Recurrent epithelioid malignant peripheral nerve sheath tumor with neurofibromatosis type 1: A case report and literature review.

Malignant peripheral nerve sheath tumors (MPNSTs) are unusual and aggressive malignant soft-tissue tumors that comprise 5-10% of all soft-tissue sarcomas. Approximately 50% of MPNST cases are associated with neurofibromatosis type-1 (NF-1). As a rare MPNST subset, the epithelioid variant of MPNST (eMPNST) is histologically characterized by the predominant presence of epithelioid tumor cells, and accounts for <5% of all MPNSTs. In addition, eMPNST is rarely associated with NF-1 when compared with conventional MPNST. Although extensive clinicopathological studies have been conducted on eMPNST, clinicians face difficulty when attempting to make an accurate diagnosis. Subsequently, the biological consequences, including recurrence, metastasis and mortality rate in patients with eMPNST remain unclear. The current study presents the case of a 71-year-old woman with eMPNST and a family history of NF-1 in whom tumors had recurred twice on the lower back. A literature search for eMPNSTs was conducted by browsing PubMed and MEDLINE for English-language articles, as well as references from review articles, and revealed 129 published cases. Only 5 cases of eMPNST were associated with NF-1. The studies were retrospectively reviewed and the clinicopathological data of the patients, including tumor site, treatment, follow-up, prognosis, and immunohistochemical positivity were collected.

METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN.

RNA methylation is emerging as an important regulator of gene expression. Dysregulation of methyltransferase that is essential for RNA modification contributes to the development and progression of human cancers. Here we show that methyltransferase-like 1 (METTL1) is upregulated in hepatocellular carcinoma (HCC) and exhibits oncogenic activities via PTEN/AKT signaling pathway. High expression of METTL1 is correlated with larger tumor size, higher serum AFP level, tumor vascular invasion, and poor prognosis in two independent cohorts containing 892 patients with HCC. Multivariate analyses suggest METTL1 as an independent factor for unfavorable overall survival. In vitro studies demonstrate that METTL1 overexpression promotes cell proliferation and migration, whereas its knockdown results in opposite phenotypes. Gene set enrichment analysis (GSEA) indicates PTEN pathway is activated in patients with low METTL1 expression. Ectopic expression of PTEN or inhibition of AKT activity significantly attenuates the METTL1-mediated malignant phenotypes. In clinical samples, METTL1 expression is reversely associated with PTEN expression. Combination of low METTL1 expression and high PTEN expression is significantly correlated with overall survival, more so than either METTL1 or PTEN expression alone. Collectively, our data suggest that METTL1 serves as a promising prognostic biomarker and that targeting METTL1/PTEN axis may provide therapeutic potential in HCC intervention. KEY MESSAGES: METTL1 is upregulated in HCC and correlated with poor outcomes. METTL1 promotes cell proliferation and migration in HCC. METTL1 exerts oncogenic activities via suppression of PTEN signaling.

CBX4 exhibits oncogenic activities in breast cancer via Notch1 signaling.

Polycomb chromobox (CBX) proteins are involved in gene silencing to function as oncogenes or tumor suppressors through the polycomb repressive complex (PRC1). CBX4 has been implicated in the progression of human cancers, but its role and clinical significance in breast cancer remain unclear. Here, we show that CBX4 is up-regulated in breast cancer and exerts oncogenic activities via miR-137-mediated activation of Notch1 signaling pathway. CBX4 expression was increased in breast cancer, compared with the nontumorous tissues. High CBX4 expression was closely correlated with tumor metastasis, advanced clinical stage and poor overall survival in a cohort of 179 patients with breast cancer. In vitro studies demonstrated that CBX4 overexpression enhanced, whereas CBX4 knockdown inhibited cell growth and migration. Mechanistically, in a PRC1-dependent manner, CBX4 inhibited the promoter activity of miR-137 and suppressed its expression. miR-137 decreased the expression of Notch1, Jag1 and Hey2 via targeting their 3'-UTRs. The suppression of Notch1 by siRNA or overexpression of miR-137 markedly attenuated CBX4-promoted phenotypes. Collectively, these findings indicate that CBX4 promotes breast cancer via miR-137-mediated Notch1 signaling. Our data, therefore, suggest that CBX4 serve as a prognostic biomarker and that targeting CBX4/miR-137 axis may provide therapeutic potent in the treatment of breast cancer.

