculated. RESULTS: Seven RCTs with 761 parturients were identified. Pool data showed that DPE technique was associated with shorter time to pain score ⩽ 3/10, higher percentage with pain score ⩽ 3/10 at 10 min and 20 min, lower incidence of epidural top-up bolus and no S2 block, higher incidence of bilateral S2 blockade at 10 min and during labor, lower incidence of epidural top-up bolus and incidence of asymmetric block. No statistical difference in side effect and parturient satisfaction between DPE and EP technique. CONCLUSION: DPE technique with 25-G spinal needles was associated with faster analgesia onset and sacral coverage, greater sacral spread, lesser requirement of epidural top-up and lower incidence of asymmetric block. DPE technique with 25-G spinal needles showed a greater benefit to parturients.

Photobiomodulation reduces spinal cord edema by decreasing the expression of AQP4 in the astrocytes of male spinal cord injury rats via the JAK2/STAT3 signaling pathway.

BACKGROUND: Spinal cord swelling commonly occurs following SCI. Previous studies suggest that PBM may reduce inflammation and scar formation after SCI. However, whether PBM can alleviate post-spinal cord injury edema and its underlying mechanisms have not yet been reported. This study aims to investigate the effects of PBM on spinal cord swelling in rats following SCI and explore the underlying mechanisms. METHODS: A rat model of SCI was established, and the rats received continuous PBM therapy for two weeks. Tissue hydration, motor function, AQP4 expression, and pathological changes in the spinal cord were evaluated at different time points. In vitro, astrocytes were subjected to PBM and treated with either cucurbitacin I or TGN020 following OGD. RESULTS: The results indicate that PBM reduces tissue swelling in rats with SCI, improves motor function recovery, and inhibits the upregulation of AQP4 and GFAP associated with SCI. In vitro, PBM reduces abnormal activation of the JAK2/STAT3 signaling pathway in astrocytes, leading to decreased AQP4 synthesis and astrocyte activation. CONCLUSIONS: These findings suggest that PBM reduces spinal cord swelling in rats after injury. This effect is associated with the inhibition of JAK2/STAT3 signaling pathway activation in astrocytes and the reduction in AQP4 expression.

PRL-3 activates NF-κB signaling pathway by interacting with RAP1.

Phosphatase of regenerating liver (PRL-3) promotes cancer metastasis through enhanced cell motility and invasiveness, however its role in tumorigenesis remains unclear. Herein, we reported that PRL-3 interacts with telomere-related protein RAP1. PRL-3 promotes the cytosolic localization of RAP1, which is counteracted by silencing of PRL-3. Immunohistochemical staining of colon cancer tissue array (n=170) revealed that high level of PRL-3 associates with cytosolic localization of RAP1 (p=0.01). Microarray analysis showed that PRL-3 regulates expression of diverse genes and enhances phosphorylation of p65 subunit of NF-κB in a RAP1-dependent manner. Furthermore, PRL-3 transcriptionally activates RAP1 expression, which is counteracted by ablating p65. Therefore, our results demonstrate PRL-3 as a novel regulator of NF-κB signaling pathway through RAP1.

Dural Puncture Epidural with 25-G Spinal Needles versus Conventional Epidural Technique in Conjunction with PIEB for Labor Analgesia: A Randomized Trial.

Purpose: To compare the effect of Dural puncture epidural (DPE) and conventional epidural (EP), in conjunction with programmed intermittent epidural bolus (PIEB) and low-concentration ropivacaine strategy. Methods: After written informed consent was obtained, healthy nulliparous women with singleton pregnancies, vertex presentation at 38-42 weeks' gestation, cervical dilation of 3-5 cm, and a desire for pain relief were randomly assigned to DPE or EP group. Dural matter was puncture with 25G Whitacre needle in DPE group. Analgesia was initiated with 15 mL of 0.1% ropivacaine over 5 minutes and was maintained by PIEB (8 mL of 0.08% ropivacaine with 2 µg/mL fentanyl every 40 min). Primary outcome was the percentage of adequate analgesia, defined as NRPS ≤1, at 30 minutes after the initiation of the epidural bolus. Results: Out of 130 enrolled parturients, 127 were included in final analysis (64 in DPE group, 63 in EP group). No significant difference was found in percentage of adequate analgesia at 30 minutes (risk ratio: 1.09; 95% confidence interval: 0.90-1.31; P = 0.366). At 8, 12, 14, and 16 minutes, percentage of adequate analgesia was higher in DPE group (P = 0.023, 0.027, 0.016 and 0.033, respectively). NPRS scores in DPE group decreased more dramatically within the first 30 min. The incidence of S2 sensory blocks at 20 and 30 min in DPE group was higher (P = 0.010 and 0.006, respectively). There were no differences in patient satisfaction, delivery mode, adverse effects, fetal bradycardia, and Apgar scores at 1 and 5 minutes. Conclusion: The combination of the use of DPE technique with 25G spinal needle and PIEB technique for labor analgesia appears to enhance the quality of labor analgesia by accelerating onset and providing improved sacral blockade, without increasing adverse effects.

