Single nucleotide polymorphisms of matrix metallopeptidase 3 and risk of gliomas in a Chinese Han population.

Matrix metallopeptidases (MMPs) play an important role in central nervous system tumor growth, invasion and spreading. The currently available data provide clear evidence for the involvement of MMP3 in the pathophysiology of glioma. The study aims to explore the association of single nucleotide polymorphisms (SNPs) across the MMP3 gene with glioma risk. Three haplotype tagging and additional two promoter SNPs were genotyped among 766 glioma patients and 824 cancer-free controls from East China. None of these polymorphisms alone had a significant effect on risk of gliomas. However, when three promoter polymorphisms were evaluated together by the number of putative risk of genotypes (i.e., rs645419AA, 632478CA+AA, rs522616AA), a statistically significantly increased risk of gliomas was associated with the combined genotypes with two to three risk genotypes, compared with those with zero to one risk genotypes (adjusted odds ratio (OR) = 1.32; 95% confidence interval (CI) = 1.03-1.68). This increased risk was also more pronounced among adults (adjusted OR = 1.14, 95%CI = 1.02-1.27), males (adjusted OR = 1.19, 95%CI = 1.05-1.36), smokers (adjusted OR = 1.28, 95%CI = 1.07-1.52), subjects with no family history of cancer (adjusted OR = 1.21, 95%CI = 1.07-1.37), and patients with nonastrocytic gliomas (adjusted OR = 1.23, 95%CI = 1.06-1.43). In summary, our results suggest that any one of MMP3 variants may not have a substantial effect on glioma risk, but a joint effect of MMP3 promoter polymorphisms may contribute to risk of gliomas, particularly for adult gliomas.

Identification of CD105 (endoglin)-positive stem-like cells in rhabdoid meningioma.

To investigate the tumor-initiating cells (TICs) in rhabdoid meningioma (RM), a population of CD105-positive cells isolated from a fresh RM surgical sample was analyzed for proliferative activity, self-renewal ability, tumorigenic ability, multilineage differentiation potential, as well as chromosomal aberrations. The results showed that isolated CD105-positive cells could be maintained for more than 50 generations in vitro. These cells exhibited increased proliferative activity and single-cell tumor sphere-formation ability compared with CD105-negative cells. In vivo experiments showed that CD105-positive cells possessed much greater potential to reconstitute the original human RM in nude mice as compared with CD105-negative cells. Phenotypically, CD105-positive cells shared some surface markers with mesenchymal progenitor cells (MPCs), but karyotype analysis showed chromosomal abnormalities characteristic of malignant meningioma, thus distinguishing them from supportive stroma-derived MPCs. In addition, in contrast to CD105-negative cells, CD105-positive cells could differentiate into adipocytes and osteocytes in response to specific induction agents. Finally, CD105-positive cells with stem-like features were also isolated from xenograft tumors. In conclusion, a population of CD105-positive TICs with some traits of MPCs was identified in RM and might provide a promising therapeutic target in management of malignant meningioma.

A genetic variant in the APE1/Ref-1 gene promoter -141T/G may modulate risk of glioblastoma in a Chinese Han population.

BACKGROUND: The human apurinic/apyrimidinic endonuclease 1/Redox effector factor-1 (APE1/Ref-1) is implicated in tumor development and progression. Recently, the APE1/Ref-1 promoter -141T/G variant (rs1760944) has been reported to be associated with lung cancer risk. Given the importance of APE1/Ref-1 in both DNA repair and redox activity, we speculate that the -141T/G polymorphism may confer individual susceptibility to gliomas or its subtypes. METHODS: The APE1/Ref-1 -141T/G polymorphism was analyzed in a case-control study including 766 glioma patients (among them 241 glioblastoma, 284 astrocytomas except for glioblastoma and 241 other gliomas) and 824 cancer-free controls from eastern China. Genotyping was performed with Sequenom MassARRAY iPLEX platform by use of allele-specific MALDI-TOF mass spectrometry assay. We estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditional logistic regression. A test of trend was calculated using the genotype as an ordinal variable in the regression model. For each statistically significant association identified, we estimated the false positive reporting probability (FPRP). FPRP values less than 0.2 were consider to indicate robust associations. RESULTS: The significant association between the APE1/Ref-1 promoter -141T/G polymorphism and glioma risk was not observed. However, the stratified analysis by histology revealed the variant allele G significantly decreased glioblastoma risk (OR = 0.80, 95% CI = 0.65-0.98, P = 0.032). Individuals with the homozygous -141GG genotype exhibited 46% reduced risk of glioblastoma (adjusted OR = 0.54, 95% CI 0.34-0.87, P = 0.012), compared with the TT homozygote. This result remained robust given the prior probabilities of 25% (FPRP = 0.052) and 10% (FPRP = 0.140), but not with a prior probability of 1% (FPRP = 0.643). The P-associated with the trend test was 0.014. CONCLUSIONS: Our results suggest that a specific genetic variant located in the APE1/Ref-1 promoter may modulate risk of glioblastoma, but not for other histological gliomas. Larger studies with more APE1 polymorphisms are required to validate these preliminary findings.

Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia.

