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  • 1
    Keywords: APOPTOSIS ; CANCER ; GROWTH ; GENE-EXPRESSION ; STEM-CELLS ; CENTRAL-NERVOUS-SYSTEM ; neuroblastoma ; N-MYC ; BRAIN-TUMORS ; TUMOR-SUPPRESSOR
    Abstract: Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option. (c) 2014 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 25348795
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  • 2
  • 3
    ISSN: 0378-1119
    Keywords: Human-rodent cell hybrids ; cosmids ; ligation artifacts ; orphon ; recombinant DNA ; restriction maps
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Der Nervenarzt 70 (1999), S. 504-508 
    ISSN: 1433-0407
    Keywords: Schlüsselwörter Mitochondriale Erkrankungen ; Mitochondriale DNA ; Genetische Beratung ; Pränatale Diagnostik ; Key words Mitochondrial diseases ; Mitochondrial DNA ; Genetic counselling ; Prenatal diagnosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Since mitochondrial diseases lead frequently to severe phenotypes and are often hereditary, there is a need for genetic counselling of the affected families. The specific features of mitochondrial genetics, however, hamper straightforward definition of recurrence risks as in Mendelian diseases. Empirical risks were recently provided for MELAS and MERRF syndromes and for Leber hereditary optic neuropathy. In MELAS and MERFF, higher levels of mutant mtDNA in the mothers’ blood were associated with an increased frequency of affected offspring. Chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome are in general sporadic disorders without increased recurrence risks in the offspring. As Leigh syndrome is found with maternal, autosomal recessive or X chromosomal transmission, the definition of the molecular defect is crucial for genetic counselling. Prenatal diagnosis was reported only in one case of mitochondrial disease so far, and in our opinion it remains questionable because of the uncertain correlation of the proportion of mutant DNA in chorionic villi and in clinically relevant tissues such as brain.
    Notes: Zusammenfassung Mitochondriale Erkrankungen sind häufig sehr schwere, meist hereditäre Krankheitsbilder, so daß eine genetische Beratung der betroffenen Familien wünschenswert ist. Auf Grund der Besonderheiten der mitochondrialen Genetik läßt sich das Wiederholungsrisiko jedoch nicht wie bei den nach Mendelschen Regeln vererbten Erkrankungen mathematisch ableiten. Empirisch lassen sich inzwischen aber Wiederholungsrisiken für MELAS, MERRF und die Lebersche Optikusneuropathie angeben. Dabei zeigt sich bei MELAS und MERRF, daß der Anteil betroffener Kinder vom Anteil mutanter DNA bei der Mutter abhängt. Die chronisch progressive externe Ophthalmoplegie und das Kearns-Sayre-Syndrom treten i.allg. sporadisch auf, so daß kein erhöhtes Risiko für die Nachkommen besteht. Beim Leigh-Syndrom gibt es maternale, autosomal rezessive und X-chromosomale Erbgänge, so daß die Definition des molekularen Defekts entscheidend für die genetische Beratung ist. Eine pränatale Diagnostik wurde bisher nur in einem Fall einer mitochondrialen Erkrankung beschrieben, und ist unseres Erachtens wegen der unsicheren Korrelation des Mutationsanteils in Chorionzotten und dem in Hirn und anderen klinisch relevanten Geweben äußerst problematisch.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0533
    Keywords: Chronic progressive external ophthalmoplegia ; Kearns-Sayre syndrome ; Mitochondrial DNA deletion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Mitochondrial DNA (mtDNA) deletions have been found in the majority of patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. A large number of different mtDNA deletions have been identified. They generally spare the two origins of replication and are frequently flanked by direct or indirect repeats. We have found a 3.1-kb deletion of mtDNA in a patient with Kearns-Sayre syndrome that has some unusual features. First, it encompasses nucleotides 11259 to 14368, a localization that was not described before. Second, the deletion is not flanked by direct or indirect repeats, supporting the view that homologous recombination and slip-replication do not account for all mtDNA deletions.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0533
