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1.
J Mol Neurosci ; 51(2): 371-9, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23649504

ABSTRACT

Medulloblastoma is the most frequent type of embryonal tumour in the paediatric population. The disease progression in patients with this tumour may be connected with the presence of stem/tumour-initiating cells, but the precise source and characteristics of such cells is still a subject of debate. Thus, we tried to analyse biomarkers for which a connection with the presence of stem/tumour-initiating cells was suggested. We evaluated the transcriptional level of the ATOH1, FUT4, NGFR, OTX1, OTX2, PROM1 and SOX1 genes in 48 samples of medulloblastoma and analysed their usefulness in the prediction of disease outcome. The analyses showed a strong correlation of PROM1, ATOH1 and OTX1 gene expression levels with the outcome (p ≤ 0.2). On the basis of the multivariate Cox regression analysis, we propose a three-gene model predicting risk of the disease, calculated as follows: RS(risk score) =( 0:81 x PROM1) + (0:18 x OTX1) + (0:02 x ATOH1). Survival analysis revealed a better outcome among standard-risk patients, with a 5-year survival rate of 65 %, compared to the 40 % rate observed among high-risk patients. The most promising advantage of such molecular analysis consists in the identification of molecular markers influencing clinical behaviour, which may in turn be useful in therapy optimization.


Subject(s)
Antigens, CD/metabolism , Basic Helix-Loop-Helix Transcription Factors/metabolism , Glycoproteins/metabolism , Medulloblastoma/genetics , Neoplasms, Germ Cell and Embryonal/genetics , Otx Transcription Factors/metabolism , Peptides/metabolism , Transcription, Genetic , AC133 Antigen , Adolescent , Antigens, CD/genetics , Basic Helix-Loop-Helix Transcription Factors/genetics , Child , Child, Preschool , Female , Fucosyltransferases/genetics , Fucosyltransferases/metabolism , Glycoproteins/genetics , Humans , Infant , Lewis X Antigen/genetics , Lewis X Antigen/metabolism , Male , Medulloblastoma/diagnosis , Medulloblastoma/metabolism , Neoplasms, Germ Cell and Embryonal/diagnosis , Neoplasms, Germ Cell and Embryonal/metabolism , Neoplastic Stem Cells/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Otx Transcription Factors/genetics , Peptides/genetics , Prognosis , Receptors, Nerve Growth Factor/genetics , Receptors, Nerve Growth Factor/metabolism , SOXB1 Transcription Factors/genetics , SOXB1 Transcription Factors/metabolism
2.
Prion ; 7(3): 244-7, 2013.
Article in English | MEDLINE | ID: mdl-23406923

ABSTRACT

The PRNP gene encodes the cellular isoform of prion protein (PrP (c) ). The M129V polymorphism influences the risk of prion diseases and may modulate the rate of neurodegeneration with age. We present the first study of the polymorphism among Polish centenarians. In the control group (n = 165, ages 18 to 56 years) the observed M129V genotype frequencies agreed with those expected according to the Hardy-Weinberg equilibrium (MM, MV, VV): 43%, 44%, 13% (HWE p > 0.05). Among centenarians (n = 150, ages 100 to 107) both homozygotes were more common than expected and HWE was rejected: 46%, 37%, 17% (expected 42%, 46%, 13%; HWE p = 0.025). This finding is consistent with a higher mortality rate among heterozygotes. However, the observed allele and genotype frequencies did not differ significantly between the oldest-old and the young controls. The genotypic frequencies were not related to severe cognitive impairment among the centenarians.


Subject(s)
Cognition Disorders/genetics , Longevity , Polymorphism, Single Nucleotide , Prions/genetics , Adolescent , Adult , Aged, 80 and over , Female , Homozygote , Humans , Male , Middle Aged , White People/genetics , Young Adult
3.
Exp Gerontol ; 48(4): 391-4, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23384821

