High PIVKA-II level and ASAP score predict 1-year risk of hepatocellular carcinoma in non-cirrhotic chronic hepatitis B patients.

Protein induced by Vitamin K absence or antagonists-II (PIVKA-II) is a diagnostic marker of hepatocellular carcinoma (HCC). We aimed to investigate the predictive role of PIVKA-II and ASAP score for development of HCC in 1 year among untreated patients of chronic hepatitis B (CHB). We conducted this case-control study to include untreated CHB patients followed at the National Taiwan University Hospital and grouped into HCC and matched non-HCC groups. Their archived serum samples were assayed for PIVKA-II levels 1 year before HCC, at HCC or their last serum sample. A total of 69 HCC cases and 102 non-HCC controls were recruited. Baseline PIVKA-II level was significantly higher in the HCC group than in the control group and it could predict HCC development in 1 year with an area under the receiver operating characteristic curve of 0.76. Multivariable analysis adjusting age, sex, liver function and alpha-fetoprotein level showed that baseline PIVKA-II ≥31 mAU/mL (vs. <31 mAU/mL) increased 12.5-fold risk (95% CI: 4.9-31.7) of HCC in 1 year, and even in patients with normal alpha-fetoprotein levels. The ASAP score, a combination of age, sex, alpha-fetoprotein and PIVKA-II, increases the predictability for HCC in 1 year. We concluded that both high PIVKA-II level and ASAP score may predict HCC development in 1 year in untreated CHB patients, especially in patients with normal alpha-fetoprotein level.

Association between growth differentiation factor 15 levels and gestational diabetes mellitus: A combined analysis.

Objective: Gestational diabetes mellitus (GDM) is a common glucose metabolism disease occurs in pregnancy that affects both maternal and neonatal health. Recently, increasing studies have attached importance to the relationship between growth differentiation factor 15 (GDF-15) and GDM, but the results were inconclusive. Therefore, we conducted a meta-analysis to examine the association between GDF-15 and GDM. Materials and methods: A systematical search was performed in Gene Expression Omnibus (GEO), PubMed and Google Scholar till Oct 27, 2022. We first calculated the mean and standard deviation of GDF-15 expression levels from the included eligible datasets and articles. Then, a meta-analysis was conducted to depict the difference in GDF-15 mRNA or GDF-15 protein expression between case and control groups by using conservative random effect model. Moreover, the potential publication bias was checked with the aid of Begg's test and Egger's test. Finally, sensitivity analyses were performed by changing the inclusion criteria. Results: In summary, 12 GEO datasets and 5 articles were enrolled in our study, including 789 GDM patients and 1202 non-GDM pregnant women. It was found that the expression levels of GDF-15 mRNA and GDF-15 protein in late pregnancy were significantly higher in GDM patients compared with non-GDM pregnant women, with the standard mean difference (SMD) and 95% confidence interval (95% CI) of 0.48 (0.14, 0.83) and 0.82 (0.32-1.33), respectively. Meanwhile, a slightly weakened association between GDF-15 protein levels and GDM was also observed in the middle pregnancy, with SMD (95% CI) of 0.53 (0.04-1.02). Conclusion: In all, our results suggested that the expression levels of GDF-15 were significantly higher in GDM patients compared with non-GDM pregnant women, especially in the late pregnancy.

Evolution of m6A-related genes in insects and the function of METTL3 in silkworm embryonic development.