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Three patients with chronic progressive external ophthalmoplegia of adult-onset, generalized muscle atrophy and myalgia are described. Two patients fulfilled the histological criteria for centronuclear myopathy, the third those for fiber-type disproportion. Additionally, typical ragged red fibers were found in all muscle specimens, and several muscle fibers were cytochrome c oxidase negative. NADH and succinate dehydrogenase stains showed increased subsarcolemmal accumulation of mitochondria. To determine whether these findings are coincidental or whether they indicated an additional mitochondrial disorder, all patients were investigated using biochemical analysis of the respiratory chain, molecular genetics, magnetic resonance spectroscopy of quadriceps muscle and ergometry. These tests suggested an additional mitochondrial dysfunction. Mitochondrial dysfunction seems to be more common in this group of myopathies than previously estimated, and may be of importance in the pathogenesis of these disorders.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0533
    Keywords: Myopathy ; Kearns-Sayre-syndrome ; Cytochrome c oxidase deficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We report on the progression of myopathology by comparing two biopsies from a patient with a Kearns-Sayre-Syndrome. The first biopsy was taken in 1979 and showed 10% ragged-red fibers. Myopathic changes were slight including internal nuclei and fiber splitting in 10% of the fibers. Electron microscopy revealed typical mitochondrial abnormalities with regard to number and shape. In 1989 a second biopsy was performed for an extended analysis of mitochondrial DNA. This time less than 5% of all fibers were ragged-red. Severe myopathic changes could be detected which so far has rarely been reported in mitochondrial cytopathy.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-0533
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Three patients with chronic progressive external ophthalmoplegia of adult-onset, generalized muscle atrophy and myalgia are described. Two patients fulfilled the histological criteria for centronuclear myopathy, the third those for fiber-type disproportion. Additionally, typical ragged red fibers were found in all muscle specimens, and several muscle fibers were cytochrome c oxidase negative. NADH and succinate dehydrogenase stains showed increased subsarcolemmal accumulation of mitochondria. To determine whether these findings are coincidental or whether they indicated an additional mitochondrial disorder, all patients were investigated using biochemical analysis of the respiratory chain, molecular genetics, magnetic resonance spectroscopy of quadriceps muscle and ergometry. These tests suggested an additional mitochondrial dysfunction. Mitochondrial dysfunction seems to be more common in this group of myopathies than previously estimated, and may be of importance in the pathogenesis of these disorders.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-0533
    Keywords: Key words Chronic progressive external ; ophthalmoplegia ; Kearns-Sayre syndrome ; Mitochondrial DNA deletion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Mitochondrial DNA (mtDNA) deletions have been found in the majority of patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. A large number of different mtDNA deletions have been identified. They generally spare the two origins of replication and are frequently flanked by direct or indirect repeats. We have found a 3.1-kb deletion of mtDNA in a patient with Kearns-Sayre syndrome that has some unusual features. First, it encompasses nucleotides 11259 to 14368, a localization that was not described before. Second, the deletion is not flanked by direct or indirect repeats, supporting the view that homologous recombination and slip-replication do not account for all mtDNA deletions.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-0533
    Keywords: Key words Friedreich’s ataxia ; Trinucleotide repeat ; expansion ; Frataxin gene ; Intrafamilial variability ; Genetic counseling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Friedreich’s ataxia (FA) is most frequently caused by intronic trinucleotide repeat expansions in the frataxin gene on chromosome 9. The broad clinical spectrum includes late-onset FA (LOFA) and FA with retained reflexes (FARR). The size of the GAA expansions accounts for most, but not all, of the clinical variability. We report the unusual occurrence of LOFA and FARR in two siblings of patients with classical early-onset FA in two families. In spite of the markedly different course of the disease, the respective siblings harboured GAA repeat expansions of similar size in leucocytes. Since haplotype-related variability is not likely among siblings, we suppose that this intrafamilial phenotype variability is due to somatic mosaicism, with the more severely affected siblings harbouring the larger expansions in spinal cord and other affected tissues. In view of these results, genetic counseling and predictions on the course of FA are particularly difficult, even if an expansion mutation is found.
    Type of Medium: Electronic Resource
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