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  • 1
    Language: English
    In: Cell (Cambridge), 2014-02-27, Vol.156 (5), p.1072-1083
    Description: In most mammals, neurons are added throughout life in the hippocampus and olfactory bulb. One area where neuroblasts that give rise to adult-born neurons are generated is the lateral ventricle wall of the brain. We show, using histological and carbon-14 dating approaches, that in adult humans new neurons integrate in the striatum, which is adjacent to this neurogenic niche. The neuronal turnover in the striatum appears restricted to interneurons, and postnatally generated striatal neurons are preferentially depleted in patients with Huntington’s disease. Our findings demonstrate a unique pattern of neurogenesis in the adult human brain. [Display omitted] •Nuclear-bomb-test-derived 14C in human striatal neurons reveals adult neurogenesis•Striatal neuronal turnover occurs within the interneuron fraction•Annual turnover rate is 2.7% within the renewing fraction in adult humans•Postnatally generated striatal neurons are depleted in Huntington’s disease A previously unknown brain area of adult neurogenesis is discovered in humans to be the striatum. Adult-born neurons in the striatum are depleted in Huntington’s disease
    Subject(s): Interneurons - physiology ; Brain - cytology ; Humans ; Huntington Disease - pathology ; Neurons - cytology ; Basal Ganglia - pathology ; Hippocampus - cytology ; Basal Ganglia - physiology ; Brain - physiology ; Neurogenesis ; Basal Ganglia - cytology ; Animals ; Models, Biological ; Olfactory Bulb - physiology ; Adult ; Interneurons - cytology ; Mice ; Neurons - metabolism ; Hippocampus - physiology ; Olfactory Bulb - cytology ; Brain ; Radiocarbon dating ; Adults ; Index Medicus ; Life Sciences ; Dynamical Systems ; Mathematics ; Cellular Biology ; Medicin och hälsovetenskap
    ISSN: 0092-8674
    ISSN: 1097-4172
    E-ISSN: 1097-4172
    Source: Backfile Package - All of Back Files EBS [ALLOFBCKF]
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 2
    Language: English
    In: International journal of cancer, 2016-05-15, Vol.138 (10), p.2322-2333
    Description: In 2011, a novel form of genome instability was reported by Stephens et al., characterized by tens to hundreds of locally clustered rearrangements affecting one or a few chromosome(s) in cancer cells. This phenomenon, termed chromothripsis, is likely due to a single catastrophic event leading to the simultaneous formation of multiple double‐strand breaks, which are repaired by error‐prone mechanisms. Since then, the occurrence of chromothripsis was detected in a wide range of tumor entities. In this review, we will discuss potential mechanisms of chromothripsis initiation in cancer and outline the prevalence of chromothripsis across entities. Furthermore, we will examine how chromothriptic events may promote cancer development and how they may affect cancer therapy.
    Subject(s): genome instability ; catastrophic genomic rearrangement ; chromothripsis ; Genomic Instability ; Neoplasms - therapy ; Animals ; Neoplasms - genetics ; Cell Transformation, Neoplastic - genetics ; Humans ; Chromosome Aberrations ; Genomics ; Cancer cells ; Cancer ; Index Medicus
    ISSN: 0020-7136
    E-ISSN: 1097-0215
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 3
    Language: English
    In: The Journal of clinical investigation, 2008-05, Vol.118 (5), p.1739-1749
    Description: The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.
    Subject(s): Gene Duplication ; MAP Kinase Signaling System - physiology ; Humans ; Brain Neoplasms - pathology ; Cyclins - genetics ; Male ; Astrocytoma - pathology ; Cyclins - metabolism ; Microarray Analysis ; Astrocytoma - enzymology ; Female ; Cyclin D ; Child ; Proto-Oncogene Proteins B-raf - metabolism ; Astrocytoma - genetics ; Nucleic Acid Hybridization - methods ; Brain Neoplasms - enzymology ; Enzyme Inhibitors - metabolism ; Brain Neoplasms - genetics ; Proto-Oncogene Proteins B-raf - genetics ; Chromosome Aberrations ; Cell Cycle - physiology ; Mitogen-Activated Protein Kinases - genetics ; Enzyme Activation ; Mutation ; Mitogen-Activated Protein Kinases - metabolism ; Care and treatment ; Prognosis ; Gene mutations ; Genetic aspects ; Diagnosis ; Research ; Identification and classification ; Health aspects ; Astrocytoma ; Risk factors ; Methods ; Cancer ; Index Medicus ; Abridged Index Medicus
    ISSN: 0021-9738
    E-ISSN: 1558-8238
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: PubMed Central
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 4
    Language: English
    In: Nature communications, 2018-11-12, Vol.9 (1), p.4760-4760
    Description: Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent complex genomic rearrangements (n = 16/26) in brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or non-homologous-end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n = 68) and glioblastomas (n = 32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumors with complex genomic rearrangements.