N6-methyladenosine (m6A) plays a key role in many biological processes. However, the function and evolutionary relationship of m6A-related genes in insects remain largely unknown. Here we analysed the phylogeny of m6A-related genes among 207 insect species and found that m6A-related genes are evolutionarily conserved in insects. Subcellular localization experiments of m6A-related proteins in BmN cells confirmed that BmYTHDF3 was localized in the cytoplasm, BmMETTL3, BmMETTL14, and BmYTHDC were localized in the nucleus, and FL2D was localized to both the nucleus and cytoplasm. We examined the expression patterns of m6A-related genes during the embryonic development of Bombyx mori. To elucidate the function of BmMETTL3 during the embryonic stage, RNA sequencing was performed to measure changes in gene expression in silkworm eggs after BmMETTL3 knockdown, as well as in BmN cells overexpressing BmMETTL3. The global transcriptional pattern showed that knockdown of BmMETTL3 affected multiple cellular processes, including oxidoreductase activity, transcription regulator activity, and the cation binding. In addition, transcriptomic data revealed that many observed DEGs were associated with fundamental metabolic processes, including carbon metabolism, purine metabolism, amino acid biosynthesis, and the citrate cycle. Interestingly, we found that knockdown of BmMETTL3 significantly affected Wnt and Toll/Imd pathways in embryos. Taken together, these results suggest that BmMETTL3 plays an essential role in the embryonic development of B. mori, and deepen our understanding of the function of m6A-related genes in insects.

Clairvoyant Melon Maturity Detection Enabled by Doctor-Blade-Coated Photonic Crystals.

Climacteric fruits are harvested before they are ripened to avoid adverse damages during transport. The unripe fruits can undergo ripening processes associated with rind color changes on exposure to ethanol vapors. Although rind coloration is a common indicator showing fruit maturity, the attribute does not provide reliable assessment of maturity especially for melons. Herein, we report the achievement of sensitive and reversible melon maturity detection using macroporous hydrogel photonic crystals self-assembled by a roll-to-roll compatible doctor-blade-coating technology. The consumption of applied ethanol vapor during melon ripening results in less condensation of ethanol vapor in the pores (250 nm in diameter), leading to a distinct blue-shift of the optical stop band from 572 to 501 nm and an obvious visual colorimetric readout from yellow green to blue. Moreover, the dependence of the color change on Brix value within the melon has also been evaluated in the study.

Water-Soluble Chemical Vapor Detection Enabled by Doctor-Blade-Coated Macroporous Photonic Crystals.

Water-soluble chemicals, involving a wide range of toxic chemicals in aqueous solutions, remain essential in both daily living or industrial uses. However, most toxicants are evaporated with water through their use and thus cause deleterious effects on the domestic environment and health in humans. Unfortunately, most current low-dose chemical vapor detection technologies are restricted by the use of sophisticated instruments and unable to promptly detect the quantity of diverse toxicants in a single analysis. To address these issues, this study reports the development of simple and fast chemical vapor detection using doctor-blade-coated macroporous poly(2-hydroxyethyl methacrylate)/poly(ethoxylated trimethylolpropane triacrylate) photonic crystals, in which the poly(2-hydroxyethyl methacrylate) has strong affinity to insecticide vapor owing to a favorable Gibbs free energy change for their mixing. The condensation of water-soluble chemical vapor therefore results in a significant reflection peak shift and an obvious color change. The visual colorimetric readout can be further improved by increasing the lattice spacing of the macroporous photonic crystals. Furthermore, the dependence of the reflection peak position on vapor pressure under actual conditions and the reproducibility of vapor detecting are also evaluated in this study.

Self-Assembled Mechanochromic Shape Memory Photonic Crystals by Doctor Blade Coating.

Mechanochromic shape memory photonic crystals can memorize their original structures and recover the inherent structural colors in response to external stimuli; thereby they have rendered various important optical applications. Unfortunately, most existing shape memory polymers are thermoresponsive, and the corresponding mechanochromic characteristics are limited by the heat-demanding programming process. Besides that, a great majority of current fabrication methodologies suffer from low throughput, hindering the practical applications. Herein, a scalable technology is developed to engineer macroporous shape memory photonic crystals by self-assembling silica colloidal crystals in a polyurethane acrylate/polyethoxylated trimethylolpropane triacrylate/poly(ethylene glycol) diacrylate matrix, followed by a wet etching treatment to selectively remove silica colloids. The as-created photonic crystals display a brilliant structural color, which is reversibly tunable with mechanical deformation at ambient conditions. Upon stretching, the reduced interlayer lattice spacing of the photonic crystals leads to a blueshift of the reflection peak position and a significant color change. Importantly, the stretched macroporous film can fix its temporary structures without applying any contact force and simultaneously recover its original configuration and appearance by applying ethanol evaporation-induced capillary pressures. The reversibility and the dependence of templated silica colloid size on mechanochromic characteristics have also been investigated in the research.

