Mapping cell diversity in human sporadic cerebral cavernous malformations.

BACKGROUND: Cerebral cavernous malformation (CCM) is a low-flow, bleeding-prone vascular disease that can cause cerebral hemorrhage, seizure and neurological deficits. Its inheritance mode includes sporadic or autosomal dominant inheritance with incomplete penetrance, namely sporadic CCM (SCCM) and familial CCM. SCCM is featured by single lesion and single affection in a family. Among CCM patients especially SCCM, the pathogenesis of the corresponding phenotypes and pathological features or candidate genes have not been fully elucidated yet. METHODS: Here, we performed in-depth single-cell RNA sequencing (scRNA-Seq) and bulk assay for transposase-accessible chromatin sequencing (ATAC-Seq) in SCCM and control patients. Further validation was conducted for the gene of interest using qPCR and RNA in situ hybridization (RNA FISH) techniques to provide further atlas and evidence for SCCM generative process. RESULTS: We identified six cell types in the SCCM and control vessels and found that the expression of NEK1, RNPC3, FBRSL1, IQGAP2, MCUB, AP3B1, ESCO1, MYO9B and PVT1 were up-regulated in SCCM tissues. Among the six cell types, we found that compared with control conditions, PVT1 showed a rising peak which followed the pseudo-time axis in endothelial cell clusters of SCCM samples, while showed an increasing trend in smooth muscle cell clusters of SCCM samples. Further experiments indicated that, compared with the control vessels, PVT1 exhibited significantly elevated expression in SCCM samples. CONCLUSION: In SCCM conditions, We found that in the process of development from control to lesion conditions, PVT1 showed a rising peak in endothelial cells and showed an increasing trend in smooth muscle cells at the same time. Overall, there was a significantly elevated expression of NEK1, RNPC3, FBRSL1, IQGAP2, MCUB, AP3B1, ESCO1, MYO9B and PVT1 in SCCM specimens compared to control samples.

Augmented reality technology shortens aneurysm surgery learning curve for residents.

OBJECTIVES: We aimed to prospectively investigate the benefit of using augmented reality (AR) for surgery residents learning aneurysm surgery. MATERIALS AND METHODS: Eight residents were included, and divided into an AR group and a control group (4 in each group). Both groups were asked to locate an aneurysm with a blue circle on the same screenshot after their viewing of surgery videos from both AR and non-AR tests. Only the AR group was allowed to inspect and manipulate an AR holographic representation of the aneurysm in AR tests. The actual location of the aneurysm was defined by a yellow circle by an attending physician after each test. Localization deviation was determined by the distance between the blue and yellow circle. RESULTS: Localization deviation was lower in the AR group than in the control group in the last 2 tests (AR Test 2: 2.7 ± 1.0 mm vs. 5.8 ± 4.1 mm, p = 0.01, non-AR Test 2: 2.1 ± 0.8 mm vs. 5.9 ± 5.8 mm, p < 0.001). The mean deviation was lower in non-AR Test 2 as compared to non-AR Test 1 in both groups (AR: p < 0.001, control: p = 0.391). The localization deviation of the AR group decreased from 8.1 ± 3.8 mm in Test 2 to 2.7 ± 1.0 mm in AR Test 2 (p < 0.001). CONCLUSION: AR technology provides an effective and interactive way for neurosurgery training, and shortens the learning curve for residents in aneurysm surgery.

FOXM1 maintains fatty acid homoeostasis through the SET7-H3K4me1-FASN axis.

Reprogramming of metabolic genes and subsequent alterations in metabolic phenotypes occur widely in malignant tumours, including glioblastoma (GBM). FOXM1 is a potent transcription factor that plays an oncogenic role by regulating the expression of many genes. As a SET domain containing protein, SET7 is a protein lysine methyltransferase which monomethylates histone proteins and other proteins. The epigenetic modification of histones regulates gene expressions by epigenetically modifying promoters of DNAs and inter vening in tumor development. Activation of FASN increased de novo fatty acid (FA) synthesis, a hallmark of cancer cells. Here, we report that FOXM1 may directly promote the transcription of SET7 and activate SET7-H3K4me1-FASN axis, which results in the maintenance of de novo FA synthesis.

Ticagrelor is related to nuisance bleeding after flow diversion of unruptured intracranial aneurysms.