    Subject(s): DNA End-Joining Repair - genetics ; Humans ; Brain Neoplasms - pathology ; Tumor Suppressor Protein p53 - metabolism ; Brain Neoplasms - genetics ; N-Myc Proto-Oncogene Protein - genetics ; Apoptosis - genetics ; DNA Repair - genetics ; Neural Stem Cells - pathology ; DNA-Binding Proteins - metabolism ; Animals ; Gene Amplification ; Karyotyping ; Cell Line, Tumor ; DNA Damage - genetics ; Homologous Recombination - genetics ; Mice ; Proto-Oncogene Proteins c-myc - genetics ; Gene Rearrangement - genetics ; Genome ; Neural Stem Cells - metabolism ; Index Medicus
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: Directory of Open Access Journals
    Source: PubMed Central
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 5
    Article
    Article
    2015
    ISSN: 1545-7885  ISSN: 1544-9173 
    Language: English
    In: PLoS biology, 2015-01, Vol.13 (1), p.e1002045-e1002045
    Description: New neurons are continuously generated in specific regions in the adult brain. Studies in rodents have demonstrated that adult-born neurons have specific functional features and mediate neural plasticity. Data on the extent and dynamics of adult neurogenesis in adult humans are starting to emerge, and there are clear similarities and differences compared to other mammals. Why do these differences arise? And what do they mean?
    Subject(s): Neocortex - physiology ; Humans ; Transcriptome ; Organ Specificity ; Neurogenesis ; Biological Evolution ; Animals ; Neuronal Plasticity ; Corpus Striatum - physiology ; Olfactory Bulb - physiology ; Adult ; Models, Neurological ; Hippocampus - physiology ; Lateral Ventricles - physiology ; Index Medicus ; Medicin och hälsovetenskap ; Huntingtons disease ; Neurons ; Memory ; Carbon ; Monkeys & apes ; Studies ; Brain research ; Rodents ; Deoxyribonucleic acid ; DNA ; Stem cells ; Primates ; Behavior ; Animal cognition
    ISSN: 1545-7885
    ISSN: 1544-9173
    E-ISSN: 1545-7885
    Source: Directory of Open Access Journals
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 6
    Language: English
    In: Haematologica (Roma), 2018-01, Vol.103 (1), p.e17-e20
    Subject(s): Cell Cycle - genetics ; Genetic Predisposition to Disease ; Prognosis ; Genetic Association Studies ; Leukemia, Myeloid, Acute - pathology ; Humans ; Biomarkers, Tumor ; Abnormal Karyotype ; Chromothripsis ; Tumor Suppressor Protein p53 - genetics ; Leukemia, Myeloid, Acute - mortality ; Polymorphism, Single Nucleotide ; Mutation ; Leukemia, Myeloid, Acute - genetics ; Online Only
    ISSN: 0390-6078
    E-ISSN: 1592-8721
    Source: Directory of Open Access Journals
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 7
    Language: English
    In: Genes chromosomes & cancer, 2021-05, Vol.60 (5), p.303-313
    Description: In vitro assays for clustered DNA lesions will facilitate the analysis of the mechanisms underlying complex genome rearrangements such as chromothripsis, including the recruitment of repair factors to sites of DNA double‐strand breaks (DSBs). We present a novel method generating localized DNA DSBs using UV irradiation with photomasks. The size of the damage foci and the spacing between lesions are fully adjustable, making the assay suitable for different cell types and targeted areas. We validated this setup with genomically stable epithelial cells, normal fibroblasts, pluripotent stem cells, and patient‐derived primary cultures. Our method does not require a specialized device such as a laser, making it accessible to a broad range of users. Sensitization by 5‐bromo‐2‐deoxyuridine incorporation is not required, which enables analyzing the DNA damage response in post‐mitotic cells. Irradiated cells can be cultivated further, followed by time‐lapse imaging or used for downstream biochemical analyses, thanks to the high throughput of the system. Importantly, we showed genome rearrangements in the irradiated cells, providing a proof of principle for the induction of structural variants by localized DNA lesions.
    Subject(s): genomic rearrangements ; DNA damage ; chromothripsis ; DNA repair ; Chromosomes ; Genomics ; Stem cells ; Index Medicus
    ISSN: 1045-2257
    E-ISSN: 1098-2264
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 8
    Language: English
    In: Nature communications, 2020-05-08, Vol.11 (1), p.2320-2320
    Description: Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. Here we analyse chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals insights in the clonal evolution of tumours with chromothripsis.