Developmental exposure to chlorpyrifos causes neuroinflammation via necroptosis in mouse hippocampus and human microglial cell line.

Neurodevelopmental exposure to chlorpyrifos (CPF) could increase risks for neurological disorders, such as autism spectrum disorder, cognitive impairment, or attention deficit hyperactivity disorder. The potential involvement of microglia reactive to inflammatory stimuli in these neurological disorders has been generally reported. However, the concrete effects and potential mechanisms of microglia dysfunction triggered by developmental CPF exposure remain unclear. Therefore, we established mouse and human embryonic microglial cells (HMC3 cell) models of developmental CPF exposure to evaluate the effects of developmental CPF exposure on neuroinflammation and underlying mechanisms. The results showed that developmental exposure to CPF enhanced the expression of Iba1 in hippocampus. CPF treatment increased inflammatory cytokines levels and TSPO expression in hippocampus and HMC3 cells. The levels of necroptosis and necroptosis-related signaling RIPK/MLKL were increased in hippocampus and HMC3 cells following CPF exposure. Furthermore, the expression of TLR4/TRIF signaling was increased in hippocampus and HMC3 cells subjected to CPF exposure. Notably, the increased levels of TLR4/TRIF signaling, RIPK/MLKL signaling, necroptosis and pro-inflammatory cytokines induced by CPF treatment were remarkably inhibited by TAK-242 (a specific TLR4 inhibitor). Additionally, the necroptosis and pro-inflammatory cytokines production induced by CPF treatment were significantly relieved by Nec-1 (a specific RIPK1 inhibitor). In general, the above results suggested that activated microglia in hippocampus subjected to developmental CPF exposure underwent RIPK1/MLKL-mediated necroptosis regulated by TLR4/TRIF signaling.

Androgen Receptor-Related Non-coding RNAs in Prostate Cancer.

Prostate cancer (PCa) is the second leading cause of cancer-related death among men in the United States. Androgen receptor (AR) signaling is the dominant oncogenic pathway in PCa and the main strategy of PCa treatment is to control the AR activity. A large number of patients acquire resistance to Androgen deprivation therapy (ADT) due to AR aberrant activation, resulting in castration-resistant prostate cancer (CRPC). Understanding the molecular mechanisms underlying AR signaling in the PCa is critical to identify new therapeutic targets for PCa patients. The recent advances in high-throughput RNA sequencing (RNA-seq) techniques identified an increasing number of non-coding RNAs (ncRNAs) that play critical roles through various mechanisms in different diseases. Some ncRNAs have shown great potentials as biomarkers and therapeutic targets. Many ncRNAs have been investigated to regulate PCa through direct association with AR. In this review, we aim to comprehensively summarize recent findings of the functional roles and molecular mechanisms of AR-related ncRNAs as AR regulators or targets in the progression of PCa.

Study protocol for a randomised controlled clinical trial comparing desflurane-based versus propofol-based anaesthesia on postanaesthesia respiratory depression in patients with obstructive sleep apnoea after major abdominal surgery.