Nuisance bleeding (NB) without urgent medical attention is rarely characterized despite its frequent occurrence in patients with cerebral aneurysms undergoing flow diversion (FD) who are maintained on dual antiplatelet therapy (DAPT). This study explored the risk factors for NB. Patients with unruptured cerebral aneurysms who underwent intervention using FD (July 2018 to May 2022) and had follow-up data were enrolled. Patient demographics, clinical characteristics, aneurysm features and follow-up data were analysed. Bleeding complications were classified as NB, internal bleeding and alarming bleeding. NB was characterized by easy bruising, bleeding from small cuts and nonfatal petechiae and ecchymosis. Univariate and multivariate logistic regression analyses were performed to determine risk factors for NB. This study assessed 121 patients. Of these, 52 (43.0%) patients had NB. Compared with the non-bleeding group, the NB group had more females (82.7% vs. 56.5%; p = 0.003), lower smoking rate (7.7% vs. 23.2%; p = 0.027) and smaller aneurysms (6.65 mm [4.60-9.60 mm] vs. 8.82 mm [5.65-15.65 mm]; p = 0.007) and had more patients maintained on ticagrelor-containing DAPT regimen (90.4% vs. 66.7%; p = 0.002). Multivariate logistic regression revealed that ticagrelor-containing DAPT regimen (odds ratio, 3.91; 95% confidence interval, 1.29-11.87; p = 0.016) was associated with NB. These results suggest that NB is a common bleeding complaint in patients on DAPT. In patients undergoing FD, DAPT with ticagrelor was the only independent risk factor for NB.

Operative treatment of cystic prolactinomas: a retrospective study.

BACKGROUND: The optimal therapeutic approach for cystic prolactinomas remains unclear. This study aimed to evaluate the remission rates of prolactinoma patients after surgical treatment and the risk factors affecting postoperative remission in cystic prolactinoma patients. METHODS: The clinical data were retrospectively compiled from 141 patients with prolactinomas (including 41 cases of cystic prolactinomas, 21 cases of solid microprolactinomas and 79 cases of solid macroprolactinomas) who underwent transsphenoidal surgery (TSS) between April 2013 and October 2021 at the First Affiliated Hospital of Sun Yat-sen University. RESULTS: Early postoperative remission was achieved in 65.83% (n = 27/41) of cystic prolactinomas, 80.95% (n = 17/21) of solid microprolactinomas and 40.51% (n = 32/79) of solid macroprolactinomas. The mean length of follow up in all patients was 43.95 ± 2.33 months (range: 6-105 months). The follow-up remission rates were 58.54%, 71.43% and 44.30% in cystic, solid micro- and solid macroprolactinomas, respectively. For cystic prolactinomas, the early postoperative remission rates in the patients with preoperative dopamine agonists (DA) treatment were significantly higher than those without preoperative DA treatment (p = 0.033), but the difference in the follow-up remission rates between these two groups was not significant (p = 0.209). Multivariate stepwise logistic regression analysis indicated that tumor size and preoperative prolactin (PRL) levels < 200 ng/ml were independent predictors for early postoperative remission in cystic prolactinomas. CONCLUSION: For cystic prolactinomas, tumor size and preoperative PRL levels were independent predictors of early postoperative remission. Preoperative DA therapy combined with TSS may be more beneficial to cystic prolactinoma patients.

Transsphenoidal surgery for prolactinomas in male patients: a retrospective study.

Male patients with prolactinomas usually present with typical hyperprolactinemia symptoms, including sexual dysfunction and infertility. However, clinical factors related to sexual dysfunction and surgical outcomes in these patients remain unclear. This study aimed to investigate the outcomes of male patients with prolactinomas after transsphenoidal surgery and the risk factors affecting sexual dysfunction. This study was conducted on 58 male patients who underwent transsphenoidal surgery for prolactinomas between May 2014 and December 2020 at the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. We evaluated the sexual function of patients before and after surgery through International Index of Erectile Function-5 scores, libido, and frequency of morning erection. Of the 58 patients, 48 (82.8%) patients had sexual intercourse preoperatively. Among those 48 patients, 41 (85.4%) patients presented with erectile dysfunction. The preoperative International Index of Erectile Function-5 scores in patients with macroprolactinomas were significantly higher than those in patients with giant prolactinomas (17.63 ± 0.91 vs 13.28 ± 1.43; P = 0.01). Postoperatively, the incidence of erectile dysfunction was 47.9%, which was significantly lower than that preoperatively (85.4%; P = 0.01). Twenty-eight (68.3%) patients demonstrated an improvement in erectile dysfunction. Tumor size and invasiveness were significantly correlated with the improvement of erectile dysfunction. Preoperative testosterone <2.3 ng ml-1 was an independent predictor of improvement in erectile dysfunction. In conclusion, our results indicated that tumor size and invasiveness were important factors affecting the improvement of sexual dysfunction in male patients with prolactinoma. The preoperative testosterone level was an independent predictor related to the improvement of erectile dysfunction.