ABSTRACT

APBB2 gene encodes for ß-amyloid precursor protein-binding family B member 2, (APBB2, FE65-like, FE65L1), an adaptor protein binding to the cytoplasmatic domain of ß-amyloid precursor protein (ßAPP). Over-expression of APBB2 promotes formation of ß-amyloid (Aß), the main constituent of senile plaques. Polymorphisms within APBB2 gene have been proposed as candidate risk factors for Alzheimer's disease. However, their association with longevity has never been investigated. Here we present the first attempt to analyze APBB2 polymorphisms in centenarians. We used a PCR-RFLP method to analyze two intronic nucleotide substitutions: hCV1558625 (rs17443013) and rs13133980. We found no differences in genotype or allele distribution between centenarians and young controls. After stratification of centenarians upon their cognitive performance, the APBB2 rs13133980 G allele was over-represented in centenarians with severe cognitive impairment compared to individuals without this disability. Also the hCV1558625-rs13133980 AG haplotype increased relative risk for severe cognitive impairment in centenarians. Our results support the concept of APBB2 polymorphism association with cognitive performance in the oldest age.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Cognition Disorders/genetics , Aged, 80 and over , Amyloid beta-Protein Precursor/genetics , Cognition Disorders/diagnosis , Diagnostic and Statistical Manual of Mental Disorders , Female , Genetic Predisposition to Disease , Humans , Intelligence Tests , Introns , Male , Plaque, Amyloid/genetics , Polymorphism, Single Nucleotide , Psychiatric Status Rating Scales
4.
Clin Neuropathol ; 32(2): 114-21, 2013.
Article in English | MEDLINE | ID: mdl-23211433

ABSTRACT

The aim of our study was to evaluate the frequency of deletions on chromosomes 1, 9, 10, 14, 18 and 22 in 75 benign and 15 atypical meningiomas and correlate them with clinical findings. Paired normal and tumor DNA samples were analyzed for loss of heterozygosity (LOH), using 24 microsatellite markers and PCR techniques. Statistical analysis showed that deletions on chromosomes 14 and 18 were significantly associated with tumor grade of meningiomas (p = 0.048 and p = 0.03, respectively). In addition, we found a marginally increased frequency of LOH on chromosome 9 in atypical meningiomas (p = 0.06). Interestingly, LOH on chromosome 14 was significantly associated with tumor size (p = 0.049), as the risk of developing a tumor of more than 4 cm in diameter was 6-times the risk of developing tumor with diameter below 4 cm. The most frequent genetic abnormality in meningiomas is 22 LOH, which seems to be confirmed by the present study in which high frequency of such abnormality was observed (67%). We found associations between chromosome 22 status and histological subtype. LOH on chromosome 22 was more frequent in fibrous meningiomas than in the meningothelial variant (p = 0.001). Besides that, we found a relationship between 22 LOH status and tumor localization: the frequency of LOH in skull base-localized tumors was significantly lower compared to parasagittal meningiomas (p = 0.0004). Our results indicated that allelic loss on chromosomes 9, 10, 14, 18 and 22 may be associated with meningioma pathogenesis and progression.


Subject(s)
Meningeal Neoplasms/genetics , Meningioma/genetics , Chromosome Deletion , Female , Humans , Male , Meningeal Neoplasms/pathology , Meningioma/pathology , Middle Aged , Neoplasm Grading
5.
J Neurooncol ; 102(3): 395-407, 2011 May.
Article in English | MEDLINE | ID: mdl-20803305

ABSTRACT

Glioblastoma cell cultures in vitro are frequently used for investigations on the biology of tumors or new therapeutic approaches. Recent reports have emphasized the importance of cell culture type for maintenance of tumor original features. Nevertheless, the ability of GBM cells to preserve EGFR overdosage in vitro remains controversial. Our experimental approach was based on quantitative analysis of EGFR gene dosage in vitro both at DNA and mRNA level. Real-time PCR data were verified with a FISH method allowing for a distinction between EGFR amplification and polysomy 7. We demonstrated that EGFR amplification accompanied by EGFRwt overexpression was maintained in spheroids, but these phenomena were gradually lost in adherent culture. We noticed a rapid decrease of EGFR overdosage already at the initial stage of cell culture establishment. In contrast to EGFR amplification, the maintenance of polysomy 7 resulted in EGFR locus gain and stabilization even in long-term adherent culture in serum presence. Surprisingly, the EGFRwt expression pattern did not reflect the latter phenomenon and we observed no overexpression of the tested gene. Moreover, quantitative analysis demonstrated that expression of the truncated variant of receptor-EGFRvIII was preserved in GBM-derived spheroids at a level comparable to the initial tumor tissue. Our findings are especially important in the light of research using glioblastoma culture as the experimental model for testing novel EGFR-targeted therapeutics in vitro, with special emphasis on the most common mutated form of receptor-EGFRvIII.