Recent Advances in Biosensors for Nucleic Acid and Exosome Detection.

Biosensors are analytical devices for biomolecule detection that compromise three essential components: recognition moiety, transducer, and signal processor. The sensor converts biomolecule recognition to detectable signals, which has been applied in diverse fields such as clinical monitoring, in vitro diagnostics, food industry etc. Based on signal transduction mechanisms, biosensors can be categorized into three major types: optical biosensors, electrochemical biosensors, and mass-based biosensors. Recently, the need for faster, more sensitive detection of biomolecules has compeled researchers to develop various sensing techniques. In this review, the basic structure and sensing principles of biosensors are introduced. Additionally, the review discusses multiple recent works about nucleic acid and exosome sensing.

Knockdown of PEBP4 inhibits human glioma cell growth and invasive potential via ERK1/2 signaling pathway.

Phosphatidylethanolamine (PE)-binding protein 4 (PEBP4) is an antiapoptotic protein that is aberrantly expressed in various malignancies. We previously demonstrated that PEBP4 expression is dramatically induced in human gliomas and positively correlated with tumor grade and patient survival. However, the function of PEBP4 in human glioma development and underlying mechanisms remain largely unknown. By stable lentiviral vector-mediated silencing of PEBP4, we examined the effects of PEBP4 knockdown on the growth, apoptosis, and invasion of U251 and U373 human glioma cell lines using MTT, Transwell, colony formation, and flow cytometric assays. We examined the in vivo role of PEBP4 in tumor growth by inoculation of BALB/c nu/nu male mice with PEBP4-deficient U251 and U373 cells. The expression of cell cycle- and apoptosis-related proteins was analyzed by Western blotting and immunostaining. Knockdown of PEBP4 significantly reduced the proliferation and invasion of human glioma cells while inducing cell apoptosis by altering the expression of cell cycle- and apoptosis-related proteins. Mechanistically, PEBP4 knockdown led to activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway, an effect that could be reversed by U0126, a selective inhibitor of MEK1/2 (upstream of ERK1/2), suggesting involvement of ERK1/2 signaling in the regulation of glioma development and progression by PEBP4. We identified PEBP4 as a novel regulator mediating human glioma cell proliferation, invasion, and apoptosis as well as tumor formation and growth. Therefore, PEBP4 may be a potential therapeutic target in human glioma treatment.

High ATP2A2 expression correlates with better prognosis of diffuse astrocytic tumor patients.

Novel molecular markers are required for defining subsets of diffuse astrocytic tumor patients with differing prognoses. Here, we examined ATP2A2 expression in 109 human diffuse astrocytic tumor samples (39 grade II diffuse astrocytoma (DA), 19 grade III anaplastic astrocytoma (AA), 51 grade IV glioblastoma) and its correlation with patient clinicopathologic characteristics. ATP2A2 expression significantly correlated with tumor grade and survival (P<0.05). High ATP2A2 expression was detected in 35.3% (18/51) of glioblastoma patients, compared to 61.5% (24/39) in grade II, and 52.6% (10/19) in grade III astrocytoma patients (P=0.043). The median survival was 45±5.3 (95% CI, 34.7-55.3) months in patients with high ATP2A2 expression and 16±5.0 (95% CI, 6.3-25.7) months in patients with low ATP2A2 expression (P<0.0001). Additionally, high grade astrocytoma patients with high ATP2A2 expression showed longer survival (median, 31.0±4.9 months, 95% CI, 21.4-40.7) than those with low ATP2A2 expression (median: 13.0±1.6 months, 95% CI, 9.9-16.1; P=0.027). Furthermore, both ATP2A2 overexpression and IDH1 mutation were detected in secondary glioblastoma, AA developed from DA and oligodendrogiomas with IDH1 mutation. The MTT assays showed that lentiviral ATP2A2 overexpression significantly suppressed the clonogenic growth of glioblastoma U251MG cells (P<0.05). Xenografts stably overexpressing ATP2A2 were markedly smaller in size 4 weeks post inoculation (P<0.05). Our findings identified high ATP2A2 expression in a subset of astrocytoma patients that was associated with better prognosis and ATP2A2 suppressed astrocytoma growth.