Risk Factors for Cerebral Infarction After Microsurgical Clipping of Hunt-Hess Grade 0-2 Single Intracranial Aneurysm: A Retrospective Study.

OBJECTIVE: The study aimed to explore risk factors for cerebral infarction after microsurgical clipping in patients with Hunt-Hess grade 0-2 single intracranial aneurysms. METHODS: A total of 137 patients with Hunt-Hess grade 0-2 single intracranial aneurysms treated with microsurgical clipping between March 2017 and December 2020 were retrospectively enrolled. Patients were divided into 2 groups on the basis of the occurrence of cerebral infarction after surgery. RESULTS: Of 137 enrolled patients, 14 (10.22%) showed cerebral infarction symptoms after surgery. Univariate analysis indicated that ruptured aneurysm status, aneurysm rupture during surgery, history of transient ischemic attack (TIA)/stroke, aneurysm size ≥7 mm, temporary clipping, intraoperative systolic hypotension (IOH), and occurrences of intraoperative motor-evoked potentials change were significantly related to postoperative cerebral infarction (PCI). However, using multivariate regression, only history of TIA/stroke (odds ratio = 0.124; 95% confidence interval [CI] = 0.021-0.748, P = 0.023) and IOH (odds ratio = 0.032; 95% CI = 0.005-0.210, P < 0.001) were independent predictors for PCI. Receiver operating characteristic curve analysis showed that the critical duration of temporary clipping and IOH that minimized the risk of PCI was 5.5 minutes and 7.5 minutes, respectively. CONCLUSIONS: Our study identified history of TIA/stroke and IOH as independent risk factors for cerebral infarction after microsurgical clipping.

Comprehensive Analysis of Blood-Based m6A Methylation in Human Ischemic Stroke.

Alterations of N6-methyladenosine (m6A) methylation have been reported in the cerebral cortices of mouse and rat models of ischemic stroke (IS). However, the role of m6A methylation in human IS is still unknown. We assessed m6A levels in peripheral blood from patients with IS and healthy controls. A transient middle cerebral artery occlusion and reperfusion (tMCAO/R) mouse model, and an oxygen-glucose deprivation/reperfusion (OGD/R) model in A172 cells were established to further assess m6A levels. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing were performed in the peripheral blood of patients with IS and healthy controls. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to identify underlying biological processes. In this study, we found that global m6A levels were elevated in the peripheral blood of patients with IS, in the cerebral cortex of mice after tMCAO/R treatment and in A172 cells after OGD/R treatment. MeRIP-seq analysis identified 2115 altered m6A peaks in patients with IS, 1052 upregulated and 1063 downregulated. Downregulated methylated mRNAs were enriched in Hippo signaling pathway, cytokine-cytokine receptor interaction, NF-kappa B signaling pathway, etc. Upregulated methylated mRNAs were enriched in calcium signaling pathways, Hedgehog signaling pathway, MAPK signaling pathway, etc. Moreover, a total of 84 differentially expressed mRNAs with altered m6A peaks were identified and enriched in EGFR tyrosine kinase inhibitor, Hematopoietic cell lineage, and cytokine-cytokine receptor interactions. This study is the first to profile the transcriptome-wide m6A methylome of peripheral blood in human IS and uncover increased global m6A levels in the peripheral blood of patients with IS.

Network Pharmacology and Molecular Docking to Explore the Mechanism of Kangxian Decoction for Epilepsy.

