Demonstration of Nanosecond Operation in Stochastic Magnetic Tunnel Junctions.

Magnetic tunnel junctions operating in the superparamagnetic regime are promising devices in the field of probabilistic computing, which is suitable for applications like high-dimensional optimization or sampling problems. Further, random number generation is of interest in the field of cryptography. For such applications, a device's uncorrelated fluctuation time-scale can determine the effective system speed. It has been theoretically proposed that a magnetic tunnel junction designed to have only easy-plane anisotropy provides fluctuation rates determined by its easy-plane anisotropy field and can perform on a nanosecond or faster time-scale as measured by its magnetoresistance's autocorrelation in time. Here, we provide experimental evidence of nanosecond scale fluctuations in a circular-shaped easy-plane magnetic tunnel junction, consistent with finite-temperature coupled macrospin simulation results and prior theoretical expectations. We further assess the degree of stochasticity of such a signal.

Methylation Status of the RIZ1 Gene Promoter in Human Glioma Tissues and Cell Lines.

Retinoblastoma protein-interacting zinc-finger gene 1 (RIZ1), a strong tumor suppressor, is silenced in many human cancers. Our previous studies showed that RIZ1 expression was negatively correlated with the grade of glioma and was a key predictor of patient survival. Therefore, RIZ1 could be a potential tumor suppressor during glioma pathogenesis, although the mechanism underlying RIZ1 gene inactivation in gliomas is unknown. We investigated the methylation status of the RIZ1 promoter in human glioma tissues and four glioblastoma (GBM) cell lines, and verified the effect of the methyltransferase inhibitor 5-aza-2-deoxycytidine (5-aza-CdR) on RIZ1 transcription and cell proliferation. Methylation-specific PCR (MSP) was performed to determine RIZ1 promoter methylation in human glioma specimens. The correlation between RIZ1 hypermethylation in tumors and clinicopathological features also was analyzed. 5-Aza-CdR treatment was used to reactivate gene expression silenced by hypermethylation in the U87 glioblastoma cell line, and real-time PCR was then used to measure RIZ1 expression. The ability of 5-aza-CdR to inhibit the proliferation of glioma cell lines whose RIZ1 promoters were hypermethylated was measured by bromodeoxyuridine (BrdU) incorporation. Among 51 human glioma specimens, RIZ1 promoter methylation was detected in 23 cases. Clinicopathological evaluation suggested that RIZ1 hypermethylation was negatively associated with tumor grade and patient age (P < 0.05). Hypermethylation of the RIZ1 promoter was detected in the U87 and U251 cell lines. RIZ1 mRNA expression in U87 cells was upregulated after treatment with 5-aza-Cdr, which correlated with inhibition of cell proliferation in a time- and concentration-dependent manner. Promoter hypermethylation may play an important role in the epigenetic silencing of RIZ1 expression in human glioma tissues and GBM cell lines.

RLIP76 Depletion Enhances Autophagic Flux in U251 Cells.

Our previous study showed that RalA-binding protein 1 (RLIP76) is overexpressed in gliomas and is associated with higher tumour grade and decreased patient survival. Furthermore, RLIP76 downregulation increases chemosensitivity of glioma cells to temozolomide by inducing apoptosis. However, other mechanisms underlying RLIP76-associated chemoresistance are unknown. In this study, we investigated the effect of RLIP76 depletion on autophagy. RLIP76 was knocked down in U251 glioma cells using shRNA and autophagy-related proteins, and PI3K/Akt signalling components were evaluated. RLIP76 depletion significantly increased cell autophagy as demonstrated by a significant increase in LC3 II, autophagy protein 5 (ATG-5), and Beclin1, and a decrease in p62 expression levels. Furthermore, RLIP76 knockdown increased autophagic flux in U251 cells as autolysosome numbers increased relative to autophagosome numbers. Autophagy induced by RLIP76 knockdown resulted in increased apoptosis that was independent of temozolomide treatment. Moreover, RLIP76 knockdown decreased PI3K and Akt activation. RLIP76 depletion also resulted in decreased levels of the anti-apoptotic protein Bcl2. LY294002, a PI3K/Akt pathway inhibitor, led to increased autophagy and apoptosis in U251 RLIP76-depleted cells. Therefore, RLIP76 knockdown increased autophagic flux and apoptosis in U251 glioma cells, possibly through inhibition of the PI3K/Akt pathway. Thus, this study provides a novel mechanism for the role of RLIP76 in glioma pathogenesis and chemoresistance.