Antibacterial Property and Cytotoxicity of a Poly(lactic acid)/Nanosilver-Doped Multiwall Carbon Nanotube Nanocomposite.

A novel method was used to synthesize a nanosilver-doped multiwall carbon nanotube (MWCNT-Ag), and subsequently, the novel poly(lactic acid) (PLA)- and MWCNT-Ag-based biocompatible and antimicrobial nanocomposites were prepared by melt blending. Based on energy dispersive X-ray spectrometry images, an MWCNT-Ag was successfully synthesized. The effect of the MWCNT-Ag on the PLA bionanocomposites was investigated by evaluating their thermal and mechanical properties, antifungal activity, and cytotoxicity. The nanocomposites exhibited a high degree of biocompatibility with the MWCNT-Ag content, which was less than 0.3 phr. Furthermore, tensile strength testing, thermogravimetric analysis, differential scanning calorimetry, and antibacterial evaluation revealed that the tensile strength, thermostability, glass transition temperature, and antibacterial properties were enhanced by increasing the MWCNT-Ag content. Finally, hydrolysis analysis indicated that the low MWCNT-Ag content could increase the packing density of PLA.

Culture conditions tailored to the cell of origin are critical for maintaining native properties and tumorigenicity of glioma cells.

BACKGROUND: Cell culture plays a pivotal role in cancer research. However, culture-induced changes in biological properties of tumor cells profoundly affect research reproducibility and translational potential. Establishing culture conditions tailored to the cancer cell of origin could resolve this problem. For glioma research, it has been previously shown that replacing serum with defined growth factors for neural stem cells (NSCs) greatly improved the retention of gene expression profile and tumorigenicity. However, among all molecular subtypes of glioma, our laboratory and others have previously shown that the oligodendrocyte precursor cell (OPC) rather than the NSC serves as the cell of origin for the proneural subtype, raising questions regarding the suitability of NSC-tailored media for culturing proneural glioma cells. METHODS: OPC-originated mouse glioma cells were cultured in conditions for normal OPCs or NSCs, respectively, for multiple passages. Gene expression profiles, morphologies, tumorigenicity, and drug responsiveness of cultured cells were examined in comparison with freshly isolated tumor cells. RESULTS: OPC media-cultured glioma cells maintained tumorigenicity, gene expression profiles, and morphologies similar to freshly isolated tumor cells. In contrast, NSC-media cultured glioma cells gradually lost their OPC features and most tumor-initiating ability and acquired heightened sensitivity to temozolomide. CONCLUSIONS: To improve experimental reproducibility and translational potential of glioma research, it is important to identify the cell of origin, and subsequently apply this knowledge to establish culture conditions that allow the retention of native properties of tumor cells.

Increased expression of phosphatidylethanolamine-binding protein 4 (PEBP4) strongly associates with human gliomas grade.

Abnormal expression of phosphatidylethanolamine-binding protein 4 (PEBP4) has been found in various types of malignancies. However, the PEBP4 expression in human gliomas is still unclear. In this study, we aim to compare the expression of PEBP4 in tumor samples derived from 58 patients with different grades of gliomas with that in 5 non-neoplastic brain samples and to investigate the clinical significance of PEBP4 expression in gliomas. The mRNA and protein expressions of PEBP4 were measured by real-time quantitative polymerase chain reaction and western blot, respectively. The intracellular expressions of PEBP4 in samples were examined by immunohistochemistry. The association between PEBP4 expression and the clinicopathologic characteristics of gliomas patients were analyzed. Our results demonstrated that the mRNA and protein levels of PEBP4 were upregulated in gliomas tissues, especially in high-grade (World Health Organization Grades III and IV) gliomas, when compared to normal control (p < 0.01). Immunohistochemical analysis indicated that PEBP4 was highly expressed in 82.4% (28/34) of high-grade gliomas, when compared to 41.7% (10/24) of high expression in low-grade gliomas and 20.0% (1/5) in non-neoplastic brain samples (p = 0.001). Multivariate Cox regression analysis revealed that increased PEBP4 expression was an independent prognostic factor for gliomas. Patients with low level of PEBP4 had longer survival time compared to those with high PEBP4 expression (p = 0.003). These data indicate a clinical significance of PEBP4 for predicting the tumor grade and the prognosis in patients with gliomas.

