Triple B←N Lewis Pair-Functionalized Triazatruxenes with Large Stokes Shifts.

A novel class of multiple B←N Lewis pair-functionalized polycyclic aromatic hydrocarbons with different BR2 groups (R = Cl or Et) directly attached at positions 1, 6, and 11 of triazatruxene was synthesized. The triazatruxene backbone of 4 displays a bowl shape, and its molecular skeleton shows a highly twisted propeller-like structure with C3 symmetry. The introduction of B←N Lewis pairs not only results in a large decrease in the HOMO-LUMO gap but also lowers the LUMO to -3.00 eV. Both compounds show excellent stability with large Stokes shifts of ≤8234 cm-1 and solvatochromic emission in solvents of different polarities.

Al2 O3 -Stabilized Pt Nanozymes: Peroxidase Mimetics and Application in Glucose Detection.

As promising alternatives for natural enzymes, much attention has been paid to nanozymes. And our recent study showed that the medium acid sites on the support are the active sites for the adsorption and oxidation of the substrate. Thus, in this work, due to the abundance of medium acid sites, Al2 O3 was chosen as the support to prepare Pt/Al2 O3 nanozymes. Through the Pt/Al2 O3 samples, we further proved that the distribution of the Pt clusters and the amount of the medium acid sites can significantly influence the peroxidase-like activity. Then the Pt/Al2 O3 sample was used for the detection of glucose. And as low as 0.96 µM glucose could be detected with a linear range from 5-60 µM via our method. This work showed the great potential applications of the easily prepared Pt/Al2 O3 samples in varieties of simple, robust, and easy-to-make analytical approaches in the future.

A miRNA-based gene therapy nanodrug synergistically enhances pro-inflammatory antitumor immunity against melanoma.

MicroRNA (miRNA)-based gene therapy is a robust approach to treating human cancers. However, the low target specificity and safety issues associated with viral vectors have limited the clinical use of miRNA therapeutics. In the present study, we aimed to develop a biocompatible nanocarrier to deliver the tumor suppressor miR-30a-5p for gene therapy of ocular melanoma. The quasi-mesoporous magnetic nanospheres (MMNs) were prepared by polyelectrolytes-mediated self-assembling Fe3O4 nanocrystals; the cationic polymer capped quasi-mesoporous inner tunnels of the MMNs facilitate high miRNA loading and protect from nuclease degradation. Then, the outer layer of the MMNs was modified with a disulfide bond bridged very low molecular weight polyethyleneimine (PEI) network to form redox-responsive nanospheres (rMMNs) that enhance the miRNA payload and enable miRNA release under glutathione-dominant tumor microenvironment. The miR-30a-5p loaded rMMNs nanodrug (miR-30a-5p@rMMNs) upregulated miR-30a-5p level and inhibited malignant phenotypes of ocular melanoma by targeting the transcription factor E2F7 both in vitro and in vivo. Additionally, rMMNs act as an enhancer to increase cancer cell apoptosis by modulating M1-like macrophage polarization and activating Fenton reaction. Thus, the rMMNs is a promising miRNA carrier for gene therapy and could enhance pro-inflammatory immunity in melanoma and other cancers. STATEMENT OF SIGNIFICANCE: • miR-30a-5p@rMMNs inhibited malignant phenotypes of ocular melanoma both in vitro and in vivo. • The rMMNs promoted M1 macrophage polarization thus synergistically enhancing pro-inflammatory anti-tumor immunity against melanoma. • The rMMNs showed no obvious toxicity under the injection dose.

Integrated Analysis of Multiomics Data Identified Molecular Subtypes and Oxidative Stress-Related Prognostic Biomarkers in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is a glioma in IV stage, which is one of the most common primary malignant brain tumors in adults. GBM has the characters of high invasiveness, high recurrence rate, and low survival rate and with a poor prognosis. GBM implicates various genetic changes and epigenetic and gene transcription disorders, which are crucial in developing GBM. With the progression and enhancement of high-throughput sequencing technologies, the acquirement and administering approaches of diverse biological omics data on distinctive levels are developing more advanced. However, the research of GBM with multiomics remains largely unknown. We identified GBM-related molecular subtypes by integrated multiomics data and exploring the connections of gene copy number variation (CNV) and methylation gene (MET) change data. The expression of CNV and MET genes was examined through cluster integration analysis. The present study confirmed three clusters (iC1, iC2, and iC3) with distinctive prognosis and molecule peculiarities. We also recognized three oxidative stress protecting molecules (OSMR, IGFBP6, and MYBPH) by contrasting gene expression, MET, and CNV in the three subtypes. OSMR, IGFBP6, and MYBPH were differentially expressed in the clusters, suggesting they might be recognized as characteristic markers for the three clusters in GBM. Through integrative investigation of genomics, epigenomics, and transcriptomics, we offer novel visions into the multilayered molecules of GBM and facilitate the accuracy remedy for GBM sufferers.