    Subject(s): Index Medicus ; Cancer genetics ; Cancer genomics
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: Directory of Open Access Journals
    Source: PubMed Central
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 9
    Language: English
    In: International journal of cancer, 2016-06-15, Vol.138 (12), p.2905-2914
    Description: Chromothripsis is a recently discovered form of genomic instability, characterized by tens to hundreds of clustered DNA rearrangements resulting from a single dramatic event. Telomere dysfunction has been suggested to play a role in the initiation of this phenomenon, which occurs in a large number of tumor entities. Here, we show that telomere attrition can indeed lead to catastrophic genomic events, and that telomere patterns differ between cells analyzed before and after such genomic catastrophes. Telomere length and telomere stabilization mechanisms diverge between samples with and without chromothripsis in a given tumor subtype. Longitudinal analyses of the evolution of chromothriptic patterns identify either stable patterns between matched primary and relapsed tumors, or loss of the chromothriptic clone in the relapsed specimen. The absence of additional chromothriptic events occurring between the initial tumor and the relapsed tumor sample points to telomere stabilization after the initial chromothriptic event which prevents further shattering of the genome. What's new? Chromothripsis is characterized by extensive locally clustered genomic rearrangements, whereby chromosome shattering is followed by rejoining of the DNA fragments by error‐prone repair mechanisms. The present study elaborates on a previously proposed role in the initiation of chromothripsis for telomere erosion and breakage‐fusion‐bridge (BFB) cycles, in which chromosomes repeatedly break and are rejoined. In cells lacking normal mechanisms for genome preservation, telomere attrition and BFB cycles induced chromothripsis. Subsequent activation of tumor‐specific telomere maintenance mechanisms prevented further chromosomal shattering. The findings suggest that telomere maintenance pathways may represent therapeutic targets in chromothripsis‐positive tumors.
    Subject(s): genomic catastrophe ; genome instability ; telomere ; chromothripsis ; Genomic Instability ; Gene Expression ; Ependymoma - enzymology ; Cerebellar Neoplasms - enzymology ; Humans ; Cerebellar Neoplasms - genetics ; Ependymoma - genetics ; Telomere Homeostasis ; Case-Control Studies ; Telomerase - genetics ; Chromosome Disorders - enzymology ; Telomerase - metabolism ; Medulloblastoma - genetics ; Chromosome Disorders - genetics ; Medulloblastoma - enzymology ; Analysis ; Genomics ; Tumors ; Index Medicus
    ISSN: 0020-7136
    E-ISSN: 1097-0215
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 10
    Language: English
    In: Neuro-oncology (Charlottesville, Va.), 2012-01, Vol.14 (1), p.64-78
    Description: The role of microglia, the brain-resident macrophages, in glioma biology is still a matter of debate. Clinical observations and in vitro studies in the mouse model indicate that microglia and macrophages that infiltrate the brain tumor tissue in high numbers play a tumor-supportive role. Here, we provide evidence that human microglia isolated from brain tumors indeed support tumor cell growth, migration, and invasion. However, after stimulation with the Toll-like receptor 3 agonist poly (I:C), microglia secrete factors that exerted toxic and suppressive effects on different glioblastoma cell lines, as assessed in cytotoxicity, migration, and tumor cell spheroid invasion assays. Remarkably, these effects were tumor-specific because the microglial factors impaired neither growth nor viability of astrocytes and neurons. Culture supernatants of tumor cells inhibited the poly (I:C) induction of this microglial M1-like, oncotoxic profile. Microglia stimulation before coculture with tumor cells circumvented the tumor-mediated suppression, as demonstrated by the ability to kill and phagocytose glioma cells. Our results show, for the first time to our knowledge, that human microglia exert tumor-supporting functions that are overridden by tumor-suppressing activities gained after poly (I:C) stimulation.
    Subject(s): Poly I-C - pharmacology ; Cell Proliferation ; Microglia - drug effects ; Neoplasm Invasiveness ; Coculture Techniques ; Humans ; Cells, Cultured ; Toll-Like Receptor 3 - agonists ; Brain Neoplasms - metabolism ; Glioma - metabolism ; Microglia - physiology ; Cell Line, Tumor ; Antineoplastic Agents - pharmacology ; Cell Movement ; glioma ; poly (I:C) ; Basic and Translational Investigations ; antitumor response ; human microglia
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    Source: Oxford Journals 2016 Current and Archive A-Z Collection
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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