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  • 1
    Keywords: CELL LUNG-CANCER ; GENE-EXPRESSION ; PROTEINS ; BREAST-CANCER ; METASTASIS ; WIDE ANALYSIS ; HISTONE H3 ; nuclear speckles ; SPLICING REGULATION ; TDP-43
    Abstract: The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a bona fide long noncoding RNA (lncRNA). MALAT1, also known as nuclear-enriched transcript 2 (NEAT2), was discovered as a prognostic marker for lung cancer metastasis but also has been linked to several other human tumor entities. Recent work established a critical regulatory function of this lncRNA in lung cancer metastasis and cell migration. Moreover, MALAT1 is an interesting target for antimetastatic therapy in non-small cell lung carcinoma. Two alternative modes of action have been proposed for MALAT1: regulation of gene expression or alternative splicing. Although the exact mechanism of action in different physiological and pathological conditions still needs to be elucidated, MALAT1 acts as a regulator of gene expression. Although MALAT1 is highly evolutionary conserved in mammals and plays an important role in cancer and metastasis, MALAT1 is not essential for development in a knockout mouse model under normal physiological conditions. Hence, one central question for the future is finding the right stressor and the pathological or environmental condition which requires MALAT1 expression in vivo and entailing its strong evolutionary conservation. Here, we summarize the current knowledge about this important lncRNA. We introduce its discovery, biogenesis, and regulation and describe its known functions, mechanisms of action, and interaction partners.
    Type of Publication: Journal article published
    PubMed ID: 23529762
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  • 2
    ISSN: 1600-051X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract. The aim of the present study was to evaluate periodontal tissue alterations during the maintenance phase following GTR therapy. 18 patients (average age 54 years, range 39–79 years) with 19 local periodontal defects were monitored longitudinally using clinical periodontal parameters and radiographic assessments of bone level changes. 6 out of originally 24 patients were not available at the 4-year examination (2 patients were unwilling to participate and in 4 patients root amputations or tooth extractions had to be performed). Evaluations were perfomed at baseline. 3 months, 1 year and 4 years following GTR therapy (using non-resorbable Gore-Tex® Periodontal Material). The changes observed at the deepest site of each tooth treated by GTR were compared to those encountered in the entire dentition. Supportive periodontal therapy was performed according to the patient's individual needs between 3 and 12 times between the 1 and 4 years examination. The plaque index and the gingival index at the 4 years examination were assessed and had increased to almost double the value of baseline, although the BOP remained lower compared to baseline data. Between the 1 and 4 years examinations, 1.27 mm of clinical attachment was lost as a mean. Regarding the site of each tooth treated with GTR with the initially deepest probing pocket depth, 1.42 mm of clinical attachment was lost during the maintenace phase. However, compared to baseline data, 1.37 mm of new attachment could be maintained. The clinical attachment level was maintained within ±1 mm in 12 out of 19 sites during the 4 years of maintenance. At 7 sites, a loss between 2 and 5 mm occurred during the maintenance phase. Compared to the baseline values, 4 sites had lost ≥2 mm of clinical attachment resulting in a net loss. Between the 1 and 4 years observation, no significant change in bone height was observed. Multiple regression analyses showed correlations between the maintenance of the new attachment (expressed as change in probing attachment level) and a combination of factors such as number of recall visits during maintenance phase, age of the patient and % of loser sites in the corresponding dentitions. It was concluded that a low incidence of gingival inflammation was a. prerequisite for the maintenance of attachment levels gained by the GTR technique.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1365-2044
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Children with cerebral palsy and severe mental retardation who present for operation may require lower concentrations of inhalational anaesthetics than healthy children. The minimum alveolar concentration (MAC) for halothane was measured in 36 children and adolescents, aged 4–18 years, who underwent orthopaedic surgery. The control group consisted of 12 healthy children (group 1). Children with cerebral palsy and severe mental retardation were allocated to one of two groups: those taking chronic anticonvulsant medication (group 2) (n = 12) and those who did not take any drugs (group 3) (n = 12). The mean (SEM) MAC value for halothane (expressed in volume per cent) was 0.90 (0.02) for healthy children. Children with cerebral palsy had significantly lower MAC values whether they took anticonvulsant drugs or not (0.62 (0.03) and 0.71 (0.10), respectively).
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1600-0757
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1600-0501
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The aim of this investigation was to test the hypothesis that membrane permeability is necessary in bone formation using the principle of guided tissue regeneration. On the forehead of 8 rabbits. titanium test cylinders were anchored in the calvaria. These cylinders were either covered by an expanded polytetrafluoroethylene (e-PTFE) membrane generating a chamber for bone formation or they were sealed off by cast titanium. The implanted cylinders were covered by resuturing the periosteum and the cutaneous flap. After 8 months of healing. new bone had formed in all cylinders in all animals irrespective of whether the chamber for bone formation was sealed off by cast titanium or the e-PTFE membrane. Based on these results, we conclude that permeability of the membrane is not necessary in the guided generation of new bone.