A 41-Year-Old Woman with a Late Cerebral Metastasis 16 Years After an Initial Diagnosis of Cutaneous Melanoma.

BACKGROUND Late cerebral metastasis more than 10 years after the diagnosis of cutaneous melanoma is very rare. This report is of a woman with late cerebral metastasis 16 years after an initial diagnosis of cutaneous melanoma. CASE REPORT A 41-year-old woman had been diagnosed with malignant melanoma 16 years prior from a biopsy of a dish-pattern tumor on the back, for which she received chemotherapy for 5 times (therapeutic regimen and medications were not available). She had not had a diagnosis of skin melanoma in the past 16 years. Before presentation to the Emergency Department, she had a progressive disturbance of consciousness for 6 weeks and sudden coma for 6 h. A head computed tomography scan indicated intracranial masses located at the right frontal and temporal lobes. The patient underwent surgery for tumor and hematoma removal. During surgery, dural metastasis with widespread dissemination in adjacent temporal bone, temporalis, and hypodermis was confirmed. Postoperative histopathology analysis confirmed the diagnosis of malignant melanoma metastasis. On the second day after surgery, the patient developed recurrent bleeding in the right frontal lobe, which led to deteriorated consciousness. She received hematoma evacuation and craniectomy and lived in a poor condition with drowsiness and hemiplegia of the left limb for 3 months and died 5 months after craniectomy. CONCLUSIONS This report has presented a rare occurrence of late cerebral metastasis 16 years after the initial diagnosis of a primary cutaneous melanoma. More recent primary melanoma of the skin was not identified, which supports the need for long-term follow-up of patients with a history of primary cutaneous melanoma.

[Corrigendum] SNHG15 affects the growth of glioma microvascular endothelial cells by negatively regulating miR­153.

Following the publication of this article, the authors have realized that they had inadvertently used the same western blotting data to show the GAPDH control western blots in Figs. 1C and 4D. In examining their original data, the authors realized that the data for Fig. 1C had been placed incorrectly in the figure. The corrected version of Fig. 1, showing the correct GAPDH bands, is shown below. The authors sincerely apologize for the error made during the preparation of this Figure, thank the Editor for granting them the opportunity to publish this Corrigendum, and regret any inconvenience that this mistake may have caused. [the original article was published in Oncology Reports 38: 3265­3277, 2017; DOI: 10.3892/or.2017.5985].

Gene Expression Signature of Traumatic Brain Injury.

Background: Traumatic brain injury (TBI) is a brain function change caused by external forces, which is one of the main causes of death and disability worldwide. The aim of this study was to identify early diagnostic markers and potential therapeutic targets for TBI. Methods: Differences between TBI and controls in GSE89866 and GSE104687 were analyzed. The two groups of differentially expressed genes (DEGs) were combined for coexpression analysis, and the modules of interest were performed using enrichment analysis. Hub genes were identified by calculating area under curve (AUC) values of module genes, PPI network analysis, and functional similarity. Finally, the difference in immune cell infiltration between TBI and control was calculated by ssGSEA. Results: A total of 4,817 DEGs were identified in GSE89866 and 1,329 DEGs in GSE104687. They were clustered into nine modules. The genes of modules 1, 4, and 7 had the most crosstalk and were identified as important modules. Enrichment analysis revealed that they were mainly associated with neurodevelopment and immune inflammation. In the PPI network constructed by genes with top 50 AUC values in module genes, we identified the top 10 genes with the greatest connectivity. Among them, down-regulated RPL27, RPS4X, RPL23A, RPS15A, and RPL7A had similar functions and were identified as hub genes. In addition, DC and Tem were significantly up-regulated and down-regulated between TBI and control, respectively. Conclusion: We found that hub genes may have a diagnostic role for TBI. Molecular dysregulation mechanisms of TBI are associated with neurological and immune inflammation. These results may provide new ideas for the diagnosis and treatment of TBI.