Hereditary endotheliopathy with retinopathy and encephalopathy: pathological and genetic studies of a family.

BACKGROUND: The objective of this study was to examine the clinical, pathological and genetic features of a family suffering from hereditary endotheliopathy with retinopathy and encephalopathy. METHODS: The index case was male, and his symptoms were detected at 18 years of age. The clinical manifestation included recurrent headache, fever, consciousness disturbances and haemiplegia. Bilateral cerebral hemispheric lesions were detected via MRI as low signals on T1 and high signals on T2 and FLAIR, with moderate enhancement. Video EEG revealed an increase in the slow wave frequency. An EMG displayed neurogenic atrophy. Similar clinical and imaging characteristics were detected in his mother and his uncle. Pathological examinations of the brain, muscle and sural nerve were performed on the index case. Sequence analysis of the TREX1 gene was performed on the index case, his sister and his father. RESULTS: A brain biopsy revealed spongiform alterations as well as inflammatory cell infiltration in a few small vessels. Neurogenic muscular atrophy was detected based on a biopsy of the muscle. Demyelination was detected based on a biopsy of the sural nerve. Electron microscopic examination of the sural nerve revealed thickening and delamination of the basement membrane. No reported TREX1 gene mutation was detected for any of the patients. CONCLUSION: Hereditary endotheliopathy presented with peripheral nerve involvement. Multi-laminar thickening of the basement membrane of the capillaries also appeared in the extracerebral tissue. The involvement of a novel gene should be further examined.

Peroxisome proliferator-activated receptor-γ agonist pioglitazone ameliorates white matter lesion and cognitive impairment in hypertensive rats.

AIMS: Cerebrovascular white matter lesion (WML) is a major subtype of cerebral small vessel disease. Clinical drugs are not available for WML. We investigated whether peroxisome proliferator-activated receptor-γ agonist pioglitazone, with properties of vascular protection and antiinflammation, exerts beneficial effect in hypertensive WML rats. METHODS: Stroke-prone renovascular hypertensive rats (RHRSP) were treated with pioglitazone for 12 weeks. Morris water maze experiment was conducted to assess cognition. WML was observed by Luxol fast blue staining. Smooth muscle actin-alpha, collagen I, collagen IV, glial fibrillary acidic protein, and ionized calcium-binding adaptor molecule-1 were evaluated by immunohistochemistry. Interleukin-1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) in brain and soluble intercellular adhesion molecule-1 (sICAM-1) in serum were detected. RESULTS: Pioglitazone significantly attenuated WML in corpus callosum, caudate putamen, external capsule, and internal capsule. Cognitive impairment in RHRSP was ameliorated by pioglitazone. Pioglitazone attenuated arteriolar remodeling and reduced sICAM-1 level in serum. Pioglitazone decreased the proliferation of microglia and astrocyte and lowered the expression of proinflammatory cytokines IL-1ß and TNF-α in the white matter. CONCLUSIONS: Long-term treatment of pioglitazone has beneficial effect on hypertension-induced WML and cognition decline, which may partly through its effect on attenuation of arteriolar remodeling, endothelial activation, and brain inflammation.

Marine cyclotripeptide X-13 promotes angiogenesis in zebrafish and human endothelial cells via PI3K/Akt/eNOS signaling pathways.

Cyclotripeptide X-13 is a core of novel marine compound xyloallenoide A isolated from mangrove fungus Xylaria sp. (no. 2508). We found that X-13 dose-dependently induced angiogenesis in zebrafish embryos and in human endothelial cells, which was accompanied by increased phosphorylation of eNOS and Akt and NO release. Inhibition of PI3K/Akt/eNOS by LY294002 or L-NAME suppressed X-13-induced angiogenesis. The present work demonstrates that X-13 promotes angiogenesis via PI3K/Akt/eNOS pathways.

dl-3n-Butylphthalide promotes angiogenesis via the extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase/Akt-endothelial nitric oxide synthase signaling pathways.