Tissue thioredoxin-interacting protein expression predicted recurrence in patients with meningiomas.

BACKGROUND: The redox regulatory protein, thioredoxin-interacting protein (TXNIP), has been confirmed as an important tumor suppressor gene in various types of human cancers. In previous studies, we found that overexpression of tumor suppressor gene RIZ1 in meningiomas can significantly improve the expression of TXNIP by microarray data analysis. Therefore, we hypothesized that TXNIP was associated with the initiation and progression of meningiomas. METHODS: First, we evaluated the expression of TXNIP and Ki-67 in meningioma tissues from 65 patients using immunohistochemistry. We also analyzed the correlation between TXNIP immunoreactivity and clinicopathological features, as well as patient prognostic factors. RESULTS: According to immunohistochemistry results, high-grade meningioma tissues had significantly lower expression of TXNIP than benign meningioma tissues (29.31 ± 18.70 vs 74.61 ± 7.51, P < 0.0001). TXNIP and Ki67 were negatively correlated (P < 0.0001). Moreover, the expression of TXNIP was higher in nonrecurrent high-grade meningiomas (P < 0.05). In addition, Kaplan-Meier analysis indicated that expression of TXNIP and Ki-67 was related to recurrence-free time. Multivariate Cox analysis showed that TXNIP expression level was the only independent predictor for meningioma prognosis. CONCLUSION: Our results demonstrated that high expression of TXNIP indicates a lower pathological grade of meningnioma, and is also associated with longer recurrence-free time. Therefore, TXNIP could be regarded as a potential molecular marker to predict recurrence in patients with meningiomas.

Anti-tumor activity of phenoxybenzamine hydrochloride on malignant glioma cells.

Phenoxybenzamine hydrochloride (PHEN) is a selective antagonist of both α-adrenoceptor and calmodulin that exhibits anticancer properties. The aim of this study was to explore the anti-tumor function of PHEN in glioma. Cell proliferation assay was used to assess glioma cell growth. Migration and invasion capacity of glioma cells was monitored by wound-healing and transwell assay, respectively. Neurosphere formation test was adopted for the tumorigenesis of glioma cells, which was also confirmed by soft agar cloning formation test in vitro and a nude mouse model in vivo. Finally, we explored the potential pathway utilized by PHEN using Western blot and immunofluoresce staining. PHEN exhibited a significant inhibitory effect on the proliferation of both U251 and U87MG glioma cell lines in a positive dose-dependent manner. PHEN apparently attenuated the malignancy of glioma in terms of migration and invasion and also suppressed the tumorigenic capacity both in vitro and in vivo. Mechanism study showed that PHEN promoted tumor suppression by inhibiting the TrkB-Akt pathway. The results of the present study demonstrated that PHEN suppressed the proliferation, migration, invasion, and tumorigenesis of glioma cells, induced LINGO-1 expression, and inhibited the TrkB-Akt pathway, which may prove to be the mechanisms underlying the anti-tumor effect of PHEN on glioma cells.

RNA interference against TMEM97 inhibits cell proliferation, migration, and invasion in glioma cells.