Subject(s)
Brain Neoplasms/pathology , ErbB Receptors/metabolism , Glioblastoma/pathology , Animals , Bromodeoxyuridine/metabolism , Cell Adhesion/physiology , Cell Cycle/physiology , Cell Proliferation , ErbB Receptors/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , Models, Animal , RNA, Messenger/metabolism , SOXB1 Transcription Factors/metabolism , Spheroids, Cellular/pathology , Time Factors , Tumor Cells, Cultured
6.
Childs Nerv Syst ; 27(1): 79-86, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20717685

ABSTRACT

INTRODUCTION: Medulloblastoma is the most frequent type of embryonal tumor in the pediatric population, accounting for 20-25% of all brain tumors in children. Recently, the suspected contribution of the Polycomb group (PcG) genes in medulloblastoma development was described. PcG genes play an important role in developmental processes; they are also involved in the self-renewal of hematopoietic and neural stem cells as well as in malignant transformation. PURPOSE: In this study, we evaluated the expression of BMI1and PCGF2, members of family of PcG genes, and their potential target, MYC oncogene, and analyzed their association with demographic and clinical data. MATERIALS AND METHODS: Thirty-one children (18 males and 13 females, aged from 0.4 to 17 years) with medulloblastoma were included in this study. The gene's expression level was measured by quantitative real-time PCR, obtained using the two-color multiplexing technique. RESULTS: We found that the higher expression levels of BMI1 and PCGF2 genes were associated with significantly decreased patient survival (p = 0.02 and p = 0.012, respectively). Significant differences between gender were found, with a higher expression level of the PCGF2 gene observed among females (p = 0.02). CONCLUSION: Our analysis showed correlation between BMI1 and PCGF2 gene's expression and survival in children with medulloblastoma.


Subject(s)
Biomarkers, Tumor/genetics , Cerebellar Neoplasms/genetics , Medulloblastoma/genetics , Nuclear Proteins/biosynthesis , Proto-Oncogene Proteins/biosynthesis , Repressor Proteins/biosynthesis , Adolescent , Cerebellar Neoplasms/metabolism , Cerebellar Neoplasms/mortality , Child , Child, Preschool , Female , Gene Expression , Humans , Infant , Kaplan-Meier Estimate , Male , Medulloblastoma/metabolism , Medulloblastoma/mortality , Nuclear Proteins/genetics , Polycomb Repressive Complex 1 , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction , Treatment Outcome
7.
Anal Biochem ; 408(1): 163-5, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-20849807

ABSTRACT

This study was aimed to test a panel of six housekeeping genes (GAPDH, HPRT1, POLR2A, RPLP0, ACTB, and H3F) so as to identify and validate the most suitable reference genes for expression studies in astrocytomas. GAPDH was the most stable and HPRT1 was the least stable reference gene. The effect of reference gene selection on quantitative real-time polymerase chain reaction data interpretation was demonstrated, normalizing the expression data of a selected gene of interest. Thus, GAPDH may be recommended for data normalization in gene expression studies in astrocytomas. Nevertheless, a preliminary validation of reference gene stability is required prior to every study.


Subject(s)
Astrocytoma/metabolism , Gene Expression Profiling , Polymerase Chain Reaction/methods , Actins/genetics , Actins/metabolism , Actins/standards , Astrocytoma/genetics , Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/genetics , Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/metabolism , Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/standards , Histones/genetics , Histones/metabolism , Histones/standards , Humans , Hypoxanthine Phosphoribosyltransferase/genetics , Hypoxanthine Phosphoribosyltransferase/metabolism , Hypoxanthine Phosphoribosyltransferase/standards , Polymerase Chain Reaction/standards , Reference Standards , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolism , Ribosomal Proteins/standards
8.
J Alzheimers Dis ; 17(2): 359-68, 2009.
Article in English | MEDLINE | ID: mdl-19363267

ABSTRACT

We studied eight polymorphisms within APOE, PRNP, PRND, and CYP46 genes in 213 Polish late-onset patients with Alzheimer's disease (AD) and 171 non-demented elderly controls. A latent classification approach, grade-of-membership analysis, was taken to identify three extreme pure type risk sets defined by the probabilities of being affected with AD and for genotypes found at the examined genes. Sets I and II represented high intrinsic risk, having a higher density of various genotypes compared to set III, at low intrinsic risk. A gradient of onset age depending on membership in the risk sets was also observed. Logistic regression analysis showed that the highest risk for AD was found for individuals who co-inherited APOE epsilon4 allele, PRNP codon 129 homozygosity, PRND codon 174 Thr allele, and CYP46 rs754203 g allele. AD can be influenced by genetic profiles leading to appearance of the disease, composed of genes which separately evoke a little or unnoticeable effect. Moreover, there may be multiple sufficient risk sets for AD. Looking at multiple genes together rather than analyzing them individually, may improve identification of risk alleles.