LACTB suppresses melanoma progression by attenuating PP1A and YAP interaction.

Very limited progress has been made in the management of advanced melanoma, especially melanoma of uveal origin. Lactamase ß (LACTB) is a novel tumor suppressor; however, its biological function in melanoma remains unknown. Herein we demonstrated markedly lower LACTB expression levels in melanoma tissues and cell lines. Overexpression of LACTB suppressed the proliferation, migration and invasion of melanoma cells in vitro. Mechanistically, LACTB inhibited the activity of yes-associated protein (YAP). We showed that the level of phospho-YAP (Serine 127) was increased upon LACTB overexpression, which prevented the translocation of YAP to the nucleus. Further, LACTB could directly bind to PP1A and attenuate the interaction between PP1A and YAP, resulting in decreased YAP dephosphorylation and inactivation in a LATS1-independent manner. Additionally, transfection of phosphorylation-defective YAP mutants reversed LACTB-induced tumor suppression. Upstream, we demonstrated that SOX10 binds to the LACTB promoter and negatively regulates its transcription. Overexpression of LACTB also suppressed the tumorigenicity and lung metastasis of MUM2B uveal melanoma cells in vivo. Taken together, our findings indicate a novel SOX10/LACTB/PP1A signaling cascade that renders YAP inactive and modulates melanoma progression, offering a new therapeutic target for melanoma treatment.

The role of mitochondrial dynamics in human cancers.

Mitochondria are crucial cellular organelles. Under extracellular stimulations, mitochondria undergo constant fusion and fission dynamics to meet different cellular demands. Mitochondrial dynamics is regulated by specialized proteins and lipids. Dysregulated mitochondrial dynamics has been linked to the initiation and progression of diverse human cancers, affecting aspects such as cancer metastasis, drug resistance and cancer stem cell survival, suggesting that targeting mitochondrial dynamics is a potential therapeutic strategy. In the present review, we summarize the molecular mechanisms underlying fusion and fission dynamics and discuss the effects of mitochondrial dynamics on the development of human cancers.

Circular RNA USP1 regulates the permeability of blood-tumour barrier via miR-194-5p/FLI1 axis.

Recent studies indicate circular RNAs are related to dysregulation of vascular endothelial cell function, yet the underlying mechanisms have remained elusive. Here, we characterized the functional role of circular RNA USP1 (circ-USP1) in the regulation of the blood-tumour barrier (BTB) permeability and the potential mechanisms. In the current study, the circ-USP1 expressing level was up-regulated in glioma cerebral microvascular endothelial cells (GECs) of the BTB model in vitro. Knockdown of circ-USP1 disrupted the barrier integrity, increased its permeability as well as reduced tight junction-related protein claudin-5, occludin and ZO-1 expressions in GECs. Bioinformatic prediction and luciferase assay indicated that circ-USP1 bound to miR-194-5p and suppressed its activity. MiR-194-5p contributed to circ-USP1 knockdown-induced increase of BTB permeability via targeting and down-regulating transcription factor FLI1. Furthermore, FLI1 regulated the expressions of claudin-5, occludin and ZO-1 in GECs through binding to their promoter regions. Single or combined treatment of circ-USP1 and miR-194-5p effectively promoted anti-tumour drug doxorubicin across BTB to induce apoptosis of glioma cells. Overall, this present study identified the crucial regulation of circ-USP1 on BTB permeability via miR-194-5p/FLI1 axis-mediated regulation of tight junction proteins, which might facilitate the development of therapeutics against human gliomas.

MYCN and PRC1 cooperatively repress docosahexaenoic acid synthesis in neuroblastoma via ELOVL2.