Effect of ATorvastatin On Chronic subdural Hematoma (ATOCH): a study protocol for a randomized controlled trial.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common disease that is more prevalent in older people. Surgical intervention is a safe treatment of choice. However, the recurrence rate is relatively high and the outcome is not always satisfactory among surgically treated patients. It is believed that aberrant angiogenesis and intracapsular inflammation contribute to the development of CSDH. Atorvastatin is reported to promote angiogenesis and suppress inflammation. We have recently shown that atorvastatin is effective to non-surgically reduce and eliminate CSDH with minimal side effects. Here, we report a clinical research trial protocol that is designed to evaluate the therapeutic effects of atorvastatin on CSDH. METHODS/DESIGN: We have designed a multi-center, randomized, placebo-controlled, double blind clinical trial for evaluating the efficacy of oral atorvastatin in reducing CSDH. We have so far recruited 96 patients with CT-confirmed or MRI-confirmed CSDHs from 16 medical centers in China. These patients were originally recruited for the Oriental Neurosurgical Evidence-based Study Team (ONET) study. After informed consent is provided, patients are randomized to receive either atorvastatin (oral 20 mg/night for 8 weeks) or placebo (dextrin for 8 weeks); and followed for 16 weeks after the treatment. The primary outcome is the change in hematoma volume at the end of 8-week treatment. Secondary outcomes include: changes in 1) the hematoma volume at the 4(th), 12(th), and 24(th) weeks; 2) Markwalder's Grading Scale and Glasgow Coma Scale (MGS-GCS); 3) Glasgow Outcome Score (GOS) and 4) Activities of Daily Life-the Barthel Index scale (ADL-BI). Safety will be assessed during the study by monitoring adverse events, laboratory tests, electrocardiography (ECG), measurements of vital signs (temperature, pulse, and blood pressure) and body weight. DISCUSSION: Results of this trial will provide critical information regarding whether atorvastatin is an effective and safe alternative to surgical treatment of CSDH. TRIAL REGISTRATION: ClinicalTrials.gov Identifier--NCT02024373 The date of trial registration: 7 August 2013.

Does Early Postsurgical Temozolomide Plus Concomitant Radiochemotherapy Regimen Have Any Benefit in Newly-diagnosed Glioblastoma Patients? A Multi-center, Randomized, Parallel, Open-label, Phase II Clinical Trial.

BACKGROUND: The radiochemotherapy regimen concomitantly employing temozolomide (TMZ) chemotherapy and radiotherapy (RT) 4 weeks after surgery, followed by 6 cycles of TMZ is a common treatment for glioblastoma (GBM). However, its median overall survival (OS) is only 14.6 months. This study was to explore the effectiveness and safety of early TMZ chemotherapy between surgery and chemoradiotherapy plus the standard concomitant radiochemotherapy regimen. METHODS: A randomized, parallel group, open-label study of 99 newly diagnosed GBM patients was conducted at 10 independent Chinese neurosurgical departments from June 2008 to June 2012. Patients were treated with concomitant radiochemotherapy regimen plus early postsurgical temozolomide (early TMZ group) or standard concomitant radiochemotherapy regimen (control group). Overall response was assessed based on objective tumor assessments, administration of corticosteroid and neurological status test. Hematological, biochemical, laboratory, adverse event (AE), and neurological condition were measured for 24 months of follow-up. The primary efficacy endpoint of this study was overall survival (OS). The secondary endpoint was progression free survival (PFS). RESULTS: The median OS time in the early TMZ group was 17.6 months, compared with 13.2 months in the control group (log-rank test P = 0.021). In addition, the OS rate in the early TMZ group was higher at 6, 12, and 18 months than in the control group, respectively (P < 0.05). The median PFS time was 8.7 months in the early TMZ group and 10.4 months in the control group (log-rank test P = 0.695). AEs occurred in 29 (55.8%) and 31(73.8%) patients respectively in early and control groups, including nausea (15.4% vs. 33.3%), vomiting (7.7% vs. 28.6%), fever (7.7% vs. 11.9%), and headache (3.8% vs. 23.8%). Only 30.8% and 33.3% were drug-related, respectively. CONCLUSIONS: Addition of TMZ chemotherapy in the early break of the standard concomitant radiochemotherapy regimen was well tolerated and significantly improved the OS of the GBM patients, compared with standard concomitant radiochemotherapy regimen. However, a larger randomized trial is warranted to verify these results.