Subject(s)
Alzheimer Disease/genetics , Apolipoproteins E/genetics , Genetic Predisposition to Disease , Polymorphism, Genetic/genetics , Prions/genetics , Steroid Hydroxylases/genetics , Age Factors , Aged , Aged, 80 and over , Chi-Square Distribution , Cholesterol 24-Hydroxylase , Female , GPI-Linked Proteins , Gene Frequency , Genotype , Humans , Kaplan-Meier Estimate , Logistic Models , Male , Middle Aged , Prion Proteins , Risk Factors
9.
Neurosci Lett ; 447(2-3): 164-6, 2008 Dec 12.
Article in English | MEDLINE | ID: mdl-18852029

ABSTRACT

The accumulation of beta-amyloid (Abeta) in the brain plays a central role in the pathogenesis of Alzheimer's disease (AD). The processing of Abeta precursor protein to Abeta is modulated by binding proteins including APBB2 [amyloid beta precursor protein-binding family B member 2, FE65-like, FE65L1]. We investigated two intronic SNPs within the APBB2 gene: rs13133980 and hCV1558625 (rs17443013), among Polish AD patients and healthy controls (n=213, 171). The frequencies of rs13133980 alleles and genotypes did not differ between cases and controls, irrespective of age of onset or APOE epsilon4 carrier status. The hCV1558625 G allele was over-represented in patients with onset under age 70 compared to controls in the same age range (57% vs. 43%, p=0.03). The association between the hCV1558625 G allele and susceptibility for AD at relatively young ages needs to be confirmed in other samples.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Alzheimer Disease/genetics , Polymorphism, Single Nucleotide/genetics , Aged , Aged, 80 and over , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged
10.
BMC Biotechnol ; 8: 56, 2008 Jul 19.
Article in English | MEDLINE | ID: mdl-18638414

ABSTRACT

BACKGROUND: Although extensive research has been performed to control differentiation of neural stem cells - still, the response of those cells to diverse cell culture conditions often appears to be random and difficult to predict. To this end, we strived to obtain stabilized protocol of NHA cells differentiation - allowing for an increase in percentage yield of neuronal cells. RESULTS: Uncommitted GFAP and SOX2 positive neural progenitors - so-called, Normal Human Astrocytes (NHA) were differentiated in different environmental conditions to: only neural cells consisted of neuronal [MAP2+, GFAP-] and glial [GFAP+, MAP2-] population, non-neural cells [CD44+, VIMENTIN+, FIBRONECTIN+, MAP2-, GFAP-, S100beta-, SOX2-], or mixture of neural and non-neural cells.In spite of successfully increasing the percentage yield of glial and neuronal vs. non-neural cells by means of environmental changes, we were not able to increase significantly the percentage of neuronal (GABA-ergic and catecholaminergic) over glial cells under several different cell culture testing conditions. Supplementing serum-free medium with several growth factors (SHH, bFGF, GDNF) did not radically change the ratio between neuronal and glial cells--i.e., 1,1:1 in medium without growth factors and 1,4:1 in medium with GDNF, respectively. CONCLUSION: We suggest that biotechnologists attempting to enrich in vitro neural cell cultures in one type of cells - such as that required for transplantology purposes, should consider the strong limiting influence of intrinsic factors upon extracellular factors commonly tested in cell culture conditions.


Subject(s)
Cell Differentiation/drug effects , Neuroglia/cytology , Neuroglia/physiology , Neurons/cytology , Neurons/physiology , Stem Cells/drug effects , Stem Cells/physiology , Astrocytes/drug effects , Astrocytes/physiology , Biomarkers/analysis , Biomarkers/metabolism , Cell Culture Techniques/methods , Cell Lineage/drug effects , Cell Lineage/physiology , Cells, Cultured , Culture Media, Serum-Free/pharmacology , DNA-Binding Proteins/analysis , Fibroblast Growth Factors/pharmacology , Fibronectins/analysis , Glial Fibrillary Acidic Protein/analysis , HMGB Proteins/analysis , Humans , Hyaluronan Receptors/analysis , Microtubule-Associated Proteins/analysis , Nerve Growth Factors/analysis , Nerve Growth Factors/pharmacology , Nerve Tissue Proteins/analysis , Nerve Tissue Proteins/drug effects , S100 Calcium Binding Protein beta Subunit , S100 Proteins/analysis , SOXB1 Transcription Factors , Stem Cells/cytology , Transcription Factors/analysis , Vimentin/analysis
11.
Brain Res ; 1186: 65-73, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17996224