    Type of Medium: Electronic Resource
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  • 6
    Keywords: INVASION ; proliferation ; HEPATOCELLULAR-CARCINOMA ; GENE-EXPRESSION ; CHROMATIN ; COMPONENT ; MIGRATION ; EPITHELIAL-MESENCHYMAL TRANSITION ; ADENOCARCINOMA TRANSCRIPT 1 ; HALLMARKS
    Abstract: The long noncoding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), also known as MALAT-1 or NEAT2 (nuclear-enriched abundant transcript 2), is a highly conserved nuclear noncoding RNA (ncRNA) and a predictive marker for metastasis development in lung cancer. To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements using zinc finger nucleases. The achieved 1,000-fold MALAT1 silencing provides a unique loss-of-function model. Proposed mechanisms of action include regulation of splicing or gene expression. In lung cancer, MALAT1 does not alter alternative splicing but actively regulates gene expression including a set of metastasis-associated genes. Consequently, MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft. Antisense oligonucleotides (ASO) blocking MALAT1 prevent metastasis formation after tumor implantation. Thus, targeting MALAT1 with ASOs provides a potential therapeutic approach to prevent lung cancer metastasis with this ncRNA serving as both predictive marker and therapeutic target. Finally, regulating gene expression, but not alternative splicing, is the critical function of MALAT1 in lung cancer metastasis. In summary, 10 years after the discovery of the lncRNA MALAT1 as a biomarker for lung cancer metastasis, our loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis.
    Type of Publication: Journal article published
    PubMed ID: 23243023
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  • 7
    Keywords: EXPRESSION ; DISEASE ; transcription ; ACTIVATION ; STAT5B ; CANCER DEVELOPMENT ; INSULIN-RESISTANCE ; NONALCOHOLIC STEATOHEPATITIS ; FATTY LIVER-DISEASE ; LIPID-METABOLISM ; CORTICOSTEROID-BINDING GLOBULIN
    Abstract: Growth hormone (GH)-activated signal transducer and activator of transcription 5 (STAT5) and the glucocorticoid (GC)-responsive glucocorticoid receptor (GR) are important signal integrators in the liver during metabolic and physiologic stress. Their deregulation has been implicated in the development of metabolic liver diseases, such as steatosis and progression to fibrosis. Using liver-specific STAT5 and GR knockout mice, we addressed their role in metabolism and liver cancer onset. STAT5 single and STAT5/GR double mutants developed steatosis, but only double-mutant mice progressed to liver cancer. Mechanistically, STAT5 deficiency led to the up-regulation of prolipogenic sterol regulatory element binding protein 1 (SREBP-1) and peroxisome proliferator activated receptor gamma (PPAR-gamma) signaling. Combined loss of STAT5/GR resulted in GH resistance and hypercortisolism. The combination of both induced expression of adipose tissue lipases, adipose tissue lipid mobilization, and lipid flux to the liver, thereby aggravating STAT5-dependent steatosis. The metabolic dysfunctions in STAT5/GR compound knockout animals led to the development of hepatic dysplasia at 9 months of age. At 12 months, 35% of STAT5/GR-deficient livers harbored dysplastic nodules and similar to 60% hepatocellular carcinomas (HCCs). HCC development was associated with GH and insulin resistance, enhanced tumor necrosis factor alpha (TNF-alpha) expression, high reactive oxygen species levels, and augmented liver and DNA damage parameters. Moreover, activation of the c-Jun N-terminal kinase 1 (JNK1) and STAT3 was prominent. Conclusion: Hepatic STAT5/GR signaling is crucial for the maintenance of systemic lipid homeostasis. Impairment of both signaling cascades causes severe metabolic liver disease and promotes spontaneous hepatic tumorigenesis.
    Type of Publication: Journal article published
    PubMed ID: 21725989
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  • 8
    Keywords: EXPRESSION ; CELL LUNG-CANCER ; GENOME ; IDENTIFICATION ; METASTASIS ; ARCHITECTURE ; BINDING PROTEIN ; BODIES ; BIOGENESIS ; ADENOCARCINOMA TRANSCRIPT 1
    Abstract: The metastasis-associated lung adenocarcinoma transcript 1, MALAT1, is a long non-coding RNA (lncRNA) that has been discovered as a marker for lung cancer metastasis. It is highly abundant, its expression is strongly regulated in many tumor entities including lung adenocarcinoma and hepatocellular carcinoma as well as physiological processes, and it is associated with many RNA binding proteins and highly conserved throughout evolution. The nuclear transcript MALAT-1 has been functionally associated with gene regulation and alternative splicing and its regulation has been shown to impact proliferation, apoptosis, migration and invasion. Here, we have developed a human and a mouse knockout system to study the loss-of-function phenotypes of this important ncRNA. In human tumor cells, MALAT1 expression was abrogated using Zinc Finger Nucleases. Unexpectedly, the quantitative loss of MALAT1 did neither affect proliferation nor cell cycle progression nor nuclear architecture in human lung or liver cancer cells. Moreover, genetic loss of Malat1 in a knockout mouse model did not give rise to any obvious phenotype or histological abnormalities in Malat1-null compared with wild-type animals. Thus, loss of the abundant nuclear long ncRNA MALAT1 is compatible with cell viability and normal development.