Overexpression of RLIP76 Required for Proliferation in Meningioma Is Associated with Recurrence.

The GTPase-activating protein RLIP76 is overexpressed in and correlates with the pathological grade of many malignant tumor cells. But the potential correlation between RLIP76 and clinical outcomes in patients with meningioma remains unknown. In this study, we examined the expression of RLIP76 in meningioma and correlated the RLIP76 expression to the patient outcome. RLIP76 expression in tumor tissues was examined with immunohistochemistry, quantitative reverse-transcription polymerase chain reaction(RT-PCR) and Western-blot. Immunohistochemistry showed an increased RLIP76 immunostaining score in anaplastic and atypical meningiomas versus classical meningiomas. Statistical analyses revealed that RLIP76 immunostaining positively correlated with immunostaining for Ki-67, a nuclear protein highly expressed in proliferating cells(r=0.29, p=0.034 by Spearman's correlation coefficient). Clinicopathological evaluation suggested that RLIP76 expression be associated with tumor grade and recurrence(P<0.05). Univariate and Cox analysis indicated that RLIP76 was an independent prognostic factor for tumor recurrence. Furthermore, the human malignant meningioma cell lines IOMM-Lee and CH157-MN stably transfected with short hairpin RNA (siRNA) targeting RLIP76 were then examined by in vitro growth assays, and apoptosis assays. RLIP76 knockdown in IOMM-Lee and CH157-MN cells inhibited cell proliferation and induced apoptosis. Western blot analysis revealed that cells underexpressing RLIP76 exhibited decreased B-cell lymphoma-2(Bcl-2) expression but increased apoptosis effector caspase-3 expression. These findings demonstrate that high RLIP76 expression is associated with a poor outcome of meningioma and may provide a new gene therapy approach for patients with malignant meningiomas.

miR­27a suppresses the clonogenic growth and migration of human glioblastoma multiforme cells by targeting BTG2.

miR-27a and BTG2 are implicated in gliomagenesis and glioma progression. However, hitherto, a link between miR-27a and BTG2 in glioma has not been reported. In the present study, we investigated the effects of miR-27a on the proliferation and invasiveness of glioblastoma cells in vitro and in a mouse xenograft model and further studied the relation between miR­27a expression and its target gene BTG2, which was identified by computation prediction algorithms. Our MTT and clonogenic assays showed that miR-27a overexpression significantly increased the clonogenic growth of glioblastoma U87MG and U251MG cells. The Transwell assays further revealed that miR-27a overexpression markedly increased the number of migrated U87MG and U251MG cells. TargetScan and other prediction algorithms identified BTG2 as a target gene of miR-27a, which was confirmed by EGFP reporter and immunoblotting assays showing an inverse relation between miR-27a expression and endogenous BTG2 expression. BTG2 overexpression also increased the proliferation and invasiveness of glioblastoma cells and BTG2 functioned downstream of miR-27a in modulating the proliferation and migration of glioblastoma cells. In conclusion, miR-27a modulates human glioblastoma growth and invasion by targeting BTG2.

Higher LRRFIP1 expression in glioblastoma multiforme is associated with better response to teniposide, a type II topoisomerase inhibitor.