BACKGROUND AND PURPOSE: Evidence suggests that activated microglia are detrimental to the survival of new hippocampal neurons, whereas blocking inflammation has been shown to restore hippocampal neurogenesis after cranial irradiation and seizure. The aim of this current study is to determine the effect of minocycline on neurogenesis and functional recovery after cerebral focal ischemia. METHODS: Four days after temporary middle cerebral artery occlusion, minocycline was administered intraperitoneally for 4 weeks. BrdU was given on days 4 to 7 after middle cerebral artery occlusion to track cell proliferation. The number of remaining new neurons and activated microglia were quantified in the dentate gyrus. Infarct volume was measured to assess the treatment effect of minocycline. Motor and cognitive functions were evaluated 6 weeks after middle cerebral artery occlusion. RESULTS: Minocycline delivered 4 days after middle cerebral artery occlusion for 4 weeks did not result in reduction in infarct size but significantly decreased the number of activated microglia in the dentate gyrus. Minocycline also significantly increased the number of newborn neurons that coexpressing BrdU and NeuN without significantly affecting progenitor cell proliferation in the dentate gyrus. Lastly, minocycline significantly improved motor coordination on the rotor rod, reduced the preferential use of the unaffected limb during exploration, reduced the frequency of footfalls in the affected limb when traversing on a horizontal ladder, and improved spatial learning and memory in the water maze test. CONCLUSIONS: Minocycline reduces functional impairment caused by cerebral focal ischemia. The improved function is associated with enhanced neurogenesis and reduced microglia activation in the dentate gyrus and possibly improved neural environment after chronic treatment with minocycline.

Upregulated gene expression of local brain-derived neurotrophic factor and nerve growth factor after intracisternal administration of marrow stromal cells in rats with traumatic brain injury.

OBJECTIVE: To examine the effects of rat marrow stromal cells (rMSCs) on gene expression of local brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) after injection of rMSCs into Cistern Magnum of adult rats subjected to traumatic brain injury (TBI). METHODS: A modified Feeney's TBI model was created in 48 adult rats. rMSCs were harvested from 3-month-old rats, and injected into Cistern Magnum in 24 rats subjected to TBI (Group cell transplantation). Saline was given through Cistern Magnum to another 24 rats subjected to TBI (Group saline control). Animals were sacrificed 1, 2 and 3 weeks after intervention, and special brain tissue blocks were dissected for total RNA extraction from each block. BDNF and NGF mRNA were reverse-transcribed into cDNA and further expanded by polymerase chain reaction (PCR). The expression of target genes was evaluated using semi-quantitative methods. RESULTS: Group cell transplantation had higher BDNF and NGF gene expressions than Group saline control during a period of less than 3 weeks (P<0.05). CONCLUSIONS: rMSCs transplantation via Cistern Magnum in rats subjected to traumatic brain injury can enhance expressions of local brain NGF and BDNF to a certain extent.

Watershed protection and landscape enhancement by utilization of river water.

A scheme for watershed protection and landscape enhancement (WPLE) by utilization of river water was proposed to renovate water resources and protect ecological environment in Qiongshan City, Hainan Province, China. Utilization of river water may diminish the drought and flood risks. The scheme is beneficial to solve the problems of water resources shortage, groundwater declines and saltwater intrusion in the watershed. The object of the WPLE scheme is to achieve a sustainable integrated development of environment, ecology, economy and society. A kind of physically beautiful and functionally vivid landscape may exert its synthetical function on the diversity of landscape and the enjoyment of inhabitants. Feasibility of the scheme will be demonstrated by more experiments and tests, as well as observations in a long term.

Association of genetic variants in the retinoblastoma binding protein 6 gene with the risk of glioma: a case-control study in a Chinese Han population.

OBJECT: The retinoblastoma binding protein 6 (RBBP6) gene plays an important role in the induction of apoptosis and regulation of the cell cycle, and interacts with both p53 and retinoblastoma protein in carcinogenesis. Recently, many studies investigating the function of the RBBP6 gene, including its roles in lung cancer and breast cancer, have been reported. However, the association between RBBP6 variants and glioma was unknown. Therefore, to uncover the association between single nucleotide polymorphisms (SNPs) of RBBP6 and glioma, a hospital-based case-control study was performed in a Chinese Han population. METHODS: Ten common tagging SNPs of the RBBP6 gene (covering 100% of all SNPs) were genotyped with the Sequenom MassARRY iPLEX platform, including 992 cases and 1008 controls, according to the HapMap database based on a pairwise linkage disequilibrium r(2) threshold of 0.8, minor allele frequency of 0.05, and Hardy-Weinberg equilibrium of 0.05. RESULTS: The authors found that 4 SNPs were significantly associated with glioma (rs2033214, p = 0.013, adjusted OR 2.46, 95% CI 1.18-5.14; rs11860248, p = 8.64 × 10-(6), adjusted OR 1.59, 95% CI 1.23-2.05; rs9933544, p = 3.65 × 10(-4), adjusted OR 1.39, 95% CI 1.13-1.87; rs13332653, p = 0.004, adjusted OR 1.49, 95% CI 1.14-1.95). Stratification analyses revealed that rs2033214 was only significantly associated with low-grade gliomas; rs9933544 and rs13332653 were only significantly associated with glioblastoma multiforme; and rs11860248 was significantly associated with both low-grade gliomas and glioblastoma multiforme, compared with the common wild-type homozygous genotype. Further stratified analysis revealed that rs11860248 was more pronounced in certain subgroups: adults, males, histological types, and family history of cancer. What's more, the haplotype and diplotype analyses consistently revealed that the subjects carrying 1 copy of haplotype CCGCC had a 53% increased glioma risk compared with their corresponding noncarriers (p = 0.018, adjusted OR 1.53, 95% CI 1.08-2.17). CONCLUSIONS: The authors' results suggested that RBBP6 gene variants are associated with glioma and contribute to glioma susceptibility, which was first reported elsewhere. Individuals with the so-called risk alleles might have an increased risk of glioma. These results might provide new insight into the occurrence of glioma.