    Type of Publication: Journal article published
    PubMed ID: 22858678
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  • 9
    Keywords: LUNG-CANCER ; HEPATOCELLULAR-CARCINOMA ; GENE-EXPRESSION ; GENOME ; IDENTIFICATION ; C-MYC ; POOR-PROGNOSIS ; INCREASED EXPRESSION ; CODING REGION ; CRD-BP
    Abstract: Selected long non-coding RNAs (lncRNAs) have been shown to play important roles in carcinogenesis. Although the cellular functions of these transcripts can be diverse, many lncRNAs regulate gene expression. In contrast, factors that control the expression of lncRNAs remain largely unknown. Here, we investigated the impact of RNA binding proteins on the expression of the liver cancer-associated lncRNA HULC (Highly Up-regulated in Liver Cancer). First, we validated the strong up-regulation of HULC in human hepatocellular carcinoma. To elucidate post-transcriptional regulatory mechanisms governing HULC expression, we applied an RNA affinity purification approach to identify specific protein interaction partners and potential regulators. This method identified the family of IGF2BPs (IGF2 mRNA-binding proteins) as specific binding partners of HULC. Depletion of IGF2BP1, also known as IMP1, but not of IGF2BP2 or -3, led to an increased HULC half-life and higher steady-state expression levels, indicating a post-transcriptional regulatory mechanism. Importantly, HULC represents the first IGF2BP substrate that is destabilized. To elucidate the mechanism by which IGF2BP1 destabilizes HULC, the CNOT1 protein was identified as a novel interaction partner of IGF2BP1. CNOT1 is the scaffold of the human CCR4-NOT deadenylase complex, a major component of the cytoplasmic RNA decay machinery. Indeed, depletion of CNOT1 increased HULC half-life and expression. Thus, IGF2BP1 acts as an adaptor protein that recruits the CCR4-NOT complex and thereby initiates the degradation of the lncRNA HULC. Conclusion: Our findings provide important insights into the regulation of lncRNA expression and identify a novel function for IGF2BP1 in RNA metabolism.
    Type of Publication: Journal article published
    PubMed ID: 23728852
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  • 10
    Keywords: IN-VITRO ; LUNG-CANCER ; GENES ; GENOME ; PROGRESSION ; C-MYC ; POOR-PROGNOSIS ; INCREASED EXPRESSION ; CRD-BP ; LIVER-CANCER CELLS
    Abstract: Hepatocarcinogenesis is a stepwise process. It involves several genetic and epigenetic alterations, e.g., loss of tumor suppressor gene expression (TP53, PTEN, RB) as well as activation of oncogenes (c-MYC, MET, BRAF, RAS). However, the role of RNA-binding proteins (RBPs), which regulate tumor suppressor and oncogene expression at the posttranscriptional level, are not well understood in hepatocellular carcinoma (HCC). Here we analyzed RBPs induced in human liver cancer, revealing 116 RBPs with a significant and more than 2-fold higher expression in HCC compared to normal liver tissue. We focused our subsequent analyses on the Insulin-like growth factor 2 messenger RNA (mRNA)-binding protein 1 (IGF2BP1) representing the most strongly up-regulated RBP in HCC in our cohort. Depletion of IGF2BP1 from multiple liver cancer cell lines inhibits proliferation and induces apoptosis in vitro. Accordingly, murine xenograft assays after stable depletion of IGF2BP1 reveal that tumor growth, but not tumor initiation, strongly depends on IGF2BP1 in vivo. At the molecular level, IGF2BP1 binds to and stabilizes the c-MYC and MKI67 mRNAs and increases c-Myc and Ki-67 protein expression, two potent regulators of cell proliferation and apoptosis. These substrates likely mediate the impact of IGF2BP1 in human liver cancer, but certainly additional target genes contribute to its function. Conclusion: The RNA-binding protein IGF2BP1 is an important protumorigenic factor in liver carcinogenesis. Hence, therapeutic targeting of IGF2BP1 may offer options for intervention in human HCC.
    Type of Publication: Journal article published
    PubMed ID: 24395596
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