Purpose: Kangxian decoction (KXD) has been used in clinical practice to treat epilepsy. The purpose of this study was to explore the active components of KXD and clarify its antiepileptic mechanism through network pharmacology and molecular docking. Methods: The components of KXD were collected from the Encyclopedia of Traditional Chinese Medicine (ETCM) database and the literature was searched. Then, active ingredients were screened by SwissADME and potential targets were predicted by the SwissTargetPrediction database. Epilepsy-related differentially expressed genes were downloaded from the Gene Expression Omnibus database. A component-target-pathway network was constructed with Cytoscape. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein‒protein interaction network analysis revealed the potential mechanism and critical targets. Receiver operating characteristic (ROC) curves and box plots in microarray data validated the good diagnostic value and significant differential expression of these critical genes. Molecular docking verified the association between active ingredients and essential target proteins. Results: In our study, we screened the important compounds of KXD for epilepsy, including quercetin, baicalin, kaempferol, yohimbine, geissoschizine methyl ether, baicalein, etc. KXD may exert its therapeutic effect on epilepsy through the following targets: PTGS2, MMP9, CXCL8, ERBB2, and ARG1, acting on the following pathways: neuroactive ligand-receptor interactions, arachidonic acid metabolism, IL-17, TNF, NF-kappa B, and MAPK signaling pathways. The molecular docking results showed that the active ingredients in KXD exhibited good binding ability to the key targets. Conclusion: In this study, we explored the possibility that KXD for epilepsy may act on multiple targets through multiple active ingredients, involving neurotransmitters and neuroinflammatory pathways, providing a theoretical basis for subsequent clinical and experimental studies that will help develop effective new drugs to treat epilepsy.

Analysis of expression profiles and bioinformatics suggests that plasma exosomal circular RNAs may be involved in ischemic stroke in the Chinese Han population.

Circular RNAs (circRNAs) have been confirmed to be associated with ischemic stroke(IS), but the involvement of exosomal circRNAs in plasma still needs to be extensively discussed. Therefore, we aimed to investigate the expression profile of exosomal circRNAs in plasma and the potential roles and mechanisms of exosomal circRNAs in the pathogenesis of ischemic stroke in the Chinese Han population. In this study, the plasma exosomal circRNA expression profiles of three IS patients and three healthy controls were analyzed using circRNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and circRNA-miRNA-mRNA regulatory network analysis were performed for the aberrantly expressed genes. Protein-protein interaction (PPI) networks and molecular complex detection algorithms (MCODEs) were analyzed by STRING and Cystoscope for functional annotation and construction, respectively. RNA-Seq analysis revealed that a total of 3540 circRNAs were aberrantly expressed in exosomes, 1177 circRNAs were significantly upregulated, and 2363 circRNAs were downregulated in IS patients compared to healthy controls. Bioinformatics analysis revealed that the parental genes of differentially expressed circRNAs as well as the mRNAs predicted in the circRNA-miRNA-mRNA regulatory network are enriched for signaling pathways associated with IS pathology, such as the MAPK signaling pathway, lipid and atherosclerosis, neurotrophic factor signaling pathways, mTOR signaling pathway, the p53 signaling pathway etc. Then, 10 hub genes were identified from the PPI and module networks, including FBXW11, FBXW7, UBE2V2, ANAPC7, CDC27, UBC, CDC5L, POLR2H, POLR2F and RBX1. Overall, the present study provides evidence of an altered plasma exosomal circRNA expression profile and its potential function in IS. Our findings may contribute to the study of the pathogenesis of circRNAs in IS and provide ideas for studying potential diagnostic biomarkers and therapeutic targets for IS.

Assessing the Anti-inflammatory Mechanism of Reduning Injection by Network Pharmacology.

Reduning Injection (RDNI) is a traditional Chinese medicine formula indicated for the treatment of inflammatory diseases. However, the molecular mechanism of RDNI is unclear. The information of RDNI ingredients was collected from previous studies. Targets of them were obtained by data mining and molecular docking. The information of targets and related pathways was collected in UniProt and KEGG. Networks were constructed and analyzed by Cytoscape to identify key compounds, targets, and pathways. Data mining and molecular docking identified 11 compounds, 84 targets, and 201 pathways that are related to the anti-inflammatory activity of RDNI. Network analysis identified two key compounds (caffeic acid and ferulic acid), five key targets (Bcl-2, eNOS, PTGS2, PPARA, and MMPs), and four key pathways (estrogen signaling pathway, PI3K-AKT signaling pathway, cGMP-PKG signaling pathway, and calcium signaling pathway) which would play critical roles in the treatment of inflammatory diseases by RDNI. The cross-talks among pathways provided a deeper understanding of anti-inflammatory effect of RDNI. RDNI is capable of regulating multiple biological processes and treating inflammation at a systems level. Network pharmacology is a practical approach to explore the therapeutic mechanism of TCM for complex disease.