Gliomas are the most common form of primary brain tumor in the adult central nervous system. Altered expression and prognostic value of transmembrane protein 97 (TMEM97) has been recently reported in different types of human tumors. However, the association of TMEM97and glioma is poorly defined. Here, we reported that TMEM97 was significantly increased in glioma tissues compared to non-tumorous brain tissues. Furthermore, TMEM97 levels were progressively increased with increasing histologic tumor grade in glioma. Higher TMEM97 expression level was correlated with shorter survival time of patients with glioma. Downregulation of TMEM97 through RNA interference inhibited cell proliferation and G1/S transition in two glioma cell lines, U87 and U373. More importantly, TMEM97 silencing induced a significant decrease in the expression of G1/S transition key regulators, cyclin D1, cyclin E, CDK2, and CDK4. Additionally, downregulation of TMEM97 in glioma cells notably repressed cell migration and cell invasion. Further analysis suggested that the decreased invasion was associated with alterations in EMT markers, including E-cadherin, ß-catenin, and Twist. Since expression of TMEM97 seems to be associated with the oncogenic potential of glioma, and suppression of its expression can inhibit cancer cell growth and metastasis, TMEM97 may be a potential therapeutic target in human glioma.

RIZ1: a potential tumor suppressor in glioma.

BACKGROUND: Retinoblastoma protein-interacting zinc-finger gene 1 (RIZ1) displays strong tumor suppressive activities, and its expression is often silenced in many types of human tumors. However, the relationship between RIZ1 expression and glioma prognosis remains unclear. METHODS: The dysregulation of RIZ1 was evaluated using real-time polymerase chain reaction, western blot, and immunohistochemical analysis of gliomas from 51 patients. Correlation analysis was performed to examine relationships between RIZ1 immunoreactivity, clinicopathological features, and patient prognosis. Also, human malignant glioma U87 and U251 cell lines were stably transduced with ectogenic RIZ1 using a lentiviral vector to investigate the effects of induced expression of RIZ1 on cell proliferation, cell cycle, and apoptosis. RESULTS: Real-time polymerase chain reaction and western blot analysis showed that RIZ1 was downregulated in high-grade gliomas compared with low-grade gliomas and normal brain tissue. Immunohistochemistry showed less RIZ1 labeling in high-grade gliomas than in low-grade gliomas. There was a negative correlation between RIZ1 and Ki-67 immunoreactivity. Clinicopathological evaluation revealed that RIZ1 expression was negatively correlated with tumor grade and patient age. Kaplan-Meier survival analysis showed a positive correlation between RIZ1 immunoreactivity level and progression-free and overall survival times. Multivariate analysis showed that high RIZ1 expression was an independent prognostic factor for patients with gliomas. Induced expression of RIZ1 in U87 and U251 cells reduced cell proliferation and increased apoptosis, and cell cycle analysis revealed that a majority of cells were arrested at G2-M. Moreover, transfection with a RIZ1 expression vector increased p53 and caspase-3 expression and decreased p-IKBα and p-AKT protein levels, suggesting that RIZ1 may stimulate p53-mediated apoptosis and inhibit p-IKBα and p-AKT signaling pathways. CONCLUSIONS: Our results suggest that high RIZ1 labeling is indicative of lower grades of gliomas and is associated with better progression-free and overall survival rates. Therefore, RIZ1 may be a promising therapeutic target for patients with gliomas.

Effects of hypoxia inducible factor-1α on apoptotic inhibition and glucocorticoid receptor downregulation by dexamethasone in AtT-20 cells.

BACKGROUND: Hypoxia inducible factor-1α (HIF-1α) is the central transcriptional regulator of hypoxic responses during the progression of pituitary adenomas. Although previous immunohistochemical studies revealed that HIF-1α is expressed in adreno-cortico-tropic-hormone (ACTH) pituitary adenomas, the role of HIF-1α remains unclear. METHODS: AtT-20 cells were incubated under hypoxic conditions (1 % O2) for 12 h. HIF-1α mRNA and protein expression levels were measured by real-time PCR and western blotting, respectively. BrdU was used to determine the effects of hypoxia on cell viability. AtT-20 cells were transfected with siRNA targeting HIF-1α, followed by hypoxia (1 % O2) for 12 h. Apoptosis was determined by annexin V-FITC flow cytometry and Tdt-mediated dUTP nick end-labelling (TUNEL) assay. In addition, we examined interactions between HIF-1α, glucocorticoid receptor (GR), and dexamethasone under both normoxic and hypoxic conditions. RESULTS: Hypoxia triggered the time-dependent proliferation of AtT-20 cells in association with increased HIF-1α mRNA and protein levels. However, the viability of AtT-20 cells decreased greatly when they were first transfected with HIF-1α-siRNA and then exposed to hypoxia. According to flow cytometry (annexin V-FITC and PI staining) and TUNEL analyses, a greater percentage of cells were apoptotic when transfected with HIF-1α siRNA and subsequently cultured under hypoxic conditions compared to those in the normoxia and mock groups. After AtT-20 cells were cultured in 1 % O2 and then treated with dexamethasone, HIF-1α levels significantly increased or decreased in normoxic or hypoxic conditions, respectively. Dexamethasone suppressed GR expression to a higher degree in hypoxic than normoxic conditions. Downregulation of GR by dexamethasone was greatly prevented in cells that were transfected with HIF-1α siRNA. CONCLUSIONS: These findings strongly suggest that HIF-1α exerts an antiapoptotic role and participates in the downregulation of GR by dexamethasone in hypoxic AtT-20 cells.