We have previously demonstrated that dl-3n-butylphthalide (NBP) has a potential angiogenic activity. In this study, we investigated the angiogenic effect of NBP and the molecular mechanisms underlying NBP-mediated angiogenesis. Zebrafish embryos and human umbilical vein endothelial cells were treated with various doses of NBP and several signaling pathway inhibitors. NBP induced ectopic subintestinal vessel production in zebrafish embryos and induced invasion, migration, and endothelial cell tube formation of human umbilical vein endothelial cells in a dose-dependent manner. These NBP-induced angiogenic effects were partially suppressed by SU5402, a fibroblast growth factor receptor 1 inhibitor; U0126, an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor; LY294002, a phosphatidylinositol 3-kinase inhibitor; 1L6-hydroxymethyl-chiro-inositol-2-(R)-2-O-methyl-3-O-octadecyl-sn-glycerocarbonate, an Akt inhibitor; cavtratin, an endothelial nitric oxide synthase (eNOS) inhibitor and completely inhibited by a combination of U0126 and LY294002. NBP enhanced phosphorylation of ERK1/2 and fibroblast growth factor receptor 2 expression, which were inhibited by U0126. NBP increased the phosphorylation of Akt and eNOS at serine 1177, which was blocked by LY294002. NBP-stimulated nitric oxide production, which was reduced by LY294002. Our data demonstrated that (1) NBP promoted angiogenesis and (2) the angiogenic effects of NBP were mediated by the ERK1/2 and phosphatidylinositol 3-kinase/Akt-eNOS signaling pathways. Our findings suggest that NBP could be a novel agent for therapeutic angiogenesis in ischemic diseases.

Decrease of tight junction integrity in the ipsilateral thalamus during the acute stage after focal infarction and ablation of the cerebral cortex in rats.

1. Whether damage to the blood-brain barrier (BBB) occurs in remote areas after a focal cortical lesion remains unknown. The present study investigated tight junction-related proteins and tight junction microstructure in the ipsilateral thalamus during the acute stage after middle cerebral artery occlusion (MCAO) and cortical aspiration lesion (CAL) in rats. 2. Thirty-six hypertensive and normotensive rats were subjected to MCAO or CAL; another 18 rats in each group were submitted to sham operation. Zonula Occluden (ZO)-1, occludin and albumin were detected by western blotting 12 and 24 h after surgery. Tight junction microstructure was evaluated using electron microscopy, whereas albumin location in the ipsilateral thalamus was determined using double immunostaining for albumin and occludin or albumin and neuronal nuclei (NeuN) 24 h after surgery. 3. Twenty-four hours after MCAO or CAL, occludin expression was reduced to 78.4% and 81.3%, respectively, compared with control. A reduction in ZO-1 expression in the ipsilateral thalamus (to 79%) was seen only after CAL (P < 0.05). Membrane contact at the tight junction was discontinuous in the ipsilateral thalamus in both MCAO and CAL rats. Albumin levels were 23.2% and 82.5% higher in the ipsilateral thalamus after MCAO and CAL, respectively (P < 0.05). The percentage of the albumin-positive area that coincided with the occludin-positive area in the MCAO and CAL groups was 76.8% and 64.6%, respectively, indicating that albumin was mainly localized around the microvessels. 4. The results of the present study suggest that tight junction integrity decreases during the acute stage in the ipsilateral thalamus after MCAO and CAL in rats.

[Changes in DNA repair enzymes in rat ventroposterior nucleus of the thalamus after cerebral cortex infarction].