Endovascular treatment of complex middle cerebral artery aneurysms using TuBridge flow diverters.

BACKGROUND: The safety and efficacy of the TuBridge flow diverter in treating middle cerebral artery aneurysms remains unknown. In this study, we report our preliminary experience treating complex middle cerebral artery aneurysms using the TuBridge flow diverter. METHODS: A prospectively maintained database of intracranial aneurysms treated with the TuBridge flow diverter was retrospectively reviewed, and patients with middle cerebral artery aneurysms were included in this study. Demographics, aneurysm features, complications, and clinical and angiographic outcomes were assessed. Evaluation of the angiographic results included occlusion grade of aneurysm (O'Kelly-Marotta grading scale), patency of jailed branch(es), and in-stent stenosis. RESULTS: Eight patients with eight middle cerebral artery aneurysms were included in this study. The mean aneurysm size was 11.8 ± 6.8 mm. There were no procedure-related complications and there was no morbidity or mortality at a mean follow-up of 11.3 ± 3.6 months. All patients had follow-up angiograms at a mean of 7.5 ± 4.0 months after surgery. Of the eight patients, there was 1 (12.5%) O'Kelly-Marotta grading scale A, 3 (37.5%) O'Kelly-Marotta grading scale B, 1 (12.5%) O'Kelly-Marotta grading scale C, and 3 (37.5%) O'Kelly-Marotta grading scale D. Of the seven patients with jailed branch, the blood flow of jailed branch was unchanged in 4 (57.1%), decreased in 2 (28.6%), and occluded in 1 (14.3%). In-stent stenosis was mild in 2 (25%) patients and moderate in 1 (12.5%) patient. CONCLUSION: Midterm results suggest that endovascular treatment of middle cerebral artery aneurysms using the TuBridge flow diverter is safe and associated with good outcomes. The TuBridge flow diverter may be an option for complex middle cerebral artery aneurysms that are difficult to treat with either clipping or coiling.

Pollution characteristics of ambient PM2.5-bound benzo[a]pyrene and its cancer risks in Beijing.

The purpose of this study was to reveal the pollution characteristics of ambient PM2.5-bound benzo[a]pyrene (B[a]P) in Beijing and to assess the lifetime cancer risk from respiratory pathway exposure. The average daily dose was evaluated by the annual concentrations of ambient PM2.5-bound B[a]P, combined with Chinese human exposure factors and the age sensitivity factors. The 70-year lifetime cancer risks of different groups were assessed by the exposure assessment and stochastic analysis method recommended by California Environmental Protection Agency. The groups were divided by age and gender. The results showed that the ambient PM2.5-bound B[a]P concentration during the cold season was 15.7 times greater than that during the warm season in Beijing. The annual average concentrations of PM2.5-bound B[a]P in outdoors and indoors were 1.67 ng/m3 and 1.04 ng/m3, respectively, which exceeded the limit of Chinese National Ambient Air Quality Standard. The cancer risks of PM2.5-bound B[a]P in males, females, and the general population were 9.085 × 10-6, 8.050 × 10-6, and 8.740 × 10-6, respectively. The cancer risk constituent ratios of ambient PM2.5-bound B[a]P in early life (≤16 years of age) for males, females, and the general population were 70.9%, 71.4%, and 71.3%, respectively. The males' cancer risk of PM2.5-bound B[a]P in Beijing was higher than that of the females. The early life cancer risk exposure to PM2.5-bound B[a]P should be paid more attention.

A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma.

Circular RNAs (circRNAs) are a large class of transcripts in the mammalian genome. Although the translation of circRNAs was reported, additional coding circRNAs and the functions of their translated products remain elusive. Here, we demonstrate that an endogenous circRNA generated from a long noncoding RNA encodes regulatory peptides. Through ribosome nascent-chain complex-bound RNA sequencing (RNC-seq), we discover several peptides potentially encoded by circRNAs. We identify an 87-amino-acid peptide encoded by the circular form of the long intergenic non-protein-coding RNA p53-induced transcript (LINC-PINT) that suppresses glioblastoma cell proliferation in vitro and in vivo. This peptide directly interacts with polymerase associated factor complex (PAF1c) and inhibits the transcriptional elongation of multiple oncogenes. The expression of this peptide and its corresponding circRNA are decreased in glioblastoma compared with the levels in normal tissues. Our results establish the existence of peptides encoded by circRNAs and demonstrate their potential functions in glioblastoma tumorigenesis.