A retrospective study on the aetiology, management, and outcome of brain abscess in an 11-year, single-centre study from China.

BACKGROUND: Brain abscesses continue to pose diagnostic and therapeutic challenges in developed and developing countries. Their aetiology and management remain complex and unclear, making improvement of treatments and outcome difficult. METHODS: To determine the demographics, management, and the variables that affect the outcome in subjects with brain abscesses treated at a single centre over an 11-year period, we retrospectively analysed data in 60 patients with brain abscesses surgically treated with stereotactically guided aspiration or open craniotomy excision in Shanghai Changzheng Hospital between January 2001 and December 2011. Such variables as age, gender, Glasgow Coma Scale (GCS) score at admission, clinical presentation, location, number of lesions, predisposing factors, mechanism of infection, aetiological agent, and therapy were analysed independently. RESULTS: Our analysis demonstrated that patient age and gender were factors that influence the occurrence of brain abscess; female patients and patients greater than 40 years of age were most likely to suffer a brain abscess. We also found that a patient's GCS score upon admission did not influence outcome. While frequency of successful culturing of the infectious agent was low, positive cultures were obtained in only 8 of the cases (13.33%), in which the most common isolate was Streptococcus milleri. Outcome was favourable in 78.33% of the subjects, while the mortality rate was 20%. The outcome of one patient was poor due to the abscess in the basal ganglia region. CONCLUSIONS: Stereotactically guided aspiration is an effective treatment for brain abscess with an overall favourable outcome. Mortality due to brain abscess was not directly related to surgery nor surgical technique. Additional studies will continue to reveal patients trends that may improve treatment for brain abscess.

RLIP76 is overexpressed in human glioblastomas and is required for proliferation, tumorigenesis and suppression of apoptosis.

The guanosine triphosphatase-activating protein RLIP76 is overexpressed in many malignant tumor cells, but it is unclear if RLIP76 overexpression contributes to the high proliferative potential of glioma cells. We demonstrate that RLIP76 messenger RNA and protein expression are positively correlated with glioma grade and that higher RLIP76 expression correlates with shorter patient survival. Immunohistochemical staining revealed that RLIP76 expression was positively correlated with the expression of Ki-67, a biomarker for cell proliferation. Inhibition of RLIP76 expression in U87 and U251 glioma cell lines by stable transfection of a targeted siRNA suppressed anchorage-independent growth and enhanced apoptosis in vitro. Conversely, overexpression of RLIP76 in SW1088 and U251 cell lines enhanced proliferation and reduced apoptosis. Inhibition of RLIP76 in U251 cells also significantly suppressed tumorigenicity and induced apoptosis in an endotopic xenograft mouse model. Moreover, we demonstrate that knockdown of RLIP76 increases apoptosis in different human gliomas independently of p53 status. In addition, a constitutively active Rac1 reversed both the suppression of proliferation and the promotion of apoptosis induced by the RLIP76-targeted siRNA, indicating that RLIP76 is an upstream activator of Rac1. Rac1-mediated suppression of apoptosis and promotion of proliferation were dependent on intact c-jun N-terminal kinase (JNK) signaling. Furthermore, we demonstrate that RLIP76 promotes proliferation and suppresses glioma cell apoptosis through a mechanism independent of Rho-selective GTPase-activating protein. Instead, we found that the adenosine triphosphatase function of Rlip76 modulates Rac1 activity by regulating Rac1 protein ubiquitylation and degradation. These data demonstrate that RLIP76 may suppress apoptosis and promote the proliferation of glioma cells by direct adenosine triphosphate-dependent xenobiotic transport and by activating the Rac1-JNK signaling pathway. Inhibition of RLIP76 signaling is a potential treatment for malignant glioma.