Previous studies from this laboratory indicated that microRNA-21 (miR-21) contributes to chemoresistance of glioblastoma multiforme (GBM) cells to teniposide, a type II topoisomerase inhibitor. We also showed that LRRFIP1 is a target of miR-21. In this study, we found that higher baseline LRRFIP1 expression in human GBM tissue (n=60) is associated with better prognosis upon later treatment with teniposide. Experiments in cultured U373MG cells showed enhanced toxicity of teniposide against U373MG cells transfected with a vector that resulted in LRRFIP1 overexpression (vs. cells transfected with control vector). Experiments in nude mice demonstrated better response of LRRFIP1 overexpressing xenografts to teniposide. These findings indicate that high baseline LRRFIP1 expression in GBM is associated with better response to teniposide, and encourage exploring LRRFIP1 as a target for GBM treatment.

Ubiquitin-specific protease 2a stabilizes MDM4 and facilitates the p53-mediated intrinsic apoptotic pathway in glioblastoma.

The mouse double minute 4 (MDM4) oncoprotein may inhibit tumorigenesis by regulating the apoptotic mediator p53. Ubiquitin-specific protease 2a (USP2a) is a deubiquitinating enzyme that protects MDM4 against degradation, so USP2-MDM4 interaction may be a key determinant of the malignant potential of human cancers. MDM4 and USP2a, as well as the MDM4-USP2a complex, were more highly expressed in glioblastoma multiforme tissue samples from patients with good prognosis compared with patients with poor prognosis. Analysis of the prognostic parameters indicated that MDM4 expression was positively correlated with an increased likelihood for survival. Compared with the poor prognosis patients, mitochondria from good prognosis glioma patients contained higher levels of both MDM4 and the proapoptotic protein p53Ser46(P). In U87MG glioma cell line, the overexpression of MDM4 enhanced ultraviolet (UV)-induced cytochrome c release and apoptosis. In contrast, MDM4 knockdown decreased mitochondrial p53Ser46(P) levels and rescued cells from UV-induced apoptosis. The expression of MDM4 and USP2a were positively correlated with each other. MDM4-USP2a complexes were found only in the cytoplasmic fraction, whereas the mitochondrial fraction contained MDM4-p53Ser46(P) and MDM4-Bcl-2 complexes. Overexpression of USP2a increased p53 and p53Ser46(P) levels in the mitochondria, whereas simultaneous MDM4 knockdown completely reversed this effect. UV-induced apoptosis was reduced by USP2a knockdown but restored by the simultaneous overexpression of MDM4. This apoptotic response was reduced by knockdown of p53 but not p21. Our results suggest that USP2a binds to and stabilizes MDM4; thus in turn, it enhances the mitochondrial localization of p53 and promotes apoptosis in glioma cells.

Surgery for primary filum terminale ependymomas: outcome and prognostic factors.

INTRODUCTION: Primary filum terminale ependymoma (PFTE) is a unique type of ependymomas and locates on extramedullary site. However, the clinical features and prognostic factors of PFTE are still unknown due to its rarity. AIM: This study aimed to evaluate the clinical features, outcomes, and prognostic factors of PFTE in the largest series of cases. RESULT: Thirty-eight patients were included in this study. Gross total removal (GTR) of the tumors was achieved in 33(87%) patients. Five (13%) patients had subtotal resection (STR). For the residual tumors, postoperative radiotherapy increased the interval between the first surgery and tumor regrowth (P = 0.063). Six patients had local recurrence/progression. Univariate analysis identified STR(P = 0.001), unencapsulated tumor (P = 0.018), tumor involving more than two vertebral columns (P = 0.005), and tumor invading sacral canal(P < 0.001) as predictors of tumor recurrence. In addition, 36 (95%) patients had stable or improved neurological status directly after surgery. Klekamp-Samii score was better correlated with the symptoms than McCormick scale. CONCLUSION: Extent of surgical removal, tumor size, tumor location, and the integrity of tumor capsule are the prognostic factors of PFTEs, and the intrasacral PFTEs always have a poor prognosis.