OBJECTIVE: To investigate the damage within the ventroposterior nucleus (VPN) of the thalamus after focal cortical infarction and its mechanism, and explore the effect of ebselen on the oxidative damage after cerebral cortex infarction in hypertensive rats. METHODS: Middle cerebral artery occlusion (MCAO) was induced in stroke-prone renovascular hypertensive rats (RHRSP), and the rats were divided into four groups by table of random number: sham operation group, model group, vehicle group and ebselen group, each group consisted of 8 rats. In animals subjected to sham surgery the middle cerebral artery was exposed only. Ebselen (5 ml/kg) or vehicle (a mixed solvent consisting of 0.5% carboxymethyl cellulose and 0.02% Tween 20, 5 ml/kg) was given by gastric gavage starting 24 hours after cerebral cortical infarction. Two weeks after the MCAO, the rats were sacrificed, and VPN from each group was sectioned and stained with hematoxylin-eosin (HE), and apurinic/apyrimidinic endonuclease (APE) and Escherichia coli MutY DNA glycosylase (MYH) were determined by immunohistochemistry. RESULTS: HE staining showed that ebselen ameliorated the VPN damage induced by ischemia. Immunohistochemical imaging analysis revealed a distinct nuclear staining of APE and nuclear and cytoplasm distribution of MYH in the entire region of the VPN. Compared with sham operation group, the number of APE and MYH positive cells decreased in model group and vehicle group (APE: 57.0±14.7, 49.4±12.5 vs. 101.0±13.6, MYH: 15.0±4.7, 10.4±2.5 vs. 56.0±13.2, all P<0.05). Compared with model group and vehicle group, the number of APE and MYH positive cells increased significantly in ebselen group (APE: 72.2±7.6 vs. 57.0±14.7, 49.4±12.5, MYH: 32.2±7.6 vs. 15.0±4.7, 10.4±2.5, all P<0.05); the difference of the number of APE and MYH positive cells between model group and vehicle group showed no statistical significance. CONCLUSION: After 2 weeks of MCAO, there is a marked decrease of APE and MYH in VPN; ebselen can obviously increase the level of APE and MYH, and ebselen may protect the VPN of the thalamus from damage after focal cortical infarction in rats.

Association between interleukin-6 gene promoter -572C/G polymorphism and the risk of sporadic Alzheimer's disease.

Inflammation is a key component of Alzheimer's disease (AD), and we have examined the effect of two polymorphisms (-174G/C and -572C/G) in the promoter of the inflammatory cytokine interleukin-6 (IL-6) gene on risk of AD in 318 AD patients. Significant differences in genotype and allele frequencies of -572C/G IL-6 promoter polymorphism were observed between AD patients and controls. The GG genotype was associated with a decreased risk of developing AD (OR 0.423, 95% CI 0.200-0.894). Similarly, logistic regression analysis revealed that G allele was a protective factor for AD (OR 0.732, 95% CI 0.567-0.945). For -174G/C variability, no C variability was found in all the subjects. The frequency of the IL-6 -174G/C promoter polymorphism is very low or no variability in Henan Han population. The -572C/G polymorphism of IL-6 gene promoter region is associated with AD, and G allele is an independent protective factor for AD.

Enhanced angiogenesis with dl-3n-butylphthalide treatment after focal cerebral ischemia in RHRSP.

Appropriate restoration of blood flow via angiogenesis is critical for the recovery from ischemic stroke. Previously, we reported that treatment with dl-3n-butylphthalide (NBP) increases the number of local potent cerebral microvessels. However, the underlying mechanism remained unclear. The present study was conducted to test whether NBP enhances post-ischemic cerebral angiogenesis via vascular endothelial growth factor (VEGF) and hypoxia induced factor-1 alpha (HIF-1 alpha). Stroke-prone renovascular hypertensive rats (RHRSP) were used to create middle cerebral artery occlusion (MCAO) model. NBP was given 80 mg/kg per d for 10 consecutive days, starting 12, 24, 48 and 72 h respectively after MCAO. Neurological function was assessed daily and infarct volume as well as the expressions of CD31, VEGF, HIF-1 alpha and bFGF was detected 13 days after MCAO. The administration of NBP starting within 24 h after MCAO enhanced recovery of neurobehavioral function, reduced infarct volume, increased the quantity of CD31 positive vessels, and up-regulated expressions of VEGF and HIF-1 alpha. These findings suggest that treatment with NBP within 24 h post-ischemic stroke rescues brain tissue by enhancing angiogenesis associated with up-regulation of VEGF and HIF-1 alpha expressions.