Knockdown of RLIP76 expression by RNA interference inhibits invasion, induces cell cycle arrest, and increases chemosensitivity to the anticancer drug temozolomide in glioma cells.

RLIP76, a GTPase-activating protein, is a central regulator in multiple pathways that respond to redox states and control cell growth, motility, division, and apoptosis in many malignant cancer cells. In this study, human glioblastoma cell lines U87 and U251 were stably transfected with a lentivirus vector expressing a short hairpin RNA (shRNA) targeting RLIP76. shRNA knockdown of RLIP76 induced cell cycle arrest in U87 and U251 cells and inhibited their invasiveness. Quantitative Western blot analysis revealed that cells stably underexpressing RLIP76 showed lower expression of cyclin D1 and decreased expression and activity of matrix metalloproteinase 2 compared to cells stably transfected with a control vector. Furthermore, RLIP76 expression levels were correlated with IC(50) values for the antitumor drug temozolomide (TMZ). Compared with TMZ alone (17.19 ± 1.78 and 22.18 ± 1.99 µg/mL in U87 and U251 cells, respectively) or combined shGFP and TMZ (18.04 ± 1.07 and 23.040 ± 1.77 µg/mL in U87 and U251 cells, respectively), combined shRNA and TMZ therapy resulted in a significant decrease in IC(50) value (7.61 ± 2.99 and 6.91 ± 2.59 µg/mL in U87 and U251 cells, respectively). Combined RLIP76 knockdown and TMZ treatment inhibited cell proliferation in vitro more effectively than either treatment alone. Furthermore, RLIP76 downregulation enhanced chemosensitivity to TMZ without affecting protein expression of MDR1 and MRP1. The results indicate that inhibition of RLIP76 expression may be an effective means for overcoming RLIP76-associated chemoresistance in human malignant glioma cells and may represent a potential gene-targeting approach for glioma treatment.

[Surgical treatment of hemangioblastoma in medulla oblongata:a report of 12 cases].

OBJECTIVE: To explore the clinical characteristics, diagnostic strategies and surgical techniques of hemangioblastoma (HB) in medulla oblongata. METHODS: The clinical and radiological characteristics, therapeutic processes and outcomes of 12 HB cases treated at our department from 2002 to 2012 were studied by retrospective analysis. RESULTS: Headache, somatic numbness and limb muscle weakness were the major symptoms of oblongata HB. Magnetic resonance imaging before surgery revealed a total of 12 single tumors. Among these tumors, upper (n = 1), middle (n = 7) and lower (n = 4) parts of medulla oblongata were involved. The locations were surface (n = 9) and intramedullary (n = 3). Three tumors had cyst. Digital subtraction angiography (DSA) was performed on 5 cases and it revealed that the main blood supply arteries of tumors were branches of posterior inferior cerebellar artery (PICA) and anterior inferior cerebellar artery (AICA).One case underwent pre-surgical embolism during angiography. Eleven tumors were totally resected and 1 was fulgurized.Symptoms improved (n = 8) and worsened (n = 2). And two patients died. All survivors were followed up for 3 months to 10 years and had a McCormick functional grading of I-II.One case relapsed 7 year later. CONCLUSION: For Cystic HB, small or medium sized substantial HB in middle and lower part of oblongata, surgical removal is often safe and symptoms may be lessened.It can be used as a first-line treatment. For large ( ≥ 3 cm) substantial HB or HB in upper part of oblongata, serious postoperative complications such as respiratory failure, neurogenic pulmonary edema or acute obstructive hydrocephalus may occur. Thus surgical resection should be prudently considered and possible consequences thoroughly discussed with the patients.