Source Apportionment and Influencing Factor Analysis of Residential Indoor PM2.5 in Beijing.

In order to identify the sources of indoor PM2.5 and to check which factors influence the concentration of indoor PM2.5 and chemical elements, indoor concentrations of PM2.5 and its related elements in residential houses in Beijing were explored. Indoor and outdoor PM2.5 samples that were monitored continuously for one week were collected. Indoor and outdoor concentrations of PM2.5 and 15 elements (Al, As, Ca, Cd, Cu, Fe, K, Mg, Mn, Na, Pb, Se, Tl, V, Zn) were calculated and compared. The median indoor concentration of PM2.5 was 57.64 µg/m³. For elements in indoor PM2.5, Cd and As may be sensitive to indoor smoking, Zn, Ca and Al may be related to indoor sources other than smoking, Pb, V and Se may mainly come from outdoor. Five factors were extracted for indoor PM2.5 by factor analysis, explained 76.8% of total variance, outdoor sources contributed more than indoor sources. Multiple linear regression analysis for indoor PM2.5, Cd and Pb was performed. Indoor PM2.5 was influenced by factors including outdoor PM2.5, smoking during sampling, outdoor temperature and time of air conditioner use. Indoor Cd was affected by factors including smoking during sampling, outdoor Cd and building age. Indoor Pb concentration was associated with factors including outdoor Pb and time of window open per day, building age and RH. In conclusion, indoor PM2.5 mainly comes from outdoor sources, and the contributions of indoor sources also cannot be ignored. Factors associated indoor and outdoor air exchange can influence the concentrations of indoor PM2.5 and its constituents.

Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis.

Background: Circular RNAs (circRNAs) are RNA transcripts that are widespread in the eukaryotic genome. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. However, whether circRNAs encode functional proteins remains elusive, although translation of several circRNAs was recently reported. Methods: CircRNA deep sequencing was performed by using 10 pathologically diagnosed glioblastoma samples and their paired adjacent normal brain tissues. Northern blotting, Sanger sequencing, antibody, and liquid chromatograph Tandem Mass Spectrometer were used to confirm the existence of circ-FBXW7 and its encoded protein in in two cell lines. Lentivirus-transfected stable U251 and U373 cells were used to assess the biological functions of the novel protein invitro and invivo (five mice per group). Clinical implications of circ-FBXW7 were assessed in 38 pathologically diagnosed glioblastoma samples and their paired periphery normal brain tissues by using quantitative polymerase chain reaction (two-sided log-rank test). Results: Circ-FBXW7 is abundantly expressed in the normal human brain (reads per kilobase per million mapped reads [RPKM] = 9.31). The spanning junction open reading frame in circ-FBXW7 driven by internal ribosome entry site encodes a novel 21-kDa protein, which we termed FBXW7-185aa. Upregulation of FBXW7-185aa in cancer cells inhibited proliferation and cell cycle acceleration, while knockdown of FBXW7-185aa promoted malignant phenotypes invitro and invivo. FBXW7-185aa reduced the half-life of c-Myc by antagonizing USP28-induced c-Myc stabilization. Moreover, circ-FBXW7 and FBXW7-185aa levels were reduced in glioblastoma clinical samples compared with their paired tumor-adjacent tissues (P < .001). Circ-FBXW7 expression positively associated with glioblastoma patient overall survival (P = .03). Conclusions: Endogenous circRNA encodes a functional protein in human cells, and circ-FBXW7 and FBXW7-185aa have potential prognostic implications in brain cancer.

Metadherin/Astrocyte elevated gene-1 positively regulates the stability and function of forkhead box M1 during tumorigenesis.