[EphB2-Fc promotes activation of endogenous neural stem cells after cerebral cortex infarction: experimental with hypertensive rats].

OBJECTIVE: To explore the effects of intraventricular injection of EphB2-Fc on activation of inherent neural stem cells after cerebral cortex infarction. METHODS: Stroke-prone renovascular hypertension model was established in 96 SD rats by two-kidney, two-clip method. Middle cerebral artery occlusion (MCAO) model was established in 72 of these 96 stroke-prone renovascular hypertensive rats and the other 24 rats were used as sham operation group. Then the 72 rats were randomly divided into 3 equal groups: cerebral infarction group without any treatment after the MCAO, MCAO + EphB2-Fc group undergoing stereotaxical infusion of EphB2-Fc at the dose of 20 microl x 200 microg/ml into the lateral ventricle 4 days after the distal ligation of right middle cerebral artery, and MCAO + IgG-Fc group undergoing stereotaxical infusion of IgG-Fc at the dose of 20 microl x 200 microg/ml into the lateral ventricle 4 days after the distal ligation of right middle cerebral artery. By the ends of the first and fourth weeks after the MCAO procedure 12 rats from each group were killed and their brains were taken out to undergo in situ hybridization, immunohistochemistry and Western blotting analysis in order to determine the expression of EphB2 protein and mRNA, nestin and polysialic acid-neural cell adhesion molecule (PSA-NCAM). RESULTS: One week after the distal ligation of right middle cerebral artery, the EphB2 protein and mRNA expression levels in the ipsilateral cortex and subventricular zone (SVZ) of the cerebral infraction group were both lower than those of the sham operation group (P < 0.05), such levels of the MCAO + EphB2-Fc group were higher than those of the MCAO + IgG-Fc group (both P < 0.05), but there was no significant difference between the cerebral infraction group and IgG-Fc group (both P > 0.05), and there were no differences in such levels between the cerebral infarction group and MCAO + IgG-Fc group (both P > 0.05); the nestin and PSA-NCAM expression levels in the ipsilateral SVZ of the cerebral infraction group were both higher than those of the sham operation group (both P < 0.05), such levels of the MCAO + EphB2-Fc group were both higher than those of the MCAO + IgG-Fc group (both P < 0.05), and migration of PSA-NCAM positive cells to corpus callosum could be seen. Four weeks after, there were no significant differences in the expression levels of EphB2 protein and mRNA among different groups (all P > 0.05), the nestin and PSA-NCAM expression levels in the ipsilateral SVZ decreased in all groups, there were no significant differences in the expression of nestin among all groups, but the PSA-NCAM expression in the ipsilateral SVZ of the cerebral infraction group was still higher than that of the sham operation group. CONCLUSION: Disruption of EphB2 signal promotes the proliferation and migration of endogenous neural stem cells in the SVZ after cerebral cortex infarction.

Role of mitogen activated protein kinase cascade pathway and anti-stress response in liver transplantation.

OBJECTIVE: To explore the changes of mitogen activated protein kinase (MAPK) cascade pathway and anti-stress response of hepatocytes after liver transplantation. METHODS: Ten normal liver specimens and 18 punctured donor liver specimens were divided into 3 groups: A (control:10), B (no rejection:10) and C (acute rejection:8). MAPK, Ras, Jun and heat shock protein 70 (HSP70) were tested immunohistochemically while Ras and HSP70 were tested by in situ hybridization. All sections were subjected to image analysis. RESULTS: Protein expressions of MAPK, Ras and Jun were increased by an ascending order of groups A, B and C. The protein expression of HSP70 was the highest in group B but lower in group C. Expressions of Ras and HSP70 mRNA were consistent with those of protein. CONCLUSIONS: The changes of the MAPK cascade pathway and anti-stress response of hepatocytes after liver transplantation are one of regulation mechanisms for protecting the hepatocytes from damage after liver transplantation. This mechanism is active to support individual survival