The learning curve of endoscopic endonasal transsphenoidal surgery for pituitary adenomas with different surgical complexity.

Objective: To investigate the learning curve under different surgical complexity in endoscopic transsphenoidal approach for pituitary adenoma. Methods: 273 patients undergoing endoscopic transsphenoidal surgery for pituitary adenoma were collected retrospectively and divided into three groups chronologically (early, middle, and late periods). Surgical complexity was differentiated based on Knosp classification (Knsop grade 0-2 vs. Knosp grade 3-4), tumor maximum diameter (MD) (macroadenomas vs. giant adenomas), and history of previous surgery for pituitary adenoma (first operation vs. reoperation). Then the temporal trends in operative time, surgical outcomes, and postoperative complications were evaluated from early to late. Results: The median operative time decrease from 169 to 147 min across the three periods (P = 0.001). A significant decrease in operative time was seen in the simple groups [Knosp grade 0-2 adenoma (169 to 137 min, P < 0.001), macroadenoma (166 to 140 min, P < 0.001), and first operation (170.5 to 134 min, P < 0.001)] but not in their complex counterparts (P > 0.05). The GTR rate increased from 51.6% to 69.2% (P = 0.04). The surgical period was an independent factor for GTR in the simple groups [Knosp grade 0-2 adenoma: OR 2.076 (95%CI 1.118-3.858, P = 0.021); macroadenoma: OR = 2.090 (95%CI 1.287-3.393, P = 0.003); first operation: OR = 1.809 (95%CI 1.104-2.966, P = 0.019)] but not in the complex groups. The biochemical cure rate increased over periods without statistical significance (from 37.5% to 56.3%, P = 0.181). Although intraoperative CSF leakage rose (from 20.9% to 35.2%) and postoperative CSF leakage reduced (from 12.1% to 5.5%), there was no statistically significant trend across the three time periods (P > 0.05). Conclusion: This study showed that complex operations might have a prolonged learning curve. Differentiating surgical difficulty and using multivariate combined analysis may be more helpful in clinical practice.

Knockdown of cyclin D1 inhibits proliferation, induces apoptosis, and attenuates the invasive capacity of human glioblastoma cells.

Elevated cyclin D1 (CCND1) in human glioblastoma correlates with poor clinical prognosis. In this study, the human glioblastoma cell lines SHG-44 and U251 were stably transfected with short hairpin RNA (shRNA) targeting cyclin D1 or with ectogenic cyclin D1 by lentivirus-mediated transfection. Glioblastoma cells overexpressing or underexpressing cyclin D1 were then examined by in vitro growth assays, apoptosis assays, cell cycle analysis, and invasion assays. Cyclin D1 knockdown in SHG-44 cells inhibited cell proliferation, induced apoptosis, and attenuated migration across Matrigel, a model of invasive capacity. Western blot analysis and quantitative reverse-transcription polymerase chain reaction (RT-PCR) revealed that cells underexpressing CCND1 exhibited decreased multidrug resistance protein 1 (MDR1) and B-cell lymphoma-2 (Bcl-2) expression, but enhanced apoptosis effector caspase-3 expression. In contrast, cyclin D1 overexpression promoted cell proliferation, attenuated apoptosis, and enhanced invasive capacity. Furthermore, cyclin D1 overexpression was associated with increased expression of MDR1 and Bcl-2, and decreased caspase-3 expression. Results using the U251 cell line confirmed the effects of CCND1-targeted shRNA and lentivirus-mediated overexpression on proliferation and apoptosis of glioblastoma cells. Overexpression of cyclin D1 enhanced the proliferation and invasive potential of human glioblastoma cells, while reducing apoptosis. The ability to suppress the malignant phenotype by downregulating cyclin D1 expression may provide a new gene therapy approach for patients with malignant glioma.