ABSTRACT

PrP(c) is a cellular isoform of the prion protein with an unknown normal function. One of the putative physiological roles of this protein is its involvement in cell differentiation. Recently, in vitro and in vivo studies showed that GFAP-positive cells have characteristics of stem/progenitor cells that generate neurons and glia. We used an in vitro model of human neurogenesis from GFAP-positive progenitor cells to study the expression of PrP(c) during neural differentiation. Semi-quantitative multiplex-PCR assay and Western blot analysis revealed a significant increase of PRNP expression level in differentiated cells compared to undifferentiated cell population. As determined by immunocytochemistry followed by a quantitative image analysis, the PrP(c) level increased significantly in neuronal cells and did not increase significantly in glial cells. Of note, glial and neuronal cells showed a very large heterogeneity of PrP(c) expression. Our results provide the basis for studying the role of PrP(c) in cell differentiation and neurogenesis from human GFAP-positive progenitor cells.


Subject(s)
Astrocytes/metabolism , Cell Differentiation/physiology , Fetal Stem Cells/cytology , Neurons/metabolism , PrPC Proteins/metabolism , Astrocytes/cytology , Cell Line , Cerebrum/cytology , Cerebrum/metabolism , Fetal Stem Cells/metabolism , Glial Fibrillary Acidic Protein/metabolism , Humans , Neurons/cytology , Prion Proteins , Prions/metabolism
12.
Neurol Neurochir Pol ; 41(4): 333-9, 2007.
Article in Polish | MEDLINE | ID: mdl-17874342

ABSTRACT

Oligodendroglial tumours represent a type of tumours in which molecular alterations may become a significant prognostic factor. During the last decade, enormous progress in understanding of these alterations has been accomplished. Oligodendrogliomas show distinct genetic alterations, allowing us to distinguish them from other types of gliomas. The loss of heterozygosity (LOH) on chromosomes 1p and 19q were reported to be the most frequently observed alterations. While loss of heterozygosity on chromosome 1p is a statistically significant predictor of chemosensitivity, combination with deletions on chromosome 19q was reported to be associated with both chemosensitivity and longer recurrence-free survival after therapy. Conversely, allelic loss on chromosome 10q, observed in many anaplastic oligodendrogliomas, predicts rather poor outcome. The present paper is a compilation of the newest information on the characteristics of the genetic alterations related to the clinical course of oligodendrogliomas, which seems to be important for the proper diagnostics and selection of the appropriate methods of treatment.


Subject(s)
Brain Neoplasms/genetics , Chromosomes, Human, Pair 19/genetics , Chromosomes, Human, Pair 1/genetics , Loss of Heterozygosity/genetics , Oligodendroglioma/genetics , Brain Neoplasms/diagnosis , Brain Neoplasms/therapy , Chromosome Deletion , Humans , Oligodendroglioma/diagnosis , Oligodendroglioma/therapy , Prognosis , Survival Analysis
13.
Acta Neurobiol Exp (Wars) ; 67(2): 103-12, 2007.
Article in English | MEDLINE | ID: mdl-17691218

ABSTRACT

The aim of our study was to evaluate the frequencies of loss of heterozygosity (LOH) on chromosomes 1p, 10q, and 19q in gliomas and to correlate them with the histological diagnosis and with patient age and gender. We found deletions within chromosome 1p to be significantly associated with the histological subtype of glial tumor (P < 0.05); frequency of 1p deletions increased from astrocytoma (0%) through glioblastoma (31%) and oligoastrocytoma (57%) to oligodendroglioma (63%). In patients with 1p LOH, the odds for having astrocytoma or glioblastoma were approximately 10-fold and 4-fold lower, respectively, than oligodendroglioma. The odds for having oligoastrocytoma were similar to oligodendroglioma (OR = 1.3). The frequency of 10q LOH in patients with glioblastoma was significantly higher than in patients with oligodendroglioma (89% vs. 36%; P < 0.005). In patients with oligodendroglioma, most cases with LOH on chromosome 1p also had LOH 19q (90%), one case of 1p LOH also had a deletion on 10q. Statistical analyses revealed a significant association between deletions on 1p and 19q (P < 0.05). Our data provide evidence that use of molecular genetic analyses of chromosomes 1p, 19q, and 10q might improve the diagnosis of gliomas.


Subject(s)
Chromosome Aberrations , Chromosomes, Human/genetics , Glioma/genetics , Adult , Age Factors , Aged , Chromosome Mapping , Chromosomes, Human, Pair 1/genetics , Chromosomes, Human, Pair 10/genetics , Chromosomes, Human, Pair 19/genetics , Female , Glioma/pathology , Humans , Loss of Heterozygosity , Male , Middle Aged , Sex Factors , Statistics as Topic
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