Background: Forkhead box M1 (FOXM1) is overexpressed and activates numerous oncoproteins in tumors. However, the mechanism by which the FOXM1 protein aberrantly accumulates in human cancer remains uncertain. This study was designed to clarify the upstream signaling pathway(s) that regulate FOXM1 protein stability and transcriptional activity. Methods: Mass spectrometry and immunoprecipitation were performed to identify the FOXM-metadherin (MTDH) interaction. In vivo and in vitro ubiquitination assays were conducted to test the effect of MTDH on FOXM1 stability. Chromatin immunoprecipitation assays were used to determine the involvement of MTDH in FOXM1 transcriptional activity. Cell invasion assays, tube formation assays, and in vivo tumor formation assays were performed to evaluate the cooperative activities of FOXM1 and MTDH during tumorigenesis. Results: MTDH directly interacts with FOXM1 via the N-terminal inhibitory domain of MTDH, and this interaction disrupted the binding of cadherin-1 to FOXM1, thus protecting FOXM1 from subsequent proteasomal degradation. Deleting the MTDH-binding sites of FOXM1 abolished the MTDH overexpression-mediated stabilization of FOXM1. MTDH also bound to FOXM1 target gene promoters and enhanced FOXM1 transcriptional activity. MTDH knockdown destabilized FOXM1 and attenuated its transcriptional activity, consequently inhibiting cell cycle progression, angiogenesis, and cancer cell invasion in vitro and in vivo; these effects were abolished via forced overexpression of a stabilized mutant form of FOXM1. Thus, MTDH stabilized FOXM1 and supported the sustained activation of FOXM1 target genes. Conclusion: These findings highlight a novel MTDH-regulated mechanism of FOXM1 stabilization and provide profound insight into the tumorigenic events simultaneously mediated by FOXM1 and MTDH.

[The quantification and significance of muscle segment homeobox gene Msx2, human topoisomerase II-α, HPV16 and VEGF in sinonasal inverted papilloma].

OBJECTIVE: To investigate the quantification and significance of Msx2, topoII-α; HPV16 and VEGF in sinonasal inverted papilloma(SNIP), to study the correlation among the four factors,and to discover the relationship between Msx2 and topoII-α in the process of SNIP malignant transfomation. METHOD: Real-time quantitative Polymerase Chain Reaction (RT-qPCR) was used to detect the expression of Msx2, topoII-α, HPV16 and VEGF in 13 cases of sinonasal inverted papilloma (SNIP), 10 cases of sinonasal squamous cell carcinoma(NSCC) and 10 cases of inflammatory nasal polyp paraffin (INP)tissues. According to the pathology results SNIP were divided into mild dysplasia, moderate dysplasia and severe dysplasia. All the data were analysised by SPSS17. 0, P<0. 05 was refered to statistically significant difference. RESULT: The mRNA level of Msx2, topoII-α, VEGF and HPV16 in SNIP, NSCC tissues were significantly higher than in the INP tissues (P<0. 05). The expression differences of Msx2, topoII-α, HPV16 and VEGF mRNA level in SNIP tissues which were divided into three groups according to their pathological results,were all statistically significantly different between any two of the three groups (P< 0. 05). Using Pearson correlation coefficient analysis,we found positive correlation between any two of the mRNA level of Msx2, topoII-α, VEGF and HPV16 (P<0. 05). CONCLUSION: Msx2 and topoII-α may play an important role in the process of SNIP Malignant transformation,which may be new targets for gene therapy of SNIP and NSCC.

[Expression and significance of Msx2 and topo II-alpha in sinonasal inverted papilloma].

OBJECTIVE: To investigate the expression and significance of muscle segment homeobox2 (Msx2) and topo II-alpha in sinonasal inverted papilloma (SNIP), and the relationship in the process of malignant transformation of SNIP. METHOD: Immunohistochemical method was used to detect the expression of Msx2 and topo II-alpha in 32 cases of SNIP, 30 cases of inflammatory nasal polyp (INP) and 30 cases of SNIP with carcinoma. According to the pathology results, SNIP were divided into mild atypical hyperplasia, moderate atypical hyperplasia and severe atypical hyperplasia. RESULT: The mean optical density of Msx2 in SNIP and SNIP with carcinoma tissues were 0.2183 +/- 0.0598 and 0.2521 +/- 0.0761,which were significantly higher than 0.1878 +/- 0. 0372 in the INP tissue (P<0.05 or 0.01). The mean optical density of topo II-alpha in SNIP and SNIP with carcinoma tissues were 0.2303 +/- 0.0397 and 0.2666 +/- 0.0483, which were significantly higher than 0.1978 +/- 0.0388 in the NIP tissue (P<0.01). There were significant difference of Msx2 and topo II-alpha in SNIP between any two of the three groups divided according to pathological morphology (P<0.01 or 0.05). The expression of Msx2 and topo II-alpha in SNIP were positively correlated (P<0.05). CONCLUSION: Msx2 and topo II-alpha may play an important role in the occurrence and development of SNIP. So it can be used as new therapeutic targets.