BACKGROUND: The MYCN amplification is a defining hallmark of high-risk neuroblastoma. Due to irregular oncogenes orchestration, tumor cells exhibit distinct fatty acid metabolic features from non-tumor cells. However, the function of MYCN in neuroblastoma fatty acid metabolism reprogramming remains unknown. METHODS: Gas Chromatography-Mass Spectrometer (GC-MS) was used to find the potential target fatty acid metabolites of MYCN. Real-time PCR (RT-PCR) and clinical bioinformatics analysis was used to find the related target genes. The function of the identified target gene ELOVL2 on cell growth was detected through CCK-8 assay, Soft agar colony formation assay, flow Cytometry assay and mouse xenograft. Chromatin immunoprecipitation (ChIP) and Immunoprecipitation-Mass Spectrometer (IP-MS) further identified the target gene and the co-repressor of MYCN. RESULTS: The fatty acid profile of MYCN-depleted neuroblastoma cells identified docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid with anti-tumor activity, significantly increased after MYCN depletion. Compared with MYCN single-copy neuroblastoma cells, DHA level was significantly lower in MYCN-amplified neuroblastoma cells. RT-PCR and clinical bioinformatics analysis discovered that MYCN interfered DHA accumulation via ELOVL fatty acid elongase 2 (ELOVL2) which is a rate-limiting enzyme of cellular DHA synthesis. Enforced ELOVL2 expression in MYCN-amplified neuroblastoma cells led to decreased cell growth and counteracted the growth-promoting effect of MYCN overexpression both in vitro and vivo. ELOVL2 Knockdown showed the opposite effect in MYCN single-copy neuroblastoma cells. In primary neuroblastoma, high ELOVL2 transcription correlated with favorable clinical tumor biology and patient survival. The mechanism of MYCN-mediated ELOVL2 inhibition contributed to epigenetic regulation. MYCN recruited PRC1 (Polycomb repressive complex 1), catalysed H2AK119ub (histone 2A lysine 119 monoubiquitination) and inhibited subsequent ELOVL2 transcription. CONCLUSIONS: The tumor suppressive properties of DHA and ELOVL2 are repressed by the MYCN and PRC1 jointly, which suggests a new epigenetic mechanism of MYCN-mediated fatty acid regulation and indicates PRC1 inhibition as a potential novel strategy to activate ELOVL2 suppressive functions.

Endothelial Monocyte-Activating Polypeptide-II Induces BNIP3-Mediated Mitophagy to Enhance Temozolomide Cytotoxicity of Glioma Stem Cells via Down-Regulating MiR-24-3p.

Preliminary studies have shown that endothelial-monocyte-activating polypeptide-II (EMAP-II) and temozolomide (TMZ) alone can exert cytotoxic effects on glioma cells. This study explored whether EMAP-II can enhance the cytotoxic effects of TMZ on glioma stem cells (GSCs) and the possible mechanisms associated with Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-mediated mitophagy facilitated by miR-24-3p regulation. The combination of TMZ and EMAP-II significantly inhibited GSCs viability, migration, and invasion, resulting in upregulation of the autophagy biomarker microtubule-associated protein one light chain 3 (LC3)-II/I but down-regulation of the proteins P62, TOMM 20 and CYPD, changes indicative of the occurrence of mitophagy. BNIP3 expression increased significantly in GSCs after treatment with the combination of TMZ and EMAP-II. BNIP3 overexpression strengthened the cytotoxic effects of EMAP-II and TMZ by inducing mitophagy. The combination of EMAP-II and TMZ decreased the expression of miR-24-3p, whose target gene was BNIP3. MiR-24-3p inhibited mitophagy and promoted proliferation, migration and invasion by down-regulating BNIP3 in GSCs. Furthermore, nude mice subjected to miR-24-3p silencing combined with EMAP-II and TMZ treatment displayed the smallest tumors and the longest survival rate. According to the above results, we concluded that EMAP-II enhanced the cytotoxic effects of TMZ on GSCs' proliferation, migration and invasion both in vitro and in vivo.

SNHG15 affects the growth of glioma microvascular endothelial cells by negatively regulating miR-153.