A study of UbcH10 expression and its association with recurrence of meningiomas.

BACKGROUND: UbcH10 is an important regulator for the mitotic spindle assembly checkpoint pathway that regulates cell-cycle progression. Overexpression of UbcH10 significantly correlated with advanced tumor grade and high cell proliferation. METHODS: The expression of UbcH10 and Ki-67 in meningioma tissues were evaluated immunohistochemically in 47 patients with meningiomas. The correlation of UbcH10 immunoreactivity with clinicopathological features and the prognostic value of UbcH10 in patients were also analyzed. RESULTS: Immunohistochemistry showed an increase in UbcH10 labeling index in atypical and anaplastic meningiomas versus classical meningiomas (10.53 ± 5.79% vs. 4.23 ± 2.85%, P < 0.001). There was a positive correlation between UbcH10 and Ki-67 immunoreactivity (Spearman r = 0.77, P < 0.001). Clinicopathological evaluation suggested that UbcH10 expression was associated with tumor grade and recurrence (P < 0.05). Kaplan-Meier survival analysis and Cox multivariate analysis revealed a significant correlation between high levels of UbcH10 immunoreactivity and high rates of tumor recurrence. CONCLUSION: We conclude that UbcH10 may play important roles in the development of meningioma, high UbcH10 labeling index indicates higher grade of meningioma, and UbcH10 may be a useful molecular marker for predicting the prognosis of meningioma.

Clinical features and immunohistochemical expression levels of androgen, estrogen, progesterone and Ki-67 receptors in relationship with gross-total resected meningiomas relapse.

OBJECTIVE: To investigate the recurrent risk factors of intracranial meningiomas after gross-total resection (Simpson II Grade). METHODS: We retrospectively analysed 162 meningiomas in the General Hospital of Shenyang Military Region and Changzheng Hospital in Shanghai China, which underwent nearly gross-total resection using microneurosurgery techniques from 2002 to 2007. Monofactorial and Cox regression statistics methods were carried out to analyse the relationship between the post-operation tumour relapse and some clinical features including the patient sex, age, tumour size, tumour shape, tumour pathological grade and the immunohistochemical expression levels of Ki-67, androgen receptor (AR), estrogen receptor (ER) and progesterone receptor (PR). RESULTS: There are 53 recurrent meningiomas during the follow-up period. The recurrent rate is about 32.7%. Immunohistochemistry results indicate that AR, ER, PR, Ki-67 are positively expressed on some tumour cell nuclear. Cox regression analysis reveals that tumour size, tumour shape, pathological grade and Ki-67 expression levels are significantly correlated with the tumour relapse (p <0.05). CONCLUSIONS: Our results demonstrate high recurrent rate for gross-total resection meningiomas. Tumour diameter exceeding 5 cm, irregular shape tumour, pathological grade II and III and positive expression of Ki-67 were the risk factors for post-operation meningioma relapse. The recurrent rate increases coincidentally with the follow-up period.

SIRT1 suppresses pituitary tumor progression by downregulating PTTG1 expression.

Although pituitary tumors are among the most common types of brain tumor, the underlying molecular mechanism of this disease remains obscure. To this end, the role of sirtuin 1 (SIRT1) in pituitary tumors was reported. The results of reverse transcription­quantitative PCR and immunohistochemistry revealed that sirtuin 1 (SIRT1) expression was downregulated in the tumor tissues of patients with pituitary tumors. In vitro experiments of the present study demonstrated that SIRT1 upregulation suppressed pituitary tumor cell line growth, while SIRT1 downregulation demonstrated the opposite effect. Additionally, it was determined that the enzymatic activity of SIRT1 was required for its cellular function. A mechanistic experiment determined that SIRT1 negatively regulated pituitary tumor­transforming gene 1 (PTTG1) expression through the deacetylation of histone (H)3 lysine (K)9ac at the promoter region of PTTG1. Moreover, H3K9ac levels at the PTTG1 promoter were determined to be an essential regulatory element for PTTG1 expression. Thus, it was concluded that the SIRT1/H3K9ac/PTTG1 axis contributed to pituitary tumor formation and may represent a potential therapeutic strategy.