INTRODUCTION: Patients with obstructive sleep apnoea (OSA) are more sensitive to postanaesthesia respiratory depression. Whether different anaesthetic regimens (intravenous-based or inhalational-based general anaesthesia) affect the postanaesthesia respiratory depression is controversial. Although desflurane has been reported that presents favourable rapid recovery profile in special patients including whom with OSA, the strong clinical evidence of the benefit on postanaesthesia respiratory depression is far from being revealed. This study aims to fill this knowledge gap by investigating the postanaesthesia respiratory depression in postanaesthesia care unit (PACU) in patients with OSA after major abdominal surgery, followed by desflurane-based anaesthesia compared with propofol-based anaesthesia. METHODS AND ANALYSIS: Eight hundred and fifty-four patients with OSA scheduled for elective major abdominal surgery will be randomly 1:1 assigned to desflurane-based (n=427) or propofol-based anaesthesia (n=427) using a computer-generated randomisation scheme with permuted block size maintained by a centralised randomisation centre. Patients will be assessed before and a consecutive 3 days after their surgery according to the standardised tasks. Demographic data as well as surgical and anaesthesia information will be collected for the duration of the procedure. Incidence of postanaesthesia respiratory depression in PACU as well as anaesthesia recovery, emergence delirium, postoperative nausea and vomiting, rescue analgesia, duration of PACU and hospital stay, and any other adverse events will be assessed at the given study time point. Investigators performing postoperative follow-up are not involved in both anaesthesia implementation and postoperative care. ETHICS AND DISSEMINATION: This study protocol has been approved by the ethics board at Xiang'an Hospital of Xiamen University (XAHLL2019003). The results of this study will be published in a peer-review journal and presented at national conferences as poster or oral presentations. Participants wishing to know the results of this study will be contacted directly on data publication. TRIAL REGISTRATION NUMBER: ChiCTR2000031087.

Bone Morphogenetic Protein 4 Targeting Glioma Stem-Like Cells for Malignant Glioma Treatment: Latest Advances and Implications for Clinical Application.

Malignant gliomas are heterogeneous neoplasms. Glioma stem-like cells (GSCs) are undifferentiated and self-renewing cells that develop and maintain these tumors. These cells are the main population that resist current therapies. Genomic and epigenomic analyses has identified various molecular subtypes. Bone morphogenetic protein 4 (BMP4) reduces the number of GSCs through differentiation and induction of apoptosis, thus increasing therapeutic sensitivity. However, the short half-life of BMP4 impedes its clinical application. We previously reviewed BMP4 signaling in central nervous system development and glioma tumorigenesis and its potential as a treatment target in human gliomas. Recent advances in understanding both adult and pediatric malignant gliomas highlight critical roles of BMP4 signaling pathways in the regulation of tumor biology, and indicates its potential as a therapeutic molecule. Furthermore, significant progress has been made on synthesizing BMP4 biocompatible delivery materials, which can bind to and markedly extend BMP4 half-life. Here, we review current research associated with BMP4 in brain tumors, with an emphasis on pediatric malignant gliomas. We also summarize BMP4 delivery strategies, highlighting biocompatible BMP4 binding peptide amphiphile nanostructures as promising novel delivery platforms for treatment of these devastating tumors.

Antihistamine Drug Ebastine Inhibits Cancer Growth by Targeting Polycomb Group Protein EZH2.

Enhancer of zester homolog 2 (EZH2), a histone lysine methyltransferase and the catalytic component of polycomb repressive complex 2, has been extensively investigated as a chromatin regulator and a transcriptional suppressor by methylating H3 at lysine 27 (H3K27). EZH2 is upregulated or mutated in most cancers, and its expression levels are negatively associated with clinical outcomes. However, the current developed small-molecule inhibitors targeting EZH2 enzymatic activities could not inhibit the growth and progression of solid tumors. Here, we discovered an antihistamine drug, ebastine, as a novel EZH2 inhibitor by targeting EZH2 transcription and subsequently downregulating EZH2 protein level and H3K27 trimethylation in multiple cancer cell lines at concentrations below 10 µmol/L. The inhibition of EZH2 by ebastine further impaired the progression, migration, and invasiveness of these cancer cells. Overexpression of Ezh2 wild-type and its mutant, H689A (lacking methyltransferase activity), rescued the neoplastic properties of these cancer cells after ebastine treatment, suggesting that EZH2 targeted by ebastine is independent of its enzymatic function. Next-generation RNA-sequencing analysis also revealed that C4-2 cells treated with 8 µmol/L ebastine showed a gene profiling pattern similar to EZH2-knockdown C4-2 cells, which was distinctively different from cells treated with GSK126, an EZH2 enzyme inhibitor. In addition, ebastine treatment effectively reduced tumor growth and progression, and enhanced progression-free survival in triple-negative breast cancer and drug-resistant castration-resistant prostate cancer patient-derived xenograft mice. Our data demonstrated that ebastine is a novel, safe, and potent anticancer agent for patients with advanced cancer by targeting the oncoprotein EZH2.