Malignant glioma, the most common intracranial primary tumor, is characterized by increased angiogenesis. Accumulating evidence has shown that long non-coding RNAs (lncRNAs) play an important role in a variety of biological behaviors of tumors. However, the role of lncRNAs in the regulation of glioma vascular endothelial cell function remains to be investigated. To simulate the glioma microenvironment, we applied glioma conditioned medium (GCM) to human cerebral microvascular endothelial cells (hCMECs). In the present study, the lncRNA SNHG15 was found to be highly expressed in glioma vascular endothelial cells. Cell Counting Kit-8 (CCK-8), migration and tube formation assays demonstrated that knockdown of SNHG15 inhibited glioma vascular endothelial cell proliferation, migration and tube formation in vitro. Furthermore, knockdown of SNHG15 downregulated the expression of VEGFA and Cdc42, which are known to promote angiogenesis. Bioinformatics software and dual-luciferase system analysis confirmed that SNHG15 affected endothelial cell function by targeting miR-153. Additionally, the present study showed that miR-153 targeted the 3'­untranslated region of VEGFA and Cdc42 and downregulated their expression. In conclusion, knockdown of SNHG15 downregulated the expression of VEGFA and Cdc42 by targeting miR-153, consequently suppressing glioma vascular endothelial cell proliferation, migration and tube formation. Therefore, SNHG15 and miR-153 are new potential therapeutic targets for anti-angiogenesis treatment of glioma.

PVT1 affects growth of glioma microvascular endothelial cells by negatively regulating miR-186.

Vigorous angiogenesis is one of the reasons for the poor prognosis of glioma. A number of studies have shown that long non-coding RNA can affect a variety of biological behaviors of tumors. However, the influence of long non-coding RNAs on glioma vascular endothelial cells remains unclear. To simulate the glioma microenvironment, we applied glioma-conditioned medium to human cerebral microvascular endothelial cells. The long non-coding RNA PVT1 was found to be highly expressed in glioma vascular endothelial cells. Cell Counting Kit-8, migration, and tube formation assays showed that PVT1 overexpression promoted glioma vascular endothelial cells proliferation, migration, and angiogenesis. We also found that PVT1 overexpression upregulated the expression of the autophagy-related proteins Atg7 and Beclin1, which induced protective autophagy. Bioinformatics software and dual-luciferase system analysis confirmed that PVT1 acts by targeting miR-186. In addition, our study showed that miR-186 could target the 3' untranslated region of Atg7 and Beclin1 to decrease their expression levels, thereby inhibiting glioma-conditioned human cerebral microvascular endothelial cell autophagy. In conclusion, PVT1 overexpression increased the expression of Atg7 and Beclin1 by targeting miR-186, which induced protective autophagy, thus promoting glioma vascular endothelial cell proliferation, migration, and angiogenesis. Therefore, PVT1 and miR-186 can provide new therapeutic targets for future anti-angiogenic treatment of glioma.

Verteporfin induces apoptosis and eliminates cancer stem-like cells in uveal melanoma in the absence of light activation.

Uveal melanoma (UM) is the most common primary ocular malignancy in adults. Currently, no beneficial systemic therapy is available; therefore, there is an urgent need for effective targeted therapeutic drugs. As verteporfin has shown anti-neoplastic activity in several types of cancers, here we hypothesized and investigated the efficacy of verteporfin against UM cells without light activation. MTS assay, flow cytometry analysis of apoptosis, Western blotting of relevant proteins, transwell migration and invasion assay, melanosphere culture, and measurement of ALDH+ populations, were used to evaluate the effects of verteporfin on UM cells. We found that verteporfin disrupted the interaction between YAP and TEAD4 in UM cells and decreased the expression of YAP targeted downstream genes. Verteporfin treatment decreased the cytoplasmic and nuclear levels of YAP and induced lysosome-dependent degradation of YAP protein. Verteporfin exhibited distinct inhibitory effect on the proliferation of four lines of UM cells (e.g., 92.1, Mel 270, Omm 1 and Omm 2.3), and induced apoptosis through the intrinsic pathway. Additionally, verteporfin suppressed migration and invasion of UM cells, impaired the traits of cancer stem-like cells (e.g., melanosphere formation capacity, and ALDH+ cell population). This study demonstrated the anti-neoplastic activity of verteporfin against UM cells in vitro, providing a rationale for evaluating this agent in clinical investigation.

Regulating the piezofluorochromism of 9,10-bis(butoxystyryl)anthracenes by isomerization of butyl groups.

Isomers of 9,10-bis(butoxystyryl)anthracene (DSA4), including n-butyl, i-butyl and t-butyl at ortho or para positions, were designed and synthesized. All of them display an aggregation-induced emission phenomenon. Remarkably, it was found that isomerization of butyl endgroups presents significant influences on their piezofluorochromic properties. Thus, an alternative approach to design and obtain piezofluorochromic compounds is proposed here.