Carboxyl terminus of Hsp70-interacting protein (CHIP) contributes to human glioma oncogenesis.

Malignant glioma is the most common adult primary brain tumor, and the mechanism of its oncogenesis is poorly understood. Growing evidence has shown that E3 ubiquitin ligases can promote tumorgenesis of glioma. CHIP is an E3 ubiquitin ligase that can induce ubiquitylation and degradation of many tumor-related proteins, and it has been reported to act as an upstream regulator in breast cancer; however, its role in human gliomas has not been evaluated yet. In this study, the expression of CHIP in glioma tissues was studied using immunohistochemistry. CHIP expression in glioma cells was studied by real-time RT-PCR, western blot and double immunofluorescence staining. The role of CHIP in glioma oncogenesis was investigated by lentivirus-mediated RNA interference (RNAi) and overexpression in vitro and in vivo. We showed CHIP expression in glioma samples was related to tumor grades, with stronger staining in high-grade gliomas than in low-grade gliomas. Knocking down of CHIP suppressed proliferation, colony formation of U251 and U87 glioma cells, while overexpression of CHIP resulted in enhanced proliferation and colony formation in vitro. In a nude mouse xenograft model, intratumoral injection of CHIP RNAi lentivirus significantly delayed tumor growth. In contrast, overexpression of CHIP resulted in enhanced tumor growth in vivo. After CHIP RNAi, both survivin mRNA and protein were decreased, while CHIP overexpression induced increased mRNA and protein levels of survivin. This is the first study demonstrating CHIP contributes to oncogenesis of glioma.

BRCAA1 monoclonal antibody conjugated fluorescent magnetic nanoparticles for in vivo targeted magnetofluorescent imaging of gastric cancer.

BACKGROUND: Gastric cancer is 2th most common cancer in China, and is still the second most common cause of cancer-related death in the world. How to recognize early gastric cancer cells is still a great challenge for early diagnosis and therapy of patients with gastric cancer. This study is aimed to develop one kind of multifunctional nanoprobes for in vivo targeted magnetofluorescent imaging of gastric cancer. METHODS: BRCAA1 monoclonal antibody was prepared, was used as first antibody to stain 50 pairs of specimens of gastric cancer and control normal gastric mucous tissues, and conjugated with fluorescent magnetic nanoparticles with 50 nm in diameter, the resultant BRCAA1-conjugated fluorescent magnetic nanoprobes were characterized by transmission electron microscopy and photoluminescence spectrometry, as-prepared nanoprobes were incubated with gastric cancer MGC803 cells, and were injected into mice model loaded with gastric cancer of 5 mm in diameter via tail vein, and then were imaged by fluorescence optical imaging and magnetic resonance imaging, their biodistribution was investigated. The tissue slices were observed by fluorescent microscopy, and the important organs such as heart, lung, kidney, brain and liver were analyzed by hematoxylin and eosin (HE) stain method. RESULTS: BRCAA1 monoclonal antibody was successfully prepared, BRCAA1 protein exhibited over-expression in 64% gastric cancer tissues, no expression in control normal gastric mucous tissues, there exists statistical difference between two groups (P < 0.01). The BRCAA1-conjugated fluorescent magnetic nanoprobes exhibit very low-toxicity, lower magnetic intensity and lower fluorescent intensity with peak-blue-shift than pure FMNPs, could be endocytosed by gastric cancer MGC803 cells, could target in vivo gastric cancer tissues loaded by mice, and could be used to image gastric cancer tissues by fluorescent imaging and magnetic resonance imaging, and mainly distributed in local gastric cancer tissues within 12 h post-injection. HE stain analysis showed that no obvious damages were observed in important organs. CONCLUSIONS: The high-performance BRCAA1 monoclonal antibody-conjugated fluorescent magnetic nanoparticles can target in vivo gastric cancer cells, can be used for simultaneous magnetofluorescent imaging, and may have great potential in applications such as dual-model imaging and local thermal therapy of early gastric cancer in near future.